Geriatric Medicine: A Person Centered Evidence Based Approach [5th ed. 2024] 3030747190, 9783030747190

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Michael R. Wasserman Debra Bakerjian Sunny Linnebur Sharon Brangman Matteo Cesari Sonja Rosen Editors

Geriatric Medicine A Person Centered Evidence Based Approach Fifth Edition

Geriatric Medicine

Michael R. Wasserman • Debra Bakerjian • Sunny Linnebur • Sharon Brangman • Matteo Cesari • Sonja Rosen Editors

Geriatric Medicine A Person Centered Evidence Based Approach Fifth Edition

With 155 Figures and 180 Tables

Editors Michael R. Wasserman California Association of Long Term Care Medicine Newbury Park, CA, USA

Debra Bakerjian Betty Irene Moore School of Nursing University of California, Davis Sacramento, CA, USA

Sunny Linnebur Department of Clinical Pharmacy University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences Aurora, CO, USA

Sharon Brangman Division of Geriatrics SUNY Upstate Medical University Syracuse, NY, USA

Matteo Cesari Department of Clinical Sciences and Community Health University of Milan Milan, Italy

Sonja Rosen Section of Geriatric Medicine, Division of Internal Medicine, Department of Medicine Cedars-Sinai Beverly Hills, CA, USA

ISBN 978-3-030-74719-0 ISBN 978-3-030-74720-6 (eBook) https://doi.org/10.1007/978-3-030-74720-6 1st to 4th edition: © Springer-Verlag New York, Inc. 1984, 1990, 1997, 2003 © Springer Nature Switzerland AG 2024 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface to the Fifth Edition

In the very first editorial of the Journal of the American Geriatrics Society, it was already clear that developing competencies in the geriatrics approach to care required a breadth of knowledge that spanned disciplines beyond traditional medicine.1 Today, we continue to understand that Geriatric Medicine includes other fields such as pharmacology, nursing, psychology, rehabilitation, social services, and economics. When the fourth edition of this book was published in 2003, we were in the midst of a scientific explosion in the field of aging.2 That science is still growing but can inadvertently serve as a distraction to real-world clinical decision-making and the actual care being delivered to older adults. While this textbook was previously subtitled “An EvidenceBased Approach,” the truth was that we have only been on the very cusp of having meaningful evidence-based literature for the care we deliver to older adults.3 Even today, much of the research-based evidence is still lacking. There are many reasons for this. One reason is the paucity of clearly defined outcomes, based on varying concepts of quality. Even when we have defined quality-of-life measures, studies are often compromised by the fact that older adults are often excluded from clinical research.4 When older adults are included as subjects in clinical trials, they often lack the diversity found in society.5 As an example, a lot of research on older adults has been performed in

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Thompson WO. Aging comes of age. J Am Geriatrics Soc. 1953;1:1–2. https://doi.org/10. 1111/j.1532-5415.1953.tb00001.x. 2 Cassel CK, Leipzig RM, Cohen HJ, Larson EB, Meier DE, editors. Geriatric medicine: an evidence-based approach. 4th ed. Springer; 2003; ISBN: 0-387-95514-3. 3 Ramsdale E, Dale W. Evidence-based guidelines and quality measures in the care of older adults. Am Med Assoc J Ethics. 2013;15(1):51–5. 4 Bourgeois FT, Orenstein L, Ballakur S, Mandl KD, Ioannidis JPA. Exclusion of elderly people from randomized clinical trials of drugs for ischemic heart disease. J Am Geriatr Soc. 2017;65(11):2354–61. https://doi.org/10.1111/jgs.14833. 5 Shenoy P, Harugeri A. Elderly patients’ participation in clinical trials. Perspect Clin Res. 2015;6(4):184–9. https://doi.org/10.4103/2229-3485.167099. v

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the Veterans Administration setting, where there is a preponderance of older males.6,7,8 That is definitely not representative of society as a whole, where we find a larger percentage of women as we get into the older age cohorts.9 The field of Geriatrics is also becoming more pertinent throughout the world, with Japan leading the way demographically.10 Other developed, and underdeveloped, countries have rapidly growing populations of older adults.11 The imperative of aging societies is definitely upon us. Ignatz Nascher coined the term “geriatrics” in 1909, when he wrote “Geriatrics, from geras, old age, and iatrikos, relating to the physician, is a term I would suggest as an addition to our vocabulary to cover the same field that is covered in old age that is covered by the term pediatrics in childhood, to emphasize the necessity of considering senility and its disease apart from maturity and to assign it a separate place in medicine.”12 He published Geriatrics: The Diseases of Old Age and Their Treatment in 1914.13 In the book, he had the foresight to recognize that “The old idea that the body becomes worn out like an old engine and the tissue wastes just as the material wears away in machinery or goods, is a fanciful simile without a basis of fact.”14 Despite this insightful refrain over a century ago, it is still common for physicians today to ascribe symptoms in older adults to “getting old.” Nascher knew that attitude was inappropriate over a hundred years ago, and it remains inconsistent with the geriatrics approach to care today. With the paucity of evidence-based literature, we must look carefully at whatever evidence exists. Some might liken Geriatric Medicine to “frontier medicine,” due to the relative lack of research compared to other fields, but we have at our disposal the clinical practice of Geriatric Medicine for a good part of the last century. We can take advantage of actual clinical experience and

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Vidaver RM, Lafleur B, Tong C, Bradshaw R, Marts SA. Women subjects in NIH-funded clinical research literature: lack of progress in both representation and analysis by sex. J Womens Health Gend Based Med. 2000;9(5):495–504. https://doi.org/10.1089/ 15246090050073576. 7 Goldzweig CL, Balekian TM, Rolón C, Yano EM, Shekelle PG. The state of women veterans’ health research. J Gen Intern Med. 2006;21:S82–S92. https://doi.org/10.1111/j. 1525-1497.2006.00380.x. 8 Liu KA, Mager NA. Women’s involvement in clinical trials: historical perspective and future implications. Pharm Pract (Granada). 2016;14(1):708. https://doi.org/10.18549/ PharmPract.2016.01.708. 9 Carmel S. Health and well-being in late life: gender differences worldwide. Front Med. 2019;6. https://doi.org/10.3389/fmed.2019.00218, ISSN¼2296-858X. 10 Population Projections for Japan. 2016 to 2065. National Institute of Population and Social Security Research. 2017. http://www.ipss.go.jp/pp-zenkoku/e/zenkoku_e2017/pp29_sum mary.pdf 11 World Population Prospects, Population Division, United Nations. https://population.un. org/wpp/ 12 Clarfield AM. Dr. Ignatz Nascher and the birth of geriatrics. CMAJ. 1990;143(9):944–8. 13 Cohen AB. Nascher’s geriatrics at 100, J Am Geriatr Soc. 2014;62(12):2428–9. https:// doi.org/10.1111/jgs.13155. 14 Ibid.

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incorporate the Delphi process in order to develop our approach to care.15 Geriatricians provide a valuable resource in this regard. Nascher founded the New York Geriatrics Society in 1915. The American Geriatrics Society was founded in 1942. The first Fellowship program in Geriatrics was formed in 1966, and a certifying examination in Geriatric Medicine was offered in 1988.16 Physicians were allowed to “grandfather in” to take the exam until 1993.17 The number of board-certified geriatricians peaked in the mid-1990s at around 14,000, but that number has steadily declined and presently hovers around 7,000. Nevertheless, there have been physicians who regard themselves as geriatricians for several decades. This group has been actively engaged in developing the field of geriatric medicine. The first textbook for this new field, Clinical Geriatrics, was published in 1971, and several others have subsequently followed.18 The first edition of this textbook was published in 1984.19 We’ve come a long way since Nascher intuitively recognized that getting older wasn’t a disease in and of itself. Today’s older adult population is quite heterogeneous. Nevertheless, there is still a limit to how long one lives, and the concept of a population of people nearing the end of life must be considered in the delivery of care to those persons. While end-of-life scenarios may be encountered at all ages, statistically it is far more common in older adults. Muriel Gillick recognized this in 1994 when she delineated a framework for caring for older adults that encompassed four states of health: robust, frail, demented, and dying.20 The vernacular dying has since been replaced by the term end of life. Geriatricians have long recognized this variability and the impact it has on medical decision-making. Gillick followed up this framework with a path for others in the field to follow when it came to identifying the appropriate approach to care for the individual older adult.21 This path included four steps: (1) patients prioritize their goals of care (prolongation of life, maintenance of function, and maximization of comfort); (2) physicians assign a pathway of care based on the patient’s prioritization of goals (longevous, ameliorative, or palliative); (3) expert panels define a range of feasible interventions for each pathway; and (4) medical problems are treated with interventions consistent with the pathway chosen.22 The reader will find this path interwoven into the chapters found in this textbook. While the concept of basing clinical decisions only on evidence-based literature is appealing, at the present time it is quite unrealistic. Not only are we lacking in a significant amount of evidence-based research, but very few evidence-based studies are based on a person-centered approach to care.

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Staykova MP. Rediscovering the Delphi technique: a review of the literature. Adv Soc Sci Res J. 2019;6(1):218–29. 16 Brubaker JK. The birth of a new specialty: geriatrics. J Lancaster Gen Hosp. 2008;3(3). 17 Ibid. 18 Rossman I. Clinical geriatrics. Philadelphia:JB Lippincott; 1971. 19 Cassell C. Geriatric medicine: an evidence based approach. Springer; 1984. 20 Gillick M. Choosing medical care in old age: what kind, how much, when to stop. Cambridge, MA: Harvard University Press; 1994. 21 Gillick MR. Choosing appropriate medical care for the elderly. J Am Med Dir Assoc. 2001;2(6):305–9. 22 Ibid.

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Geriatricians have invoked the concept of person-centered care from the very beginning of our field. It is appropriate that the first consensus based description of person-centered care was published in the Journal of the American Geriatrics Society.23 Unfortunately, this important concept has been buried under the sheer volume of information that has come with advances in medical science. It also gets short shrift in medical education and residency training. In these settings, it is usually taught as patient-centered care, where the term patient already objectifies the person. Often lost in the discussion of person-centered care is the fact that, in order to actually deliver it, one must actually understand the person! Person-centered care must be ingrained in the culture of medical practices and health systems.24 This requires education and training of skills that allow one to delineate and comprehend the preferences and goals of the individual.25 It’s not enough to have evidence-based literature informing our clinical decision-making. It’s not enough to have Delphi-based guidelines. Delivering true person-centered care means that we must also contextualize the decision-making process.26 We have a growing body of knowledge and information that informs us that older adults are unique individuals. We must utilize critical thinking skills in order to coordinate the evidence-based knowledge with a person-centered geriatrics approach to care. Hence, the title of the fifth edition of this textbook, Geriatric Medicine: A Person-Centered, Evidence-Based Approach. The field of Geriatric Medicine utilizes science and pathophysiology as foundational elements. While these are important from the broader scope of the science behind what is encountered in clinical practice, it has limited applicability in everyday clinical decision-making. The science of aging and the maladies that are encountered by older adults are building blocks for understanding the pathophysiology. The clinician delivering care on a dayto-day basis can appreciate the science, but their focus must be on the person. The science and pathophysiology of aging describes the average person. While population health concepts inform us about the clinical needs of various older adult cohorts, Geriatric Medicine must focus on the individual and their specific clinical findings. The geriatrics approach to care requires person centeredness. In order to understand a person’s goals and preferences, we also have to comprehend the entire world that they live in, a concept that is

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American Geriatrics Society Expert Panel on Person-Centered Care. Person-centered care: a definition and essential elements. J Am Geriatr Soc. 2016;64(1):15–8. https://doi.org/10. 1111/jgs.13866. Epub 2015 Dec 2. 24 Santana MJ, Manalili K, Jolley RJ, Zelinsky S, Quan H, Lu M. How to practice personcentred care: a conceptual framework. Health Expect. 2018;21(2):429–40. https://doi.org/ 10.1111/hex.12640. 25 Schellinger SE, Anderson EW, Frazer MS, Cain CL. Patient self-defined goals: essentials of person-centered care for serious illness. Am J Hosp Palliat Care. 2018;35(1):159–65. https://doi.org/10.1177/1049909117699600. 26 Weiner SJ, Schwartz A. Contextual errors in medical decision making: overlooked and understudied. Acad Med. 2016;91(5):657–62. https://doi.org/10.1097/ACM. 0000000000001017.

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becoming more and more understood from the perspective of social determinants of care.27 This is only the first step, albeit one often ignored or missed by most clinicians. Once we are prepared to deliver person-centered care, we must then entertain the remaining nuances of the geriatrics approach. The concept of an entire “philosophy of care” was first set forth by a group of geriatricians in 1995.28,29 These elements have withstood the test of time, and with the recent addition of purpose, the Geriatrics Approach to Care can be effectively summarized by the following elements: Focus on function Focus on purpose Focus on managing chronic disease(s) and developing chronic care treatment models Identify and manage psychological and social aspects of care Respect person’s dignity and autonomy Respect cultural and spiritual beliefs Be sensitive to the person’s financial condition Promote wellness Listen and communicate effectively Person-centered approach to care Realistically promote optimism and hope Team approach to care

Every chapter in this book endeavors to embrace the geriatrics approach to care. In a healthcare world that often looks at care from a population health perspective, the dichotomy of individuality of older adults must be respected. Many geriatricians have been taught that the focus of geriatrics is function and quality of life. Those terms, while necessary, are no longer sufficient in order to embody the entire geriatrics approach to care. Function is the sine qua non of the geriatrics approach. To have any idea of what’s important to the person, we must know their functional capacity and abilities. There are many aspects to function, starting with basic activities of daily living, and extending to instrumental activities of daily living. But those measures are just the tip of the iceberg. Function can mean different things to different people, and it is critical to understand this from the perspective of the individual person. Being able to run a mile might be important to one person, while walking a block is sufficient to another. Mobility with the use of an assistive device may be satisfactory to one person, and unacceptable to another. Evidence-based literature informs us about the negative impact of inactivity during acute hospitalization, often overriding the value of the treatment of the admitting diagnosis itself. In fact, one week of hospitalization

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Northwood M, Ploeg J, Markle-Reid M, Sherifali D. Integrative review of the social determinants of health in older adults with multimorbidity. J Adv Nurs. 2018;74:45–60. https://doi.org/10.1111/jan.13408. 28 Wasserman MR, Holthaus KM, Cosgrove K. The Med Wise Center – an innovation in primary care geriatrics. Continuum. 1998;18(1):18–23. 29 Wasserman M. Care management: from channeling to grace. In: Powers S, editor. Healthcare changes and the affordable care act. Cham: Springer International Publishing; 2015. p. 133–152, https://doi.org/10.1007/978-3-319-09510-3_8.

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following hip surgery was enough to induce significant muscle atrophy in older adults.30 The concept of “use it or lose it” has value in both physical and mental function and has been supported time and again in the literature, especially in the setting of acute hospitalization.31 Yet, it is often ignored in the approach to caring for the older adult. The concept of purpose has taken on more importance as we understand its impact. There is evidence that people with greater purpose have fewer clinical signs of Alzheimer’s disease in the face of an increased amount of amyloid plaque in their brains.32 There is growing evidence that purpose protects against cognitive decline in older adults.33 There is evidence of lower mortality in the face of higher purpose in those over the age of 50.34 While there is evidence in older adults relating purpose to fewer chronic diseases, that finding has not been extended to the oldest old.35 Older adults with less purpose in life have been found to be more likely to live alone.36 Understanding what purpose is and how that purpose matters is very individualized and truly requires a person-centered understanding of an individual’s wants and needs. Managing chronic disease is certainly not exclusive to older adults. However, there is no question as to the importance of this element regarding delivering care. There is a growing body of evidence regarding approaches to managing chronic illness.37 One of the common issues of addressing chronic illness in older adults is the challenge of multimorbidity.38 One cannot view managing chronic disease in this population from a single disease perspective. Taking a person-centered approach, which includes engaging the person themselves and their families, is a central focus for many chronic

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Kouw IWK, Groen BBL, Smeets JSJ, et al. One week of hospitalization following elective hip surgery induces substantial muscle atrophy in older patients. JAMDA. 2019;20(1): 35–42. https://doi.org/10.1016/j.jamda.2018.06.018. ISSN 1525-8610. 31 Martínez-Velilla N, Casas-Herrero A, Zambom-Ferraresi F, et al. Effect of exercise intervention on functional decline in very elderly patients during acute hospitalization: a randomized clinical trial. JAMA Intern Med. 2019;179(1):28–36. https://doi.org/10.1001/ jamainternmed.2018.4869. 32 Boyle PA, et al. Effect of purpose in life on the relation between Alzheimer disease pathologic changes on cognitive function in advanced age. Arch Gen Psychiatry. 2012;69(5):499–505. 33 Kim G, Shin SH, Scicolone MA, Patricia P. Purpose in life protects against cognitive decline among older adults. Am J Geriatr Psychiatry. 2019;27(6):593–601. https://doi.org/ 10.1016/j.jagp.2019.01.010. ISSN 1064-7481. 34 Alimujiang A, Wiensch A, Boss J, et al. Association between life purpose and mortality among US adults older than 50 years. JAMA Netw Open. 2019;2(5):e194270. https://doi. org/10.1001/jamanetworkopen.2019.4270. 35 Sayer J, Smith JL, O’Brien C, Bihary JG, O’Connor D, Basic A. Purpose and number of chronic health conditions among older adults. Innov Aging. 2019;3(Suppl 1):S841. https:// doi.org/10.1093/geroni/igz038.3096. Published 2019 Nov 8. 36 Boyle PA, Buchman AS, Bennett DA. Purpose in life is associated with a reduced risk of incident disability among community-dwelling older persons. Am J Geriatr Psychiatry. 2010;18(12):1093–102. https://doi.org/10.1097/JGP.0b013e3181d6c259. 37 Kastner M, Cardoso R, Lai Y, et al. Effectiveness of interventions for managing multiple high-burden chronic diseases in older adults: a systematic review and meta-analysis. CMAJ. 2018;190(34):E1004–E1012. https://doi.org/10.1503/cmaj.171391. 38 Salive ME. Multimorbidity in older adults. Epidemiol Rev. 2013;35(1):75–83.

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disease management approaches. It is even more critical when caring for older adults. Care coordination has been found to be an effective tool, but mostly when it occurs in settings that reflect the geriatrics approach to care.39 One of the greatest challenges to developing an approach to managing chronic disease in older adults is recognizing the importance of integrating the geriatric approach to care into the care delivery system.40 Identifying psychological and social aspects of care is profoundly important in determining effective approaches to caring for the person. The literature on the importance of social determinants of care continues to grow rapidly.41 The impact of poverty has long been known to have an effect on health outcomes.42 Social isolation is clearly important in relation to the health and well-being of older adults.43 Depression has long been understood to have an impact on a number of disease states.44 The entire concept of social determinants has grown in scope to command its own chapter in this text, and we are only on the cusp of learning how to incorporate these concepts into the care of the individual person. It is critical that these factors be contextualized and considered when approaching the individual older adult. Respecting a person’s dignity and autonomy is at the heart of medical ethics and has profound implications in the care of all persons.45,46,47,48 Ageist

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Wasserman M. Care management: from channeling to grace. In: Powers JS, editor. Healthcare changes and the affordable care act. Cham: Springer International Publishing, p. 133–52. https://doi.org/10.1007/978-3-319-09510-3_8. 40 Ibid. 41 Minahan J. Multimorbidity in older adults: can disease cluster predict depression severity? Innov Aging. 2019;3(Suppl 1):S393–S394. https://doi.org/10.1093/geroni/igz038.1450. 42 Hwang PW, dos Santos Gomes C, Auais M, et al. Economic adversity transitions from childhood to older adulthood are differentially associated with later-life physical performance measures in men and women in middle and high-income sites. J Aging Health. 2019;31(3):509–27. https://doi.org/10.1177/0898264317736846. 43 Schrempft S, Jackowska M, Hamer M, et al. Associations between social isolation, loneliness, and objective physical activity in older men and women. BMC Public Health;19(74). https://doi.org/10.1186/s12889-019-6424-y. 44 Kong D, Li M, Wang J, et al. The relationship between depressive symptoms and health services utilization in U.S. Chinese Older Adults. Gerontologist. 2019;59(3):447–55. https:// doi.org/10.1093/geront/gny010. 45 Bentwich ME, Dickman N, Oberman A. Dignity and autonomy in the care for patients with dementia: Differences among formal caretakers of varied cultural backgrounds and their meaning. Arch Gerontol Geriatr. 2017;70:19–27. https://doi.org/10.1016/j.archger. 2016.12.003. ISSN 0167-4943. 46 Sánchez-García S, García-Peña C, Ramírez-García E, Moreno-Tamayo K, Cantú-Quintanilla GR. Decreased autonomy in community-dwelling older adults. Clin Interv Aging. 2019;14:2041–53. https://doi.org/10.2147/CIA.S225479. Published 2019 Nov 18. 47 Rodríguez-Prat A, Escribano X. A philosophical view on the experience of dignity and autonomy through the phenomenology of illness. J Med Philos. 2019;44(3):279–298. https://doi.org/10.1093/jmp/jhz001. 48 Ben-Harush A, Shiovitz-Ezra S, Doron I, et al. Ageism among physicians, nurses, and social workers: findings from a qualitative study. Eur J Ageing. 2016;14(1):39–48. https:// doi.org/10.1007/s10433-016-0389-9. Published 2016 Jun 28.

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societal tendencies often run counter to the concept of autonomy, as functional and cognitive limitations lead family and caregivers to sometimes treat older adults as children.49,50,51 Nowhere is this more important than in the realm of palliative and end of life care, where understanding what matters to the individual is of primary importance. Older adults prone to delirium during an acute illness may have their dignity and autonomy ignored in a number of healthcare settings.52 Discussing advance directives with an individual is only the tip of the iceberg. Developing a deeper understanding of how a person’s goals and preferences relate to their dignity and autonomy are unequivocally necessary if we are committed to an ethical approach to care.53 Respecting cultural and spiritual beliefs is a critical and often ignored area of care.54,55 Many individuals have goals and preferences that are informed by their cultural background, and this is often intermixed with their spiritual and religious backgrounds. While this has clear implications in relation to end of life issues, it also has a significant impact in understanding other issues such as function and purpose. Connecting with a person in terms of their cultural and spiritual beliefs is also critical to the ongoing relationship between the person and the professional caring for them. Being sensitive to a person’s financial condition is important in all societies. The Medicare program itself was founded for the very reason that many older adults could not afford healthcare.56 Medication compliance can be impacted by the cost of medication.57 Older adults will often avoid spending money on necessary services out of fear of the impact on their financial well-being or spending their children’s inheritance. Ignoring a person’s financial condition risks missing an important contextual aspect of their overall health and wellbeing. In today’s always changing healthcare environment, there are a number of

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Pritchard-Jones L. Ageism and autonomy in health care: explorations through a relational lens. Health Care Anal. 2017;25:72–89. https://doi.org/10.1007/s10728-014-0288-1. 50 Swift HJ, Abrams D, Lamont RA, Drury L. The risks of ageism model: how ageism and negative attitudes toward age can be a barrier to active aging. Soc Issues Policy Rev. 2017;11:195–231. https://doi.org/10.1111/sipr.12031. 51 Nuessel F, Van Stewart A. Research summary: patronizing names and forms of address used with older adults. Names. 1999;47(4):401–9. https://doi.org/10.1179/nam.1999.47.4. 401. 52 Weir E, O’Brien AJ. Don’t go there – it’s not a nice place: older adults’ experiences of delirium. Int J Mental Health Nurs. 2019;28:582–91. https://doi.org/10.1111/inm.12563. 53 Gebremariam KM, Sadana R. On the ethics of healthy ageing: setting impermissible tradeoffs relating to the health and well-being of older adults on the path to universal health coverage. Int J Equity Health. 2019;18:140. https://doi.org/10.1186/s12939-019-0997-z. 54 Peteet J, Zaben F, Koenig H. Integrating spirituality into the care of older adults. Int Psychogeriatr. 2019;31(1):31–8. https://doi.org/10.1017/S1041610218000716. 55 Fang ML, Sixsmith J, Sinclair S, et al. A knowledge synthesis of culturally- and spiritually-sensitive end-of-life care: findings from a scoping review. BMC Geriatr. 2016;16:107. https://doi.org/10.1186/s12877-016-0282-6. 56 Blumenthal D, Davis K, Guterman S. Medicare at 50-moving forward. N Engl J Med. 2015;372(7):671–7. https://doi.org/10.1056/NEJMhpr1414856. 57 Chung GC, Marottoli RA, Cooney LM, Rhee TG. Cost-related medication nonadherence among older adults: findings from a nationally representative sample. J Am Geriatr Soc. 2019;67:2463–73. https://doi.org/10.1111/jgs.16141.

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incentive-based programs that have a financial impact on medical practices and health systems.58 These ultimately have an impact on the delivery of care. Since the founding of Medicare as a program focused on illness, the importance of promoting wellness has often been lost in the care of older adults.59 While it is traditional for medical specialties to focus on disease, health prevention and wellness are very important elements in the geriatrics approach to care. Exemplifying the importance of wellness is why we have chapters on both exercise, nutrition, and healthy aging in this textbook. Listening and communicating effectively are skills at the heart of being able to deliver a person-centered approach to care. Recognizing that someone with Parkinson’s disease might take longer to respond to a question is a great example of the importance of this skill set.60 Not doing so can lead to the inaccurate diagnosis of cognitive impairment or dementia.61,62 Having discussions related to advance directives requires communication skills that are necessary to respecting a person’s dignity and autonomy.63 Health literacy is at the heart of effective communication and is a topic that every physician should be learning.64 Most importantly, listening and asking the right questions are absolutely essential in obtaining the context necessary to deliver person-centered care.65 Realistically promoting optimism and hope is a clinical skill that is often forgotten in the setting of advanced illness or limited function.66,67 Recognizing that the individual person will always have priorities and goals, and that

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Wasserman M, Riopelle J. Incentivizing primary care physicians: opportunities and challenges. In: Primary care for older adults: models and challenges. Cham: Springer International Publishing; 2018. https://doi.org/10.1007/978-3-319-61329-1. ISBN 978-3319-61327-7. 59 Jeste DV, et al. Promoting wellness in older adults with mental illnesses and substance use disorders: call to action to all stakeholders. Am J Geriatr Psychiatry. 2018;26(6):617–30. 60 Martinez-Horta S, Horta-Barba A, Kulisevsky J. Cognitive and behavioral assessment in Parkinson’s disease. Expert Rev Neurother. 2019;19:7:613–22. https://doi.org/10.1080/ 14737175.2019.1629290. 61 Copeland JN, Lieberman A, Oravivattanakul S, Tröster AI. Accuracy of patient and care partner identification of cognitive impairments in Parkinson’s disease–mild cognitive impairment. Mov Disord. 2016;31:693–8. https://doi.org/10.1002/mds.26619. 62 Peng FCC. Dementia in Parkinson’s disease revisited: in the light of Fischer’s disease. EC Neurology. 2017;6.2:39–53. 63 Gigon F, Merlani P, Ricou B. Advance directives and communication skills of prehospital physicians involved in the care of cardiovascular patients. Medicine (Baltimore). 2015;94(49):e2112. https://doi.org/10.1097/MD.0000000000002112. 64 Manafo E, Wong S. Health literacy programs for older adults: a systematic literature review. Health Educ Res. 2012;27(6):947–60. https://doi.org/10.1093/her/cys067. 65 Weiner SJ, Schwartz A. Contextual errors in medical decision making: overlooked and understudied. Acad Med. 2016;91(5):657–62. https://doi.org/10.1097/ACM. 0000000000001017. 66 Wurm S, Benyamini Y. Optimism buffers the detrimental effect of negative selfperceptions of ageing on physical and mental health. Psychol Health. 2014;29(7):832–48. https://doi.org/10.1080/08870446.2014.891737. 67 Bergin L, Walsh S. The role of hope in psychotherapy with older adults. Aging Ment Health. 2005;9(1):7–15. https://doi.org/10.1080/13607860412331323809.

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their preferences will be informed by their present condition, is critical to identifying mechanisms to allow for optimism and hope. Human beings are remarkable for having the capacity to think positively despite seemingly negative circumstances.68 This capacity gives clinicians the opportunity to engage the individual person more effectively. The Geriatrics Approach to Care spans a broad range of disciplines. This very fact creates opportunities to utilize a team approach to care for older adults. A growing body of literature demonstrates how interdisciplinary teams are perceived positively and can more effectively achieve outcomes.69,70 The concept of QAPI, quality assurance and performance improvement, has underscored the values and opportunities that exist in utilizing a team to deliver care to older adults.71 The burgeoning field of implementation science often recognizes the value and importance of a team approach to care.72,73 Considering the breadth of disciplines that influence the geriatrics approach to care, understanding not only the importance of teamwork but the effective functioning of a team, are important elements in caring for older adults.74,75 Incorporating the elements of the geriatrics approach to care is the challenge for all clinicians delivering care to older adults. This book is about focusing on what matters to the person and how that is not always about pathology and physiology. The reader generally will not find simple solutions to symptoms, diseases, and syndromes. Throughout this text, we aim to reflect the fact that

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Charles ST, Carstensen LL. Unpleasant situations elicit different emotional responses in younger and older adults. Psychol Aging. 2008;23(3):495–504. https://doi.org/10.1037/ a0013284. 69 Temkin-Greener H, Szydlowski J, Intrator O, et al. Perceived effectiveness of home-based primary care teams in Veterans Health Administration. Gerontologist. 2020;60:494–502. https://doi.org/10.1093/geront/gny174. 70 Baroni M, Serra R, Boccardi V, et al. The orthogeriatric comanagement improves clinical outcomes of hip fracture in older adults. Osteoporos Int. 2019;30:907–16. https://doi.org/10. 1007/s00198-019-04858-2. 71 Unroe KT, Ouslander JG, Saliba D. Nursing home regulations redefined: implications for providers. J Am Geriatr Soc. 2018;66:191–4. https://doi.org/10.1111/jgs.15128. 72 Bartels SJ, Flaherty E, Tumosa N. The new geriatric interprofessional team transformation in primary care: an implementation science approach. Innov Aging. 2018;2(Suppl 1):30. https://doi.org/10.1093/geroni/igy023.111. Published 2018 Nov 11. 73 Braithwaite J, Churruca K, Long JC, et al. When complexity science meets implementation science: a theoretical and empirical analysis of systems change. BMC Med. 2018;16:63. https://doi.org/10.1186/s12916-018-1057-z. 74 Strasser DC, Falconer JA, Stevens AB, et al. Team training and stroke rehabilitation outcomes: a cluster randomized trial. Arch Phys Med Rehabil. 2008;89(1):10–5. https://doi. org/10.1016/j.apmr.2007.08.127. ISSN 0003-9993. http://www.sciencedirect.com/science/ article/pii/S0003999307016061 75 Partnership for Health in Aging Workgroup on Interdisciplinary Team Training in Geriatrics. Position statement on interdisciplinary team training in geriatrics: an essential component of quality health care for older adults. J Am Geriatr Soc. 2014;62:961–5. https://doi.org/10.1111/jgs.12822.

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the discipline of Geriatric Medicine requires the clinician to think both critically and divergently at the same time. Geriatrics encompasses multiple disciplines and spans all the subspecialties. It requires knowledge of working within an interdisciplinary team. It requires an appreciation of how quality of life varies with each individual and creates treatment and care plans that also vary. And most of all, it requires a firm commitment to first learning to truly understand the person. Only then can all of the necessary data be analyzed and integrated into a person-centered plan of care based on the best evidence available. Communicating effectively with an older adult requires knowledge of health literacy.76 Health literacy, however, isn’t only about communicating with the person, or their family. It’s about effective communication between members of the interdisciplinary team.77 It’s also about how physicians communicate with one another.78 Specialists need to be able to think beyond the organ system they are responsible for and factor in the person-centered needs of the older adult. Until we have more evidence-based research that factors in quality-of-life measures, it is incumbent upon all healthcare professionals to weave the available evidence together in their decision-making processes. This textbook stands on the shoulders of many who have come before us. I want to thank Chris Cassel for her efforts and stewardship of the previous editions of this text. I’d also like to thank Rosanne Leipzig for her longstanding efforts to bring an evidence-based approach to the field of geriatric medicine and for her inspiration in conceptualizing this edition. My co-editors reflect some of the disciplines and the teamwork necessary to deliver a geriatrics approach to care. I want to thank Debra Bakerjian, Sunny Linnebur, Sonja Rosen, Matteo Cesari, and Sharon Brangman for their editorial advice and support in bringing this textbook to fruition. A special thanks to Armin Shahrokni as the Section Editor for Cancer in Older Adults. Geriatric Medicine stands at the crossroads of integrating person-centered care into what has historically been a more traditional disease-based approach to care. In a highly heterogeneous older adult population, it is rare that our care recommendations come with anywhere close to 100% certainty. That is as it should be, for no two persons are exactly alike. It is our hope that this book challenges the reader to question every decision that they make in the care of

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Chesser AK, Keene Woods N, Smothers K, Rogers N. Health literacy and older adults: a systematic review. Gerontol Geriatr Med. 2016. https://doi.org/10.1177/ 2333721416630492. 77 Ferrell B, Buller H, Paice J, et al. End-of-life nursing and education consortium communication curriculum for interdisciplinary palliative care teams. J Palliat Med. 2019;22(9): 1082–91. 78 Lipitz-Snyderman A, Kale M, Robbins L, et al. Peers without fears? Barriers to effective communication among primary care physicians and oncologists about diagnostic delays in cancer. BMJ Qual Saf. 2017;26:892–8.

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older adults. Every guideline and recommendation should come with the caveat that incorporating the individual’s goals and preferences might lead to a different approach. After all, we are still practicing geriatric medicine. Newbury Park, USA Sacramento, USA Aurora, USA Syracuse, USA Milan, Italy Beverly Hills, USA February 2024

Michael R. Wasserman Debra Bakerjian Sunny Linnebur Sharon Brangman Matteo Cesari Sonja Rosen

Preface to the Fourth Edition

Since the publication of the third edition of Geriatric Medicine, extraordinary advances have occurred in the science of aging and the potential for biomedical research to give us answers to many, if not most, of the age-related disorders that threaten the quality of life in older years. At the most basic level, the successful mapping of the human genome was declared complete in the fall of 2000. Understanding the map of the human genome is as important as understanding the map of genomes of important laboratory species, ranging from the microscopic worms and fruitflies used in most classic genetic studies to rodents such as laboratory mice, and eventually to primates, on which much of the research on the aging human brain is done. The genetic maps of all of these species, including our own, does not answer clinical questions, but it does open the door to dramatic, rapid, and efficient answers to questions about the genetic polymorphisms related to diseases in humans. The telomerase story also unfolded since the third edition. Telomerase is an enzyme responsible for maintaining the telomeres—the redundant DNA portions at the end of chromosomes—whose shortening seems to be linked directly to cell senescence, apoptosis, and the control over cell death, which, at the level of the individual cell, seems to be linked to the decline of organ function and eventually aging and death within the organism. The potential for genetic manipulations by which telomerase maintains and restores telomere length within individual tissue cultures gives great promise for potential approaches to restoring function lost through degenerative diseases, such as macular degeneration and other disorders related to epithelial aging. In addition, the maintenance of telomeres has been intriguingly associated with the malignant immortality of cancer cells, and yet it appears possible to prevent degeneration without creating uncontrolled growth or malignancy. Understanding this single genetic mechanism may give us clues not only to degenerative neurological and epithelial disease, but also perhaps to cancer, another age-related human disease. Scientists have also discovered that stem cells from embryonic and adult tissues can potentially create new tissues and new organs. Perhaps most excitingly, it appears that brain cells themselves can be replaced through this mechanism. Thus, stem cell research holds promise for treatment of Alzheimer’s and Parkinson’s disease, as well as for potentially growing new functioning organs that could be used for transplantation with much reduced risk of rejection because they are genetically fashioned to match the recipient’s immune status. xvii

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Because of these and many more similar advances, it is more and more important for the practicing clinician to be conversant with the literature of basic science and to stay abreast of such developments. Our patients come to us having read about these developments or having seen television reports, and we should be able to answer their questions and share the excitement. We should also be educating them about the realistic limits, understanding that many of these developments will not provide immediate cures but are promising future developments. Secondly, we owe it to ourselves to share the excitement of our colleagues in basic science, as well as the general public, in recognizing that aging research has come into real prominence in the last decade. We also need to be well informed about the rampant marketing of bogus dreams of anti-aging potions that the marketplace is all too ready to foist onto our patients. The aging of the baby boomers has created a huge and growing market for antiaging therapies. Many are safe, effective, and worthwhile. However, in some instances, such as vitamin supplementation or hormone replacement, controversies exist and individual patient decision should be informed by knowledgeable and free discussions based on real science. This information can come from you, the clinician. It can also come from internet sources, but internet sources increasingly are also are full of inadequate and misleading information and, thus, it becomes even more important for us to be able to relay to our patients legitimate sources of information. Some of the most useful include the following: • On terra firma, the National Institutes of Health is a complicated maze of 75 buildings. But on the Web (http://www.nih.gov), it is a snap to move from the National Cancer Institute to Mental Health to Alternative Medicine. Log on to www.clinicaltrials.gov to search for clinical trials by disease. • The National Institute on Aging, one of 25 institutes and centers of the National Institutes of Health, leads a broad scientific effort to understand the nature of aging and to extend the healthy, active years of life. Visit http:// www.nia.nih.gov/ for a description of its mission, sponsored research programs, news and calendar of events, and health information, including NIA publications and videos, a resource directory for older adults, and various internet links of Federal websites of interest to the aging community. • At their website, the Centers for Disease Control and Prevention (www.cdc.gov) provides a calendar of events, current topics, and recent reports and publications. Click on their “Data and Statistics” for CDC health data standards, scientific data, surveillance, health statistics reports, and laboratory information. The website also includes information about grant and cooperative agreement funding opportunities, as well as press releases and current health news. On their “Publications, Software, Products” link, one can order and download brochures, catalogs, publications, software, slides, and videos. Consumers can browse their “Health Topics” from A (Acanthamoeba infection) to Z (Zoster), get the latest on health “Hoaxes and Rumors” (i.e., deodorants cause breast cancer), or check out

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the travel section to find out if they will need vaccines for a trip abroad. Or stay close to home and find a link to your local state health department. The Food and Drug Administration is the primary resource for information about safety alerts/recalls and product approvals of drugs, cosmetics, foods, medical devices, biologics, animal feed and drugs, and radiation-emitting products. Ongoing clinical trials are also profiled. Go to http://www.fda. gov. HealthWeb (http://www.healthweb.org/) is a collaborative project of the health sciences libraries of the Greater Midwest Region of the National Network of Libraries of Medicine and those of the Committee for Institutional Cooperation. Currently, there are over 20 actively participating member libraries. The goals of the Health-Web project include the development of an interface that provides organized access to evaluated noncommercial, health-related, internet-accessible resources, including those currently available, as well as new resources developed in collaboration with other organizations. The interface integrates educational information so the users has a one-stop entry point to learn skills and use material relevant to their discipline, including geriatrics and gerontology. The National Aging Information Center (http://www.aoa.gov/NAIC/) serves as a central source for a wide variety of information on aging for older people, their families, and those who work for or on behalf of older persons. NAIC resources include program and policy-related materials for consumers and practitioners and demographic and other statistical data on the health, economic, and social conditions of older Americans. The NAIC bibliographic database contains references to program- and policy-related materials on aging not referenced in any other computer system or print resource. The GeroWeb, sponsored by the Geroinformatics Workgroup at the Wayne State University Institute of Gerontology, is designed as an online resource for researchers, educators, practitioners, and others interested in aging and older individuals. (http://geroserver.iog.wayne.edu/GeroWebd/GeroWeb. html) The Alzheimer Research Forum’s intended audience is Alzheimer researchers and other researchers whose work may bring understanding to Alzheimer’s. The site has news, holds online forums, conducts online polls (“What are your 10 most wanted research tools?”), provides information on conferences, research funding, and includes a reagent company directory. Visit them at http://www.alzforum.org/home.asp. The Federal Interagency Forum on Aging-Related Statistics was initially established in 1986, with the goal of bringing together Federal agencies that share a common interest in improving aging-related data. The Forum has played a key role by critically evaluating existing data resources and limitations, stimulating new database development, encouraging cooperation and data sharing among Federal agencies, and preparing collaborative statistical reports. Their website (http://www.agingstats.gov/) provides information from their latest report. Older Americans 2000: Key Indicators

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of Well-Being, as well as links to aging-related statistical information on Forum Member websites, ongoing Federal data resources relevant to the study of aging, past products of forum activities, and agency contacts. • AgeLine is a free searchable electronic database of 60,000 summaries of publications about older adults and aging, including books, journal and magazine articles, and research reports. Coverage is sporadic between 1966 and 1977, but more comprehensive coverage exists from 1978 to present. (http://research.aarp.org/ageline/home.html) • The Centers for Medicare and Medicaid (CMS), formerly the Health Care Financing Administration (HCFA), is a federal agency within the U.S. Department of Health and Human Services. CMS runs the Medicare and Medicaid programs and the State Children’s Health Insurance Program (SCHIP), and also regulates all laboratory testing (except research) performed on humans in the U.S. By visiting the CMS website at http:// cms.hhs.gov physicians and other health care professionals can gain quick access to professional publications and program forms and learn about the Medicare program and CMS contracts with Medicare health plans, as well as statistics, data, and the latest CMS research and program analysis. Consumers can find information on what Medicare covers, who is eligible, and how to enroll. They can also get a personalized report on Medicare health plans, nursing homes, dialysis facilities, participating physicians, and prescription drug programs in their area. While we have a glut of information, we also have real ethical challenges facing us. The advances in genetic knowledge and potential alterations of genes through gene therapy have led to real caution because of highly visible adverse consequences to subjects of human studies. People are very concerned about the degree to which genetic information can be kept private and justifiably concerned that such information not fall into the hands of employers or insurers. The country will continue to be embroiled in deep disagreements about the use of human stem cells for research. The dramatic promise that they hold has come up against deep-seated religious beliefs of those who feel that embryos that are surplus and intended for discarding are indeed human life and ought not to be used for experimentation. These and other ethical issues will continue to be important as science progresses. In their chapter, Greg Sachs and Harvey Cohen discuss the ethical issues in clinical research, including the ethics of research with Alzheimer’s disease, a paradigmatic disorder where patients cannot fully make their own decisions and yet where research is very high stakes and needs to be offered to those suffering from the ravages of this disease. Ethical issues also continue to surround treatment decisions and, in particular, those around expensive potential life-prolonging and intrusive measures for older individuals. The challenge—especially in the United States—is how to balance the promise of these disorders with the increasing inequities in our health care system, in particular in a situation where more and more people under the age of 65 have no health insurance at all. All of these issues will continue to intensely involve the public, and thus clinicians will need every possible resource to stay informed as citizens and to

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provide important answers for their communities and their patients. Along these lines, we have expanded this edition by 18 chapters, devoting an entire section to the emerging field of palliative medicine and increasing our coverage on surgical issues, care management, and pharmacology. Health care providers will increasingly be called upon to practice what has come to be known as “evidence-based medicine.” So much of health care— particularly the prescribing of medications—is extremely costly and, as we know well in geriatrics, carries risks of its own. For this reason, it is more and more important that clinicians understand the evidence behind the use of any interventions, both diagnostic and therapeutic. The science of evaluating evidence is a statistical one, and the standards for doing so have been articulated by leaders in the field. One of those leaders, Rosanne Leipzig, is deputy editor of this edition of Geriatric Medicine. She has looked at every single chapter through an evidence-based lens and, whenever possible, provided upto-date information about the quality and strength of the evidence for the diagnostic and treatment recommendations included in each chapter. We are very fortunate that Dr. Leipzig has joined the Geriatric Medicine, 4/e, team and can give us this added dimension of balance and rigor to the expertise of our world-class roster of authors. I also want to thank Harvey Cohen, Eric Larsen, and Diane Meier, Associate Editors, who have contributed enormously to the production of this book. We have worked hard together and learned a great deal from each other. Thanks also to Carol Capello in her role as Managing Editor. Carol has now taken us through two editions of Geriatric Medicine, and we hope we can persuade her to work with us on the fifth edition of Geriatric Medicine. Christine K. Cassel

Preface to the Third Edition

“We who are old know that age is more than a disability. It is an intense and varied experience, almost beyond capacity at times, but something to be carried high. If it is a long defeat it is also a victory, meaningful for the initiates of time, if not for those who have come less far.” Florida Scott-Maxwell The Measure of My Days

As we embark upon the twenty-first century, are we prepared to meet the complex scientific, clinical, and social challenges of the explosive growth in the number and proportion of persons 65 and older in the United States? Over this past century, America has witnessed a success story of aging. There has been an unprecedented increase in life expectancy; whereas a child born in 1900 could expect to live to age 47, a child born today can expect to live to age 75. It is certainly a miracle of modern public health and medicine that each day approximately 6,000 Americans celebrate their 65th birthday. Many of these people will live past age 75; in fact, the 85-plus population is the fastest growing age group in the country. But what is the price of our success in dramatically increasing life expectancy? Is quantity of life synonymous with quality of life? With increased chronological age comes the increased probability of having multiple chronic illnesses. Recent studies suggest that better health accompanies longer life, that chronic disability rates among the elderly have declined, and that the prevalence of chronic disease conditions has dropped. Medical care certainly has impacted agerelated disability. Hip and knee replacement surgery can ameliorate osteoarthritis of the hips and knees that once led to major mobility disorders; effective medical regimens, as well as coronary artery and valve replacement surgery, have reduced disability from heart disease; treatment of hypertension has reduced stroke-related disability; prompt diagnosis and careful management of infection, myocardial infarction or endocrine disorder–often only presented as confusion in people with mild cognitive impairment–can keep older individuals functioning in their homes rather than in nursing homes; and technologies such as cataract surgery and hearing aids have allowed people greater function in their later years. The exciting field of molecular genetics, currently helping us better understand genetic variation and disease, may potentially lead to effective diagnosis, treatment, and preventive strategies for various diseases, such as Alzheimer’s disease. xxiii

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As a result, many older Americans are now living their later years actively and independently. However, for many others increased years of life translate into increased years of suffering from multiple illnesses and disabilities that require primary, specialty, acute care, and possibly long-term-care services. With increased population aging has come an unexpected rise in the proportion of older people who suffer from chronic nonfatal conditions–diseases and disorders largely unrelated to their ultimate cause of death. True, impressive gains have been made in postponing death. Doctors can now save the lives of many who in the past would have died from heart attacks, but these survivors often face their remaining years in a state of poor health. Postponement of death from cancer and heart disease means more years of being vulnerable to disabling diseases associated with age, such as degenerative neurological and musculoskeletal disorders, osteoporosis, Parkinson’s disease, dementia, vision and hearing impairments, and diabetes–conditions that surpass fatal disease in contributing to overall frailty and disability. Living longer means more people may live long enough to suffer from senile dementia and Alzheimer’s disease, and although we can now improve function and relieve suffering of these illnesses, we still know very little about how to prevent or postpone these conditions. One of the aims of this third edition is to help health care providers manage the complex chronic illness of our aging population. Medical technology and improved lifestyles may have added years to our lives, but to continue this miracle of successful aging, we as health care providers face the challenge of helping add quality life to these years. With active medical attention and expertise in the complex management of agerelated illnesses, even more people will be able to experience successful aging. The challenges of managing care for our older population are compounded by fragmented financing, and the aging of the population has been one of the underlying issues propelling concern about health care costs. More research is needed to provide even more effective medical interventions for chronic disabling diseases, but inevitably the function-enhancing interventions science can produce will increase costs of care as the population ages. It is our responsibility to ensure that health care resources are used as effectively as possible. Since the last edition of this book, managed care has become even more central to the provision of health care for the elderly, an increasingly important alternative to the fee-for-service arrangement. Managed care demands more efficient care, and some view it as a threat to quality care. However, if done correctly–and with ample available resources–it offers a superior model for successfully managing the comprehensive care of our elderly, allowing for innovation not available in the rigid fee-for-service model. The true managedcare system encourages appropriate care, continuity of care, and a continuum of care among the various care settings. It can help us design comprehensive, integrated programs to meet the health care needs of older people, to identify illness early, to manage concurrent problems and medications carefully, and to foster communication by developing a good relationship with patients and families. For example, under an ideal managed care system, physicians would want to increase the length of patient visits, for detecting problems earlier helps

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keep patients out of the hospital. Longer visits give physicians a better chance to get to know their patients and ascertain that patients fully understand important issues such as advance directives before leaving their office. Ideally, managed care systems for older patients can effectively and efficiently utilize resources. Not only are providers not limited to delivering only those services specifically reimbursed under the fee-for-service structure, but financial incentives may influence earlier diagnosis and intervention before a condition becomes acute. Assuring quality of life in one’s later years should include quality of care at the end of life, and this edition of Geriatric Medicine includes chapters on palliative care, pain management, and long-term care. Since the last edition, the widespread use of medical technology to sustain and prolong life has generated a rebirth of concern about death and dying, and the public debate about assisted suicide and euthanasia has intensified. The vigorous public debate about assisted suicide tells us that most Americans fear dying in our hospitals or nursing homes, which have been criticized for decades for their lack of attention to the care of dying patients. The success of an alternative model–hospice–holds lessons for all health care institutions. Patients and their families seek a more personal approach to the experience and meaning of death, and it is an essential part of our professional responsibility to assure them that they will have a dignified and gentle closure to their lives. As health care providers, we must accept that old age also includes a period of decline and dependency at the end of life. We must admit that there are limits of medical care, and we must learn to view death not as a personal or professional failure, but as a challenge–a challenge we can meet by providing competent and compassionate palliative care to dying patients, by learning to identify preventable suffering and to treat it effectively. With the completion of each edition of Geriatric Medicine, I have been astounded at the vast magnitude and complexity of the project. From inception to completion, our work spanned almost three full years, and as I moved from the University of Chicago to Mount Sinai Medical Center, the work-in-progress traveled with me. As with the other two editions, it is impossible to acknowledge every single person who helped in our effort. At the University of Chicago, Dana Levinson helped us get this project off the ground, helping organize all the details of planning the new edition, contacting new and returning authors, acting as liaison between editors, authors, and publisher and managing the trafficking of manuscripts between busy universities across the country. When I arrived at Mount Sinai, Carol Capello assumed these managerial responsibilities and saw the project through its completion, preparing manuscripts for publication and painstakingly reading through galley proofs. I also wish to acknowledge the staff at Springer-Verlag who helped ease the burden with their professional guidance and encouragement. With this edition, I have been honored to work with six associate editors, each exemplifying the very best our discipline has to offer. I thank them for giving freely of their time, patience, and expertise. I also thank the many other contributors to this volume, also top experts in their fields, for sharing with us their invaluable insights so that we may better serve our aging population.

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I want to pay a special tribute to John R. Walsh, coeditor in the first and second editions, who died last year. “Dick” (as he was known by everyone) Walsh was one of the early leaders in medicine who, as Chief of Medical Services at the Portland VA Medical Center, saw the critical importance of geriatrics to the future of our profession and to the health of the nation. He was Director of the Geriatrics program at Oregon Health Science University where, during my fellowship, he and I would talk about the lack of a larger comprehensive geriatric-medicine text to define the field for fellows and others interested in improving their understanding of this growing field. At the time, the only “big” books that were available came from the United Kingdom–excellent resources, but in many areas inevitably culturally somewhat off-target for the American reader, especially in topics related to health care system organization and financing, legal, and regulatory concerns. We decided together to create a book that would provide a major comprehensive resource for the American medical audience. As a mentor, teacher, and senior faculty colleague, I could ask for no more supportive collaborator in this huge project than Dick Walsh. He was patient, thorough, extremely knowledgeable in the broadly diverse subject matters, involved, and utterly dedicated to the quality and accuracy of the text. I am not the only one who learned a great deal from Dick Walsh–many subsequent cohorts of fellows were fortunate to train with him, including one of the associate editors of the third edition, Diane Meier. It is not an overstatement to say that this book owes its existence to John R. Walsh, and it is for that reason that we dedicate this edition to his memory. Christine K. Cassel, M.D.

Preface to the Second Edition

“The body immures the mind within a fortress; presently on all sides the fortress is besieged and in the end, inevitably, the mind has to surrender.”79

Proust’s poetic lament characterizes most people’s attitudes towards aging– The “inevitable surrender of the mind.” We now understand that not all the declines of aging are so inevitable, and just as importantly, we have better skills in caring for those declines we cannot prevent. Indeed, the siege of the body and surrender of the mind rank among modern medicine’s greatest concerns. Because of the unprecedented growth, in developed countries, of the number and proportion of elderly persons, geriatrics now has taken its place among the distinct medical disciplines. Its purview goes even beyond mind and body, to include also society and to examine questions of values and meaning. We offer this second edition of Geriatric Medicine in response to continuing refinement of the art and science of medical care for older persons. The years since publication of the first edition have seen unparalleled advances in geriatric medicine. Examples include the development of sophisticated diagnostic categories of urinary incontinence, resulting in better understanding of a condition that afflicts half of all people in nursing homes; clarification of the epidemiologic patterns of osteoporosis and falls, which, together, account for the excess burden (both morbidity and mortality) of fractures borne by elderly persons; the elucidation of discrete genetic patterns and neuropathological changes as they relate to certain forms of dementia; increasing visibility and importance of home care and of rehabilitation; and court decisions and institutional policies about end-of-life decisions that are prompting important and intense public discussion. Such progress foretells therapeutic and policy advances, some of which are nearing the horizon already. Equally dramatic has been the academic maturation of geriatric medicine. Over three-fourths of all U.S. medical schools are now affiliated with longterm care institutions. One hundred twenty-five geriatrics fellowship programs were active as of 1987. Program directors can take pride in the fact that over 90% of their graduates who took the 1988 examination for certification of Added Qualifications in Geriatric Medicine passed, while other examinees did distinctly less well. 79

Marcel Proust, Remembrance of Things Past. xxvii

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That examination, itself a benchmark for the field of geriatric medicine, was administered jointly by The American Board of Internal Medicine and the American Board of Family Practice, bespeaking the primary-care nature of the field and codifying its distinct body of knowledge. All of these events seemed to demand a second edition of this textbook, which we have focused into a single volume from the original two, a task that required doubling the number of editors. We have not eliminated topics by moving to one volume, but have focused better the rich tapestry of different disciplines that comprise the theoretical and clinical basis of geriatrics. This text combines traditional medical topics with the psychological, social, and ethical issues that are no less a part of the geriatrician’s domain. In weaving this tapestry, it was inevitable that there be overlappings of one discipline into another. We believe that such duplication, rather than being redundant, is appropriate in a comprehensive resource. The areas of overlap provide differing perspectives on the same topic and will enrich the reader’s understanding in the process. Extensive indexing and cross-referencing guide those seeking these different perspectives. Medicine finds itself enmeshed in fierce debate about its very fabric. The cost and logic of ever-increasing technological capabilities demand difficult choices. Nowhere are those choices confronted more frequently or more poignantly than in geriatrics, where a thorough understanding of technologies must go hand-in-hand with a discerning sense of judgement. The geriatrician is called upon to take seriously the role of patient advocate in all its meanings, no small act of courage. So the geriatric imperative is just that: growing numbers of older patients require competence, compassion, and judgement of their physicians. For a project such as this, it is impossible to acknowledge adequately all those who helped. As with the first edition, the effort has resulted in a spirit of communal scholarship. During the 3 years of work, innumerable persons have contributed unqualified support. At Springer-Verlag, Shelley Reinhardt and Robin Brown ensured the soundness of the final product by their professionalism and encouragement. Juliann Lundell Tarsney and Kathleen Heller lent their considerable scholarship to the copyediting process. And Lois Danker and Joyce Eberhardt successfully managed the trafficking of manuscripts between busy universities throughout the country. The contributors to this volume, who represent the very best that our discipline has to offer, have given freely of their time and expertise. We the editors thank them especially and proudly offer the second edition of Geriatric Medicine as a testimony to their excellence. Christine K. Cassel, M.D. Donald E. Riesenberg, M.D. Leif B. Sorensen, M.D., PH.D. John R. Walsh, M.D.

Preface to the First Edition

“Old age ain’t for sissies”80

In the last decade, two developments have changed the practice of medicine: the aging of the population and the dominance of medical technology. Both medical education and medical practice have responded to these events. Aging, chronic illness, and longterm care now are frequently written about in medical journals. Advances in diagnostic and therapeutic technologies have out-stripped our ability to evaluate or to pay for the new services. The field of geriatric medicine is a response to the first development and a reaction to the second. The medical response to the demographic imperative of aging has been to codify a field of medical specialization that is relevant and useful to the increasing numbers of elderly persons. The reaction is to emphasize a broadly comprehensive, humane, and personal approach to patient care. There no longer is any doubt that there exists a body of scientific knowledge, which characterizes the field of geriatrics. In addition to a distinct body of knowledge, most geriatricians also will describe a special approach and philosophy that characterizes the practice of geriatrics. There is growing awareness in academic medicine that special knowledge, skills, and attitudes are needed to deal effectively with elderly patients, particularly very old or frail patients. However, many physicians in primary care specialties such as internal medicine, family practice, and general surgery claim (and accurately so) that they function as geriatricians because many of their patients are elderly. In fact, in many instances, clinical practices of these generalists predominantly consist of elderly patients. Even with the advent of full-time geriatricians, the proportion of elderly persons in general practice populations will increase within the next two decades. Both viewpoints are correct. Geriatrics is a specialty and also an essential component of almost any clinical practice. It is true that many physicians, especially those in primary care settings, will have a large proportion of elderly patients in their practice and (to a certain extent) will be practicing geriatrics. Until recently, most graduate training programs in medicine, family practice,

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Moore H. Sayings. In: Alvarez J, Oldham P, editors. Old age ain’t for sissies. xxix

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or psychiatry did not include special consideration of geriatrics. Many physicians have learned some of the practical information on their own; however, the body of knowledge referred to in the recent Institute of Medicine report and the theoretic and scientific progress in this field had not been generally accessible.81 It also is true that we have, in the last 5 years in the United States, codified a specialty of geriatrics that includes training programs in geriatric medicine at the fellowship level. Many of the graduates of these programs will assume academic roles and bring the content of geriatrics to all relevant areas of health care education. In these volumes, we have tried to assemble the material in a way that is useful for both practicing clinicians and physicians-in-training, especially those who have selected training in geriatrics. In addition, this text is meant to be a comprehensive resource for a practitioner who needs information for the clinical demands of the moment. For a research scientist or physician in advanced training, there is an introduction to the theoretical basis to each subject and a substantial bibliography. We hope that, in this way, these volumes also will provide access to the new areas of research and the new understandings that are now emerging. Because we attempt to bring together in one place the full content of geriatric medicine, this work is deliberately compendious. Geriatrics had a broad basis; it includes clinical medicine, humanities, and the social sciences. Also, Geriatric Medicine accordingly had several sections organized into two volumes. The division into two volumes is primarily in the interest of the reader’s convenience and, thus, inevitably somewhat arbitrary. Nonetheless, our underlying concept is that the biological, the psychosocial, and the philosophical are essential parts of a single whole. We have called on a large number of contributors, in many different fields, to assure that the subject matter is treated authoritatively. Aging is an important and exciting area of biomedical research, which is represented largely in Volume I. The diseases that are the greatest scourges of old age are principally the chronic and degenerative disorders such as osteoporosis, Parkinsonism, stroke, Alzheimer’s disease, osteoarthritis, and peripheral vascular disease. Until recently, the level of research activity into the causes and treatments of these disorders has been markedly inadequate when measured against the numbers of people who are afflicted and the costs–both financial and humanitarian–to our society. However, there are areas of knowledge and research outside of biomedicine that also are critical to progress in geriatrics. These include disciplines that are based in social sciences and humanities, rather than in biology and medicine. Health services research and bioethics are especially important to geriatrics. A geriatrician may need to emulate the Renaissance scholar. The body of knowledge is broad and its relevance is undeniable. Geriatrics is unique as a medical specialty, because it is broader, rather than narrower, than the parent disciplines. An effective clinician must have some

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Institute of Medicine. Aging and medical education. Washington, DC: National Academy of Sciences; 1978.

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grasp of social gerontology, architectural design, law, psychology and psychiatry, spiritual counseling, health policy and health care economics, interprofessional sociology, epidemiology, and philosophical ethics to claim a firm competence in the care of elderly persons. For this reason, much of Volume II is devoted to chapters that are written by experts in these fields. These authors provide information that is both practical and relevant to clinicians, and that also may encourage a deeper exploration of this field. The breadth of subjects covered in these two volumes is a demonstration of the needs for interdisciplinary practice in geriatrics and gerontology. No one person can be an expert in each of these areas. Yet, each subject will be relevant to the needs of an elderly patient at one time or another. It is important for a geriatrician to be able to work effectively with other health care providers as well as with social scientists and policymakers, and to know where his or her own limits have been surpassed had where consultation is necessary. For appropriate and effective consultation, one must have a basic understanding of the sphere of knowledge of consultants. The theoretical and clinical basis of geriatrics is a rich tapestry of different disciplines. In weaving this tapestry, it was inevitable that there would be overlappings and crossings of one discipline into another. The reader occasionally may find material that is apparently redundant from one chapter to another. We feel that such duplication is appropriate in a comprehensive resource text such as this. In most cases, the areas of overlap will provide a different perspective on the same topic and will enrich the understanding of the reader in the process. We hope that the indexing and cross-referencing will provide guidance to those who are specifically seeking these different perspectives. For a projects of this magnitude, it is impossible to adequately acknowledge all those who helped. It has been a project of many rewards, both in the content and meaning of the work itself and in the expanding community of scholarship and advocacy. From inception to completion, this project has taken 3 years. During this time, innumerable persons have contributed significant support. The staff of Springer-Verlag has given us stimulating concepts and good ideas, in addition to steadfast sensible guidance. The details of organizing, phonecalling, letter-writing, library research, and manuscript preparation cannot be overemphasized in a work of this size and complexity. Special acknowledgment in these areas is due to Pamela Beere Briggs and Carol Saatzer. We also acknowledge the generous support of the Henry J. Kaiser Family Foundation. We are aware that we have jointed the beginning of a very important process. The profession of medicine is at a turning point; it is caught between the successes of scientific and technologic progress and concerns about the rising costs of care and the depersonalization of its delivery. Patients–disaffected, frustrated, and often in real need–are caught in between these unresolved issues. The moral center of the profession is at risk in the policy debates. An understanding of geriatrics requires competent familiarity with the capabilities of the latest in medical technology, a discerning sense of judgment about when and when not to use such interventions, and the courage and energy to take seriously the social role of advocate for a patient. The

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complexity, richness, and mystery of aging cannot be described better than it has been by T.S. Eliot in East Coker: Home is where one starts from. As we grow older The world becomes stranger, the pattern more complicated Of dead and living. Not the intense moment Isolated, with no before and after, But a lifetime burning in every moment And not the lifetime of one man only But of old stones that cannot be deciphered.

We choose to view the challenge posed by the geriatric imperative not as a burden, but as an opportunity for medicine to restructure its priorities and to respond to the real needs of modern society. Geriatrics can be a vehicle for returning the values of compassion, moderation, and moral judgment to both medicine and scientific progress. These volumes, in themselves, will not create the complete clinician, but they can provide the groundwork for the excellence that is possible in geriatrics. That excellence not only is possible, but it is a duty we owe to our patients, our profession, our society, and–in the final analysis–to ourselves. Christine K. Cassel, M.D. John R. Walsh, M.D.

Contents

Volume 1 Part I

What’s Different About Geriatric Medicine . . . . . . . . . . .

1

1

The Geriatrics Approach to Care . . . . . . . . . . . . . . . . . . . . . . Anna H. Chodos

3

2

Collaborative Decision-Making Aanand D. Naik

.......................

13

3

Caring for Patients in an Evidence-Limited World . . . . . . . . Ravishankar Ramaswamy and Rosanne M. Leipzig

35

4

Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership . . . . . . . . . . . . . . . . . . . . . . . . . Janice Hoffman-Simen and Tina Meyer

53

5

Social Determinants of Health . . . . . . . . . . . . . . . . . . . . . . . . Allison Moser Mays and Sonja Rosen

77

6

Legal Aspects of Geriatric Medicine Alan C. Horowitz

...................

87

7

Ethical Issues in the Care of Older Adults . . . . . . . . . . . . . . . 109 Nancy S. Jecker

8

Policy Issues in the Care of Older Adults . . . . . . . . . . . . . . . . 121 Michael R. Wasserman, Daniel Haimowitz, and Karl Steinberg

9

Age-Friendly Health Systems in an Ecosystem Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 Terry Fulmer, Leslie Pelton, Jinghan Zhang, and Wendy Huang

10

WHO Approach to Healthy Aging . . . . . . . . . . . . . . . . . . . . . 147 Tiziano Nestola and Matteo Cesari

11

Ethnogeriatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 Jeffrey de Castro Mariano and Jarrod Athen Carrol

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Contents

12

Caregiving (in the Twenty-First Century) . . . . . . . . . . . . . . . 185 Maria Torroella Carney, Marzena Gieniusz, and Edith Burns

13

Comprehensive Geriatric Assessment Sonja Rosen

14

Determination of Decision-Making Capacity . . . . . . . . . . . . . 211 Jay S. Luxenberg and Elliott M. Stein

15

Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Mikel Izquierdo

16

Nutrition in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 Carol J. Rollins and Amber Verdell

17

Health Maintenance and Prevention Maria Kristina Gestuvo

18

Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323 Matteo Cesari and Domenico Azzolino

Part II

. . . . . . . . . . . . . . . . . . 201

. . . . . . . . . . . . . . . . . . . 297

Medical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

341

19

Management of Cardiovascular Disease in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 Ifeoma Onuorah, Akanksha Agrawal, and Nanette Wenger

20

Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 John C. Landefeld, Sharad Jain, and Craig R. Keenan

21

Orthostatic (Postural) and Postprandial Hypotension in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . 401 Gabriela Sauder

22

Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 Andrea Ungar, Martina Rafanelli, Giulia Rivasi, and Irene Marozzi

23

Peripheral Arterial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 James Iannuzzi and Michael Conte

24

Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 Naushira Pandya and Meenakshi Patel

25

Thyroid Disorders in Older Adults . . . . . . . . . . . . . . . . . . . . . 475 Naushira Pandya and Elizabeth Hames

26

Infectious Diseases in Older Persons . . . . . . . . . . . . . . . . . . . 495 Dean Norman and Thomas Yoshikawa

27

Hematologic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Shakira J. Grant and Debbie C. Jiang

28

Gastrointestinal Disorders in Older Patients . . . . . . . . . . . . . 543 Jesse Stondell, Christine Shieh, Bao Sean Nguyen, Alex Zhornitskiy, and Joane A. P. Wilson

Contents

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29

Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571 Stacey-Ann Whittaker Brown and Sidney S. Braman

30

Kidney Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597 Jose Morfin and Tiana Jespersen Nizamic

31

End-Stage Kidney Disease in the Elderly Population . . . . . . 621 Nasim Wiegley and Jose Morfin

32

Dermatologic and Mucocutaneous Disorders . . . . . . . . . . . . 637 Angela Zaladonis and Rodrigo Valdes-Rodriguez

33

Changes and Diseases of the Aging Eye . . . . . . . . . . . . . . . . . 663 Mirjeta Abazaga and Robert Fechtner

34

Otologic Changes and Disorders . . . . . . . . . . . . . . . . . . . . . . 691 Kiranya E. Tipirneni and Brian D. Nicholas

35

Aging and the Oral Cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . 709 Roberto Carlos Castrejon-Perez

36

Bone and Joint Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721 Michaël R. Laurent

37

COVID-19 in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . 761 Mia Clar, Allison Walker, and Philip Solomon

Volume 2 Part III Cancer in Older Adults: An Overview . . . . . . . . . . . . . . . 781 38

Cancer and Older Adults: The Introduction . . . . . . . . . . . . . 783 Armin Shahrokni, Helen Pozdniakova, and Brandon Nightingale

39

Cancer Screening in the Older Adult . . . . . . . . . . . . . . . . . . . 801 Koshy Alexander and Beatriz Korc-Grodzicki

40

Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827 Gretell Henríquez, Nicolò Matteo Luca Battisti, Yanin Chavarri-Guerra, and Enrique Soto-Perez-de-Celis

41

Colorectal Cancer in Older Adults . . . . . . . . . . . . . . . . . . . . . 855 Armin Shahrokni, Helen Pozdniakova, and Brandon Nightingale

42

Lung Cancer in Elderly: Patient-Centered Approach for Optimal Delivery of Care . . . . . . . . . . . . . . . . 869 Ghanshyam H. Ghelani, Alina Basnet, and Ajeet Gajra

43

Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885 Jaime O. Herrera-Caceres, Neil Fleshner, and Shabbir M. H. Alibhai

44

Gynecologic Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913 Sindhuja Kadambi and William P. Tew

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Contents

Hematologic Malignancies Richard J. Lin

Part IV

. . . . . . . . . . . . . . . . . . . . . . . . . . . 919

Sexuality and the Genitourinary System . . . . . . . . . . . . .

933

46

Gynecologic and Urologic Problems in Older Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 935 Isuzu Meyer

47

Sexuality and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959 Paul N. Bryman, Leonard A. Powell, and Terrie B. Ginsberg

48

BPH and Male Lower Urinary Tract Symptoms . . . . . . . . . . 979 Theodore M. Johnson II and Anna Mirk

49

Voiding Problems and Urinary Incontinence in the Geriatric Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999 Lavern A. Wright, Paige Hamilton, George A. Kuchel, and Phillip P. Smith

Part V

Disorders of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025 . . . . . . . . . . . . . . 1027

50

Alzheimer’s Disease and Other Dementias Ian Curtis Neel

51

Cerebrovascular Disease and Stroke . . . . . . . . . . . . . . . . . . . 1047 Alison I. Thaler and Michael G. Fara

52

Parkinson’s Disease and Other Movement Disorders . . . . . . 1073 Pavan A. Vaswani and Jayne R. Wilkinson

53

Schizophrenia and Other Late-Life Psychoses . . . . . . . . . . . 1097 Francesco Saverio Bersani, Elisabeth Prevete, and Roberto Vicinanza

Part VI Diagnosis and Management of Geriatric Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109 54

Depression, Anxiety, and Other Mood Disorders . . . . . . . . . 1111 Jason Jalil, Dax Volle, Tongtong Zhu, and Michael Sassounian

55

Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1155 Giuseppe Bellelli and Alessandro Morandi

56

Pain Management in the Older Adult . . . . . . . . . . . . . . . . . . 1171 Dale Sapell, Charity Hale, Ashley Takeshita, and David Copenhaver

Contents

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57

Pressure Injury and Chronic Wounds . . . . . . . . . . . . . . . . . . 1185 Jeffrey M. Levine

58

Sarcopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213 Matteo Tosato, Emanuele Marzetti, Anna Picca, and Riccardo Calvani

59

Falls in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235 Allison Moser Mays

60

Sleep and Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1251 David Dai, Kevin J. Eng, and Cathy A. Alessi

61

Elder Mistreatment and Abuse . . . . . . . . . . . . . . . . . . . . . . . . 1267 Laura Mosqueda and Seyed Parham Khalili

Part VII Care Delivery and Systems Approaches to Geriatric Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1279 62

Primary Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1281 Michael R. Wasserman

63

Emergency Medicine and the Person-Centered Approach to the Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . 1295 Katren Tyler, Jennifer Kristjansson, Jennifer Roh, and Vaishal Tolia

64

Approach to Acute Hospital Care . . . . . . . . . . . . . . . . . . . . . 1317 Lauren W. Mazzurco, Juanita Smith, and Robert M. Palmer

65

Surgical Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 Liron Sinvani and Daniel Ari Mendelson

66

Care in the Community . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1373 George Taler and Steven Jae Won Han

67

Nursing Home Care in the USA . . . . . . . . . . . . . . . . . . . . . . . 1387 Innokentiy Bakaev, Suzanne M. Gillespie, Casey Rust, and Paul Katz

68

Palliative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1401 Katherine Wang and Diane Meier

69

Geriatric Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411 Wilco Achterberg, Van Haastregt Jolanda, Ewout Smit, and Monica van Eijk

70

Antibiotic Stewardship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 Philip D. Sloane and Christine E. Kistler

71

Population Health for Older Adults . . . . . . . . . . . . . . . . . . . . 1437 Richard G. Stefanacci and Alex Casiano

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Mechanisms of Paying for Health Care . . . . . . . . . . . . . . . . . 1451 Richard G. Stefanacci

73

Interdisciplinary Care and Care Coordination . . . . . . . . . . . 1469 Deb Bakerjian and Michael R. Wasserman

74

Improving Quality and Safety in the Care of Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1487 Deb Bakerjian

Part VIII

The Science of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1511

75

The Demography and Biodemography of Aging . . . . . . . . . . 1513 S. Jay Olshansky

76

Molecular and Biological Factors in Aging . . . . . . . . . . . . . . 1525 Rachel Litke and Charles Mobbs

77

Physiology of Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555 George E. Taffet

78

Immunology of Ageing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1567 Graham Pawelec and Ludmila Müller

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1585

About the Editors

Dr. Michael Wasserman is a geriatrician who has devoted his career to serving the needs of older adults. He serves on the Board of Directors of AMDA – The Society for Post-Acute and Long-Term Care Medicine and chairs the Public Policy Committee for the California Association of Long Term Care Medicine (CALTCM). He is a member of the Infrastructure workgroup for the National Advisory Committee on Seniors and Disasters. He served as a member of the National Academy of Science’s “A Framework for Equitable Allocation of Vaccine for the Novel Coronavirus” Committee and was a member of California’s Community Vaccine Advisory Committee. He previously served as Chief Executive Officer overseeing the largest nursing home chain in California. Prior to that, he was the Executive Director, Care Continuum, for the CMS contracted Quality Improvement Organization for California. In 2001 he co-founded Senior Care of Colorado, which became the largest privately owned primary care geriatrics practice in the country, before selling it in 2010. His books, The Business of Geriatrics and Primary Care for Older Adults: Models and Challenges were published in 2016 and 2017. In the 1990s he was President and Chief Medical Officer for GeriMed of America, a Geriatric Medical Management Company, and developed GeriMed’s Clinical Glidepaths in conjunction with Drs. Flaherty and Morley of St. Louis University’s School of Medicine Geriatric Division. In 1989, in the Journal of the American Geriatrics Society, Dr. Wasserman published “Fever, White Blood Cells and Differential Count in Diagnosing Bacterial Infection in the Elderly,” the findings of which are now part of xxxix

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About the Editors

the McGeer Criteria, used widely in nursing homes to evaluate residents for infections. Dr. Wasserman is a graduate of the University of Texas, Medical Branch. He completed an Internal Medicine residency at Cedars-Sinai Medical Center and a Geriatric Medicine Fellowship at UCLA. He spent 5 years with Kaiser-Permanente in Southern California where he founded Kaiser’s first outpatient Geriatric Consult Clinic. Dr. Wasserman was a co-founder and owner of Common Sense Medical Management (CSM2), a case management company that helped manage high risk beneficiaries of Cover Colorado. He was formerly a Public Commissioner for the Continuing Care Accreditation Commission. Dr. Wasserman was a co-founder of MESA (Medicare Experts and Senior Access) a multiyear grant from the Colorado Health Foundation to train primary care physicians in how to effectively care and bill for Medicare patients. He served on the Thousand Oaks Council on Aging and was the lead delegate from the State of Colorado to the 2005 White House Conference on Aging. He also co-chaired the Colorado Alzheimer’s Coordinating Council. Dr. Wasserman has previously served on the Boards of Wish a Lifetime from AARP, The Denver Hospice, and the American Geriatrics Society’s Foundation for Health in Aging. In 2003 he received the Francis T. Ishida Award for Customer Service from CMS, the Centers for Medicare & Medicaid Services. In 2022 he was the recipient of the Dan Osterweil Outstanding Leader in Post Acute and Long Term Care Award, from CALTCM. AMDA – The Society for Post Acute and Long Term Care Medicine honored him with the William Dodd Founder’s Award for Distinguished Service in 2022. Deb Bakerjian, PhD, APRN, FAANP, FGSA, FAAN, is the Associate Dean for Practice and a clinical professor at the Betty Irene Moore School of Nursing at UC Davis. Dr. Bakerjian was a Pat Archbold Predoctoral Scholar and Claire M. Fagin Postdoctoral Fellow at UCSF where she was also an assistant adjunct professor as well as a Gordon and Betty Moore postdoc at UC Davis. She earned a PhD in Nursing in 2006 and Master’s in Science of Nursing in 1992, both from UC San Francisco School of Nursing and her

About the Editors

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Family Nurse Practitioner and Physician Assistant certificate from UC Davis Department of Family and Community Medicine. Her doctoral study, “Utilization of Nurse Practitioners in Nursing Homes: A Comparison with Physicians,” received the 2006 Dissertation of the Year Award at UC San Francisco. Prior to coming to academia, Dr. Bakerjian owned a collaborative practice for over 20 years that provided care to nursing home residents. She is active in both state and national organizations associated with older adults, quality improvement, and patient safety. She is the incoming Chair of the Health Sciences section of the Gerontological Society of America. She is also on the Expert Panel on Aging and the Edge Runners National Advisory Council for the American Academy of Nursing, the Chair of HealthImpact the California nursing workforce center, and a past president of the California Association of Long Term Care Medicine as well as the Gerontological Advanced Practice Nurses Association. Her research focuses on healthcare workforce development, patient safety and quality improvement, and interprofessional education and collaborative practice in primary care, with a focus on older adults. Her study of the impact of music on patients with dementia was the first study on music and memory in older adults and included how nursing homes could implement a Music and Memory program as a Quality Assurance Performance Improvement project. Currently, she is the PI for several HRSA-funded grants on workforce development including Advanced NP PRACTICE, one of the first federally funded Primary Care Nurse Practitioner Residency programs; IN-LMC, a new grant that will provide funding to develop and implement a Nurse-Led Mobile Clinic to provide care to underserved populations; and a grant to enhance the knowledge of public health nursing in prelicensure nursing students. She also has funding from the Department of Labor to start a faculty residency program to facilitate experienced graduate nurses into becoming faculty. She is the co-PI on a project that enables consumers to compare nursing homes and other LTC organizations. Dr. Bakerjian is also the Editor-in-Chief of Geriatric Nursing journal, a co-Editor-in-Chief

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About the Editors

of The Textbook of Adult-Gerontology Primary Care Nursing: Evidence-Based Care for Patients Across the Lifespan as well as the AHRQ PSNet website. She has published multiple book chapters as well as over a hundred manuscripts and peer-reviewed abstracts. She has also received many honors including being inducted as a Fellow in the American Academy of Nursing, the American Association of Nurse Practitioners, the Gerontological Society of America, and into the Western Academy of Nursing. Sunny Linnebur, Pharm D, BCGP, BCPS, FCCP, FASCP, is a Professor, Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences. Dr. Linnebur graduated with her Doctor of Pharmacy degree from the University of Kansas in 1999 with Highest Distinction. She then completed a PGY1 residency at the Veterans Affairs Medical Center in Denver, Colorado, and a PGY2 Primary Care Residency at the University of Colorado. Since 2001, Dr. Linnebur has provided clinical pharmacy services in geriatrics at the University of Colorado Hospital Seniors Clinic, where she also precepts pharmacy students and residents. Her research and clinical areas of interest include transitions of care, cardiovascular disease, health promotion, osteoporosis, vitamin D, dementia, and urologic disorders. She is an active member of the American Geriatrics Society where she serves on the Expert Panel for the AGS Updated Beers Criteria® and is a past president. Dr. Linnebur is also a member of the American Board of Internal Medicine Geriatric Medicine Board. Sharon A. Brangman SUNY Upstate Medical University Syracuse, NY, USA Dr. Brangman is a graduate of Syracuse University and earned her medical degree from SUNY Upstate Medical University in Syracuse, New York. She completed internal medicine residency and geriatric fellowship training programs at Montefiore Medical Center in Bronx, New York. She is board certified in internal medicine, geriatric medicine, and hospice and palliative medicine.

About the Editors

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Dr. Brangman is a SUNY Distinguished Service Professor and Chair of the Department of Geriatrics at SUNY Upstate Medical University. Prior to this appointment, she had been the Division Chief of Geriatrics for 20 years. She is the founding Director of the geriatrics fellowship program and served in this role for 30 years. Dr. Brangman is also the Director of the Center of Excellence for Alzheimer’s Disease and is Medical Director of the Transitional Care Unit on the Upstate Community Campus and directs the Equity Research Core at SUNY Upstate Medical University. Dr. Brangman was a member of the Board of Directors of the American Geriatrics Society for 10 years and completed terms as President and Chair of the Board. She also served as Chair of the Board of the Association of Geriatric Academic Program Directors, after completing a term as its President.

Matteo Cesari is Professor of Geriatrics at the University of Milan (Milan, Italy; currently on leave) and Scientist at the Ageing and Health Unit of the World Health Organization (Geneva, Switzerland). He had previously worked at the Catholic University of the Sacred Heart (Rome, Italy), at the Wake Forest University (Winston Salem, NC, USA), at the University of FloridaInstitute on Aging (Gainesville, FL, USA), and at the University of Toulouse (Toulouse, France). His research activities have always been focused on the frailty condition and on strategies aimed at preventing the disabling cascade in older people. His most recent activities are focused on the integration of care for older persons to promote healthy aging. Dr. Cesari is among the most cited researchers (h index 90), having published more than 600 articles in scientific peer-reviewed journals in geriatrics and gerontology. He has also played roles of coordination and responsibility for scientific journals, medical societies, and international task forces in the field.

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About the Editors

Sonja Rosen, MD, FACP, AGSF Chief, Section of Geriatric Medicine, Department of Medicine, Cedars-Sinai Medical Director, Geriatrics, Cedars-Sinai Medical Care Foundation Professor of Medicine, Cedars-Sinai Professor of Medicine, UCLA David Geffen School of Medicine Dr. Sonja Rosen serves as the Chief of Geriatrics for Cedars-Sinai and the Medical Director of Geriatrics for Cedars-Sinai Medical Care Foundation. Under her leadership, the Academic Section of Geriatric Medicine at Cedars-Sinai was created, with her serving as the Inaugural Chief. She is a professor of Medicine at Cedars-Sinai and UCLA David Geffen School of Medicine. She is a fellow of the American College of Physicians and a fellow of the American Geriatrics Society. She was previously Chief of Geriatric Medicine at UCLA Medical Center, SM and Medical Director of UCLA Medical Center, SM Geriatric Inpatient Unit. Dr. Rosen completed her fellowship in Geriatric Medicine at UCLA, residency in Internal Medicine at HarborUCLA, and medical school at the University of Chicago Pritzker School of Medicine. She is board certified in Internal Medicine, Geriatric Medicine, and Hospice and Palliative Care Medicine. Dr. Rosen’s research and clinical interests include safe transitions of care and safe prescribing in older persons, geriatric co-management, delirium education, population health, Medicare Advantage population management, addressing social determinants of health, and fall prevention. She has written multiple peer-reviewed articles and chapters on this work, as well as served as book editor, and given multiple national and international presentations. She has created and implemented numerous quality improvement programs to improve geriatric models of care and has championed Cedars-Sinai’s efforts to be recognized as an Age-Friendly Health System Committed to Care Excellence in 2020. She currently serves nationally on the American Geriatrics Society Quality and Performance Measurement Committee and the workshop planning committee on Advancing Diagnostic Excellence for Older Adults for the National Academies of Sciences,

About the Editors

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Engineering, and Medicine. She has also won numerous awards for her clinical care, including being selected by peers for Southern California Super Doctors and Los Angeles Magazine Top Doctors for consecutive years.

Contributors

Mirjeta Abazaga Syracuse, NY, USA Wilco Achterberg Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands Akanksha Agrawal Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA AdventHealth, Orlando, FL, USA Cathy A. Alessi Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, North Hills, CA, USA UCLA Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA Koshy Alexander Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, New York, NY, USA Shabbir M. H. Alibhai University Health Network, Toronto, Canada Domenico Azzolino Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Innokentiy Bakaev Hebrew SeniorLife, Boston, MA, USA Deb Bakerjian Betty Irene Moore School of Nursing, University of California, Davis, Sacramento, CA, USA Alina Basnet SUNY Upstate Medical University, Syracuse, NY, USA Nicolò Matteo Luca Battisti Department of Medicine - Breast Unit, The Royal Marsden NHS Foundation Trust, London, UK Giuseppe Bellelli School of Medicine and Surgery, University of MilanoBicocca, Milan, Italy Acute Geriatric Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy Francesco Saverio Bersani Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy xlvii

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Sidney S. Braman Icahn School of Medicine at Mount Sinai, The Warren Alpert Medicine School of Brown University, Highland Beach, USA Paul N. Bryman Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA Edith Burns Division of Geriatrics and Palliative Medicine, Zucker School of Medicine at Hofstra Northwell, New Hyde Park, NY, USA Riccardo Calvani Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy Maria Torroella Carney Division of Geriatrics and Palliative Medicine, Zucker School of Medicine at Hofstra Northwell, New Hyde Park, NY, USA Jarrod Athen Carrol Faculty, Geriatrics and Palliative Medicine - Kaiser Permanente - West Los Angeles, Southern California Permanente Medical Group, Los Angeles, CA, USA Alex Casiano Inter American University of Puerto Rico, San Juan, Puerto Rico Roberto Carlos Castrejon-Perez National Institute of Geriatrics, National Institutes of Health, México D.F, Mexico Jeffrey de Castro Mariano Geriatrics and Palliative Medicine - Kaiser Permanente West Los Angeles, Department of Clinical Sciences - Kaiser Permanente Bernard J. Tyson School of Medicine, Southern California Permanente Medical Group, Los Angeles, CA, USA Matteo Cesari Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy Yanin Chavarri-Guerra Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Anna H. Chodos Division of Geriatrics, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA Mia Clar Division of Geriatrics and Palliative Medicine, Donald and Barbara Zucker School of Medcine at Hofstra/Northwell, New Hyde Park, NY, USA Michael Conte Vascular Surgery, University of California San Francisco, San Francisco, CA, USA David Copenhaver Department of Anesthesiology and Pain Medicine University of California, Davis, CA, USA David Dai Pulmonary Critical Care and Sleep, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA Monica van Eijk Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

Contributors

Contributors

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Kevin J. Eng Pulmonary Critical Care and Sleep, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA Michael G. Fara The Mount Sinai Hospital, New York City, NY, USA Robert Fechtner Ophthalmology and Visual Sciences, SUNY Upstate Medical University, Syracuse, NY, USA Neil Fleshner Surgical Oncology, University of Toronto, University Health Network, Toronto, Canada Terry Fulmer The John A. Hartford Foundation, New York, NY, USA Ajeet Gajra Hematology-Oncology Associates of CNY, Syracuse, NY, USA Exigent Research Network, Tacoma, WA, USA Maria Kristina Gestuvo Palo Alto Medical Foundation, Palo Alto, CA, USA Ghanshyam H. Ghelani SUNY Upstate Medical University, Syracuse, NY, USA Marzena Gieniusz Division of Geriatrics and Palliative Medicine, Zucker School of Medicine at Hofstra Northwell, New Hyde Park, NY, USA Suzanne M. Gillespie University of Rochester Medical Center, Rochester, NY, USA Terrie B. Ginsberg Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA Shakira J. Grant Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, USA Daniel Haimowitz Living Branches Senior Living, Souderton, PA, USA Charity Hale Department of Anesthesiology and Pain Medicine University of California, Davis, CA, USA Elizabeth Hames Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Ft. Lauderdale, FL, USA Paige Hamilton University of Connecticut School of Medicine, Farmington, CT, USA Department of Surgery/Division of Urology, University of Connecticut School of Medicine, Farmington, CT, USA Steven Jae Won Han Internal Medicine, MedStar Washington Hospital Center, Washington, DC, USA Gretell Henríquez Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Jaime O. Herrera-Caceres Department of Urology, Penn State Health, PA, USA

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Janice Hoffman-Simen Postgraduate Pharmacy Residency Program, Los Angeles Jewish Home for the Aging, Tampa, FL, USA College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA Alan C. Horowitz Arnall Golden Gregory LLP, Evergreen, CO, USA Wendy Huang The John A. Hartford Foundation, New York, NY, USA James Iannuzzi Vascular Surgery, University of California San Francisco, San Francisco, CA, USA Mikel Izquierdo Navarrabiomed, Complejo Hospitalario de Navarra (CHN)Universidad Pública de Navarra (UPNA), Navarra Institute for Health Research (IdiSNA), Navarra, Spain CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain Sharad Jain Davis School of Medicine, University of California, Sacramento, CA, USA Jason Jalil Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, California, USA Nancy S. Jecker Department of Bioethics and Humanities, University of Washington School of Medicine, Seattle, WA, USA Tiana Jespersen Nizamic UC Davis, Sacramento, CA, USA Debbie C. Jiang Department of Medicine, Division of Hematology-Oncology, University of Washington-Fred Hutchinson Cancer Research Center, Seattle, WA, USA Division of Hematology and Hematologic Malignancies, Beth Israel Deaconess Medical Center, Boston, USA Theodore M. Johnson II Birmingham/Atlanta VA GRECC, Emory University General Internal Medicine and Family and Preventive Medicine, Atlanta, USA Van Haastregt Jolanda Department of Health Services Research and Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands Sindhuja Kadambi Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA Paul Katz The Florida State University College of Medicine, Tallahassee, FL, USA Craig R. Keenan Davis School of Medicine, University of California, Sacramento, CA, USA

Contributors

Contributors

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Seyed Parham Khalili Los Angeles County Department of Health Services, Rancho Los Amigos National Rehabilitation Center and the Housing for Health Program, Los Angeles, CA, USA Christine E. Kistler Department of Family Medicine and Program on Aging and Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Beatriz Korc-Grodzicki Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, New York, NY, USA Jennifer Kristjansson Department of Emergency Medicine, University of California, Davis, Davis, CA, USA George A. Kuchel University of Connecticut School of Medicine, Farmington, CT, USA University of Connecticut Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA John C. Landefeld Davis School of Medicine, University of California, Sacramento, CA, USA Michaël R. Laurent Geriatrics Department, Imelda Hospital, Bonheiden, Belgium Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium Rosanne M. Leipzig Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Jeffrey M. Levine Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Richard J. Lin Department of Medicine, Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA Rachel Litke Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Jay S. Luxenberg On Lok, San Francisco, CA, USA Irene Marozzi Syncope Unit, University of Florence and Azienda Ospedaliero-Universitaria Careggi Florence, Florence, Italy Emanuele Marzetti Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy Allison Moser Mays Section of Geriatric Medicine, Division of Internal Medicine, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA Lauren W. Mazzurco Eastern Virginia Medical School, Norfolk, VA, USA

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Diane Meier Icahn School of Medicine at Mount Sinai, New York, NY, USA Daniel Ari Mendelson Vice President of Medical Services and Chief Medical Officer, Jewish Senior Life, Rochester, NY, USA Isuzu Meyer Department of Obstetrics and Gynecology, Division of Urogynecology and Pelvic Reconstructive Surgery, University of Alabama at Birmingham, Birmingham, AL, USA Tina Meyer College of Health Sciences, Western University of Health Sciences, Pomona, CA, USA Anna Mirk Birmingham/Atlanta VA GRECC, Emory University Geriatrics and Gerontology, Atlanta, USA Charles Mobbs Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department Geriatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Pharmacology and Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA Alessandro Morandi Intermediate Care and Rehabilitazion, Azienda Speciale Cremona Solidale, Cremona, Italy Parc Sanitari Pere Virgili and Vall d’Hebrón Institute of Research, Barcelona, Spain Jose Morfin Nephrology, UC Davis, Sacramento, CA, USA Laura Mosqueda Family Medicine and Geriatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA Ludmila Müller Max Planck Institute for Human Development, Berlin, Germany Aanand D. Naik Department of Management, Policy and Community Health, School of Public Health, University of Texas Health Science Center, Houston, TX, USA Joan and Stanford Alexander Division of Geriatrics and Palliative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA Center for Innovation in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, USA Institute on Aging, University of Texas Health Science Center, Houston, TX, USA Ian Curtis Neel Geriatrics, Gerontology, and Palliative Care, UC San Diego Health, San Diego, CA, USA Tiziano Nestola ASP IMMeS Pio Albergo Trivulzio, Milan, Italy

Contributors

Contributors

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Bao Sean Nguyen University of California, Davis, Sacramento, CA, USA Brian D. Nicholas State University of New York Upstate Medical University, Syracuse, NY, USA Brandon Nightingale Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA Dean Norman School of Medicine, San Diego VA Healthcare System, University of California, San Diego, California, USA S. Jay Olshansky School of Public Health, University of Illinois at Chicago, Chicago, IL, USA Ifeoma Onuorah Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Robert M. Palmer Eastern Virginia Medical School, Norfolk, VA, USA Naushira Pandya Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA Meenakshi Patel Department of Geriatrics, Wright State University Boonshoft School of Medicine, Dayton, OH, USA Graham Pawelec Department of Immunology, University of Tübingen, Tübingen, Germany Health Sciences North Research Institute, Sudbury, ON, Canada Leslie Pelton Institute for Healthcare Improvement, Boston, MA, USA Anna Picca Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy Leonard A. Powell Department of Geriatrics and Gerontology, Rowan University School of Osteopathic Medicine, Stratford, NJ, USA Helen Pozdniakova Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA Elisabeth Prevete Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy Martina Rafanelli Syncope Unit, University of Florence and Azienda Ospedaliero-Universitaria Careggi Florence, Florence, Italy Ravishankar Ramaswamy Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Giulia Rivasi Syncope Unit, University of Florence and Azienda Ospedaliero-Universitaria Careggi Florence, Florence, Italy Jennifer Roh Emergency Medicine, University of California, Irvine, Irvine, CA, USA Carol J. Rollins College of Pharmacy, The University of Arizona, Tucson, AZ, USA

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Sonja Rosen Cedars-Sinai Medical Center, Los Angeles, CA, USA Casey Rust The Florida State University College of Medicine, Tallahassee, FL, USA Dale Sapell Department of Anesthesiology and Pain Medicine University of California, Davis, CA, USA Michael Sassounian Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA Gabriela Sauder Geriatric Medicine, David Geffen School of Medicine, Los Angeles, CA, USA Armin Shahrokni Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA Christine Shieh University of California, Davis, Sacramento, CA, USA Liron Sinvani Division of Hospital Medicine, Department of Medicine, Zucker School of Medicine at Hofstra Northwell, Manhasset, NY, USA Philip D. Sloane Department of Family Medicine and Program on Aging and Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Cecil G. Sheps Center for Health Services Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Ewout Smit Department of Medicine for Older People, Amsterdam University, Amsterdam, The Netherlands Juanita Smith Eastern Virginia Medical School, Norfolk, VA, USA Phillip P. Smith University of Connecticut School of Medicine, Farmington, CT, USA University of Connecticut Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA Department of Surgery/Division of Urology, University of Connecticut School of Medicine, Farmington, CT, USA Philip Solomon Division of Geriatrics and Palliative Medicine, Donald and Barbara Zucker School of Medcine at Hofstra/Northwell, New Hyde Park, NY, USA Enrique Soto-Perez-de-Celis Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico Richard G. Stefanacci Jefferson College of Population Health, Thomas Jefferson University, Philadelphia, PA, USA Elliott M. Stein Geriatric Psychiatry, University of California San Francisco, San Francisco, CA, USA Phillip P. Smith: deceased.

Contributors

Contributors

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Karl Steinberg Stone Mountain Medical Associates, Inc., Oceanside, CA, USA Jesse Stondell University of California, Davis, Sacramento, CA, USA George E. Taffet Geriatrics and Cardiovascular Research, Houston Methodist Hospital and Baylor College of Medicine, Houston, TX, USA Ashley Takeshita Department of Anesthesiology and Pain Medicine University of California, Davis, CA, USA George Taler MedStr House Call Program, MedStar Health, Columbia, MD, USA William P. Tew Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Alison I. Thaler Neurology, The Mount Sinai Hospital, New York City, NY, USA Kiranya E. Tipirneni State University of New York Upstate Medical University, Syracuse, NY, USA Vaishal Tolia Emergency Medicine, Hospital Medicine, UCSD Health System, San Diego, CA, USA Matteo Tosato Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy Katren Tyler Department of Emergency Medicine, University of California, Davis, Davis, CA, USA Andrea Ungar Syncope Unit, University of Florence and Azienda Ospedaliero-Universitaria Careggi Florence, Florence, Italy Rodrigo Valdes-Rodriguez Department of Dermatology, University of Florida College of Medicine, Gainesville, FL, USA Pavan A. Vaswani Parkinson’s Disease Research Education and Clinical Center (PADRECC), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Amber Verdell Department of Pharmacy, Olive View-UCLA Medical Center, Sylmar, CA, USA Roberto Vicinanza Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA Dax Volle Department of Psychiatry, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA Allison Walker Division of Geriatrics and Palliative Medicine, Donald and Barbara Zucker School of Medcine at Hofstra/Northwell, New Hyde Park, NY, USA

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Katherine Wang Icahn School of Medicine at Mount Sinai, New York, NY, USA University of Wisconsin – Madison, Madizon, WI, USA Michael R. Wasserman California Association of Long Term Care Medicine, Newbury Park, CA, USA Nanette Wenger Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA Emory Heart and Vascular Center, Emory University School of Medicine, Atlanta, GA, USA Stacey-Ann Whittaker Brown The Johns Hopkins University School of Medicine, Baltimore, USA Nasim Wiegley Department of Internal Medicine, Division of Nephrology, University of California, Davis School of Medicine, Sacramento, CA, USA Jayne R. Wilkinson Parkinson’s Disease Research Education and Clinical Center (PADRECC), Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA Joane A. P. Wilson Duke University, Durham, NC, USA Lavern A. Wright University of Connecticut School of Medicine, Farmington, CT, USA University of Connecticut Center on Aging, University of Connecticut School of Medicine, Farmington, CT, USA Thomas Yoshikawa Department of Veterans Affairs, Geriatrics & Extended Care, Charles R. Drew University of Medicine & Science, Los Angeles, CA, USA VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA David Geffen School of Medicine at UCLA, Los Angeles, CA, USA Angela Zaladonis Department of Internal Medicine, Lankenau Hospital, Main Line Health System, Wynnewood, PA, USA Jinghan Zhang The John A. Hartford Foundation, New York, NY, USA Alex Zhornitskiy University of California, Davis, Sacramento, CA, USA Tongtong Zhu Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

Contributors

Part I What’s Different About Geriatric Medicine

1

The Geriatrics Approach to Care The 5Ms Anna H. Chodos

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

The 5Ms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . What Matters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mobility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Multimorbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5 5 6 7 7 8

Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Abstract

The 5Ms are: what Matters, Medication, Mentation, Mobility, and Multimorbidity. It is a mnemonic to quickly express what value geriatrics and related specialties bring to the care of older adults. It is a way to explain what we do. A related framework evolved in parallel: the 4Ms, which are what Matters, Medication, Mentation, Mobility. The 4Ms underpin the Age-Friendly Health System movement. The straightforward simplicity of the 4Ms or 5Ms,

whichever is chosen, has allowed it to catch fire across the country and driven the success of the Age-Friendly Health System movement. This chapter will review each domain and then provide a case of the development of an Age-Friendly Health System. Keywords

Geriatrics · 5Ms · 4Ms · What matters · Mobility · Medication · Mentation · Mind · Age-friendly health care

A. H. Chodos (*) Division of Geriatrics, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_1

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Introduction The 5Ms and the 4Ms. These unassuming and simple mnemonics represent a young but influential revolution in geriatrics. Between 2015 and 2017, experts in healthcare improvement and geriatrics across the US and Canada were collaborating and converging on concepts to better describe what geriatricians do and how they can have a real impact on the lives of medically complex and frail older adults. This seemed necessary to help improve and elevate the important work of geriatrics and its care models, long underrecognized for their value, and therefore underadopted in health care. Drs. Mary Tinetti, Allen Huang, and Frank Molnar describe how, in 2013, Dr. George Heckman proposed a simplification, a branding, of geriatrics that would help our profession communicate the core skills we bring to the table for healthcare and health systems [1]. The John A. Hartford Foundation, which had funded innumerable efforts across decades to improve the evidence base behind geriatrics care and disseminate geriatrics education across healthcare professionals, partnering with the Institute for Healthcare Improvement, drove efforts in the US to begin this rebrand [2–4]. And in Canada, professional organizations in geriatrics were similarly working on the same rethink, coming up with the “4Ms” representing Mind, Mobility, Medications, and Multicomplexity [1]. This led to Dr. Tinetti presenting a consolidated concept on April 21, 2017 during a keynote address at the Canadian Geriatrics Society Annual meeting in Toronto, Canada: the “geriatrics 5Ms” which are “mind, mobility, medications, multicomplexity, and matters most.” [1] It is simple, easy to remember (it evokes the five fingers on a hand), and directly maps to core skills that geriatricians can offer older adults and use to impact health outcomes. And it neatly summarizes the value of the geriatrics approach to care for the adults we serve best – medically and socially complex, frail – in a way that transcends the care settings in which they are being served, the discipline serving them, or the diagnosis for which they are receiving care. Surgical practices and skilled nursing facilities can use this framework

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as easily as primary care can, and it applies to older adults living with dementia and heart failure. In parallel, the John A. Hartford Foundation and the Institute for Healthcare led the core work to define the way forward in creating and fostering Age-Friendly Health Systems. They condensed a comprehensive review of evidence-based models of geriatric care into the specific elements and actions that systems should focus on to have impact on the health outcomes of older adults, and this is how they landed, ultimately, on the 4Ms: “what Matters, Medication, Mobility, and Mentation” [2]. This framework has carried the Age-Friendly Health Systems movement into real success. In conjunction with regular action communities for learning, clear criteria for implementation, and a process of formal recognition of a health care system as “age-friendly” at different levels of achievement (level 1 is “participant,” level 2 is “committed to care excellence”), the movement has resulted in 2900 health care systems recognized as providing Age-Friendly Health Care as of January 2023 [5]. The Age-Friendly Health System concept deserves a moment of explanation as well because it goes beyond the 4Ms. It describes a system that: has leadership committed to addressing ageism, care specifically tailored for older adults, staff trained in the care of older adults, shows measurable improvements for older adults, has a systematic approach for coordinating care with organizations outside of medical care, strategies to support family caregivers, and a clear process for understanding patient preferences and providing care that are concordant with these preferences [2]. In the current Age-Friendly Health System movement, it is essentially synonymous with providing evidence-based care within the 4Ms framework and it is a shift in care, not a program meant to be applied, that is done consistently and starts with champions for age-friendly care and moves on to impact more and more areas within a system [6]. IHI frames it as: “following an essential set of evidence-based practices; causing no harm; and aligning with What Matters to older adults and their family caregivers.” [7] The development of the 5Ms and the AgeFriendly Health System movement and its associated 4Ms may seem too simplistic to represent the

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complexity within the field of geriatrics or even within a straightforward geriatrics assessment. However, the success of this movement, how it has refocused the conversation for healthcare around achievable metrics that improve the care of older adults, and its embrace by the field of geriatrics speaks volumes about its brilliance. This framework has been used to show the effectiveness of care for older adults across dozens of published studies [4, 8–10]. Beyond a general toolkit, there are guides for implementation in hospital and ambulatory practices, in nursing homes, in surgical hospitals, emergency departments, and in convenient care clinics [5]. And it is setting the direction for the future, including in education and public health [11–14]. Federal funding opportunities in geriatrics and in disciplines proposing to serve older adults, for example from the Health Resources and Services Administration (HRSA) for the Geriatrics Workforce Enhancement Programs, have adopted requirements to address the program’s impact on the 4Ms and to organize educational curricula for health professions using the framework [15]. So, we have learned broadly what the 4Ms and 5Ms are and how they are essential to the AgeFriendly Health System movement. The process of achieving an Age-Friendly Health System involves not only knowing about the 4Ms, but also examining a current system’s practice by measuring and documenting the “current state” with regard to each one (e.g., how many older adults are assessed for falls, a Mobility, goal), and then making a plan to act and measure progress on making improvement. In the remainder of this chapter, we will review each of the “Ms” and more about what they mean and then how it would be operationalized, measured, and followed in age-friendly care. We will discuss the 5th “M” – multimorbidity or multicomplexity – in the context of its utility as a way to communicate where geriatrics excels. How fitting that this chapter, which discusses a way in which we are experiencing a new reframing for geriatrics, would be the first in this vital book on geriatrics and person-centered care. Across this book you will find details on each of

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the content areas, for example on dementia and mobility assessment, to help you in your work on providing age-friendly care.

The 5Ms At the heart of power of the “Ms” is that they provide a guiding paradigm for providing care to older adults and they show us how to measure the process and outcomes of the care we provide. But they naturally appear differently in their specifics across care settings and patient populations. Short examples under each “M” will illustrate this. Overarching the entire framework and crosscutting its effectiveness, is understanding the healthcare disparities that are part of all of healthcare. Building a picture, with data, in parallel with age-friendly dashboards, of the disparities in care across various patient factors, such as race, ethnicity, preferred language, income, and gender, will help any clinician and health system to apply the framework of the 4Ms or 5Ms in a way that best leverages its strengths. And finally, to decide where to begin and how to engage in making improvements in the 4Ms or 5Ms, finding champions and incentives to improve care in your system are key. Is there a quality initiative that addresses one of the Ms.? Is there an administrator or manager who is particularly passionate about improving care for older adults in your system? Finding and working in alignment with these factors is critical to success.

What Matters The domain of “what Matters” refers to knowing what matters most to the older adult with regard to their current and future healthcare. It means knowing what outcomes they are hoping for and what care preferences do they have, including around end of life care, if relevant. This, of course, would be important for people of any age, but in older adults where often the risks and benefits of medical interventions and treatments are higher, it is critical to have an understanding of a person’s

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unique goals. Generally, what Matters goes beyond the formal Advance Care Planning that involves establishing legal and medical surrogates or filling out an Advance Directive. A surgical clinic that is addressing what Matters may, for example: • Be assessing care preferences with a validated tool (e.g., from the Conversation Project: “What matters most to you right now about your healthcare?”) and introducing that this will be reviewed periodically to ensure the patient’s current preferences are known [16]. • Documenting these preferences in a standard way in the patient’s chart and giving them a printed version to bring to other healthcare visits. • Communicating them across the person’s care team through a care coordination note in the chart, or at team meetings. • Monitoring if the patient has received goalconcordant care, e.g., a nonclinical team member reviews a sample of charts to see if [1] what Matters is documented, and [2] if there is sufficient detail to suggest it could be used to guide care, [3] calls some patients to ask if they felt they received care consistent with their preferences with a brief survey. As many older adults have caregivers or care partners who provide support with health and social care, involving them in the assessment and implementation of what Matters is important to consider. For many older adults, involving these partners is a goal and a preference. Most importantly, what Matters should be the north star for a patient’s care. If there is a care decision related to another domain – Mobility, Medications, Mentation, or Multimorbidity – what Matters most to the older adult should be the guide. For example, if there is a medication that is higher risk for older people but is the most effective way for that person to relieve a symptom and would then allow them to attend an important event, what Matters most would suggest that the trade-off could be in favor of the person taking the medication around that time.

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Medications The occurrence of polypharmacy and prescription of inappropriate medications for older adults is a pervasive problem in health care and a dangerous reality for older adults in terms of the impact on their health, physical, and financial well-being, and the achievement of other 4Ms [10, 17]. The goal of addressing Medications is to have processes for categorically reducing the prescription of harmful medications in older adults, to perform accurate and regular medication reconciliation that identifies harmful and inappropriate medications, and to have a process for deprescribing harmful medications. For example, in a primary care clinic addressing Medications: • There is a list of medications behind every computer station that are high-risk for older adults and an advisory pops up in the medical record if one is prescribed to anyone over 65. • A pharmacist does a telephone visit with people 65 and older with a high-risk medication on their list to review all medications and their indications, and then recommends deprescribing and/or substituting them with safer alternatives. • The clinic tracks, using the electronic medical record, the number of people 65 and older on several classes of high-risk medications, and an interprofessional medication committee review it every month to identify areas that are not seeing improvement, e.g., patients on muscle relaxants and a back pain diagnosis, for identification of interventions they can do in clinic. For example, in an orthopedic surgical clinic: • They keep a list of all patients prescribed shortterm opioids by their providers at a follow-up visit after surgery. • Their nurses call these patients to review pain control and suggest nonopioid, nongabapentoid strategies for pain relief. • A quality improvement team sends monthly reports to the medical director of all patients

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more than 30 days postop and with an active opioid prescription to monitor the trend. High-yield interventions around optimizing medication use in older adults focus on high-risk and inappropriate medications in older adults, for which the Beers criteria is an excellent resource [17]. They can also focus on finding medications that may be having side effects and for which the person is on another medication (e.g., an anticholinergic muscle relaxant that causes dizziness, which leads to prescription for vertigo), called a prescribing cascade, for which there is no indication or no longer an indication, or for which the person is not adhering.

Mobility The domain of Mobility refers to assessing and addressing older adults’ mobility to understand their abilities around community ambulation and fall risk. Mobility and the occurrence of falls are interrelated in older adults. Assessing mobility often involves asking about mobility challenges, the use of devices (prescribed or improvised), and prior falls. Direct assessment includes assessment of balance, mobility, and fall risk with validated tools. There are excellent tools of this including the CDC’s STEADI campaign which shows how to do a structured assessment of fall risk and has many tools for patient education around mobility to prevent falls [18]. In a hospital setting, the goals may be more focused on assessing daily mobility to preserve function and mobility postdischarge. And in a nursing home setting, the focus may be on rehabilitation goals for mobility after a medical event or a surgery. For example, in a hospital: • Assessing mobility and documenting: The nurse assesses a patient’s mobility according to their goal for each shift, e.g., ambulates once each shift, and documents progress that shift. • Improving the environment for mobility: The medical team has a structured field in their daily note to assess mobility and review orders each morning for those that hinder mobility,

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e.g., unnecessary tethers and medications that affect balance. • Monitoring progress: The unit quality team reviews the data every quarter to see if people were discharged at or below preadmission mobility. This domain often addresses a key goal for patients: maintaining independence in the community and may be combined with other assessments, such as functional abilities, to support this goal.

Mentation This domain encompasses several areas of brain health for older adults: depression (or mental health conditions in general), delirium, and dementia. These conditions are common and have profound and pervasive implications for older adults’ lives; identification and care of these conditions is a key feature of an Age-Friendly Health System [10]. Depression is commonly screened for in primary care across adult age groups because it has a large impact on people’s quality of life, their family, and caregivers, and we have many evidencebased interventions to address it. However, the practice can be more age-friendly by using screening tools validated in older adults (PHQ-9, Geriatric Depression Screen) and providing interventions and resources that are more tailored to older adults and cultural and linguistic preferences. The importance of detecting delirium is underscored by its high prevalence – about one-third of hospitalized adults – and its large impact on a patient’s course; it is associated with longer lengths of stay, increased likelihood of discharge to a facility, especially in hospitalized older adults, and increased posthospitalization disability and death [19]. A goal of many hospitals and intensive care units is to implement multicomponent, nonpharmacological interventions to reduce the incidence and length of delirium in their older patients [20, 21].

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An example of an Age-Friendly inpatient unit: • Daily screen of older patients for delirium with the Confusion Assessment Method. • Patients who screen positive are flagged and nursing implements a multicomponent intervention of monitoring hydration, medications, mobility, and lines for opportunities for improvement. And third, dementia is a disease that affects all domains of a person’s cognitive functions and profoundly affects their social support system and caregivers and is highly prevalent – approximately affecting 10% of adults over 65 and closer to 30% of adults over 80 [22]. It is a progressive and pervasive syndrome of cognitive and functional decline and typically associated with a neurodegenerative disease, like Alzheimer’s disease. Fully diagnosing dementia can take time as it has variable symptoms and multiple components to establish a diagnosis, and it has been shown that generalists generally do not feel comfortable diagnosing and managing dementia [23, 24]. And providing care to someone living with dementia involves longitudinal assessment and consideration of functional needs – involving connection to community services that support people with functional decline, as well as the cognitive symptoms, such as memory loss, wandering, and behavioral changes. These are most easily done with interprofessional care teams that have specific expertise on dementia. But such teams are not available in most settings. Regardless of what is available, an important component of age-friendly care is the detection of dementia to support people with evidence-based interventions and start to detect and address the other “3Ms” of what Matters, Medications, and Mobility, all of which have heightened importance in someone living with dementia. We do have screening tools for cognitive decline, such as the mini-Cog, which are short, sensitive, and available in multiple languages [25]. Implementing this screen in a target population, e.g., all adults over 65 or all adults over 65 who report “concern for memory loss” on an annual screening questionnaire, can set a health system

on a path to regularly identifying and caring for their older adult patients with dementia.

Multimorbidity As discussed above, multimorbidity is not of a component of the Age-Friendly Health System initiative, but it was part of the original 5Ms of the geriatrics rebrand, and it is a core area of strengths in geriatrics. Multimorbidity refers to the co-occurrence of more than one chronic condition in an individual; it is a condition of having multiple conditions [26]. It can be conceptualized and measured in research and clinical care as a cluster of certain conditions or a score of the presence and/or severity of chronic conditions [27]. In geriatrics, it is a key consideration for care of an individual patient, whose unique combination of illness and their impacts makes their care particularly complex and their “what Matters” all the more important. The term also invokes the importance of considering the severity of each condition. Someone with more severe heart failure and osteoarthritis may need a different intervention to improve Mobility, compared to someone with milder symptoms of those conditions. Multimorbidity could be included in a screening or population health strategy, e.g., using problem lists to identify multimorbidity, and weighted counts of conditions is often used in research and clinical care to estimate severity of illness in patients. So, it is often a part of care in the background, but at the ground level it is still evolving as a something we can detect, monitor trajectory, and care plan around it in a standardized way as its own condition instead of, again, focusing on each condition on their own. In a way, the complexity of measuring it in a way that we can clinically address it underscores its complexity. Right now, addressing multimorbidity is often in the hands of skilled clinicians and geriatricians when available. An example of an Age-Friendly Health System approach that incorporates multimorbidity might be one that stratifies its patients according to complexity. For example, older patients who have more serious consequences of their chronic

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conditions, e.g., frequent ER visits in the last year, are targeted for an interprofessional team assessment by a “Complex Care Team” that uses the 4Ms to do their assessments and plan and track their interventions.

Case Study In the multistate network of “convenient clinics,” the MinuteClinics company committed to achieving a Level 2 designation, Committed to Care Excellence across its 1200 clinics affiliated with retail pharmacies and staffed by nurse practitioners and physician assistants [28]. Their patient population was 20% older adults: approximately 809,000 patients aged 65–74, approximately 129,000 patients 75–84 years (3% of all patients), and approximately 10,700 patients 85 years and older. Programmatically, they developed a plan for educating their providers (which number over 3000), provide infrastructure and protocols for their providers to implement the 4Ms, and formed an academic partnership to help them measure their impact. Some examples of infrastructure consisted of practice and systems level support, such as data analytic tools, electronic medical record (EMR) tools to prompt clinicians to do the 4Ms and document care accordingly, dashboards, and regular huddles for managers to get support in implementation, and examples of protocols consisted of workflow maps and decision trees for clinical care. Their 4Ms framework: “M” Domain What matters Medication

Mobility

Mentation

Tool for assessment Asked “what matters to you with regard to your health care?” or similar question to assess goals Medication reconciliation performed and medications that are on beers list are identified Assessed as patient walks into the exam room Timed up-and-go performed during visit PHQ-2 (depression screen) Mini-cog (cognitive screen)

At the presentation of an older patient there for more than a quick vaccine, this “eligible visit”

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would be targeted for a 4Ms framing to the care using the components in the table above. At the conclusion of a visit, the clinician reviews the plan to ensure it is consistent with the patient’s stated goals, provides a written summary to the patient, and documents the encounter in their EMR according to the 4Ms. The EMR prompts and requires the clinician to document in each 4M area. The initiative started in January 2020, and they measured weekly documentation of the 4Ms in eligible patients 65 and older and being seen for a visit. It also showed that by February 2022, 66% of their providers had taken the required 4Ms training. When they had slow progress initially in the first year, they implemented “best practice alerts” in their EMR which prompted providers to assess the 4Ms which have a noticeable impact. In another improvement phase, they implemented PDSA cycles and virtual “clinics” where providers could train on clinical scenarios to improve their skills in assessing the 4Ms. By time of publication, what Matters was assessed in 24.1% of eligible patients, Medication in 21.9%, Mobility in 12.5%, and Mentation in 9%. At the start of the initiative, 0.8% of eligible patients received care according to all 4Ms; by February 2022, the number was 5.8%. Surveys of patients found that 76.2% rated care highly with regard to “How much effort was made to include what matters most to you in choosing what to do next?” While outcomes for their patients were not reported, one advantage of the 4Ms framework is that these domains are supported by evidence to improve health outcomes. And their efforts show how that a simple approach combined with detailed attention to factors affecting application of the 4Ms and quality improvement initiatives can lead to sustained increases toward a goal of systemwide, consistent implementation of an age-friendly health system.

Conclusion/Summary The 5Ms framework is a rebranding of the core competencies of geriatrics and the 4Ms framework is an approach we can use to implement an

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Age-Friendly Health System. An Age-Friendly Health System provides an evidence-based model for health care, can be reliably implemented in wide range of settings, and delivers high-quality care for older adults. The Ms. transcend a specific environment, e.g., outpatient care versus emergency room versus hospital, are interrelated and overarching, meaning they affect older adults regardless of their social circumstances or health conditions. Their success is underscored by their uptake and assimilation into the literature and the growing community of healthcare providers designated as Age-Friendly Health Systems. Many who have trained in geriatrics and related fields may be concerned about some of the missing elements. Where do we assess for and address vision and hearing loss, elder abuse, frailty, incontinence, functional impairment that is not related to medications or mobility, among other geriatrics syndromes? It is true the comprehensiveness appears to be missing from the 5Ms and 4Ms conversation; but we can often make the Ms. more inclusive, e.g., by adding elder abuse to “What Matters” and vision, hearing, and

Fig. 1 The 4Ms of an Age-Friendly Health System

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functional impairment to “Mobility.” The power of these frameworks is their ability to summarize, communicate, and advocate for better, evidencebased care for older adults. As clinicians and systems leaders, it is up to us to know the populations we serve, insist on measuring the quality of care we provide them, and adapt the 4Ms model with consistent application to meet their needs. This movement is relatively new, but it is growing and amplifying other “age-friendly” initiatives, such as those for communities and cities [29–31]. In healthcare, we are continuing to learn through more and more examples what works and what facilitates successful implementation. The support of the John A Hartford foundation and the active community of Age-Friendly Health Systems at the IHI are continuing to build this movement and expertise in these areas. If you are interested in learning more about the 4Ms and the Age-Friendly Health System Movement, explore materials and guides for implementation on the website: https://www.ihi.org/Engage/Initia tives/Age-Friendly-Health-Systems/Pages/ default.aspx (Fig. 1).

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Learning Objectives After reading this chapter, readers will be able to: • Describe the “M”s of the 4M and 5M frameworks. • List two examples of implementation of an “M” in an Age-Friendly Health System. • Identify where the 4M framework can be flexible and inclusive of all geriatric syndromes.

References 1. Tinetti M, Huang A, Molnar F. The geriatrics 5M’s: a new way of communicating what we do. J Am Geriatr Soc. 2017;65(9):2115–5. https://doi.org/10.1111/jgs. 14979. 2. Mate KS, Berman A, Laderman M, Kabcenell A, Fulmer T. Creating age-friendly health systems – a vision for better care of older adults. Healthcare. 2018;6(1):4–6. https://doi.org/10.1016/j.hjdsi.2017. 05.005. 3. Fulmer T, Mate KS, Berman A. The age-friendly health system imperative. J Am Geriatr Soc. 2018;66(1):22– 4. https://doi.org/10.1111/jgs.15076. 4. Fulmer T, Reuben DB, Auerbach J, Fick DM, Galambos C, Johnson KS. Actualizing better health and health care for older adults. Health Aff. 2021;40 (2):10.1377/hlthaff. https://doi.org/10.1377/hlthaff. 2020.01470. 5. https://www.ihi.org/Engage/Initiatives/Age-FriendlyHealth-Systems/Pages/Recognition.aspx. Accessed 30 June 2023. 6. Fulmer T, Pelton L, Zhang J, Huang W. Age-friendly health systems: a guide to using the 4Ms while caring for older adults. Institute for Healthcare Improvement (IHI); 2022. 7. Institute for Healthcare Improvement. Age-friendly health systems: guide to using the 4ms in the care of older adults; 2020. Accessed 30 June 2023. https:// www.ihi.org/Engage/Initiatives/Age-Friendly-HealthSystems/Documents/IHIAgeFriendlyHealthSystems_ GuidetoUsing4MsCare.pdf 8. Adler-Milstein J, Lyles C, Rogers S. Health system implementation, scaling, and impact of the 4ms framework to advance age-friendly care. Innov Aging. 2022;6(Suppl 1):536–6. https://doi.org/10.1093/ geroni/igac059.2038. 9. Adler-Milstein JR, Krueger GN, Rosenthal SW, Rogers SE, Lyles CR. Health system approaches and experiences implementing the 4Ms: Insights from 3 early adopter health systems. J Am Geriatr Soc. Published online 2022; https://doi.org/10.1111/jgs.18417

11 10. Mate K, Fulmer T, Pelton L, et al. Evidence for the 4Ms: interactions and outcomes across the care continuum. J Aging Heal. 2021;33(7–8):469–81. https://doi. org/10.1177/0898264321991658. 11. Wolfe M, French M, Shean J. Start at the center: age-friendly public health systems and healthy brain initiative frameworks. Innov Aging. 2020;4(Suppl 1): 720–0. https://doi.org/10.1093/geroni/igaa057.2545. 12. Biasi AD, Wolfe M, Carmody J, Fulmer T, Auerbach J. Creating an age-friendly public health system. Innov Aging. 2020;4(1):igz044. https://doi.org/10.1093/ geroni/igz044. 13. Johnson BP, Dyck MJ, Hovey S, Shropshire MD. Gerontological nursing competencies: a crosswalk with the 4Ms framework of the age-friendly initiative. Gerontol Geriatr Educ. 2023;44(1):51–8. https://doi.org/10.1080/02701960.2021.1974430. 14. Emery-Tiburcio EE, Berg-Weger M, Husser EK, et al. The geriatrics education and care revolution: diverse implementation of age-friendly health systems. J Am Geriatr Soc. 2021;69(12):E31–3. https://doi.org/10. 1111/jgs.17497. 15. GWEP Coordinating Center. Accessed 30 June 2023. https://www.americangeriatrics.org/programs/gwepcoordinating-center 16. The conversation project. Accessed 30 June 2023. https://theconversationproject.org/ 17. Panel B. The 2019 AGSBCUE. American Geriatrics Society 2019 updated AGS beers criteria ® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–94. https://doi.org/ 10.1111/jgs.15767. 18. STEADI--Older Adult Fall Prevention. Accessed 30 June 2023. https://www.cdc.gov/steadi/index.html 19. Hshieh TT, Inouye SK, Oh ES. Delirium in the elderly. Clin Geriatr Med. 2020;36(2):183–99. https://doi.org/ 10.1016/j.cger.2019.11.001. 20. LaHue SC, Maselli J, Rogers S, et al. Outcomes following implementation of a hospital-wide, multicomponent delirium care pathway. J Hosp Med. 2021;16(7):397–403. https://doi.org/10.12788/jhm. 3604. 21. Donovan AL, Braehler MR, Robinowitz DL, et al. An implementation-effectiveness study of a perioperative delirium prevention initiative for older adults. Anesthesia Analg. 2020;131(6):1911–22. https://doi.org/10. 1213/ane.0000000000005223. 22. Gale SA, Acar D, Daffner KR. Dementia. Am J Med. 2018;131(10):1161–9. https://doi.org/10.1016/j. amjmed.2018.01.022. 23. Sideman AB, Alagappan C, de Jesus AH, et al. Challenges and approaches when addressing dementia in the context of chronic comorbid conditions in primary care settings. Alzheimer’s Dement. 2023;19 (S5) https://doi.org/10.1002/alz.065962. 24. Lesser S, Zakharkin S, Louie C, Escobedo MR, Whyte J, Fulmer T. Clinician knowledge and behaviors

12 related to the 4Ms framework of Age-Friendly Health Systems. J Am Geriatr Soc. 2022;70(3):789–800. https://doi.org/10.1111/jgs.17571. 25. Seitz DP, Chan CC, Newton HT, et al. Mini-Cog for the detection of dementia within a primary care setting. Cochrane Database Syst Rev. 2021;2021(7): CD011415. https://doi.org/10.1002/14651858. cd011415.pub3. 26. Skou ST, Mair FS, Fortin M, et al. Multimorbidity. Nat Rev Dis Prim. 2022;8(1):48. https://doi.org/10.1038/ s41572-022-00376-4. 27. Johnston MC, Crilly M, Black C, Prescott GJ, Mercer SW. Defining and measuring multimorbidity: a systematic review of systematic reviews. Eur J Public Heal. 2018;29(1):182–9. https://doi.org/10.1093/eurpub/ cky098. 28. Pohnert AM, Schiltz NK, Pino L, et al. Achievement of age-friendly health systems committed to care

A. H. Chodos excellence designation in a convenient care health care system. Health Serv Res. 2023;58(Suppl 1): 89–99. https://doi.org/10.1111/1475-6773.14071. 29. Jeste DV, Blazer DG, Buckwalter KC, et al. Age-friendly communities initiative: public health approach to promoting successful aging. Am J Geriatr Psychiatry. 2016;24(12):1158–70. https://doi.org/10. 1016/j.jagp.2016.07.021. 30. Fulmer T, Patel P, Levy N, et al. Moving toward a global age-friendly ecosystem. J Am Geriatr Soc. 2020;68(9):1936–40. https://doi.org/10.1111/jgs. 16675. 31. Plouffe L, Kalache A. Towards global age-friendly cities: determining urban features that promote active aging. J Urban Heal. 2010;87(5):733–9. https://doi. org/10.1007/s11524-010-9466-0.

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Collaborative Decision-Making Identifying and Aligning Care with the Health Priorities of Older Adults Aanand D. Naik

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Success and Challenges of Chronic Illness Care for Older Adults . . . . . . . . . . . . . . . . . . Elderhood Today . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Disease-Oriented Approach to Medical Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges of the Single-Disease Approach in the Care of Older Adults . . . . . . . . . . . . . . . Satisfactory Trade-Offs Require a Process of Collaborative Decision-Making . . . . . . . . .

15 15 16 17 19

Model of Collaborative Decision-Making for Older Adults with Multiple Morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Key Concepts Related to Collaborative Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . An Overview of the Model for Collaborative Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . A Pathway for Identifying Health Outcome Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Pathway for Aligning Care with Health Outcome Goals . . . . . . . . . . . . . . . . . . . . . . . . . . .

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What Most Matters: Building an Evidence-Base for Collaborative Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 The Patient Priorities Care Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Examples and Evidence of Patient Priorities Care in Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

A. D. Naik (*) Department of Management, Policy and Community Health, School of Public Health, University of Texas Health Science Center, Houston, TX, USA Joan and Stanford Alexander Division of Geriatrics and Palliative Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA Center for Innovation in Quality, Effectiveness, and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, USA Institute on Aging, University of Texas Health Science Center, Houston, TX, USA e-mail: [email protected] © This is a U.S. Government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_2

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A. D. Naik Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Abstract

Older adults’ experiences with their healthcare are burdensome and often do not address what matters most. This dilemma arises because clinical decision-making is guided by singledisease guidelines rather than the health priorities of older adults. Most older adults have multiple chronic conditions that require a more collaborative approach to decisionmaking. The Model of Collaborative Decision-Making consists of two intersecting pathways. The first engages older adults to frame what matters to them into specific, realistic, and actionable health outcome goals based on the constraints of their personal lives and health trajectory. In the second pathway, older adults offer their preferences regarding which care is helpful and bothersome to inform clinician recommendations for care that aligns with patients’ health outcome goals. In this paradigm of priorities-aligned care, the value of healthcare derives from how well it achieves patients’ outcome goals, and its appropriateness is based on if patients are willing and able to use it. Patient Priorities Care is an evidence-based approach to collaborative decision-making for older, multimorbid adults and their clinicians. Patient Priorities Care results in care that is less burdensome and more aligned with the health outcome goals and care preferences identified by older adults. Patient Priorities Care holds promise as a favored healthcare approach for older adults with multiple morbidities. Keywords

Older Adults · Multiple Chronic Conditions · Patient-Centered Care · Collaborative Decision-Making · Patient Health Priorities · Collaborative Goal-Setting · Patient Priorities Care · Priorities-Aligned Decision-Making · Patient-Clinician Relations

Introduction The National Academy of Medicine’s landmark Crossing the Quality Chasm introduced an enduring framework for understanding and measuring healthcare quality [1]. The framework proposes six dimensions: safety, timeliness, effectiveness, efficiency, equity, and patient centeredness. Each dimension offers an independent contribution to perceptions and measurement of quality that is not subordinate to another. Deficits in any one dimension can negatively shape overall perceptions of the quality of care at the level of a hospital ward or community program. Patient centeredness is the dimension of quality framed by the subjective assessments of patients and caregivers. This is particularly important for older adults with multiple morbid conditions because the objective outcomes that serve as criterion standards for the other dimensions of quality may not be as relevant in this population. Deliberately asking about and measuring how healthcare helps older adults achieve “what matters most” to them is increasing salient. However, there are few examples of how to reliably elicit the outcome goals and care preferences of older adults in clinical practice. The examples that do exist are often fuzzy, inconsistent in their application, and are not based on rigorous theoretical models. The current chapter seeks to address this challenge through the following objectives. First, the chapter describes gaps in the current approach to chronic illness care for older, multimorbid adults. Second, the chapter discusses the importance of engaging older adults in the identification of their health priorities and collaborating with their clinicians to align care with those priorities. Next, the chapter provides a conceptual model for collaborative decision-making among older adults with multiple morbidities and their clinicians. Finally, the chapter describes the approach and evidence supporting Patient Priorities Care – an empirical collaborative care intervention for older adults

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and their clinicians. After completing this chapter, readers should comprehend the following learning objectives: 1. Describe the epidemiology of chronic illness among older adults. 2. Provide the key factors why single-disease guidelines are inappropriate for older adults with multiple chronic conditions. 3. Delineate the two key components of patientcentered care and how to best measure them. 4. Differentiate the components of the model for collaborative decision-making for older adults with multiple morbidities and their clinicians. 5. Compare the structure of the Patient Priorities Care approach with the underlying model for collaborative decision-making. 6. Recite the key findings from studies that evaluated the Patient Priorities Care model in routine care settings for older adults.

Success and Challenges of Chronic Illness Care for Older Adults Elderhood Today Populations across the world are experiencing a steady increase in the number and proportion of older adults. In the United States, over 17% of the population was 65 years or older in 2020, including almost 14 million aged 80 years and older. By 2030, one in five Americans will reach older adult status. Older adults are also living longer. For adults who reach the age of 65, the average life expectancy is another two decades (19.4 years for males and 21.6 years for females) [2]. While adults are living longer and more functional lives, they increasingly live with a high prevalence of chronic illnesses and limitations (morbidities). With the ever-expanding availability of treatments, chronic illness is manageable within daily life. This situation results in a high prevalence of multiple morbidities (multimorbidity) among older adults.

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Epidemiology of Multiple Morbidity Estimates across different countries suggest 22–46% of older adults have three or more morbidities [3]. Patterns of multimorbidity vary; influenced by factors such as gender, socioeconomic status, genetics, behavior, and environment. Certain combinations are so commonly observed, such as hypertension, diabetes, arthritis, and cardiovascular diseases, that they have become synonymous with the experience of elderhood. Multimorbidity can have a significant impact on the health and functioning of older adults. The presence of multiple chronic conditions can lead to complex interactions between diseases, increased healthcare use and costs, functional impairment, and reduced quality of life. Multimorbidity can also complicate the management and treatment of individual conditions. Older adults with multimorbidity often require frequent medical visits, hospitalizations, polypharmacy (multiple medications), and referrals to multiple specialists. These every day experiences place a significant burden on the older adult, their caregivers, and healthcare systems. Understanding Multimorbidity Through Mrs. Jones To better appreciate the experiences of older adults with multiple morbidities, let us consider the all too mundane case of Mrs. Jones. Mrs. Jones is a 79-year-old widow who lives alone in her own home. She has a daughter and grandchildren who live in a nearby city. She goes on daily walks unaided with her dog around the neighborhood and is independent in her daily activities including her medications. Her family helps with some of her bill paying. Mrs. Jones has significant multimorbidity, including atrial fibrillation, diabetes mellitus managed without insulin, controlled depression, gastroesophageal reflux disease, heart failure with preserved ejection fraction, hypertension, osteoarthritis. She manages this significant burden of illness by taking on a remarkable burden of care. Her management strategies include taking 14 doses

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of ten medications each day to manage these conditions as well as monitoring her blood pressure and getting regular exercise. She visits her primary care provider every 8 to 12 weeks as well as recent visits to an endocrinologist, cardiologist, physical therapist, and gastroenterologist. These healthcare professionals address her symptoms of fatigue, pain, dyspnea, and urinary frequency. She and her clinicians regularly address a number of trade-offs when handling her conditions. For example, her regular ibuprofen use enables her to go on her daily walks with minimal pain. However, this medication was stopped due to recent upper gastrointestinal tract bleeding arising from gastritis from nonsteroidal anti-inflammatory use. Similarly, her cardiologist recently prescribed a diuretic medication to help manage her dyspnea presumed to be from her heart failure and hypertension. While it improves her shortness of breath, this medication contributes to worsening urinary frequency that interferes with her sleep and planning her daily activities. Mrs. Jones’ case is remarkable for how unremarkable it is. This high degree of illness and care burdens are common and viewed by most clinicians as routine. We have become oblivious to the healthcare services use, costs, and significant daily load and emotional drain this approach has on older adults, their caregivers, and health systems more broadly.

Disease-Oriented Approach to Medical Decision-Making How Clinicians Make Treatment Decisions Treatment decisions for chronic conditions remain predicated on a decades-old acute illness paradigm of the sick role and the clinician’s professional obligation to identify the singular cause of the ailment and provide the appropriate cure [4]. This paradigm (i.e., Occam’s razor) works effectively when the clinical encounter fits neatly into the parameters of an acute, single-disease presentation for an otherwise healthy patient. In

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these straight-forward cases, clinicians use their acumen to identify the disease that is causing the patient’s ailment or symptoms. Once the singular disease is found, the clinician finds the appropriate treatment that could cure the disease. If there is not a reasonable cure, then the next best option is to recommend the treatment that could modify the course of the disease. The patient defers to the authority of the physician with the expectation that he would return to health as soon as possible [4]. This traditional expectation of patient-physician relationships was professionalized with the emergence of evidence-based medicine [5]. The central tenant of evidence-based medicine is the clinical practice guideline. Practice guidelines summarize the available evidence for the presentation, diagnosis, and treatment of diseases. The overwhelming proportion are singledisease guidelines. As a result, practice guidelines are typically governed by disease-centric, specialty, or professional organizations within their narrow spheres. As a guideline gains acceptance, it is often taken up by governmental bodies authorized to define the parameters of high-quality care [6, 7]. There a number of assumptions that underly practice guidelines. First, the gold standard for most guidelines is evidence confirming prevention of mortality as the primary outcome for any treatment. When the gold standard is not feasible, modification of the disease is confirmed using validated biomarkers of disease progression and processes. The ability to accurately and reliable measure these outcomes requires that guidelines remain focused on single diseases and often within narrow patient characteristics.

How Practice Guidelines Are Translated into Health Outcomes in Usual Care While the evidence base for practice guidelines and the underlying evidentiary foundations are transparent and clear, outcome goals of individual treatments are typically not explicitly stated during routine clinical encounters. Clinicians make decisions based on these same outcome

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assumptions, but do so implicitly in most instances. These implied outcome goals are: 1. Survival in the case of more acute illness. 2. Longevity in chronic maintenance care. 3. Prevention to promote long-term survival and reduce disability. In the context of acute exacerbations of chronic illness, clinicians and patients have the shared implicit assumption that treatment will remove the acute problems so the patient can go back to living their life. We have found this to be the case even among patients with end-stage liver disease experiencing an acute cirrhotic exacerbation that requires hospitalization [8, 9]. As Ken Rockwood has eloquently stated, this paradigm is based on a patient’s expectation of “hoping you treat what I have” meeting the clinician’s “hoping you have what I treat” [10]. In too many cases, the implicit, unstated goal of the patient is to “get back to my normal life.” It is then left to the clinician to define for herself what the intended (even if fuzzy) outcomes of a treatment are and how likely the treatment is to reach that outcome. The focus on survival and longevity has some obvious positive effects. This approach has contributed to the dramatic expansion of life expectancy and function for all adults, including older adults who now live routinely into their eighth and nineth decades.

Challenges of the Single-Disease Approach in the Care of Older Adults Older adults typically have two or more chronic conditions and present to care with a wider and more atypical spectrum of clinical signs and symptoms. Furthermore, their presentation has poorer correlation with the common pathophysiology of any single disease. A more recognizable pattern arises from the interplay of several conditions acting together, often idiosyncratically, to produce signs or symptoms – characterizing a geriatric syndrome [11]. These more varied presentations of comorbid disease; confluence of

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biological, psychological, and social factors; processes of frailty and aging; and the less predictable patient preferences for care render medical care guided by single-disease practice guidelines less likely to succeed, and with greater potential to cause unintended harms. This dominant singledisease guideline approach to care must be seriously questioned in the context of older adults with multiple chronic conditions [12].

Costs Outweigh Benefits of Single-Disease Guidelines for Older Adults with Multimorbidity The noteworthy successes of clinical practice guidelines include improved mortality and morbidity rates for adults who have the disease in question and are representative of the characteristics of patients enrolled in the studies from which the relevant guideline is based. However, most older adults do not meet these expectations. There are few clinical trials that enroll older adults, and those that do are narrow in their eligibility criteria [13]. Older adults with multiple chronic conditions are often excluded from clinical trials due to the presence of comorbid conditions or because their condition is at a stage that meets exclusion criteria, e.g., diminished glomerular filtration rates [14]. As a consequence, there are simply too few clinical trials that inform practice guidelines for the typical older adult. Furthermore, the evidence for benefit is likely less than described in the clinical trials for the small population for whom the guidelines maybe applicable. While not being explicitly ineligible for these trials, older adults have comorbidities, age-related physiological changes, and differing pharmacodynamics than the median subject enrolled in the trial. They are often less likely to experience the same level of benefits described in the trial and subsequent guidelines, and may have more exposure to harms and side effects of the treatment. Observational studies find that one in three older adults with multiple chronic conditions receives a guideline-recommended medication that harms a coexisting condition resulting in an adverse event, including hospital admissions [15].

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Understanding the Relevant Outcome Goals for Older Adults with Multimorbidity The limited benefits versus costs for singledisease guidelines come into further scrutiny when considering that longevity or survival is the outcome undergirding the strength of evidence for most guidelines. Prolonged survival benefit may not be the primary or only outcome goal that older adults care about. Older adults with multimorbidity have a high degree of variability in the outcomes that matter most to them [16]. Over 40% describe maintaining current function is most important, even if it means a reduction in longevity. Almost one-third identify symptom relief as their main outcome goal when considering a treatment. Over one-quarter continue to identify living longer as the primary goal, even if the focus on longevity impacts their functioning. The balancing of multiple and even conflicting outcome goals further calls into question the validity of practice guidelines in the care of older adults with multimorbidity. Since these guidelines are grounded on the assumption that treatment effectiveness is determined by survival benefits, their validity for measuring treatment effectiveness as it relates to other patient-defined outcomes is unproven or unclear at best. Alternative methods for measuring effectiveness aligned with the variety of patient reported outcome goals are needed. Burdensome Treatments and Care as a Meaningful Variable in Clinical Decision-Making In an effort to identify treatments for their multiple chronic conditions, older adults often seek care from a number of primary and specialty care physicians and other healthcare professionals. Each of these clinicians, using singledisease guidelines typically recommend their own medications, medical tests and visits, selfcare tasks at home, and other therapies. In aggregate, older adults with multimorbidity take 15 or more medications, see several clinicians every month, and spend 2 h per day on healthcare tasks [17]. Given the functional, mobility, and sensory limitations that are common for older

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adults, even a simple trip to the doctor’s office for a laboratory visit can result in a full ½ day of activities from getting dressed, obtaining transportation, parking, and getting around the clinic, sitting in waiting rooms, and returning home. Simply put, care for older adults with multiple chronic conditions is burdensome and may result in a reasonable decision not to always be adherent to treatment recommendations. Care for older adults with multimorbidity can be frustrating for clinicians as well. As experts in medical decision-making, clinicians are fully aware of the limitations of single-disease guidelines. This awareness translates into a crisis of confidence in the evidence-base guiding medical decisions for their older patients. The lack of trustworthiness causes uncertainty that manifests as having no right or best answer for how to treat an older, multimorbid patient. In addition to uncertainty, there can be conflicting recommendations around a particular treatment arising from different diseases with competing evidence. Clinicians also have frustrations related to their older patients who do not always do what is recommended. In these circumstances, the clinician believes the patient is being nonadherent to doctor’s orders. However, the patient is thinking, “I just can’t tolerate this treatment” or “I’m skeptical this will help me do what’s important for me.” These contrasting sentiments undermine trust within the patient-clinician relationship, and the ability to manage the clinical trade-offs that arise in multimorbidity care.

Need for Trade-Offs in Multimorbidity Care The interaction of symptoms, side effects, and even intended clinical processes from multiple conditions and their treatments often shapes the everyday lived experiences of healthcare for older adults with multimorbidity. Trade-offs are plainly relevant for this clinical context. Clinical tradeoffs are the balance achieved between two desirable but incompatible treatments or outcomes. In multimorbidity care, trade-offs are also viewed as the best available option in the all too common occurrence of (a) drug-drug, (b) drug-disease, and (c) disease-disease interactions. Older patients

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with multimorbidity and their clinicians need tools to guide them through the process of considering trade-offs in clinical decisions. There is a paucity of effective tools for guiding collaborative decision-making for the purpose of making tradeoffs. Single-disease guidelines are ineffective tools for arriving at useful trade-offs. As stated previously, clinical practice guidelines provide a strong evidence base for identifying potentially effective treatments regarding the single disease they are focused on. This evidence base should not be ignored. However, clinicians cannot use guidelines-based recommendations as the sole or dominant method for arriving at clinical decisions for older adults with multiple morbid conditions. By themselves, single-disease guidelines do not provide sufficient clarity for clinicians to address trade-offs for older adults with multimorbidity. Clinicians need an effective counterbalance for the inherent imprecision and error arising from single-disease guidelines. Since the older adult is the person who faces the consequences of this potential imprecision and error, an appropriate counterbalance would be the engagement of the older adult in the decision-making process. This engagement begins by asking older adults what they want out of their healthcare and what are the outcomes that define their desired level of health.

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Satisfactory Trade-Offs Require a Process of Collaborative Decision-Making Patients’ Perspectives on What Is High-Quality Healthcare The National Academy of Medicine developed a framework for measuring healthcare quality that endures after more than two decades. The model proposes six dimensions: safe, timely, effective, efficient, equitable, and patient-centered care [1]. Honoring and measuring each dimension is vital to understanding how individuals frame the quality of care they receive. This becomes particularly valid when measures of effectiveness and safety lack clarity. The two dimensions of timeliness and patient centeredness (see Fig. 1) are notable for the prominent role that patients’ subjective perceptions play in measuring quality. Measures of timeliness can include objective measurements. However, patients’ subjective perceptions that “I can get an appointment when I need to see my doctor urgently” or “the nurse responds in a timely manner to my messages” sway overall judgments about the timeliness of care. Similarly, patient centeredness is the quality dimension based primarily on patients’ perceptions that their care is respectful of and responsive to their preferences and needs guided by their identified

Fig. 1 Dimensions of healthcare quality based on patents’s assessments

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values. These two dimensions cannot be fully assessed without gathering patients’ subjective assessments and contributions. Figure 1 describes two features of patient centeredness. Both require assessment through patients’ subjective reports. The first evaluates how well the experience of receiving health care from a specific healthcare provider or the care environment is respectful of patients’ preferences and values [18]. In addition to its normative worth, measures of patient experience have empiric weight. Evidence demonstrates that patient experience correlates with health outcomes when experiences are assessed in a timely manner and as a specific interaction between a patient and healthcare provider or a specific care experience [19]. The Centers for Medicare and Medicaid Services (CMS) administers and publicly reports the results of the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey for Medicare Advantage beneficiaries since 1998. The CAHPS survey elicits patient’s subjective experience of care and perceptions of the timeliness of care. The results of CAHPS surveys correlate with process and outcome measures of outpatient chronic illness care including medication adherence, blood pressure, and glycemic control, and guideline-defined selfmanagement [7]. The second aspect of patient centeredness moves beyond patient experiences of care. This aspect focuses on the outcomes that patients want to achieve from their healthcare. The outcomes are defined by patients, and clarified more effectively by using a structured, reliable process that identifies health outcome goals and care preferences. Decisions for which care options to select should then be aligned with the identified patient outcome goals and care preferences. Similar to patient experience measures, efforts to identify patient-reported outcomes and align treatment decisions to those patient-reported outcomes have the positive externality (side effects) of achieving disease-specific process and outcome measures, especially for common chronic conditions like hypertension, diabetes, and asthma care [20].

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These findings suggest that conceptual models of healthcare quality rely on two patient-reported dimensions, namely timeliness and patient centeredness. Data suggest that more timely and patient-centered care results in improved healthcare outcomes. When considering patient centeredness, two aspects are critical: (1) the patient experience of care and (2) patient health priorities as a guide for healthcare decisions. Therefore, a patient-centered approach to care requires a process for identifying health priorities and is respectful of how patients experience care. The bottom line for older adults with multimorbidity is arriving at care decisions that seek to achieve outcome goals that matter most to them using only the care that they are willing and able to receive to achieve their goals. What is missing in most cases is a reliable and structured process for identifying and aligning care with older patients’ health priorities.

Collaborative Decision-Making to Address Clinical Equipoise Collaborative decision-making is an established approach that involves clinicians and patients collaborating in making healthcare decisions. It recognizes the importance of patient engagement that respects their values, preferences, and rights to be involved in decisions about their own care. The normative need for collaborative decision-making is grounded within the presence of clinical equipoise. In the context of cancer and surgery-related treatments, where collaborative decision-making first arose, clinical equipoise exists when two or more treatments are equally balanced in terms of their comparative effectiveness. For example, there exists honest doubt among clinicians regarding the optimal treatment approach for patients diagnosed with early-stage prostate cancer. Treatment options may include active surveillance, surgery, radiation therapy, or emerging treatments. Decisions regarding the most appropriate treatment depend on various factors, including the patient’s age, overall health, cancer characteristics, and patient preferences. Clinical equipoise in early-stage prostate cancer implies that there is no consensus or clear evidence favoring one

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treatment option over the others as the definitive best choice for all patients with this diagnosis. It acknowledges that individual patients may have different values, goals, and preferences, and the decision-making process should consider these factors alongside available evidence and clinical expertise. Clinical equipoise in multimorbidity care underscores the importance of engaging patients in discussions about treatment options, potential benefits, risks, and trade-offs. It recognizes that patients with multimorbidity have unique health needs and may prioritize certain outcomes differently based on their personal values and preferences. Collaborative decision-making in multimorbidity care involves collaboration between clinicians and patients to develop a comprehensive care plan that considers the complexity of multiple conditions and aims to optimize overall health outcomes defined by patients while minimizing treatment burden and potential harm.

Model of Collaborative Decision-Making for Older Adults with Multiple Morbidities Key Concepts Related to Collaborative Decision-Making The elaboration of a model for collaborative decision-making for older, multimorbid adults and their clinicians begins with naming of key terms and their definitions (see Box 1). Health priorities is the umbrella concept describing all the features of the patient perspective informing decisions for their health and healthcare. Health priorities subsume the additional concepts of health values, outcome goals, and healthcare preferences. These key concepts form the primary nodes of the model for collaborative decisionmaking.

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Box 1 Key Concepts in the Model for Collaborative Decision-Making

Health Priorities. Health priorities consist of the health and life outcomes that older adults most want out of their healthcare given the care they are willing and able to receive. Health priorities is the umbrella term that includes the concepts of health outcomes goals, healthcare preferences, and health values. Health Values. Health values comprise a finite set of discrete factors that guide individuals’ sense of well-being and motivations for action to preserve and improve health and well-being. They provide a subjective assessment of one’s biopsychosocial homeostasis [21]. Outcome Goals. Health and life outcomes (i.e., activities, abilities, roles or health states) that people desire from their care. To better inform decision-making, outcome goals should be specific (i.e., contain parameters of what, when, where, how, and how long or often), realistic, actionable, and aligned with what matters most to the individual [22]. Outcome goals are objective, measurable, and serve as the dependent variable in clinical decision-making. Healthcare Preferences. Care options that people are willing and able (or not willing or able) to perform, undergo, or receive in the service of their outcome goals [22]. Healthcare preferences are moderators in the clinical decision-making process. Healthcare Options. The variety of things that can be provided to help patients achieve their outcome goals. These things include medications, devices, diagnostic testing, referrals, interventions and procedures, home and community services, and self-care tasks.

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When to Use the Model for Collaborative Decision-Making Older adults and their clinicians are encouraged to use collaborative decision-making in all possible clinical contexts including acute hospital care and for surgery and invasive interventions. While those are possible settings, the more favorable contexts are in ambulatory and long-term care where more time and resources are available for meaningful conversation with a focus on longitudinal chronic care. At its foundation, the collaboration is between a patient and a primary healthcare provider willing to identify outcome goals and discuss the alignment of care options with those goals. Most decisions are more complex, requiring involvement of additional individuals, including:

• Facilitating Healthcare Professionals – members of the healthcare team who have dedicated training on how to elicit health priorities including health values, health outcome goals, and healthcare preferences. This role can be fulfilled by a wide range of health professionals, support staff within a clinic, and lay personnel with training. • Specialty Healthcare Professionals – healthcare specialists can support the process of identifying care options within their area of expertise. Specialists participating in aligning care can coordinate their care option recommendations with patients and primary care providers based on how they align with health outcomes goals.

• Care Partners – caregivers, family members, and others who serve as confidants for patients during and around clinical encounters to support the process of identifying and aligning care with health priorities.

An Overview of the Model for Collaborative Decision-Making

Fig. 2 Model for collaborative decision making with older, multimorbid adults and their clinicians. The figure illustrates the two complementary flows of the collaborative decision-making model for older adults and their

clinicians. The blue dashed line describes the pathway for identifying health outcomes goals. The gray dashed line illustrates the pathway for how care options are aligned with health outcome goals

Figure 2 illustrates the full model of collaborative decision-making for older, multimorbid adults

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and their clinicians. The model places each of the key concepts within a flow that begins (blue dashed line) with identifying health values and works to contextualize those values into health outcome goals. There is a complementary flow (gray dashed line) that identifies care options and makes recommendations that are aligned with the health outcome goals after integration of care preferences for helpful care and against burdensome care.

A Pathway for Identifying Health Outcome Goals Describing What Matters Most: Health Values Health values comprise a finite set of discrete factors that guide individuals’ sense of wellbeing and motivations for action to preserve and improve health and well-being. They are subjective assessment of one’s biopsychosocial homeostasis [21]. On a biological level, health values derive from innately prepared subjective intuitions (cognitions, feelings, emotions, and motivations) that are “organized ahead of experience” by human evolution [23]. Psychologically, health values are consistent with system 1 thinking in dual process models of human cognition and decision-making. System 1 thinking has the properties of being automatic, intuitive, and effortless compared with system 2 thinking that is deliberative and effortful. In this manner, health values are influenced by emotions and affected by implicit cognitive bias and heuristics that sway motivations and action [24, 25]. At their core, health values are the psychological motivators for our health seeking behaviors. Health values are also appreciated as social intuitions [24]. Health values have significant social contributions such that intuitions about our health are interpreted by learning that is shaped by time, place, and culture [26]. We interpret our intuitions about our health using descriptions of how we use our health for functional purposes (for doing in the world). In acute illness, intuitions about health are simply about avoiding

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morbidity, suffering, and death. This life/death dichotomy or spectrum is consistent with the normative basis for most single-disease guidelines. Once the mortality threat of acute illness subsides, individuals are motivated to “live their lives” as they did before illness. Chronic illnesses do not have cures and typically change the way we live our lives. In chronic care, our descriptions of how we value our health provide reasons for why we act in response to the signs and symptoms of persistent chronic illness. Treatment decisions are about helping us to do the things that chronic illness is limiting, changing, or even preventing us from doing that we describe as consistent with our well-being. Because there are many ways we demonstrate the value of our health over time, there is likely to be a plurality of health values.

An Empirically Grounded Set of Health Value Dimensions Among Older, Multimorbid Adults A prior study asked older, multimorbid adults – who in the prior 12 months had faced the existential threat of cancer diagnosis and treatment – the following questions: (1) Now that you have had cancer and may face ongoing decisions about medical care in the future, what would you want your family, friends, and doctors to know about you, in terms of what is most important to you in your life? (2) If your cancer were to recur, is there anything you would want to be sure your loved ones knew about you and your goals of care? [27] Responses from the 146 participants were qualitatively analyzed using inductive coding balanced with deductive codes drawn from a factor analysis of survey responses from a similar study of health values [28]. Participants in this study described five values dimensions that were important to them and seemed to frame their preferences and decision-making processes throughout their chronic care experiences following cancer survivorship. These results are conceptually similar to other studies describing older adults’ health values [27]. The five dimensions of health values for older adults with multiple chronic conditions include the following:

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• Connection – motivations to further connect with the people, places, and spiritual practices that provide meaning, happiness, and contentment in one’s life. • Life Enjoyment – participating in activities that are pleasurable, provide personal growth or meaning, or enhance one’s sense of self. • Function (Independence and Dignity) – having or desiring the capacity to perform one’s self-care needs (independence) or maintaining self-respect (dignity) when needing assistance to perform self-care tasks. • Managing Health (Balance between quality and quantity of life) – balancing the desire for maintaining how one feels today (quality of life) with the desire to live as long as possible (longevity). • Engagement in Care (Balance between active and passive engagement) – balancing the desire to be actively engaged in all aspects of decisions regarding one’s health and health care with the desire to allow family, care partners, and clinicians to help make decisions on one’s behalf.

Placing Broad Values Within the Context and Realities of Patients’ Health and Lives Older adults are likely to endorse one or more of the values dimensions in the process of elaborating health values. When first elicited, values are often inchoate, described with fuzzy and imprecise language, or overly broad in description. At this level, values have an emotive quality providing positive or negative valence around the broadly worded value. This valence offers a motivation and general direction for decision-making. However, values at this “fuzzy” representation are not effective at framing a measurable, attainable outcome. Nor are they as useful for guiding clinicians in selecting from among treatment options. The process of bringing context to health values involves providing bounds and constraints regarding one’s life around the broad value. Providing context takes an inchoate health value (e.g., “being fit” or “losing weight”) and conforms it

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to the individual’s capacity, desired level of activity, and social and environmental circumstances of an individual’s life (e.g., “It is fun to walk around my neighborhood park”). Living according to one’s health values in chronic care also requires an understanding of what is realistic. This understanding involves the subjective perceptions of patients, which include emotions, fears, and aspirations, as well as the support they receive from caregivers and their community (e.g., “I feel safer and would appreciate if my neighbor joined me on my walks”). Input by clinicians and other healthcare professionals provides additional information related to the patient’s health trajectory, functional status, and awareness about the prognosis of their condition. Being transparent about what is uncertain or unknown helps improve the pragmatism of developing contextual values that are appropriate within an individual’s life.

Arriving at Collaborative Health Outcome Goals Providing personal and social details and constraints, complemented by an understanding and communication of health trajectory and functional status facilitate the process of identifying collaborative health outcome goals. Through this dialogue, patients and clinicians provide contextual details that fashion broad health values into actionable goals. Health outcome goals are most effective when they are collaboratively developed by patients and clinicians. A large body of literature demonstrates that goals motivate behavior, and thus goal attainment, when the goals have specific characteristics [29]. These characteristics are captured by the SMART acronym (see Box 2), and include being specific, measurable, achievable (or actionable), realistic, and time-based in orientation [30]. Within the limitations of typical healthcare encounters, it may not be possible to achieve the full rigor of SMART characteristics. For the collaborative decision-making model, health outcome goals should at least hold the characteristics of being specific, realistic, and actionable.

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Box 2 The Characteristics of Outcome Goals Associated with Goal Attainment

Specific – A goal should be clear and described in sufficient detail to elaborate the who, what, where, when, and how of striving. Measurable – A goal should have parameters that allow tracking of goal progress. Achievable/Actionable – You can take actions to achieve the goal and determine goal attainment. Realistic – A goal should be challenging but possible to achieve in the near term. Time-Based – There is a target date or event for determining goal attainment.

In addition to SMART criteria, effective outcome goals are meaningful, due to the fact of being derived from the older adult’s health values. The criteria of being meaningful corresponds to the “What Matters M” of the 4-Ms framework. The Institute for Healthcare Improvement (IHI) promotes the Age Friendly Health System movement grounded on this 4-Ms framework. The fulcrum of this framework is the What Matters “M” because the other three “M” (medication, mentation, and mobility) are oriented around how they achieve what matters most to the older adult. Similarly, in the model for collaborative decision-making (see Fig. 2), the blue dashed pathway culminates in the identification of one or more specific, realistic, and actionable health outcome goals rooted in what matters most to the older adult.

The Pathway for Aligning Care with Health Outcome Goals Identifying Care Options that May Facilitate Goal Attainment In Fig. 2, the gray dashed line pathway begins with the process of clinicians identifying potentially relevant care options. This pathway is

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initiated after identifying an older adult’s health outcome goals. Healthcare options include the variety of things that can be provided to help older, multimorbid patients achieve their outcome goals. Specific examples of relevant care options include medications, devices, diagnostic testing, referrals, interventions and procedures, home and community services, and self-care tasks. In an effort to recognize the most relevant care options, a clinician would likely start with a review of current care and a determination of whether that care aligned with the identified outcome goals and the degree of goal-attainment achieved. Referencing clinical practice guidelines now becomes appropriate if/when there is a determination that substantive changes in current care or additional care are necessary for better alignment with outcome goals. In this context, practice guidelines offer the best menu of evidence-based treatments and care strategies that may be most relevant for the goals at hand. Given our prior discussion of significant levels of clinical equipoise and uncertainty, the guidelines serve as a starting but not finishing point for making care recommendations. Savvy clinicians will pick from among these evidence-based care options to select one or more that may help to attain the identified health outcome goals.

Patients’ Care Preferences Modify Selection of Care Options Patients and their care partners often have important preferences favoring or disfavoring particular care options. Personal experiences or the experiences of others they are close to commonly shape older adults’ preferences for specific care options. Preferences favoring a care option typically arise from helpful experiences, such as with a particular medication or physical therapy. In many instances, older adults and their care partners will proactively report care they find helpful or beneficial. In these circumstances, healthcare preferences are often the tipping points in helping clinicians decide which care options to recommend. Further, clinicians who engage with their patients about their perceptions of prior experiences with care or preferences for new options

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will benefit from greater likelihood of adherence and persistence with chronic care recommendations. By aligning helpful care preferences with the identified outcome goals, patients and clinicians can judge whether a favored treatment is actually helping to attain an outcome goal – as the measure of that favored treatment’s success. On the flip side, negative personal or proxy experiences with a particular medication, referral, or therapy should play a significant role in clinicians not choosing a particular care option. Negative experiences arise from adverse events, unintended effects, and interactions with other treatments. The other negative aspects of care relate to the burdens of care (e.g., time-consuming visits, frequent medication doses, costs of referrals and procedures, and hassles of frequent travel and time off work). These burdens contribute significantly to preferences for a particular care option and, perhaps more significantly, effect persistence with care – even care options that initially have neutral preferences. These burdens and negative experiences come together as “bothersome” healthcare and should be reported to clinicians as a key type of healthcare preference. Both positive and bothersome preferences about specific healthcare options integrate in the decision-making pathway as moderators of clinicians’ recommendations for care options. When selecting a care plan in the model for collaborative decision-making, clinicians first translate evidence from population-driven guidelines to how well a potential care option aligns with personal outcome goals. Second, clinicians’ recommendations are further honed by the preferences of older adults and their care partners regarding specific care options. From these collaborative decisions among older adults, their clinicians, and care partners (when appropriate), specific recommendations arise for a care plan that aligns with identified health outcome goals within the context of what older adults are willing and able to do.

Revisit Care Options Based on Goal Attainment The model of collaborative decision-making for older, multimorbid adults and their clinicians has

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an iterative and recursive aspect. The blue dashed line pathway within the model generates identified health outcome goals and the gray dashed line pathway selects care options that align with the outcomes within the context of care preferences. Once both pathways have received their appropriate initial attention, older adults and their clinicians will meet periodically to determine how well their outcome goals are attained and discuss any significant modifications in their healthcare preferences due to new experiences with their care. When outcome goals are not met, the collaborative decision-making process facilitates (1) iterative efforts to refine the outcome goals if they were not sufficiently specific, realistic, or actionable; and (2) decisions to modify or stop current care and/or consider additional new care options. In this manner, collaborative decision-making keeps the focus on the older adult’s health priorities, especially their outcome goals and care preferences. Changes in care recommendations reflect how well care is aligned with the health priorities and attaining identified outcome goals. Furthermore, when significant changes occur in the health trajectory, functional status, or social support – the whole process may need to be revisited anew. However, the focus remains on the older adult’s health outcome goals and care preferences.

What Most Matters: Building an Evidence-Base for Collaborative Decision-Making The Patient Priorities Care Approach Patient’s Health Priorities Are What Matters to Older Adults The Institute for Healthcare Improvement (IHI) offers an inspiring use of the 4-Ms as a framework for achieving Age Friendly Health Systems. Central to the 4Ms is the What Matters most concept. By elaborating “What Matters,” older adults provide a compass for guiding clinicians in how to approach the other three Ms. – mentation, mobility, and medication. By understanding What Matters, clinicians can identify and implement the

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most appropriate diagnostic, treatment, prevention, and monitoring healthcare processes and interventions to achieve What Matters [31, 32]. Much of the pragmatic experience with the What Matters M centers around advanced care planning or health services preferences [32]. More evidence from approaches that use What Matters to focus on collaborative decision-making is needed [31]. To address this gap, the Patient Priorities Care (PPC) approach offers an evidence-based framework for identifying and aligning care with What Matters. PPC is being implemented throughout the Geriatrics and Extended Care Service Line in the Veterans Administration as well as national sites for the Program of All-Inclusive Care for the Elderly (PACE). The PPC approach uses patients’ health priorities as the practical method for identifying what matters most to older adults. Consistent with the IHI’s vision, PPC identifies health priorities (what matters to older adults) and aligns care (i.e., mentation, mobility, medication) with those priorities.

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Overview of the Patient Priorities Care Approach PPC was developed by clinicians, older adults, caregivers, health system leaders, and payers to help focus all decision-making and healthcare on patients’ own identified health priorities. PPC is a “current care planning” approach that is beneficial for anyone, but is particularly well suited for older adults with multiple conditions. Older, multimorbid adults are more likely to receive medical care that is burdensome and may not address what matters most to them. PPC recognizes that, when faced with trade-offs, older adults differ in what they want to achieve from their healthcare (health outcome goals) and what they are willing or able to do to achieve these goals (care preferences). PPC is consistent with the model for collaborative decision-making for older adults with multiple morbidities and their clinicians. The PPC process consists of two core components: (1) Identify health priorities and (2) Align care with health priorities (Fig. 3: https://patientprior itiescare.org/how-it-works/the-process/). These core

Fig. 3 The patient priorities care (PPC) process including the steps in the two core components: (1) Identify health priorities and (2) align care with health priorities

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components are analogous to the blue and gray dashed line pathways of the collaborative decision-making model.

Identifying Health Priorities Core Component of PPC The identify health priorities component is completed by an older adult (with assistance from a caregiver, as needed/desired) using an interactive website (https://myhealthpriorites.org); or in collaboration with a member of the interdisciplinary healthcare team during a variety of clinical encounter options [22]. The four steps of the identify health priorities component include the following: 1. Identify what matters: The initial step in health priorities identification focuses on eliciting what matters to the older adult. In the PPC framework, what matters is organized into four health values categories of connecting, enjoying live, functioning, and managing health. 2. Set an actionable, specific, and realistic health outcome goal: The older adult then develops actionable, specific, and realistic health outcome goals based on their identified values. Health outcome goals are the ways older adults want to put their values into action and are the activities they want their healthcare to help them achieve. 3. Healthcare preferences: Next, older adults will identify their healthcare preferences. This includes care which is helpful and bothersome. Older adults should also consider any healthrelated condition or other problem preventing them from reaching their goals. This may be a bothersome condition or symptom, healthcare task, or a life/social circumstance. They will also consider trade-offs. These include what the patient would be willing and able to do to reach their health outcome goals and what would be too onerous. 4. The One Thing: The final step in the identifying health priorities component of PPC is for older adults to choose what they want their healthcare focused on, specified as the One Thing. The One Thing combines one bothersome issue (i.e., symptom, health problem,

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healthcare task, or medication) the older adult believes is keeping him from reaching his health outcome goal. The One Thing provides a starting place for clinicians as they transition to the care alignment portion of PPC. These steps correspond to the Model for Collaborative Decision-Making, especially the blue dashed line pathway for identifying health outcome goals.

Aligning Care with Health Priorities Core Component of PPC The second core component of PPC, aligning care with health priorities, is led by a clinician on the healthcare team. Aligning care with identified health priorities has two key steps. The initial step of care alignment is known as the “consider step.” This is when clinicians consider if current care is consistent with the identified health outcome goals, including the “One Thing,” and aligned with care preferences. It is important to reflect on what current or potential tests or referrals, medical, rehabilitative, or psychosocial interventions might address the contributing factors identified as preventing the older adult from achieving their outcome goal. Based on this, care may need to be started, stopped, changed, or continued. It is especially important to consider if interventions the older adult identified as burdensome can be changed or stopped, especially if it unlikely to help the most bothersome problem or assist in goal achievement. The second step involves clinicians using structured decisional strategies during clinical encounters with their older patients. As an overarching strategy, clinicians use the identified health priories as the focus of decision-making and communication. Discussions of health care options will be conducted in relation to the older adult’s health priorities, not just disease-based trade-offs. Additional strategies include: 1. Using the priorities to guide serial trials of starting, stopping, or continuing interventions over time. 2. Acknowledging uncertainty and the fact that it may not be possible to identify one best treatment.

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3. Using health priorities to align decisions with other health professionals, especially when differing perspectives or recommendations exist.

Managing health – Keeping her strength and balance when climbing steps. Enjoying life – Walking her dog.

These decisional strategies provide a structure for selecting the most appropriate care options that align with the identified priorities. Future clinical encounters focus on how well the selected care plan aligns with the older adult’s health priorities, especially attaining their health outcome goals. It is important to realize that what matters to older adults is not static. While what matters most to older adults (values) is relatively constant over the lifespan, health outcome goals will need to be revisited and modified with significant life and health changes. This will ensure clinical care remains aligned and is helping older adults achieve their health priorities.

Using these values, the clinic nurse worked with Mrs. Jones to develop health outcome goals. These are the specific, realistic activities or outcomes that show that she is doing what matters. Mrs. Jones identified two goals:

Examples and Evidence of Patient Priorities Care in Action Patient Priorities Care Case Study Mrs. Jones is a cognitively intact 79-year-old widow with past medical history significant for atrial fibrillation, diabetes mellitus managed without insulin, controlled depression, gastroesophageal reflux disease, heart failure with preserved ejection fraction, hypertension, and osteoarthritis. She has a daughter and grandchildren living in a nearby city. She previously went on daily walks unaided with her dog around the neighborhood and remains independent in her daily activities including her medications. Her family helps with some of her bill paying. Mrs. Jones participated in a visit with the nurse manager at her primary care provider’s clinic focused on identifying her health priorities. She identified the following as What Matters within the PPC values categories: Connecting – Relationship with her grandchildren. Functioning – Maintaining as much independence as possible to stay in her home.

1. Walking and climbing bleachers at her granddaughter’s school to watch her basketball games once a week. 2. Being able to walk around the neighborhood with her dog every day. Next, the nurse facilitator explored Mrs. Jones’ health care preferences (care she found helpful and bothersome) and trade-offs. Mrs. Jones identified home physical therapy and ibuprofen as helpful for her strength and pain control to help her walking. She identified traveling a long distance for frequent specialty medical appointments and taking her diuretic as bothersome. She noted that the ibuprofen contributed to a recent bleeding episode and now her pain is less controlled. Finally, the facilitator worked with Mrs. Jones to elicit the “One Thing” interfering with her most desired outcome goal. Mrs. Jones wanted to address her knee pain so she could climb the bleachers at her granddaughter’s school. In the case of Mrs. Jones, the information obtained during the identification of her health priorities were shared with her primary care clinician using a structured EHR note template. Text Box 3 (see below) provides an example of a brief and succinct Patient Health Priorities Note based on the particulars of Mrs. Jones’ case. Box 3 Example of Electronic Health Record Note of Patient’s Health Priorities

Patient Health Priorities Note. 79 y/o functionally and cognitively independent widow with multiple chronic conditions. (continued)

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Box 3 Example of Electronic Health Record Note of Patient’s Health PrioritiesPatient priorities care (PPC) approach (continued)

What Matters Most (Values). Connecting – Relationship with her grandchildren. Functioning – Maintaining independence as possible to stay in her home. Managing health – Keeping her strength and balance when climbing steps. Enjoying life – Walking her dog. Most Important Health Goals 1. Walking and climbing bleachers at granddaughter’s school to watch her basketball games once a week. 2. Being able to walk around the neighborhood with her dog every day. Health Care Preferences. Helpful care, including medications: 1. Home physical therapy for strength and walking. 2. Ibuprofen for pain control. Burdensome care, including medications: 1. Traveling long distance for frequent medical appointments. 2. Taking diuretics that keep her from going out of the house. Most bothersome symptoms or problems interfering with health goals: 1. Knee pain and weakness that get in the way of walking What “ONE THING” do you most want to focus on today? Reduce my knee pain and weakness so I can climb the bleachers at my granddaughter’s school.

After “considering” the information in Mrs. Jones’ Patient Health Priorities Note, her primary care clinician met with her to discuss possible interventions in keeping with her healthcare preferences that might address the “One Thing” and achieve her main outcome goal. They discussed a trial of physical therapy focused on strengthening and fitting a hard knee brace she can use for pain and stability whenever she walks longer distances. Additionally, Mrs. Jones was prescribed a topical nonsteroidal anti-inflammatory gel applied to her knee 30 minutes before her granddaughter’s game for pain. She was reluctant to use a knee brace previously for fear it would make her “look old.” However, after discussing possible interventions with her primary care clinician, Mrs. Jones felt the trade-offs would be acceptable if he could more easily and safely walk to her granddaughter’s school and climb the bleachers. In this case, the clinician used Mrs. Jones’ priorities to guide trials of starting interventions (physical therapy, knee brace, and topical analgesia) and as the focus of communication for the impetus behind these interventions. Mrs. Jones and her primary care clinician made plans for a follow-up visit in 6 weeks to check back in on her ability to walk and climb bleachers with less pain. Similar to the Patient Health Priorities Note, documentation in the EHR by the primary care provider visit should clearly reference changes in care related to the identified health priorities. During follow-up visits, success of the treatment plan is measured by progress toward goal achievement.

Benefit of Aligning Health Care with Health Priorities There are several benefits to aligning care with health priorities. Using this approach, older adults feel listened to and are engaged and motivated, which may result in increased adherence [33]. Second, health priorities can offer a compass for decision-making involving older adults with multiple morbidities, especially where there is clinical equipoise resulting in uncertainty, trade-offs or the lack of one best care option. Further, achieving the older adult’s health priorities becomes the more appropriate measure for treatment effectiveness. Finally, aligning care with health priorities

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enables everyone (clinicians, caregivers, and the older adult) to direct their efforts toward the same target.

Evidence Supporting the Effectiveness of Patient Priorities Care Several recent studies evaluated the outcomes of PPC implementation in a variety of primary care settings (i.e., urban, suburban, private practice, VA, house calls, and academic) in locations across the country. Chief among these is a large nonrandomized clinical trial with propensity adjustment conducted in a multisite primary care practice serving over 15% of Connecticut’s residents [34]. The study enrolled older adults, on average 76 years of age with 3.9 chronic conditions (19% had five or more) and seven prescribed medications. The intervention arm included 163 eligible patients cared for by ten primary care providers and five cardiologists who received training in aligning care with priorities, and two health professionals who received training with priorities identification. The comparison group included 203 matched patients receiving usual primary care from seven primary care providers. At follow-up, decision-making during patient-clinician encounters focused on health priorities in two-thirds (101 of 163) of PPC enrolled patients and virtually none in usual care. Among these health priorities, patients reported their outcome goals as encompassing activities with family and friends (24.2%), shopping (6.1%), exercising (4.6%), and living independently (4.4%). Medications most commonly cited as helpful by users were nonopioid pain medications (65.5%), sleep medications (52.9%), and inhalants (42.2%). Whereas statins (25.8%) and antidepressants (32.5%) were the most commonly reported bothersome medications by users [35]. In a summative analysis, patients reported that the health priorities identification process is valuable leading to enhanced knowledge, activation, and communication about their treatment options and preferences [33]. This study also found compelling results when comparing the PPC approach with usual care. There was a statistically significant five-point reduction in self-reported treatment burden in the

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PPC group compared to usual care using the validated Treatment Burden Questionnaire [34]. The study reported significant differences in treatment recommendations between the two groups. Compared with usual care, patients enrolled in PPC were more likely to have medications stopped (52.0% vs. 33.8%), and less likely to have selfmanagement tasks (57.5% vs. 62.1%) and diagnostic tests (80.8% vs. 86.4%) ordered [34]. These findings suggest that PPC may be associated with reduced treatment burden and unwanted health care. Aligning care with patients’ health priorities proved to be feasible and effective for older, multimorbid adults. Another study conducted as a demonstration project at a regional VA geriatrics clinic enrolled 70 patients (n ¼ 35 received priorities identification and alignment and n ¼ 35 received usual care) cared for by the same three primary care providers [36]. Health priorities identification was performed by an additional health professional (PPC facilitator) in the clinic who received dedicated training on the PPC process. The PPC facilitator identified health priorities and reported them using the structured EHR note and a verbal hand-off. In usual care, the primary care providers preceded with routine geriatrics care without formal priorities identification. Primary care providers reported that they were very familiar with patients in both study arms, but in numerous instances the PPC approach identified outcome goals and “One Thing” examples that were new to the providers and instigated novel changes in care. Compared to usual care, participants in the PPC approach, on average, had fewer medications added (P ¼ 0.05), more referrals to community services and supports (P ¼ 0.03), and more priorities-aligned self-management tasks added (P ¼ 0.005) [36]. In contrast to the Connecticut study, PPC participants in the VA study had more goal-aligned recommendations for selfmanagement and home and community services. This may reflect the greater availability of home and community services in the VA system, with cross-over implications for the appropriateness of PPC within Medicare Advantage programs. As a result of these studies, PPC has been adopted as one of the select evidence-based

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practices championed by the Geriatrics and Extended Care Service Line in the national VA health system. PPC is disseminated across VA specialty geriatrics programs using a mentorpartner site approach. Similarly, multiple Program for All-Inclusive Care of the Elderly (PACE) sites are implementing and evaluating PPC using a mentor-partner site training approach. Additional studies evaluating PPC in primary care are underway at the Cleveland Clinic and a randomized clinical trial conducted at two regional VA primary care centers (Southeast Texas and Connecticut). Results of these studies will add to our understanding of how PPC performs in settings outside of specialty geriatrics care.

Lessons Learned PPC provides a structured framework to address older adults health priorities through a two-step process: (1) Identify health priorities and (2) Align care with health priorities. Implementation of PPC is feasible in a variety of clinical settings and results in priorities-aligned changes to care compared the usual care, specifically fewer medication added and diagnostic tests ordered, and more referrals to community services and supports. PPC is associated with lower treatment burdens for older adults compared to usual care. Educational resources and implementation tools on PPC are available at the Patient Priorities Care website (www.patientprioritiescare.org), which can enhance the feasibility of integrating the PPC approach into routine primary care practices.

Summary Collaborative decision-making is a model of delivering patient-centered, chronic illness care to older adults with multiple chronic conditions. The model for collaborative decision-making shifts the paradigm for chronic care from adherence to single-disease guidelines to a focus on identifying health outcome goals and aligning care options to achieve those outcome goals. Attainment of patients’ health outcome goals, within the constraints of what they are willing and able to do (care preferences) to achieve

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those goals, is the measure of treatment success. The process of identifying health priorities is rooted in the simplicity of asking what matters most to an older, multimorbid adults. The Patient Priorities Care approach is a user-centered clinical intervention inspired by the model for collaborative decision-making. Patient Priorities Care has been implemented in a variety of locations and clinical contexts. Evaluations of these implementation efforts demonstrate that Patient Priorities Care is a structured and reliable method for identifying patient health priorities that are integrated into the electronic health record. Patients who use PPC report consistent reductions in treatment burden. Clinicians who recommend care options within the structure of the PPC approach are more likely to align those care options to patients’ identified health priorities. Patient Priorities Care holds promise as a pragmatic approach that results in patient-centered chronic illness care focused on attaining patients’ health priorities.

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Caring for Patients in an Evidence-Limited World Evidence-Based Medicine and Geriatrics Ravishankar Ramaswamy and Rosanne M. Leipzig

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Internal Validity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 Clinically Meaningful Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Applicability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Treatment Studies: Applying Results to Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 Patient–Disease Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Disease Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 Patient Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Treatment Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Patient–Treatment Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Diagnosis Studies – Diagnostic Tests, Differential Diagnosis, Screening, and Clinical Prediction Rules: Applying Results to Older Adults . . . . . . . . . . . . . . . . . . 46 Prognosis Studies: Applying Results to Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Clinical Trials and Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49 ..

Abstract

R. Ramaswamy (*) · R. M. Leipzig Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_3

Evidence-based medicine (EBM) integrates three elements: scientific evidence, clinician’s expertise, and patient’s goals and values. The practice of EBM requires a clinician to ask questions, acquire best evidence, appraise literature for validity and applicability, and apply it at the bedside. Specific to EBM in older 35

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adults, there is a relative lack of valid therapies and tools for decision-making. Most clinical trials have limited inclusion of older adults, particularly the oldest old and those with comorbidities, so results may be less applicable. This makes eliciting patients’ values and preferences more critical in decision-making. Knowledge of key EBM concepts and terminology and the ability to utilize the limited available evidence to treat older patients and to communicate decisions at the bedside are core competencies for geriatrics practitioners. Keywords

Evidence-based medicine · Evidence-based decision-making · Evidence-based clinical practice · Critical appraisal · Randomized controlled trials · Observational studies · Prognostication

Introduction The goal of evidence-based medicine (EBM) is provision of care guided by the most up-to-date, scientifically sound evidence after careful investigation of the patient’s history, physical condition, and expectations. EBM is a term coined in 1992 by a group of clinical epidemiologists based at McMaster University in Hamilton, Ontario, Canada, to describe their transition from teaching clinicians how to read the medical literature [1] to teaching us how to use the literature in the care of an individual patient (Fig. 1) [2, 3]. It starts with framing the clinical question in the PICO format (Population/Patient, Intervention, Comparator, Outcome). EBM emphasizes three basic concepts: internal validity, clinically meaningful results, and applicability.

Internal Validity The first concept is that all evidence is not created equal. Before we can accept the findings of the literature we review, we must ensure it is valid. In other words, do we believe that the research

methodology is sound and therefore, can we trust the published findings? Depending on the type of clinical question – that is, therapeutic, diagnostic, prognostic, etc. – there is a hierarchy among study designs in terms of their ability to provide an accurate, less biased answer. For example, the Heart and Estrogen/Progestin Replacement Study (HERS) trial demonstrated in a randomized controlled trial (RCT) that hormone replacement therapy (HRT) given as 0.625 mg conjugated equine estrogens and 2.5 mg medroxyprogesterone acetate did not improve survival or decrease coronary events in women with existing coronary artery disease, even though several prospective cohort trials suggested that it would [4]. Results from two other RCTs support this finding [5]. In the HRT observational trials, women who were offered and chose to take HRT differed systematically at baseline from those who did not; for example, they were more likely to be upper middle class, to be well educated, and to participate in more health promotion and disease prevention activities and were therefore less at risk for death and coronary disease. These factors may account for their better outcomes after taking HRT [6, 7]. RCTs are superior to prospective cohort studies of the same population because the groups being compared are at equal risk of the outcome being studied, except for exposure to the intervention being tested. Risk factors associated with an outcome, whether they are known or not yet identified, are randomly distributed in RCTs. An observational trial can only identify known risk factors and then attempt to statistically adjust for discrepancies between them in the study groups. Most clinical questions fall into one of five categories: therapy/prevention, harm/etiology, differential diagnosis, diagnosis, and prognosis. Table 1 provides examples of important criteria that should be met to maximize the ability of clinical research to answer each type of clinical question [3]. Some of these criteria have been used to create the “clinical query” search strategies on PubMed (https://www.ncbi.nlm.nih.gov/ pubmed/clinical/) and provide a filter for obtaining high-quality studies relating to therapy, harm, diagnosis, and prognosis. Studies that meet

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1. ASK: Convert daily clinical need for information into answerable questions. 2. ACQUIRE: Find best available evidence with which to answer each question. 3. APPRAISE: Appraise the evidence critically and systematically with particular attention to its

internal and external validity. 4. APPLY: Integrate the evidence with the patient’s unique biopsychosocial situation and the clinician’s

own expertise. 5. ASSESS: Evaluate clinical performance as well as the process of acquiring, integrating, and

applying the new evidence. Fig. 1 5A cycle of evidence-based medicine

these validity criteria have been identified and are published monthly as the American College of Physicians (ACP) Journal Club in the Annals of Internal Medicine. BMJ Best Practice (from the British Medical Journal) and the Cochrane Library are two other sources of systematic reviews of high-quality studies designed to answer specific medical questions (Table 2).

Clinically Meaningful Results The second concept is that clinical, not statistical, significance is what matters for clinicians and patients. Outcomes that are statistically significant (typically indicated by p
0.05) may not be patient-important outcomes. Study investigators may use laboratory or physiologic measures (in place of patient-important endpoints) as outcomes in order to conduct smaller, shorter, and more feasible trials. When these “surrogate endpoints” are accepted, the interventions may not lead to the intended benefit or, worse, may even harm our patient. For example, before definitive studies that reported patient-important outcomes, suppression of ventricular premature beats (VPB) was considered beneficial, as was increasing bone mineral density with fluoride. Yet when carefully designed studies with patient-important outcomes were done, it was found that suppressing VPBs with certain agents increases patient mortality and increasing bone mineral density with fluoride increases fractures [8, 9]. Clinical significance also means that the magnitude of the “benefits” is worth the “costs” of the intervention, including the complications, adverse events, and psychologic or emotional as well as

financial burdens. The usual way of indicating a benefit, the relative risk reduction (RRR), may be quite large when the absolute risk reduction (ARR), or absolute benefit, is small (Table 3). For example, a treatment reduces the risk of an outcome by 50% for an outcome that only occurs once in every million patients treated. In EBM, a term often used to define the size of the treatment benefit is the number needed to treat (NNT), which is the number of people who would need to be treated with the active intervention, rather than the control, over a specific time period to prevent one additional patient from having the bad outcome the treatment was given to prevent. These terms are illustrated in Fig. 2, where stroke, the primary outcome of the Systolic Hypertension in the Elderly Program trial, is shown to occur in approximately 8% of control patients and 5% of treated patients [10]. Here, the ARR is 3%, the RRR is 36%, and the NNT is 33 over 4.5 years. In other words, treating 33 patients with isolated systolic hypertension (ISH) over 4.5 years will result in one fewer stroke than would have occurred if the ISH had not been treated. Similar terms describe the results of diagnostic tests, including the likelihood ratio, which compares the probability that people with an abnormal test actually have the disease in question to the probability that they have an abnormal test result but not the disease.

Applicability The third concept is that studies are done on populations but clinicians need to apply them to an individual patient. This approach is relatively

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Table 1 Evidence-based medicine (EBM) criteria for evaluating studies Criteria Validity (risk of bias)

Results

Therapy/ prevention Were the groups similar at the start of the trial? Was the assignment of patients to treatments randomized? Was randomization concealed? Were patients, health workers, and study personnel “blind” to treatment? Aside from the experimental intervention, were the groups treated equally? Were all the patients who entered the trial properly accounted for and attributed at its conclusion? Was follow-up complete? Were patients analyzed in the groups to which they were randomized?

Differential diagnosis Did the investigators define the clinical problem clearly? Were study patients collected from all relevant clinical settings? Were study patients recruited consecutively? Did the study patients represent the full spectrum of those with this clinical problem? Was the diagnostic evaluation definitive?

How large was the treatment effect? How precise was the estimate of the treatment effect?

What were the diagnoses and their probabilities? How precise were the estimates of disease probability?

Diagnostic tests Did study patients constitute a representative sample of those presenting with a diagnostic dilemma? Did investigators compare the test to an appropriate and independent reference standard? Were those interpreting the test and reference standard “blind” to the other result? Did all study patients receive the same reference standard irrespective of the test results? Were the methods for performing the test described in sufficient detail to permit replication?

What likelihood ratios were associated with the range of possible test results?

Harm/etiology Cohort study: Aside from exposure of interest, did the exposed and control groups start and finish with the same risk for outcome? Were patients similar for prognostic factors that are known to be associated with the outcome or did statistical adjustment address the imbalance? Were the circumstances and methods for detecting the outcome similar? Was follow-up sufficiently complete? Case-control study: Did cases and controls have the same risk for being exposed in the past? Were cases and controls similar with respect to indication or circumstances that would lead to exposure or did statistical adjustment address the imbalance? Were the circumstances and methods for detecting exposure similar for cases and controls? How strong was the association between exposure and outcome? How precise was the estimate of the risk?

Prognosis Was the sample of patients representative? Were the patients classified into prognostically homogenous groups? Was follow-up sufficiently complete? Were outcome criteria objective and unbiased? Was there adjustment for important prognostic factors?

How likely were the outcomes over time? How precise were the estimates of likelihood? (continued)

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Table 1 (continued) Criteria Applicability

Therapy/ prevention Were study patients similar to my patient? Were all patientimportant outcomes considered? Are the likely treatment benefits worth the potential harm and costs?

Differential diagnosis Were study patients and clinical setting similar to mine? Is it unlikely that disease possibilities and probabilities have changed since this evidence was gathered?

Diagnostic tests Will the reproducibility of test results and their interpretation be satisfactory in my clinical setting? Are study results applicable to patients in my practice? Will test results change my management strategy? Will patients be better off as a result of this test?

Harm/etiology Were study patients similar to patients in my practice? Was follow-up sufficiently long? Is the exposure similar to what might occur in my patient? What is the magnitude of risk? Are there any benefits known to be associated with exposure?

Prognosis Were study patients and their management similar to those in my practice? Was follow-up sufficiently long? Can I use the results in my practice, for counseling or reassuring patients?

Table 2 Select EBM resources Online resources UpToDate DynaMed Cochrane Collaboration BMJ Best Practice Centre for Evidence-Based Medicine National Center for Complementary and Integrative Health

www.uptodate.com www.dynamed.com www.cochrane.org www.bestpractice.bmj.com www.cebm.net www.nccih.nih.gov/research/researchresults www.essentialevidenceplus.com www.acpjournals.org/topic/category/ journal-club https://hsl.lib.unc.edu/services/evidencebased-practice-resources

Essential Evidence Plus (includes POEMs) ACP Journal Club University of North Carolina at Chapel Hill EBM Resources Databases/tools PubMed Clinical Queries TRIP (Turning Research Into Practice) Database CEBM: EBM Tools Books Users’ Guides to the Medical Literature: A Manual for EvidenceBased Clinical Practice, 3rd edition

easy when the patient sitting in front of you meets the study inclusion and exclusion criteria, but it is more challenging when the patient resembles those seen in most geriatric practices – old, possibly frail, with multiple medical conditions and

www.ncbi.nlm.nih.gov/pubmed/clinical http://www.tripdatabase.com/ www.cebm.ox.ac.uk/resources/ebm-tools Guyatt G, et al. Evidence-Based Medicine Working Group, American Medical Association. Chicago: AMA Press; 2015.

taking multiple medications, possibly with some cognitive, functional, or mood impairment. In geriatrics, the primary challenge to practicing evidence-based medicine is the lack of highquality studies that include older adults [11]. In

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Table 3 Glossary of evidence-based vocabulary Terms relevant to study design Case-control study Case-control studies examine outcomes that are rare or take a long time to develop. Cases are identified in which the outcome occurred; controls are then selected with similar age, sex, and medical conditions excepting the target outcome. Investigators assess the relative frequency of exposure to the alleged harmful agent, controlling for differences in the variables Case series Descriptions of a series of patients; case series lack a control group Cohort study Involves identification of two or more groups (cohorts) of patients, one which did receive the exposure of interest and one which did not, and following these cohorts forward for the outcome of interest Double-blind (DB) A trial in which neither the patient nor the physician knows whether drug or placebo is being taken or at what dosage External validity How well results fit populations other than the one in which the model was generated Heterogeneity In a meta-analysis, results of individual studies suggest that they were performed in different populations. Can compromise the validity of a meta-analysis; significant heterogeneity indicates decreased likelihood that chance alone is responsible for any observed differences in treatment effects between studies Internal validity How well results fit the population in which the model was generated Meta-analysis Quantitative review of systematically chosen literature, the hallmark of which is statistical synthesis of the numerical outcomes of several trials that all asked the same question Multicenter A clinical trial conducted at more than one site, but following the same protocol at all locations Placebo-controlled (PC) A trial in which the effectiveness of the drug is compared to that of a placebo Prospective cohort study An observational study that follows a large group (a cohort) of people forward in time Randomized controlled Experiment in which individuals are randomly allocated to receive or not receive an trial (RCT) experimental preventative, therapeutic, or diagnostic procedure and then followed to determine the effect of the intervention. Systematic review Explicit, structured presentation of results of an unbiased literature review, using predetermined search and appraisal definitions. Based on deductive, rather than inductive, reasoning Terms relevant to study results Absolute risk reduction The difference between the control event rate (CER) and the experimental event rate (ARR) (EER). Use restricted to a beneficial intervention ARR ¼ CER  EER 95% confidence interval An estimate of the precision of a measurement by determining, with 95% accuracy, that (CI) the measurement includes the “true” value for the population. The broader the CI range, the more uncertain is the true value of the measurement; CIs that cross zero do not reach clinical significance Control event rate (CER) Rate of the outcome in the control group Experimental event rate Rate of the outcome in the experimental treatment group (EER) Intention to treat (ITT) Results that include every individual originally randomized, regardless of whether or not they completed the trial Likelihood ratio (LR) Positive LR ¼ probability of an abnormal diagnostic or screening test result (including clinical signs or symptoms) in patients with the disorder of interest compared to the probability of the abnormal result in patients without the disorder (Sn/1  Sp) Negative LR ¼ probability of a normal diagnostic or screening test result (including clinical signs or symptoms) in patients without the disorder of interest compared to the probability of a normal result in patients with the disorder (Sp/1  Sn) Negative predictive value The proportion of patients testing negative for the disorder who are actually disease-free, of all the patients testing negative (continued)

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Table 3 (continued) Number needed to treat (NNT) Number needed to harm (NNH) Odds ratio (OR) Per protocol analysis Positive predictive value Relative risk reduction (RRR) Sensitivity (Sn)

Specificity (Sp)

The number of patients who must be treated with this intervention (rather than the control) over a specified time period to prevent one additional bad outcome NNT ¼ 1/ARR (as a decimal) The number of patients who would need to be treated over a specific time period before one adverse side effect of the treatment will occur The odds of an experimental patient suffering an adverse event relative to a control patient Results that do not take into account all persons originally randomized, only those participants who followed the study protocol The proportion of patients testing positive for the disorder who actually have the disease, of all the patients testing positive Percent reduction in “bad” outcome events in the experimentally treated groups relative to the control groups RRR ¼ (CER  EER) / CER * 100 The proportion of diseased patients actually testing positive for the disorder, of all the diseased patients SnNout: When a test has a high Sensitivity, a Negative test rules OUT the diagnosis The proportion of disease-free patients actually testing negative for the disorder, of all the disease-free patients SpPin: When a test has a high Specificity, a Positive result rules IN the diagnosis

Fig. 2 Stroke incidence in patients with isolated systolic hypertension

general, there is a paucity of evidence on treating or diagnosing common conditions in older adults. For example, heart failure is overwhelmingly a disorder of the older adult population, yet very few clinical trials have been successful in establishing the treatment paradigm for older adults with heart failure. Heart failure with preserved ejection fraction (HFpEF) occurs almost exclusively in older adults, while most of the literature and clinical trials focus on therapies for heart failure with reduced ejection fraction (HFrEF). While more than 100 randomized clinical trials with over 50,000 participants have studied HRrEF, the average age of participants in these clinical trials is ~59 years [12]. Yet we know from population-based studies that almost 50% of

new-onset Congestive Heart Failure (CHF) occurred in people aged 80 or older and that approximately 50% of these had HFrEF [13]. Attempting to reverse the age bias, some recent trials like the ELITE, I-PRESERVE, and TOPCAT have minimum age for entry of 60 years. Despite that, it has been challenging to include those older adults with multiple comorbidities in trials. How, then, should older patients with HFrEF with comorbidities be treated? How should we treat those with HFpEF? Will 80-year-olds be able to tolerate the recent standards for systolic heart failure therapy, which include the addition of three to five new medications [i.e., angiotensin-converting enzyme (ACE) inhibitor, beta-blocker, HMG (3-hydroxy3-methylgluaryl)-CoA reductase inhibitors, diuretics, digoxin]? Unfortunately, definitive answers to these questions or guidelines to therapy in older adults are still without valid evidence [14, 15]. In recent years, there is greater funding and impetus for clinical trials to enroll older adults, so we are beginning to have more reliable evidence for our older adult population. In addition, trials with a pragmatic design that evaluate effectiveness of interventions in real-life and routine

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practice conditions are more generalizable for all patients [16]. That said, an RCT may not always be feasible or ethical to determine outcomes in older adults. Although RCTs have demonstrated the benefit of mammography screening for breast cancer in women between 50 and 69 years, none of the screening trials include women above age 74 years. An area of ambiguity for clinicians caring for older women is about when to stop screening, with limited evidence to encourage or discourage screening after age 75 years. A creative approach to study the efficacy of continuing screening mammography in older women involved emulating a pragmatic target trial, where two identical clones were created for every woman who met eligibility criteria and assigned to each of the two strategies being compared (i.e., continue screening or stop screening)

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[17]. Then, the hazard ratios were estimated by using the per protocol analysis and a pooled logistic regression model. With this approach, we learned that among female Medicare beneficiaries who have high probability of surviving another 10 years and had undergone mammography screening, continuing to screen those between 70 and 74 years of age would reduce 8-year mortality by one death per 1000 women, whereas continuing to screen those aged 75 years or older would not affect 8-year breast cancer mortality.

Treatment Studies: Applying Results to Older Adults Figure 3 depicts several of the areas where differences in older adults might impact the benefit/risk ratio of a treatment. Several of these are key

Fig. 3 Applicability of treatment study results to older adults: domains to consider

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principles in geriatric medicine and overlap the specific biologic, social, economic, and epidemiologic issues discussed in the User’s Guide: How to Decide on the Applicability of Clinical Trial Results to Your Patient [18]. In this chapter, disease, patient, and treatment differences that can influence the application of study results to older adults as well as the intersections of each of these are discussed.

Patient–Disease Interactions Despite the concerns about reduced therapeutic efficacy that follow, it is important to recognize that older adults are often the group most likely to benefit from treatment of a given disorder. Benefits are almost always greatest in the population most likely to experience the bad outcome that the treatment is intended to avoid or improve. Treatment of hypertension can be used as an example. The most recent Cochrane systematic review of antihypertensive treatment in 60+ age group demonstrated a modest reduction in total mortality (RR, 0.90; NNT, 83.3 over 4.5 years) and significant reduction in cardiovascular mortality and morbidity (RR, 0.72; NNT, 23.2 over 4.5 years) [19]. Interestingly, the magnitude of benefit depends on multiple factors including their baseline risk of cardiovascular complications of hypertension. People with more cardiovascular risk factors (e.g., diabetes, family history of heart disease, left ventricular hypertrophy, etc.) had a greater likelihood of a reduction in cardiovascular events by antihypertensive therapy. In general, older adults have a similar decrease in relative risk and the same or a smaller NNT than middleaged or younger adults, particularly when risks of treatment are small. In other words, the 5-year absolute morbidity and mortality benefit of antihypertensive therapy is greater for older than younger adults [20]. Lowering of blood pressure results in similar relative but higher absolute

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effect in these people at advanced age and hence at high risk.

Disease Differences Age-related differences in disease pathophysiology or in the multifactorial nature of a condition can decrease treatment efficacy. For example, agents effective at treating pneumonia in community-dwelling adults may be less effective when treating nursing home-acquired pneumonia due to differences in the causative organisms and resistance patterns [21, 22]. Sulfonylureas are effective in treating type II diabetes, but the lack of endogenous insulin makes them of little use in treating type I diabetes. The symptom complex of nocturia and leg edema may suggest CHF, yet diuretics will not improve nocturia caused by age-related temporal shifts in fluid elimination that are a result of loss of the circadian rhythm of antidiuretic hormone secretion, decreased secretion of renin-angiotensin-aldosterone, increased secretion of atrial natriuretic hormone, and diminished renal concentrating and sodiumconserving ability [23], or leg edema that is secondary to venous insufficiency. Classic differential diagnosis teaches us to use Occam’s razor; that is, scientists should assume no more causes than are absolutely necessary to explain their observations. A single diagnosis should be sought to account for all the patient’s signs and symptoms. Many geriatric disorders, however, are multifactorial in that several different conditions contribute to the symptom complex [24]. With multifactorial disorders, identifying and treating a single condition may result in some but not complete improvement. Intermediate outcomes may be improved, yet patients may not be aware of any improvement. For example, the single diagnoses most responsible for dyspnea on exertion (DOE) are pneumonia, asthma or chronic obstructive pulmonary disease (COPD),

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angina, and CHF. Specific treatment for the correct diagnosis results in resolution of the symptom. In older patients, a number of chronic conditions may contribute to the complaint of DOE. In addition to the disorders already noted, kyphosis, intrinsic lung disease, deconditioning, valvular heart disease, left ventricular dysfunction, tachyarrhythmias, and mild anemia may all exacerbate the patient’s symptoms. Only some of these can be reversed, and treatment of any one ameliorates only some of the dyspnea, even if the laboratory or radiology results for that condition normalize.

Patient Differences Older adults are more pathophysiologically heterogeneous than people at other stages of life as a result of the effects of aging itself, disease, lifestyle, and genetics. Older adults differ greatly in their physiologic and functional reserves and capacities, in how resilient and how vulnerable they are. While the “one-size-fits-all” approach may work more for younger or middle-aged people, it likely will not work for older adults. The concept of applying study results to “older adults” is actually misleading, as there appear to be multiple subsets with significantly different prognostic trajectories: successful agers, usual agers, chronically ill, frail, dementing, or terminally ill agers. Even within each of these groups, the life expectancy trajectory has been shown to differ [25–28]. Prognostic indexes are better for some conditions than others, but generally even these only provide data on time to death or, occasionally, the need for institutional-type care. Comorbid and age-related conditions can significantly alter the potential benefits and risks of treatment. The impact of comorbid illness on life expectancy can negate the benefit of treating certain conditions including early prostate cancer, where no outcome difference is seen between treatment and watchful waiting over 10 years [29], and high cholesterol, where benefits are initially seen after 2 full years and reach a maximum at 5 years [30]. Other comorbidities allow

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parsimonious treatment to occur, resulting in an intervention having even greater benefit than usual: examples include anticoagulation in a person with both deep venous thrombosis (DVT) and atrial fibrillation, or colchicine in someone with gout and significant obstipation. Comorbidities can also reduce the effect of treatment by producing a bad outcome through mechanisms not affected by the treatment. For example, cataract removal in older adults may not improve vision substantially if the patient has underlying macular degeneration or diabetic retinopathy, which is less likely to occur in middle-aged or younger adults. The Systolic Blood Pressure Intervention Trial (SPRINT) compared intensive versus standard BP management in ~10,000 patients 50 years of age without diabetes mellitus or prior stroke who were at elevated risk for cardiovascular events; intensive BP control was associated with fewer primary outcome events (5.2% vs. 6.8%; NNT, 63) and a reduction in all-cause mortality (3.3% vs. 4.5%; NNT, 83) [31, 32]. Although secondary and subgroup analyses demonstrated that even frail patients seemed to benefit from intensive control, there was no benefit in those with cognitive impairment (MoCA score 75 years) and those with dementia, cancer, and paralysis [59]. The study methodology utilized propensity scores to increase the similarity of the groups with the exception of statin prescription [60]. Statin initiation was seen to be associated with lower cardiovascular-related and all-cause mortality compared to non-statin users, even in those above age 90 years. This association was evident within 2 years. The generalizability of the article was limited because it was done on a Veterans Health Affairs dataset composed mostly of Caucasian males. Given also the lack of significant adverse events associated with the use of statin at advanced age, the likelihood of benefit in older adults seemed promising. Hence, after discussion of the potential side effects and using shared decision tools on the computer, Ms. G started on a statin medication with a close follow-up in 4–6 weeks [61].

Case Study Conclusion/Summary Ms. G is an 82-year-old female with a past medical history of osteoporosis, mild cognitive impairment, osteoarthritis of knees, and mild COPD who presents for an initial visit at a geriatrics outpatient clinic. You determine after taking a history and doing a physical examination that she is in great health overall, with a good prognosis and life expectancy in the upper quartile of women of her age. As you discuss health maintenance issues, you wonder if she would be a candidate for initiation of statin for primary prevention of cardiovascular disease. Your usual first step before initiating statin for primary prevention is to calculate the 10-year ASCVD risk using the estimator app on your phone. Currently, the ASCVD estimator does not provide risk and guidance for those above age 75 years due to paucity of data. You are reminded of a recent article published in the Journal of the

Time pressures on the clinician make careful critique of individual trials difficult. Evidence-based resources such as those noted in Table 2 provide pre-scrutinized summaries for clinicians and allow one to be more informed of the results of high-quality studies that evaluate outcomes of concern to patients, not just to the disease. Table 3 defines some of the terms commonly used in this chapter. Multi-complexity is a foundational concept in the practice of geriatrics. Managing multiple medical conditions, social and environmental determinants, and physiologic changes of aging practically to conform to the varied and changing goals and outcomes of care can be challenging and mystifying. Some key takeaways for reviewing and applying evidence for older adults are noted below.

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• One-size-fits-all approach will not work for older adults. If you have seen one 80-yearold, you have seen one 80-year old. • Utilize general evidence resources like UpToDate and DynaMed to get a general overview of the breadth and depth of evidence in the topic of interest. • Before accepting conclusions from these sources, you may need to review the referenced article, or frame a PICO question and identify an appropriate article, to better understand whether these conclusions apply to your patient. Review inclusion and exclusion criteria closely, especially with relation to age and comorbidities of participants. • What is your patient’s functional status? Are they fit, vulnerable, or frail? Most clinical trials do not enroll frail patients. • Look in the Methods and Discussion sections to see if adjusted analysis was attempted. Did authors consider the influence of cognitive or functional impairment and other comorbidities? • Review subgroup analyses with caution, but they can be useful before you apply available evidence to your older adult patient. • Finally, individualized decision-making is the cornerstone of excellent geriatric patient care. A thorough assessment of your patient preferences and their physical, mental, and social function should always drive your choice of management plan.

References 1. How to read clinical journals: I. Why to read them and how to start reading them critically. Can Med Assoc J. 1981; 124(5):555–8. https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC1705173/. 2. Oxman A, Sackett D, Guyatt G. Users’ guides to the medical literature. I. How to get started. The EvidenceBased Medicine Working Group. JAMA. 1993;270 (17):2093–5. 3. Guyatt G, Rennie D, Meade MO, Cook DJ, editors. JAMA evidence user’s guides to the medical literature: a manual for evidence based clinical practice. 3rd ed. New York: McGraw-Hill; 2014. 4. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.

49 Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280(7):605–13. 5. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33. 6. Grady D, Hulley SB. Hormones to prevent coronary disease in women: when are observational studies adequate evidence? Ann Intern Med. 2000;133(12):999– 1001. 7. Barrett-Connor E. Postmenopausal estrogen and prevention bias. Ann Intern Med. 1991;115(6):455–6. 8. Epstein AE, Hallstrom AP, Rogers WJ, et al. Mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction. The original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA. 1993;270(20):2451–5. 9. Riggs BL, Hodgson SF, O’Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med. 1990;322(12):802–9. 10. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265(24):3255–64. 11. Mooijaart SP, Broekhuizen K, Trompet S, et al. Evidence-based medicine in older patients: how can we do better? Neth J Med. 2015;73(5):211–8. 12. Kitzman DW, Rich MW. Age disparities in heart failure research. JAMA. 2010;304(17):1950–1. https://doi. org/10.1001/jama.2010.1592. 13. Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991. Circulation. 1998;98(21):2282–9. 14. Butrous H, Hummel SL. Heart failure in older adults. Can J Cardiol. 2016;32(9):1140–7. https://doi.org/10. 1016/j.cjca.2016.05.005. 15. Jankowska EA, Vitale C, Uchmanowicz I, Tkaczyszyn M, Drozd M, Ponikowski P. Drug therapy in elderly heart failure patients. Eur Heart J Suppl. 2019;21(Suppl L):L8–L11. https://doi.org/10.1093/ eurheartj/suz237. 16. Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci. 2011;13(2):217–24. 17. García-Albéniz X, Hernán MA, Logan RW, Price M, Armstrong K, Hsu J. Continuation of annual screening mammography and breast cancer mortality in women older than 70 years. Ann Intern Med. 2020;172(6): 381–9. https://doi.org/10.7326/M18-1199. 18. Dans AL, Dans LF, Guyatt GH, Richardson S. Users’ guides to the medical literature. XIV. How to decide on the applicability of clinical trial results to your patient. Evidence-Based Medicine Working Group. JAMA. 1998;279(7):545–9.

50 19. Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hypertension in the elderly. Cochrane Database Syst Rev. 2009;(4):Art. No.: CD000028. https://doi.org/10.1002/14651858. CD000028.pub2. 20. Mulrow CD, Cornell JA, Herrera CR, Kadri A, Farnett L, Aguilar C. Hypertension in the elderly. Implications and generalizability of randomized trials. JAMA. 1994;272(24):1932–8. 21. Yoshikawa TT, Norman DC. Infectious disease in the aging: a clinical handbook. Totowa: Humana Press; 2001. 22. Naughton BJ, Mylotte JM. Treatment guideline for nursing home-acquired pneumonia based on community practice. J Am Geriatr Soc. 2000;48(1):82–8. 23. Miller M. Nocturnal polyuria in older people: pathophysiology and clinical implications. J Am Geriatr Soc. 2000;48(10):1321–9. 24. Pelleg A, Ramaswamy R. Differential diagnoses in the setting of advanced age and multiple conditions. In: Chun A, editor. Geriatric practice. Cham: Springer; 2020. https://doi.org/10.1007/978-3-030-19625-7_7. 25. Rowe JW, Kahn RL. Human aging: usual and successful. Science. 1987;237(4811):143–9. 26. Zanetti O, Solerte SB, Cantoni F. Life expectancy in Alzheimer’s disease (AD). Arch Gerontol Geriatr. 2009;49(Suppl 1):237–43. https://doi.org/10.1016/j. archger.2009.09.035. 27. Verduzco-Aguirre HC, Gomez-Moreno C, ChavarriGuerra Y, Soto-Perez-de-Celis E. Predicting life expectancy for older adults with cancer in clinical practice: implications for shared decision-making. Curr Oncol Rep. 2019;21(8):68. https://doi.org/10.1007/s11912019-0821-3. 28. Wei MY, Mukamal KJ. Multimorbidity, mortality, and long-term physical functioning in 3 prospective cohorts of community-dwelling adults. Am J Epidemiol. 2018;187(1):103–12. https://doi.org/10. 1093/aje/kwx198. 29. Lu-Yao GL, Yao SL. Population-based study of longterm survival in patients with clinically localised prostate cancer. Lancet. 1997;349(9056):906–10. 30. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J. 1994;308(6925):367–72. 31. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years: a randomized clinical trial. JAMA. 2016;315 (24):2673–82. 32. Pajewski NM, Berlowitz DR, Bress AP, et al. Intensive vs standard blood pressure control in adults 80 years or older: a secondary analysis of the systolic blood pressure intervention trial. Secondary analysis. J Am Geriatr Soc. 2020;68:496–504. 33. Sunderland T, Tariot PN, Cohen RM, Weingartner H, Mueller EA III, Murphy DL. Anticholinergic sensitivity in patients with dementia of the Alzheimer type and

R. Ramaswamy and R. M. Leipzig age-matched controls. A dose-response study. Arch Gen Psychiatry. 1987;44(5):418–26. 34. Dubois B, Danze F, Pillon B, Cusimano G, Lhermitte F, Agid Y. Cholinergic-dependent cognitive deficits in Parkinson’s disease. Ann Neurol. 1987;22(1):26–30. 35. Davidson MH. Differences between clinical trial efficacy and real-world effectiveness. Am J Manag Care. 2006;12(15 Suppl):S405–11. 36. Naidoo N, Nguyen VT, Ravaud P, et al. The research burden of randomized controlled trial participation: a systematic thematic synthesis of qualitative evidence. BMC Med. 2020;18:6. https://doi.org/10.1186/ s12916-019-1476-5. 37. Wieland D, Stuck AE, Siu AL, Adams J, Rubenstein LZ. Meta-analytic methods for health services research – an example from geriatrics. Eval Health Prof. 1995;18(3):252–82. 38. Applegate W, Deyo R, Kramer A, Meehan S. Geriatric evaluation and management: current status and future research directions. J Am Geriatr Soc. 1991;39 (9 pt 2):2S–7S. 39. Rodriguez RD, Schocken DD. Update on sick sinus syndrome, a cardiac disorder of aging. Geriatrics. 1990;45(1):26–30, 33–36. 40. Drinka PJ, Gravenstein S, Krause P, Schilling M, Miller BA, Shult P. Outbreaks of influenza A and B in a highly immunized nursing home population. J Fam Pract. 1997;45(6):509–14. 41. Anderson GD, Pak C, Doane KW, et al. Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia. Ann Pharmacother. 1997;31(3):279–84. 42. Shannon M. Predictors of major toxicity after theophylline overdose. Ann Intern Med. 1993;119(12):1161–7. 43. Thiemann DR, Coresh J, Schulman SP, Gerstenblith G, Oetgen WJ, Powe NR. Lack of benefit for intravenous thrombolysis in patients with myocardial infarction who are older than 75 years. Circulation. 2000;101 (19):2239–46. 44. Soumerai SB, McLaughlin TJ, Ross-Degnan D, Christiansen CL, Gurwitz JH. Effectiveness of thrombolytic therapy for acute myocardial infarction in the elderly: cause for concern in the old-old. Arch Intern Med. 2002;162(5):561–8. 45. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med. 1990;113(9):664–70. 46. Mehr DR, Binder EF, Kruse RL, Zweig SC, Madsen RW, D’Agostino RB. Clinical findings associated with radiographic pneumonia in nursing home residents. J Fam Pract. 2001;50(11):931–7. 47. Faggiano A, Del Prete M, Marciello F, Marotta V, Ramundo V, Colao A. Thyroid diseases in elderly. Minerva Endocrinol. 2011;36(3):211–31. 48. Engberding N, Wenger NK. Acute coronary syndromes in the elderly. F1000Res. 2017;6:1791. https://doi.org/ 10.12688/f1000research.11064.1. PMID: 29043079; PMCID: PMC5627582.

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49. Goch A, Misiewicz P, Rysz J, Banach M. The clinical manifestation of myocardial infarction in elderly patients. Clin Cardiol. 2009;32(6):E46–51. https://doi. org/10.1002/clc.20354. PMID: 19382276; PMCID: PMC6653078. 50. Palmqvist S, Janelidze S, Quiroz YT, et al. Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA. 2020;324(8):772–81. https://doi.org/10. 1001/jama.2020.12134. 51. Warshaw G, Tanzer F. The effectiveness of lumbar puncture in the evaluation of delirium and fever in the hospitalized elderly. Arch Fam Med. 1993;2(3):293–7. 52. Vestal RE, Wood AJ, Shand DG. Reduced betaadrenoceptor sensitivity in the elderly. Clin Pharmacol Ther. 1979;26(2):181–6. 53. Ramaswamy R, Leipzig RM, Hung WW. Implementation of an evidence-based medicine curriculum in a fellowship program: can it influence clinical practice? Gerontol Geriatr Educ. 2020;11:1– 10. https://doi.org/10.1080/02701960.2020.1777409. 54. Epstein AS, Prigerson HG, O’Reilly EM, Maciejewski PK. Discussions of life expectancy and changes in illness understanding in patients with advanced cancer. J Clin Oncol. 2016;34(20):2398–403. https://doi.org/ 10.1200/JCO.2015.63.6696. Epub 2016 May 23. 55. Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK. Prognostic indices for older adults: a

51 systematic review. JAMA. 2012;307(2):182–92. https://doi.org/10.1001/jama.2011.1966. 56. Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham study. Neurology. 1978;28(10):973–7. https://doi.org/10.1212/ wnl.28.10.973. 57. Lockett J, Sauma S, Radziszewska B, Bernard MA. Adequacy of inclusion of older adults in NIH-funded phase III clinical trials. J Am Geriatr Soc. 2019;67(2):218–22. https://doi.org/10.1111/jgs. 15786. Epub 2019 Jan 29. 58. https://grants.nih.gov/policy/inclusion/lifespan.htm. Last accessed 20 Nov 2020. 59. Orkaby AR, Driver JA, Ho Y, et al. Association of statin use with all-cause and cardiovascular mortality in US veterans 75 years and older. JAMA. 2020;324 (1):68–78. https://doi.org/10.1001/jama.2020.7848. 60. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46(3):399–424. https://doi.org/10.1080/ 00273171.2011.568786. 61. Mayo Clinic Statin Choice Decision Aid. https:// statindecisionaid.mayoclinic.org. Last accessed 20 Nov 2020.

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Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership Janice Hoffman-Simen and Tina Meyer

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Systemic Changes in Normal Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Pharmacokinetic and Pharmacodynamic Changes with Aging . . . . . . . . . . . . . . . . . . . . . Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Failure to Thrive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Protein Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Role of Prealbumin in Tube Feeding Decisions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Herbal Supplements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adverse Drug Reactions in the Elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polypharmacy and the Prescribing Cascade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deprescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Special Considerations for Persons Over 80 Years Old . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Deprescribing During Common Chronic Disease States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55 55 56 58 59 59 59 60 60 61 61 62

Case Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 Case Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Rationale for the Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Advantages of Interdisciplinary Teams in Geriatric Patients’ Decision-Making . . . 67 Leadership Model for Healthcare Teams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Common Goals and Benefits of an Interprofessional Care Team . . . . . . . . . . . . . . . . . . . 70

J. Hoffman-Simen (*) Postgraduate Pharmacy Residency Program, Los Angeles Jewish Home for the Aging, Tampa, FL, USA College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA e-mail: [email protected] T. Meyer College of Health Sciences, Western University of Health Sciences, Pomona, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_4

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J. Hoffman-Simen and T. Meyer Challenges of Interprofessional Care Teams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Emotional Intelligence Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Abstract

People are living longer with multiple comorbid chronic disease states leading to polypharmacy and a high risk of adverse events. The presence of comorbid conditions often leads to the exclusion of older persons in clinical drug trials. Insufficient expertise regarding physiologic, pharmacokinetic, and pharmacodynamic changes of aging contributes to increased risk of inappropriate prescribing. Assessment of the whole patient to provide person-centered care, and particularly each medication, is essential to high-quality clinical decision-making. All symptoms should be carefully assessed with a keen eye toward potential side effects of existing medication as the cause to avoid the prescription cascade and polypharmacy. Consideration for deprescribing includes downward titration to the lowest amount of medication to balance treatment with the highest quality of life. Effective interprofessional care teams are superior to the parallel efforts of siloed professionals and decrease functional decline and hospital length of stay among elder persons. Fluid leadership among team members that provides for the needs of person-centered care is superior to static leadership based on position or profession. Communication among the patient, family, and care team is vital to achieving the patient’s treatment goals.

Introduction Appropriate prescribing, recognizing, and managing medication side effects and drug interactions and avoiding polypharmacy are all essential skills in prescribing medication to older adults [1]. Individuals 65 and older are the leading consumers of medications. The geriatric population accounts for 34% of prescription medications and 50% of over the counter medications [1, 2]. Over 80% of this population takes at least one medication daily. Community-dwelling older persons, on average, consumed four medications daily [1, 2]. In comparison, nursing home residents on average took nine different medications daily [1, 2]. Each year, more than nine million adverse drug reactions occurred among older Americans [3]. Appropriate prescribing in older adults is a complicated task that involves more than avoiding potentially inappropriate agents and polypharmacy [4]. In addition to specialized prescribing skills, providers need to consider the monitoring of medication used among this vulnerable population [5]. Geriatric experts have long touted the dosing titration mantra, start low, go slow, but go when medication therapy is the selected modality. This chapter reviews the main concepts affecting decision-making in prescribing for older adults.

Systemic Changes in Normal Aging Keywords

Geriatrics · Prescribing · De-prescribing · Interprofessional teams · Leadership · Pharmacokinetics · Pharmacodynamics · Polypharmacy

Erroneously, many changes that occur in older adults are attributed to aging itself. As a result, the opportunity to address malleable signs and symptoms of disease are often overlooked. For example, it stood to reason that an older person

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who may have been widowed, and was experiencing the loss of contemporaries due to isolation or dependence, illness, and death, would understandably be depressed. However, research has demonstrated that depression is not a part of normal aging, occurring in approximately 14% of older adults [6]. The Rule of Fourths addresses the realization that only approximately 1/4th of changes in functional status are due to physiologic aging. The remaining 3/4th changes are due to disease, disuse, and misuse in equal quantity [6]. Table 1 reviews some of the expected changes within systems that affect the approach to management. The overall loss of function within body systems is approximately 30% by age 70 [7]. Normal aging is associated with a blunted response at virtually every level of the immune Table 1 Functional changes with aging Functional systems Sensory losses Oral health status

Gastrointestinal function Metabolic/ endocrine changes

Renal/GU

CV function

Functional changes with aging Reduced sense of taste, smell, sight, hearing, and touch. Xerostomia – dry mouth caused by hyposalivation. Dentures and periodontal problems Hypochlorhydria Constipation Decreased glucose tolerance 15%–20% decline in resting metabolic rate Decreased thyroid function Decrease in hormones-estrogen, testosterone, and growth hormone Decreased muscle mass and strength Increased adiposity to lean tissue ratio Declined renal mass and weight Decreased GFR Electrolyte imbalances Urinary incontinence Blood vessels become less elastic, ability to relax heart decreases, and total peripheral resistance increases – Isolated systolic hypertension. Diminished baroreceptors with orthostatic hypotension and syncope. ♂: Cholesterol peak ~60 y.o. ♀: Total cholesterol + LDL continue to rise until ~70 y.o.

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system. This so-called immunosenescence extends to hematopoietic stem cells in the bone marrow affecting all cell lineages in the immune system. Hence, older adults are predisposed to a less robust physiologic margin characterized by a slowed immune response to pathogens or vaccines. Aging is associated with a low-grade, persistent proinflammatory state that serves to further predispose older adults to a slowed immune response. There are increased levels of proinflammatory cytokines such as Interleuken-6 (IL-6) and Tumor Necrosis Factor-α, acute-phase reactants such as C-Reactive Protein (CRP), and clotting factors. The so-called “inflammaging” phenomena is associated with mortality and correlates to decreased muscle mass and strength [7]. The persistent proinflammatory state sets the stage for potential overprescribing based on nonspecific inflammatory markers. For example, elevations in sedimentation rate (ESR) and CRP may not be clinically relevant or indicative of acute processes such as infection, or even mild tissue injury. Normal aging is characterized by a reduction of lean muscle mass, decreased water content, and increased body fat.

Pharmacokinetic and Pharmacodynamic Changes with Aging Pharmacokinetics describes the physiologic effects on a drug through various processes. In contrast, pharmacodynamics describes the effects of a drug on bodily functions. Pharmacokinetics mathematical calculation are predictive of how a drug will behave, but we are not able to predict through pharmacodynamics how an individual will respond to a given drug.

Pharmacodynamics Older adults frequently exhibit different pharmacodynamic responses when compared to young adults. Changes in receptor affinity, postreceptor changes at the cellular level, and changes in adaptive homeostatic responses are expected.

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Pathology in organ systems are especially clinically relevant. In general, small-dose initiation with slow titration based on the clinical response is recommended. Alterations in sensitivity to drugs with aging include increased receptor sensitivity to benzodiazepines, warfarin, and opioids. Conversely, receptor sensitivity to beta-blockers is reduced. Baroreceptor sensitivity is diminished leading to increased risk of orthostatic hypotension with the use of vasodilators, tricyclic antidepressants, and antihypertensives. The etiologies of altered pharmacodynamics in older persons are owing to receptor changes, (e.g., decrease in number of some receptors) altered reserve capacity, homeostatic changes, increased sensitivity to drug therapeutics and adverse effects, increased comorbid diseases, and increased drug interactions from polypharmacy. Clinical complications commonly associated with pharmacodynamic changes include increased risk of tardive dyskinesia and pseudoparkinsonism with antipsychotic agents, heightened sensitivity to anticholinergic effects leading to increased risk of hypotension, constipation, and urinary retention. Increased sensitivity to warfarin and risk of bleeding are also a concern. Digoxin is no longer recommended as first-line treatment for heart failure and atrial fibrillation; however, it is still widely prescribed. Increased toxicity from digoxin, especially in the presence of hypokalemia, is an important pharmacodynamic consideration. Additionally, risk of hyperkalemia with use of nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors (ACE-I), and potassium sparing diuretics are commonly observed complications of the pharmacodynamic changes in older persons. Further pharmacodynamic effects in older adults are associated with reductions in important regulatory responses. Decreased renin and aldosterone levels lead to reduced response to ACE-I. Similarly, reduced adrenergic receptor sensitivity results in a diminished response to beta blockers.

J. Hoffman-Simen and T. Meyer

Pharmacokinetics Addressing pharmacokinetic changes of aging includes considerations in drug absorption, distribution, protein binding, metabolism, and elimination. Lifestyle changes, diminished appetite and intake, fluid volume, and increased fat to lean muscle mass ratio all contribute to clinical drug therapy applications and decision-making.

Drug Absorption Drug absorption is not affected in healthy older adults. Certain conditions may affect the rate of drug absorption. Anticholinergics may decrease saliva secretion affecting the rate of absorption through the buccal mucosa and sublingual tissues. Reduced tissue perfusion may decrease the rate of absorption of subcutaneous, intramuscular, and transdermal medications. A slowing of small bowel active transport may affect the absorption of iron and vitamin B12. Table 2 [8] illustrates the expected pharmacokinetic (absorption, distribution, metabolism, and excretion) changes with aging. Drug Distribution Skeletal (lean) muscle mass and strength exhibit a steady decline after the fourth decade of life, and the rate of decline is accelerated with aging with the most losses in fast twitch fibers [9]. Mitochondrial dysfunction with advancing age gives rise to skeletal muscle apoptosis and atrophy, resulting in a reduction of lean mass, changes in protein synthesis, replacement of muscle fibers with fat, and the development of fibrosis [10]. Peripheral fat decreases while visceral and intermuscular fat increases [11]. Plasma drug concentration is inversely related to its volume of distribution. The volume of distribution is dependent on the hydrophilic and lipophilic volumes in the body. The volume of distribution of lipophilic drugs is higher in older adults resulting in increased half-life and prolonged drug effects. The potential for drug

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Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership

Table 2 Pharmacokinetics and aging Absorption

Distribution

Metabolic

Excretion

# Amount of saliva " Gastric pH # Gastric acid secretion " Gastric emptying time # Gastric surface area # Gastrointestinal motility # Active transport mechanisms # Cardiac output " Peripheral vascular resistance # Renal blood flow # Hepatic blood flow # Body water " Body fat tissue # Serum albumin levels " For lipid soluble and decrease for water soluble drugs # Microsomal hepatic oxidation # Clearance " Steady state levels " Half-lives " Levels of active metabolites # First pass metabolism due to reduced # blood flow # In renal perfusion # In renal size # In glomerular filtration rate # Tubular secretion # In tubular reabsorption

": Increased; #: Reduced ©The Author(s) 2015 Published by Baishideng Publishing Group Inc. All rights reserved. Ref. [8] URL: https://www.wjgnet.com/2220-3192/full/v4/i2/193. htm DOI: https://doi.org/10.5497/wjp.v4.i2.193

accumulation with continued use is an important consideration. Lipophilic psychiatric drugs, such as the benzodiazepines, will have a much higher volume of distribution and longer half-life due to the distribution to adipose tissue, and therefore, a higher risk of adverse effects, particularly sedation and risk of mechanical falls. The overall fluid volume is decreased with advancing age. In comparison to the long halflife of lipophilic drugs, the half-life of hydrophilic agents (aminoglycoside antibiotics, diuretics, minerals, and vitamins) are like those observed in younger adults.

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Protein Binding Most drugs bind to albumin and α-1-glycoprotein with only the unbound drug being active. The impact of changes in protein binding with age is influenced by the individual amount of the change and the properties of the drug and on its therapeutic index. It is difficult to predict the clinical importance of a specific drug. Only a few agents are known to exhibit more than 50% change in the free fraction, namely, acetazolamide, diflunisal, etomidate, naproxen, salicylate, valproate, and zimeldine [12]. Glycoproteins are found on the surface of the lipid layer of cell membranes. They are hydrophilic and act in cell-to-cell recognition and binding processes. Changes in serum albumin concentration are minimal in healthy older adults. In persons with chronic illness and malnutrition, serum albumin concentrations may be significantly reduced resulting in a reduction of bound drug and higher serum levels of free drug. Antipsychotics, phenytoin, sodium valproate, and warfarin are commonly affected, increasing the opportunity for adverse toxic effects. Particular attention must be applied when caring for frail and hospitalized older adults to avoid toxicity. Metabolism The Cytochrome YP-450 enzyme system found in the liver has many pathways that breakdown or metabolize medications. Physiologic aging results in an increased effect of drugs in the CYP 2D6 metabolic pathway as compared to the decrease in the CYP 2C 19, 1A2 pathway (Table 3) [13]. In addition to the decreases in liver mass and perfusion, many lifestyle influences can affect the CYP-450 enzyme system. Alcohol and nicotine result in enzyme induction leading to decreased drug serum levels. Clinical frailty and severe malnutrition lead to enzyme inhibition characterized by higher serum levels of circulating drug and adverse risks (Table 4) [14]. Further discussion regarding frailty and malnutrition are addressed later in the chapter (see section “Failure to Thrive”).

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J. Hoffman-Simen and T. Meyer

Table 3 Metabolic pathway changes with aging Decreased CYP 1A2 CYP 2C19

Decreased or unchanged CYP 2A CYP 2C9 CYP 3A4

Increased CYP 2D6

** If Scr < 1.0 and age > 65 round to 1.0. If Scr > 1, use actual lab value. IBWmen ¼ 50 kg þ ð2:3  inches > 5 ftÞ IBWwomen ¼ 45:5 kg þ ð2:3  inches > 5 ftÞ

Ref. [13] Table 4 Lifestyle influences on the CYP-450 enzyme system Factor Alcohol Diet Drugs Frailty Severe malnutrition Smoking

Result Enzyme induction Enzyme induction/inhibition Enzyme induction/inhibition Enzyme inhibition Enzyme inhibition Enzyme induction

Ref. [14]

Excretion Medications are eliminated via the kidneys, feces, sweat, and exhalation. The importance of renal function is the clinical significance of drug excretion. In older adults with renal impairment, renally excreted drugs are not readily eliminated, leading to an increased concentration of these agents and increased risk of toxicity due to accumulation of drug in the body. The physiologic changes of aging include decreased renal blood flow and decreased muscle mass affecting the creatinine leading to a decrease in kidney function and Creatinine Clearance. Creatinine Clearance is estimated to be reduced by 50% between ages 25 and 85 years. Serum creatinine (Scr) is a measure of muscle mass. Scr less than 1.0 is common in the elderly who are sedentary. In the presence of chronic kidney disease, the Scr is usually greater than 1.0. The best estimate ofr kidney function in the elderly is calculated using the Cockcroft-Gault equation. Cockcroft-Gault Equation CrClmen ¼ CrClwomen

ð140  AgeÞ  IBW Scr  72 ¼ CrClmen  0:85

**Rounding serum creatinine to 1.0 will give a conservative estimate of CrCl.

Failure to Thrive Thriving is dependent on the interplay of homeostatic mechanisms that balance energy expenditure and expense in the changing internal environment as aging progresses. Immunosenescence and diminished physiologic reserve set the stage for the development of clinical frailty [15, 16]. Frailty is an important predictor of adverse outcomes. The phenotype of frailty includes five characteristics: (1) unintentional weight loss, (2) physical weakness, (3) slowed gait, (4) exhaustion, and (5) low level or avoidance of activity [16]. The pervasive biological feature of aging and frailty is the presence of a chronic, mild proinflammatory state demonstrated by interleuken-6 and TNF- α [16, 17]. Geriatric experts agree that frailty should be considered a medical syndrome characterized by decreased physiologic reserve and impaired ability to respond to stressors. Reduced physiologic function, strength, and endurance increase vulnerability for developing dependency and dying of otherwise nonfatal events [16, 17]. Resting metabolic rate (RMR) is the energy required to maintain structural and functional homeostasis at rest, in fasting and neutral conditions. RMR accounts for 60–70% of the total daily energy expenditure [16]. In older adults, higher RMR is an independent risk factor for mortality and a predictor of greater burden of chronic disease [18].

4

Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership

Protein Malnutrition Oral health, stamina for chewing, transport swallowing disorders, dry buccal mucosa, and tooth loss are common challenges in maintaining adequate nutrition. Limb circumference, unintentional weight loss, and reduction in prealbumin and albumin levels are predictive of protein energy malnutrition [19]. Insufficient protein stores, particularly albumin, lead to risk of drug toxicity, especially in highly protein-bound agents such as warfarin and some anticonvulsants [20].

Role of Prealbumin in Tube Feeding Decisions Obtaining the prealbumin measurement is vital to determining the ability to absorb nutrient and in turn, the efficacy of supplemental feeding with tube insertion [21]. The average half-life of albumin is approximately 21 days [22]. The half-life of prealbumin is much shorter at 48–72 hours [20]. Prealbumin should be measured prior to initiating feeding tube insertion and reassessed twice weekly thereafter [22]. If the patient is able to absorb nutrient, the prealbumin will begin to rise within 4–8 days [22]. The use of prealbumin measurements is especially useful in clinical decision-making during terminal malnutrition to assure that no harm is associated with the discontinuation of feeding. Frail older adults suffering from malnutrition are at risk of developing Refeeding Syndrome after a period of fasting or severely diminished intake for more than 7–10 days [23]. Refeeding Syndrome results in potentially fatal shifts in fluid and electrolytes in both enteral and parenteral delivery of nutrition. These shifts result from hormonal and metabolic changes that may cause lifethreatening electrolyte imbalances [23]. Keen awareness of impending hypophosphatemia and hyponatremia are essential to detecting the onset of Refeeding Syndrome.

Wound Healing In addition to careful assessment for protein malnutrition, surgical patients benefit from extra

59

nutritional support to enhance the tissue generation cascade [24]. Low albumin is particularly associated with the development of decubitus ulcers and contributes to poor healing due to decreased stability of the collagen cascade necessary for wound healing [25]. When oral intake of nutrients is not sufficient, dietary supplementation is an important consideration. Multivitamins are not usually indicated for older adults. They typically do not contain sufficient quantities of any one property to address the clinical needs of specific deficiencies. Targeted therapy with individual vitamins and minerals is recommended [26]. Providing 30–35 kcal/kg and 1.25–1.5 g/kg of calories and protein daily has been shown to improve pressure ulcer healing significantly [24].

Herbal Supplements Many adverse interactions are possible when prescription and nonprescription remedies are taken concurrently. An estimated 40% of older adults consume approximately 40% of all over-thecounter medications in the USA [8]. Approximately 46% of older adults take OTC medications in combination with regularly prescribed medications [8]. Of those, 1 of every 25 are at risk for significant adverse interactions [7]. Herbal products are not subject to established quality control regulations. Potency is dependent upon the timing of harvesting, light exposure, temperature, and postharvest handling practices. Large variations within any brand of product occurs between manufacturer batches. Consumers may match lot numbers for consistent product identification; however, they are highly variable even when they are included in the packaging. Many consumers do not recognize herbal supplements and foods as medications and therefore are not aware that they can have significant side effects. Because they are “natural” does not mean they are safe. In one survey, more than 75% of respondents stated they did not inform their health care provider of these practices [27]. The weakness of the standard “Brown Bag” practice in Primary Care is that it requires patients to bring all medications to the visit rather than

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J. Hoffman-Simen and T. Meyer

requesting patients bring everything they take including all OTC medications, herbals, supplements, vitamins, and minerals [28]. Patient education must include advice to notify the healthcare provider of any herbal products ingested and to report any adverse effects promptly to the provider and the manufacturer.

Adverse Drug Reactions in the Elderly Any symptom in an elderly patient should be considered a drug side effect until proven otherwise. [29]

Each year more than nine million adverse drug reactions occur in older Americans [3]. For example, 32,000 older adults suffer hip fractures each year from falls due to medication-related problems [30]. Moreover, older adults, taking three or more chronic medications, have a 33% risk of rehospitalization within 6 months of discharge, with 20% of those readmissions due to Medication Related Problems (MRP) [3]. MRPs are defined as undesirable events experienced by a patient that involve or are suspected to involve drug therapy, and actually or potentially interfere with a desired patient outcome. Common examples of MRPs include (a) medical conditions that require new or additional drug therapy, (b) ineffective or inappropriate drug for the medical condition, (c) correct medication selection but inappropriate dose, (d) adverse drug reaction, (e) patient noncompliance, and (f) unnecessary medication given the present condition.

Polypharmacy and the Prescribing Cascade According to the Centers for Disease Control and Prevention (CDC), 90.8% of adults aged 65 and over took at least one prescription medication in the past month. Further evidence from the CDC illustrated that use of one prescription by adults over aged 65 years increased 17.2 percentage points in 2013–2014 when compared to the period

spanning 1988–1994. Furthermore, the CDC statistics demonstrated medication use among adults aged 65 and over, who were taking five or more prescriptions, increased 28.4 percentage points [8]. The majority of researchers applied five or more prescribed medications as the threshold in defining polypharmacy [1–3, 6]. There are a multitude of factors associated with polypharmacy in older adults, particularly the progression of a large range of comorbid chronic disease states. Polypharmacy factors related to the health care system involve increased life expectancy, development of new therapies and technologies, and increased use of preventive strategies [31]. Factors related specifically to patients are demographics, clinical conditions, socioeconomic considerations, behavioral and cultural influences, and specific medical therapies contribute to the risk of polypharmacy. Prescribers are also implicated in the risk stratification of polypharmacy. Treatment guidelines influence decision-making and may not be appropriate for aged persons. Prescribing behaviors may become habituated and fail to take aging considerations into account [32]. The patientprescriber interaction can never be discounted as a vital component to effective communication and collaboration around treatment decisions. When medications are contemplated for an older individual, prescribers are advised to first consider if the observable symptoms are adverse effects of a medication. A Prescribing Cascade is said to occur when an adverse drug reaction (ADR) is mistaken for a new medical condition and a subsequent additional medication is prescribed to treat that ADR [33]. This can lead to a plethora of inappropriate prescribing and unintended harms to the patient. The geriatric population is particularly vulnerable given age-related changes in pharmacokinetics and pharmacodynamics, copious comorbidities, and the high prevalence of polypharmacy [3, 33, 34]. In the example provided (Fig. 1), the resulting hallucinations from inappropriate prescribing likely lead to the continued cascade of additional medications to manage serious clinical complications.

4

Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership

First Drug Prescribed

61

• Angiotensin converting enzyme inhibitor (ACE-I) prescribed for hypertension

ADRs identified as a new medical condition

• Hyperkalemia and dry cough

New medications (Drug 2,3) prescribed to treat ADR

• Guaifenesin with dextromethorphan

Increased polypharmacy, increased risk of new ADRs

•Hallucinations

Fig. 1 Example of a prescribing cascade

Deprescribing Deprescribing is not about denying effective treatment to eligible patients. It is a positive, patientcentered intervention, with inherent uncertainties, and requires shared decision making, informed patient consent, and close monitoring of effect. [35]

The principles of deprescribing are rooted in identifying medications for dose reduction or discontinuation that are at risk to cause potentially more harm than benefit. Each medication is assessed in a systematic approach to align with the individual patient’s needs for quality of life goals, level of care and function, values, preferences, and life expectancy [35, 36]. Several algorithms have been validated and identified in the literature for deprescribing. The Deprescribing Protocol (Fig. 2) is a five-step process as part of the continuum of prescribing medications [35]. The deprescribing algorithm from the Good Palliative-Geriatric Practice (GPGP) [37, 38] (Fig. 3) is useful in the care of terminally ill persons, and frail elders, and when assessing individual medications for possible discontinuation of therapy. The STOPPFrail Criteria [39] (Fig. 4) process was designed in Europe to assist

medical providers with a structure for deprescribing. The STOPPFrail method is comprised of 27 criteria targeting the most potentially inappropriate medication for the frail elder with limited life expectancy in any healthcare setting [39].

Special Considerations for Persons Over 80 Years Old The over 80-year-old population continues to grow at a rapid pace worldwide yet remains underrepresented in clinical medication trials. Information and guidance for prescribers is lacking in every field of specialization. The scant research renders prescribers blind in foretelling the effects of many therapeutic agents. Expectations of drug actions observed in younger adults cannot be extrapolated to predict outcomes in the elderly due to aging principles and characteristics. While deep and visceral pain perception is often blunted due to loss of integrity in pain receptors and slowed pain transmission on afferent tracks within the spinal cord, there are no age-related changes observed in the peripheral free nerve endings [40]. Hence, older adults

62

J. Hoffman-Simen and T. Meyer

Fig. 2 Deprescribing steps and process

may not appreciate pain from ischemic heart or vascular disease but often complain of increased pain in joints, muscles, and skin. Pain management warrants special consideration and ongoing assessment for cautious prescribing. Experts agree that pain is undertreated, especially in the nursing home population. Persons with dementia may present with agitation due to pain; however, due to dysphasia and loss of language function, they are unable to express their needs. A trial of analgesia for agitation may be considered. The use of nonsteroidal antiinflammatory medications are discouraged due to gastrointestinal effects and interactions with anticoagulants. Acetaminophen is usually preferred.

Opiates have a place in managing pain as with all other patient populations and are often appropriate for short-term and targeted treatment. Careful prophylaxis against constipation and prevention of falls are critically important. Considerations for life expectancy and quality of life take precedence over concerns for maximum dose and dependence.

Deprescribing During Common Chronic Disease States The literature is inconclusive regarding the need for tight control of blood pressure in older persons. The effects of orthostasis due to decreased

4

Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership

63

Fig. 3 Alogirithim for Deprescribing. (Adapted from Deprescribing algorithm GPGP 2007 [3]; Adapted from Modified variation GPGP 2016 [4]

vascular compliance (increased afterload and peripheral resistance) commonly lead to decreased perfusion and dizziness despite elevations in blood pressure readings. Some experts suggest that slight elevations in blood pressure are an advantage to combat fall risk due to dizziness as well as to support cognitive function with increased perfusion. As persons age, antihypertensive agents may be selectively deprescribed when dizziness and syncope are a concern [41]. Treatment for hyperlipemia is less significant as people age. The goal of antilipidemic therapy is to prevent adverse cardiovascular events and achieve an old age. Life expectancy of less than 7–10 years should prompt an evaluation for deprescribing of antilipidemic agents. In addition to life expectancy, risk versus benefit assessment should include antilipidemic medication side effects, cost, drug interactions, and quality of life. In the event that antilipidemic medication is deemed beneficial, reduction in dosing may be appropriate in consideration of managing dosedependent side effects [42]. Among persons over the age of 65, the prevalence of diabetes was 26.8% [43]. Approximately 90% of affected persons have type 2 diabetes

mellitus [44]. Reasonable A1c goals range from 7.5% in healthy older adults with more than 10 years of life expectancy to 8.5% in older adults with poor health due to complex comorbid conditions [44]. A1c measurement two to four times a year is sufficient. Once adequate control is achieved, A1c measure twice a year is appropriate [44]. Random blood glucose testing by finger sticks in nursing home residents and frail older adults should be limited, unless an observable urgent clinical indication arises such as hypoglycemia, infection, or changes in condition from baseline that may suggest severe hyperglycemia. Insulin delivery by sliding scale is rarely indicated in older persons due to the heightened risk of hypoglycemic events [44].

Case Presentation A 79-year-old female was admitted to the acute psychiatric unit for paranoid delusions, insomnia, Major Depressive Disorder (MDD), and Parkinson’s disease. She had a history of falls, hypothyroidism, and bilateral lower extremity lymphedema. The patient verbalized to staff members at the skilled nursing facility where she

64

Fig. 4 STOPP Criteria

J. Hoffman-Simen and T. Meyer

4

Geriatric Prescribing Principles and Interprofessional Healthcare Team Leadership

resides that “somebody wants to attack and rape me.” She became extremely unmanageable and not redirectable. Behaviors included the following: Suspicion, paranoia, impulsivity, aggression, and resistance to care. Confusion was constant and persistent. She believed that she was in Pennsylvania where her husband currently lives. The medical history was negative for suicidal ideation or attempts, mania, and emotional, physical, or sexual abuse. Upon transfer to the emergency room, it was determined that she was unable to maintain proper care and safety and therefore, was placed on a 72-hour hold and admitted to the acute psychiatric unit for safety and stabilization. Upon admission to the psychiatric unit, the patient appeared comfortable and in no apparent distress. She was alert and oriented to herself, to the place, and partially to the current time. Staff reported that she had been sleeping well (approximately, 7.5 h per night); however, the patient woke up in the middle of the night looking for her husband and sister. With redirection, she was able to go back to sleep. No major agitation or aggressive behaviors were reported. Her appetite was somewhat fair at approximately 60%. The patient denied suicidal or homicidal ideation and tolerated her medications well. Memory was somewhat limited; insight and judgment improved but remained limited. The patient was measured at 40 1000 tall and 119 lbs. Serum creatinine was 0.91 with an estimated creatinine clearance equal to 28.5 ml/min using Cockcroft-Gault equation. Current medications Medication

Dose

Levothyroxine (Synthroid) Divalproex (Depakote sprinkles)

75 mcg PO Hypothyroidism QAM 125 mg; two Mood stabilizer Hold if SBP 20 y

0.04 0.54

0.86

0.18j

0.85 0.54 5.55

1.51

1.21

6.2

0.29

1.06

0.43

0.11

1.6

> 70 y

Men: Actual intake by age group

Carbohydrate, selenium 6 - 10 manganese, magnesium, iron, B-vitaminsf Fiber plus same nutrients 3-5 as total grains Calcium, phosphorus, 3 vitamin D Calcium, vitamin Dh NA Calcium, saturated fatsi NA Protein, B-vitamins, iron, 5.5 - 7 magnesium, vitamin E, zinc, phosphorus, potassium, vitamin B12 Omega-3 fay acids 1.1 – 1.4

Vitamin C

Vitamin C, potassium, folate, flavonoids, fiber Anthocyanins

Seafoods high in omega-3 fay acids Nuts and Seeds Omega-3, -9 fay acids, vitamin E, magnesium Soybeank Phytosterols, protein Eggs Yolk – choline, vitamin A White – protein

Fluid milkg Cheese TOTAL PROTEIN

TOTAL DAIRY

Whole Grains

TOTAL GRAINS

Citrus Fruit

e

Berries and Melonse

TOTAL FRUIT

Orange vegetablesd Carotenoids

TOTAL VEGETABLES Vitamins A and C, folate, 2.5 – 3.5 magnesium, potassium, fiber Dark Green Lutein, zeaxanthin, folate, 0.2 – 0.4 vitamins E and K vegetables Red vegetablesd Lycopene, anthocyanins 0.8 – 1

Food category

Table 4 Intake by food category and age-gender based on NHANES 2015–2016 data

0.6 – 0.7

1.1 – 1.3

NA NA 5–6

3

3–4

5–7

NA

1.5 – 2

0.6 – 0.9

0.2 – 0.3

2–3

Recommended: Womenb

0.11 0.54

0.73

0.18

0.57 0.59 5.21

1.29

0.82

5.4

0.27

0.92

0.34

0.19

1.48

> 20 y

0.12j 0.56

1.03

0.12j

0.60 0.61 5.47

1.32

0.85

5.1

0.38

0.92

0.36

0.21

1.54

50-59 y

0.07j 0.52

0.62

0.21j

0.60 0.44 4.92

1.19

0.80

4.66

0.19

0.86

0.30

0.22

1.6

60-69 y

0.05 0.45

0.61

0.20j

0.59 0.47 4.14

1.22

0.88

5.12

0.34

1.08

0.36

0.13

1.28

> 70 y

Women: Actual intake by age group

256 C. J. Rollins and A. Verdell

Total intakes for a category are highlighted in gray. Light green highlighting indicates at least minimum adequate intake was achieved for the age-gender group; however, adequate intake does not necessarily correlate with the Dietary Guidelines for Americans (e.g., meeting recommendations for total grains does not meet Dietary Guidelines for Americans unless at least half of the intake is whole grains) Fruits, vegetables, and dairy are listed as cup equivalents per day. Grain and protein are listed as ounce equivalents per day NA not available, not currently tracked as a separate category with NHANES data, or not provided in the USDA Healthy U.S.-Style Eating Pattern as a separate intake recommendation; y years a Recommended intake for men is based on USDA Healthy U.S.-Style Eating Pattern intake ranges for 2000–2800 calories per day. Recommendations given as amounts per week in the Eating Pattern are listed here as average cup or ounce equivalents per day b Recommended intake for women is based on USDA Healthy U.S.-Style Eating Pattern intake ranges for 1600–2200 calories per day. Recommended USDA Healthy U.S.-Style Eating Pattern intake ranges for calories less than 1600 daily are not intended for adults. Recommendations given as amounts per week in the Eating Pattern are listed here as average cup or ounce equivalents per day c Vegetables provide carotenoid precursors of vitamin A, not preformed vitamin A d Tracked as a single intake group in NHANES; different major nutrient(s) and phytonutrients indicated by listing on separate lines under columns 1 (food category) and 2 (key nutrients and phytochemicals provided) but a single amount under recommended and intake columns e Tracked as a single intake group in NHANES; different major nutrient(s) and phytonutrients indicated by listing on separate lines under columns 1 (food category) and 2 (key nutrients and phytochemicals provided) but a single amount under recommended and intake columns f Fortified grains have the vitamins that were removed during processing added back, otherwise refined grains would be low in these nutrients g Fluid milk includes calcium fortified soymilk. Low-fat or fat-free milk is preferred to limit intake of saturated fats h Milk is not naturally high in vitamin D; however, nearly all commercially processed milk in the United States is voluntarily enriched with vitamin D, making it a significant source i Saturated fat is an undesirable component and intake should be limited to under 10% of calories in the diet j The relative standard error exceeds 30% for this estimate k Includes soybean products except calcium fortified soymilk (included under fluid milk). USDA Healthy U.S.-Style recommended intake ranges incorporate soybean with nuts and seeds, although NHANES data tracks soybean intake separately Compiled from references [15, 19, 20]

16 Nutrition in Older Adults 257

258

2015–2016 with recommended intakes based on the United States Department of Agriculture (USDA) Healthy U.S.-Style Eating Pattern [15, 19, 20]. Recommended intakes were not met by older people in most food categories, especially categories most associated with healthy diets. Analysis of NHANES 2013–2016 data by energy-specific recommendations for people 71 years of age and older indicated that the only major food category (vegetables, fruit, grains, milk/dairy, protein, and oils) in which over 50% of participants met recommendations was 52% of men for protein foods [16]. A healthy diet, regardless of age, requires a variety of foods. Each major food category in NHANES data represents food groups which are important sources of particular nutrients within the diet, as indicated in Table 4 [15, 19, 20]. Intake below recommended amounts in any food category increases chances that individual nutrients and food components required for a healthy diet and overall health maintenance are inadequate, thereby increasing risk of malnutrition, and potentially, certain cancers and chronic diseases. In contrast, intake of certain subcategories should be limited. For example, the dairy group is recognized as a major source of readily absorbed calcium in the diet but intake of cheese should be limited due to saturated fat content. Commercially processed milk, but not cheese, is also a source of vitamin D when fortified with cholecalciferol. Fortification is voluntarily, typically with 2–3 mcg (80–120 IU vitamin D) per 8 ounces, making it essential to read labels for vitamin D content of milk products. Fat content should be considered when assessing vitamin D content of a product because absorption of vitamin D is enhanced with the concurrent presence of fat in the GI tract, although some absorption occurs without fat [8]. Nutrients of public health concern (i.e., inadequate or excess intake is correlated with a particular adverse health condition or outcome) that are under-consumed by older people and all other Americans include dietary fiber, vitamin D, calcium, and potassium, while sodium, added sugars, and saturated fats are over-consumed [12]. Underconsumed nutrients not categorized as “nutrients of public health concern” include several vitamins

C. J. Rollins and A. Verdell

(i.e., A, C, E, and K), as well as magnesium and choline, plus vitamin B12 specifically in older adults [12, 14]. Lack of designation as a “public health concern” does not diminish the vital role of these nutrients in metabolic processes. Underconsumed nutrients have not changed substantially since the 2015 DGA review. Prevalence of inadequate intake for an age-gender category is defined as the percentage of the group with intakes below the median requirement (i.e., below EAR or AI) [6]. The 2015 DGA committee reported low intake of dietary fiber among older people, with intake at or below AI in 96% of men and 87% of women [14]. Daily dietary fiber intake of 17.4 g in men aged 60–69 years and 17.9 g for men 70 years and older was reported in NHANES 2017–2018; intake for women was 15.5 g and 16 g, respectively [18]. The AI for fiber in people 50 years of age and older is 30 g for men and 21 g for women [6, 7]. Increased intake of whole grains, fruits, and vegetables would improve fiber intake. Nutrient intake using NHANES 2009–2012 data was evaluated for food/beverage intake only and for total intake (food/beverage and supplements) in three age groups, including 19–50 years of age, 51–70 years, and 71 years or higher; only combined data for men and women were reported [21]. Supplement intake had a substantial effect on raising intake above the EAR for nutrients such as calcium and vitamins D and E, especially in participants 71 years of age and older. Under-consumption of vitamin D was particularly high with 94.6–95.5% of all adults with intake below EAR without supplements. Little improvement occurred over 6 years to NHANES 2015–2018. With supplements, the percentages below EAR improved but remained over 40% in men and over 30% in women. Table 5 summarizes data for vitamin D and other nutrients from these studies when 25% or more of at least one older age subgroup had intake below EAR or AI [21–23]. Like vitamin D, calcium intake below EAR was found in a large percentage of older people, particularly women and showed an alarming increase with aging in NHANES 2009–2012, as shown in Table 5 [21–23]. Average calcium intake reported in NHANES 2017–2018 was above the

16

Nutrition in Older Adults

259

Table 5 Percent of the study population below estimated average intake (EAR) or adequate intake (AI) from food and beverages only or from food, beverages, and supplements

Nutrienta Calcium Folate DFE Magnesium Potassiumd Riboflavin Selenium Thiamine Vitamin A Vitamin B6 Vitamin C Vitamin C, smokerse Vitamin D Vitamin E Vitamin Kd Zinc

NHANES 2009–2012b Men and women combined Age 51–70 y Age
71 y 51.4 (34.6) 72.9 (47.7) 10.6 (7.4) 17 (10.3) 51.3 (41.9) 68.6 (55.2) 2.6 (1.9) 5% in 1 mo (A, C, E) >7.5% in 3 mo (A, C, E) >10% in 6 mo (C, E) >20% in 1 year (C, E) BMI

Physical exam findings of muscle loss Moderate malnutrition Mild (A, C, E) Severe malnutrition Moderate (A) Severe (C, E) Fat mass Moderate malnutrition assessed by Mild fat loss (A, C, E) physical Severe malnutrition examination Moderate fat loss (A) Severe fat loss (C, E) Ascites/edema/ Moderate malnutrition fluid retention Mild (A, C, E) based on Severe malnutrition physical Moderate to severe (A) examination Severe (C, E) Muscle function Grip strength (e.g., grip Moderate malnutrition strength) Not applicable (A, C, E) Severe malnutrition Measurable reduction (A, C, E) Cause (etiologic criteria) Reduced food Moderate malnutrition intake or 7 days (A),
1 mo assimilation or (C),
3 mo (E) malabsorption Severe malnutrition 50% of ER for
5 days (A), 75% of ER for
1 mo (C), 50% of ER for
1 mo (E) Muscle mass; lean or fat-free mass

GLIMb

MNA-FFc

SGAd

Moderate malnutrition 5–10% in 6 mo, or 10–20% in >6 mo Severe malnutrition >10% in 6 mo, or >20% in >6 mo

Loss in past 3 mo >3 kg (6.6 lb) (0) does not know (1) 1–3 kg (2.2–6.6 lb) (2) none (3)

Non-fluid change in 6 mo with amount of 10% noted Change in past 2 weeks graded as increased, no change, or decreased

Moderate malnutrition 80 years of age [32]. Apixaban has the safest bleeding profile among the DOACs. Its rate of intracranial hemorrhage is 0.33%per year in the apixaban group compared to 0.5% in the rivaroxaban study although Rocket AF enrolled a sicker population with a high CHADSVASC score. The recommended dose is 5 mg twice a day. However, 2.5 mg bid dose should be used if two out of three criteria are met: age
80 years, body weight 60 kg, or serum creatinine
1.5 mg/day. It is not recommended in patients with CrCl less than 15 ml/min or on dialysis. Edoxaban is the most recent factor X A inhibitor approved for stroke and systemic thromboembolism prevention in AF. Approved dose is 60 mg daily, but a lower dose of 30 mg should be used if one of the following is present: estimated

I. Onuorah et al.

creatinine clearance between 30 and 50 ml, weight of 60 kg, or the concomitant use of verapamil, dronedarone, or quinidine. Nonpharmacological stroke prevention: Left atrial appendage occlusion devices may be considered in selected elderly AF patients, who are not candidates for lifelong oral anticoagulation. However, there is limited RCT data in the geriatric population. Atrial Flutter Treatment management is similar to atrial fibrillation except that it is easier to treat with curative ablation therapy. There is no difference in the success or complication rate in patients
65 years treated with radiofrequency ablation compared to their younger counterpart [33]. There is a high risk of subsequent atrial fibrillation post RFA [33]. Discontinuation of anticoagulation in high stroke risk patients should be avoided. AV Reentrant (Accessory Pathway), AV Node Reentrant, and Atrial Tachycardia AV node reentrant tachycardia and AV reentrant (accessory pathway mediated) tachycardia tend to present earlier in life and are likely to be diagnosed in younger patients. High risk/malignant accessory pathways generally manifest earlier and are treated successfully with ablation procedure. Therefore, it is uncommon for these arrhythmia to present for the first time in the older adult population. In addition, there is less arrhythmic cardiomyopathy and less presentation with rapid ventricular rates due to age-related slower conduction of the AV node and accessory pathways. Asymptomatic older patients with preexcitation on EKG do not require electrophysiology study and/or ablation. AV nodal agents, i.e., beta-blockers and calcium channel blockers, are first-line treatment in AV nodal reentrant SVT but should be avoided in accessory pathway-mediated (preexisted) SVT. Atrial tachycardia is common in the elderly and accounts for about 23% of SVT seen in patients above the age of 70 years. Management can be either pharmacologic with beta-blockers, calcium channel blockers, or antiarrhythmic drugs. Catheter ablation may be preferred given its high

19

Management of Cardiovascular Disease in the Elderly

success rate; however, studies in the older adult population are limited. Atrial tachycardia carries a lower risk of systemic embolization in the absence of coexisting atrial fibrillation/flutter; chronic oral anticoagulation is usually not necessary.

Bradyarrhythmia There is age-related conduction system dysfunction with increased atrial refractory period. In Cardiovascular Health Study, the incidence of bradycardia is higher with aging in older men compared to women. The highest incidence was in 80+ years [34]. Sinus node dysfunction/sick sinus syndrome is commonly diagnosed in the seventh and eighth decade of life. Patient presents with symptoms of inadequate tissue perfusion and chronotropic incompetence, i.e., exertional intolerance, dizziness/syncope, chest pain, and sudden cardiac death. Pharmacologic treatment of tachyarrhythmia may decrease AV conduction and require pacemaker. Advancing age is a risk factor for development of bundle branch block. There is more right bundle branch block compared to left bundle branch block and bifascicular block with higher predilection in males compared to women and with pulmonary disease [35, 36]. Left bundle branch block is associated with less cardiovascular disease-free survival, hypertension, ischemic heart disease, and development of heart failure. Treatment of high bradyarrhythmia and highgrade AV block is usually pacemaker placement for symptomatic individuals. The incidence of pacemaker implantation did increase over the past decade [3], with average mean age at implantation of 75 years [37] and higher comorbidities [38]. Dual chamber pacemaker placement can improve quality of life and functional status in the older adult patients but requires longer procedure time and is associated with higher procedurerelated complications compared to a single lead pacemaker [39]. The risk of cardiac perforation and pericardial effusion especially in older female patients was estimated around 1.5% and 1.6% [39]. The estimated risk of endovascular lead infection risk is around 1.6%, and it is associated

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with significant mortality and prolonged hospital stays [40]. This risk may mitigate with leadless pacemaker; in addition, the risk of pneumothorax and pocket hematoma are much less [41, 42] making it suitable in certain elderly patients who meet indications for single chamber pacing. AV pacing has a better hemodynamic effect when compared to apical RV pacing; however, there is limited data regarding its use in the elderly population [43].

Ventricular Arrhythmias and Sudden Cardiac Death The most common etiology for ventricular arrhythmia and sudden cardiac death in older adult are ischemic heart disease and heart failure. Ablation procedure may be considered in selected older adults with reasonable functional capacity. Older adults referred for VT catheter ablation are more likely to have a lower ventricular ejection fraction, frequent procedural complication, but comparable survival rate compared to younger cohorts [44]. Numerous trials have demonstrated survival benefit of implantable cardioverter-defibrillator (ICD) in VT-aborted SCD, but few of these trials included patients
75 years of age. The pooled data from the different RCTs have been conflicting about survival benefit in older adult patients. Data from the national cardiovascular data registry ICD from 2006 to 2009 showed that among older adult patients who received ICD therapy for secondary prevention, four of five patients were alive 2 years later [45]. Baseline left ventricular ejection fraction less than 20% and renal dysfunction were the strongest predictor of outcomes after ICD implantation [46, 47]. Therefore, age should not be the main criterion for ICD implantation, rather other competing noncardiovascular disease, life expectancy, functional capacity, and patient wishes. Patient with life expectancy less than 12 months, or end-stage heart failure and not a candidate for advanced heart failure therapy, should not be offered ICD implantation. For patients at end of life or with terminal illness, it is reasonable to deactivate ICD. ICD discharge at end of life can be distressing and

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cause unnecessary suffering. It is estimated that 24–33% terminal patients are shocked within the last 24 h of life and 7–14% in the last hour of life [48, 49]. It is important to discuss this issue with patients and family, at time of initial device implantation or even during subsequent generator change. Advanced care planning and advance directives should include patient wishes for ICD management. Clinical Vignette Mr. H is a 75-year-old male with advanced COPD, atrial fibrillation on anticoagulation, history of long-standing nonischemic cardiomyopathy (EF of 15–20%), and recurrent CVA. He presents with acute left middle cerebral artery (MCA) stroke in setting of subtherapeutic INR. At baseline, he is bedbound, aphasic, and needs assistance with activities of daily living. His echocardiogram on admission is notable for left ventricular systolic EF of 15–20%, severely dilated left ventricle with moderate functional mitral regurgitation. EKG demonstrated atrial fibrillation. The neurology team is inquiring if he is an ICD candidate. Recommendation/intervention: Shared decision between family and medical team was initiated. Given frailty, poor prognosis, and much higher risk of dying from noncardiovascular cause such as respiratory failure from his advanced lung disease, ICD implantation for primary prevention was deemed inappropriate in this setting. In addition, he is at elevated risk for lead endocarditis and vascular complication with implantation. His neurological course stabilized, and he was discharged back to his nursing home.

Stable Ischemic Heart Disease and Acute Coronary Syndromes Introduction About 17.9 million people die each year from CVD worldwide with the majority of these deaths due to myocardial infarction [50]. In the United States, 18.2 million adults have CAD [3]. Advanced age is the strongest risk factor for

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CAD [51]. The lifetime risk of developing coronary disease is considerable; among the 60–79year age group, the incidence of diagnosed CAD is 19.7% in males and 12.6% in females. Men were 2.7 times more likely to already sustain a myocardial infarction in that age group compared to females (11.5% vs 4.2% [52]). However, by age >80+ years, about 31.0% and 25.4% of men and women, respectively, have CAD, and the incidence of myocardial infarction is almost equal in both sexes (17.3% vs 12.7%) [52, 53]. The average age for first myocardial infarction is 65.6 years in males and 72.0 years in females [52, 54]. Among those who die from CAD, 80% are aged 65 and older [55], and MI prognosis is worse in elderly compared to younger patients with in-hospital mortality between 6% and 8% [56, 57]. Each 10-year increase in age results in a 75% increase in in-hospital mortality [51]. In-hospitality mortality is higher in older women compared to men [58] and affects disproportionately non-Caucasians and lower economic status people [59, 60]. Despite advances made in the treatment of stable CAD and acute coronary syndromes over the years, older patients continue to remain at higher risk for poorer outcomes and are less likely to receive evidence-based care [61]. Several reasons include atypical presentations in the elderly, poor functional capacity and increased frailty, comorbidities, higher risk of bleeding, and renal dysfunction.

Pathophysiology of Myocardial Ischemia Symptomatic atherosclerotic CAD occurs because of multidecade coronary plaque deposition [62] and plaque rupture. The hallmark of acute coronary syndrome (ACS) is the sudden imbalance between myocardial oxygen consumption and demand. Complete occlusion without adequate collaterals results in acute ST segment elevation acute coronary syndrome (STEACS) and partial vessel occlusion or complete occlusion with reperfusion results in non-ST segment elevation acute coronary syndrome (NSTEACS). Increased myocardial demand from underlying

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conditions such as tachycardia, sepsis, hypoxia, and hypotension can also lead to ischemia or type 2 myocardial infarction [63].

Established Risk Factors for Atherosclerotic CAD Traditional risk factors for CAD include hypertension, dyslipidemia (see dyslipidemia chapter), metabolic syndrome/obesity, diabetes, cigarette smoking, CKD, sedentary lifestyle, and inflammatory disease. Certain risk factors lose their causal association with CAD or become attenuated with aging often related to comorbidities [64]. Cigarette smoking, obesity, and total cholesterol appear less important with increasing age although diabetes and hypertension remain a significant risk.

Clinical Presentation and Diagnosis Elderly patients are more likely to present with atypical ischemic symptoms. Ischemic symptoms are more often characterized by exertional fatigue, dyspnea, epigastric discomfort/GI symptoms and shoulder or back pain. Women are more likely to present with atypical symptoms. Typical chest pain is present in less than half of ischemic episodes [65]. Silent ischemia is also common. Consequently, many of these symptoms are difficult to differentiate from other chronic non-CAD diseases. Cognitive impairment with memory loss and dementia can make history taking challenging.

Spectrum of Coronary Artery Disease The most common presentation of coronary artery disease in men is MI (55%), followed by angina pectoris (30%) and sudden cardiac death (15%); however, in women, angina pectoris is most common (45%) followed by MI (40%) and sudden cardiac death (12%) [56]. Acute coronary syndromes range from unstable angina, non-ST elevation MI (NSTEACS or NSTEMI), and ST-Elevation MI (STEMI). Sixty percent of

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hospital admissions for acute coronary syndromes occur in patients > age 65 years of age [66]. NSTEACS is the most common presentation in older adults about 32–43% of ACS [66]. STEACS presentation accounts for about 24–28% in older adults. Older women are more likely to present with NSTEACS compared to older men given higher burden of other comorbidities such as atrial fibrillation, hypertension, heart failure, and renal insufficiency [67].

Stable Ischemic Heart Disease and Subclinical Atherosclerosis in Older Adults Older patients are more likely to have left main CAD and multivessel CAD [68]. Among patients 85 age cohort [62]. Significant coronary calcification (Agatston score >400) is frequent and is present in at least 36% of older adults [69]. High coronary calcium burden is independently associated with adverse cardiac events [69]. Testing for ischemia in patients of advanced age requires careful consideration of diagnostic utility as well as patient preferences and treatment goals. It is important to determine if a patient will be a candidate for further therapies if ischemia is identified. Functional stress testing is frequently the modality used for ischemia evaluation. Many older adults have limited exercise tolerance, and more likely to undergo pharmacological stress testing rather than exercise stress testing [70]. Pharmacological MPI can effectively risk stratified in older patients [71] although patients are more likely to be sicker at baseline and have more comorbidities. Invasive coronary angiography for SIHD may be appropriate in certain clinical circumstances such as survived sudden cardiac death, lifethreatening arrhythmias, or heart failure [72]. When contemplating cardiac catheterization, the risk of vascular complications, embolic events, neurological complications, and contrast-induced kidney injury should be evaluated [62], and correlated with patient goals of care.

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Acute Coronary Syndrome in Older Adult Patients Diagnosis Older adults with ACS are more likely to present with atypical symptoms; thus, hypervigilance is required [66]. Initial evaluation should include vital signs, EKG, and cardiac biomarkers. A 12-lead EKG should be obtained immediately on presentation as it serves as the first detection of STEACS, although interpretation can be limited in the setting of left bundle branch block and paced rhythm, common findings in the elderly. Cardiac troponin elevation of levels above the 99th percentile of the upper reference limit (URL) with evidence of ischemia (dynamic ST segment changes, development of pathologic Q waves) indicate myocardial infarction. It is important to perform serial cardiac troponins, as about 20% of elderly patients have elevated troponins at baseline due to abnormal renal clearance [73]. It is important to consider other causes of non-MI troponin elevation such as acute pulmonary embolism, acute aortitis, aortic dissection, rapid atrial fibrillation, decompensated heart failure, and sepsis. Risk Stratification The management strategy for ACS patients should be based on the risk of adverse cardiac events. Early invasive strategy is recommended in older patients with high-risk NSTEACS if risk of complication is modest [74]. Patients who are poor revascularization candidates based on functional, cognitive status and patient/family preferences should be managed conservatively [74]. Treatment Strategies Management of ACS in the geriatric population is comparable to the general population. Antiplatelet therapy and anti-ischemic drugs, i.e., betablockers, nitrate therapy, antithrombotic therapy, and/or invasive strategy when appropriate, must be instituted promptly. Adherence to guidelinerecommend therapies is associated with lower inhospitality in older patients [75]. Early discussion of risk and benefit is important, and clinical management is individualized for each elderly

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patient based on comorbidities, personal preference, and goals of care. Assessment of cognitive and functional status is paramount as these can interfere with the ability to adhere to prescribed regimens and the likelihood of recovery [62]. Psychiatric comorbidities such as depression and anxiety must be assessed as they can impart clinical outcomes [76]. Frailty is increasingly recognized as an important metric as its prevalence in older adult MI patients is as high as 50–60% [77, 78]. Frailty is a biological syndrome of decreased physiological reserve associated with increased vulnerability to stressors [79]. Frailty carries significant morbidity and mortality postacute coronary syndrome in older patients [80], and its presence should be used to guide treatment decisions. The Fried phenotype frailty tool is relatively simple to use and predict mortality and disability in communitydwelling elderly patients with CVD; evaluative criteria include unintentional weight loss, selfreported exhaustion, muscle weakness (grip strength), walking speed (15 ft), and physical activity [81]. A diagnosis of frailty is met when more than three out of the five criteria are met. Frail patients with limited cognitive and functional status are less likely to achieve meaningful recovery with aggressive intervention; in such patients, it is appropriate to institute palliative symptom relief and end-of-life discussions. Control of traditional risk factors such as weight management, dyslipidemia, hypertension, and other lifestyle measures are an important element of CAD treatment (see chapters on heart failure, dyslipidemia) and should be addressed in all cases. Older patients are less likely to receive such interventions compared to their younger counterpart, and this should be remedied [82].

Medications Guideline-directed medical treatment (GDMT) has proven survival benefit in older adults with ACS, regardless of coronary revascularization. However, age-related changes in renal function, total body water, hepatic perfusion, and body fat/muscle mass can result in altered drug pharmacokinetics, increasing the risk of drug-adverse effect [83, 84].

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Antithrombotic therapy is prescribed for both primary and secondary prevention of ischemic events. Antiplatelet and anticoagulant therapy reduces ischemic events in ACS patients but increases bleeding risk [85]. Major bleeding in ACS is associated with a 60% increase in in-hospital death and a fivefold increase in 1-year mortality [86]. Predictors of bleeding include age >75 years, anemia, renal dysfunction, diabetes, and female sex [85]. Aspirin reduces mortality in patients older than 70 years of age as well as younger CAD patients [63]. Clopidogrel is the most studied P2Y12 receptor inhibitor and is generally well tolerated. Prasugrel should not be used in elderly patients > age 75 years due to increased risk of fatal and intracranial bleeding. A reduced dose of 5 mg may be considered in older and low-weight patients, although clinical efficacy has not been established. Ticagrelor is more potent with superior clinical efficacy compared to clopidogrel. Major bleeding rates are clopidogrel except for slight increase in non-CABGrelated bleeding [87]. Routine use of upfront glycoprotein IIb/IIIa receptor inhibitors are no longer recommended in ACS management but can be used in conjunction with PCI if coronary thrombotic burden is high. Given the elevated bleeding risk in elderly patients, these drugs should be used with caution. Bleeding rates were two to three times greater in patients receiving the GPIIB/IIA inhibitor Eptifibatide in addition to standard therapy [88]. A shorter duration of dual antiplatelet therapy (DAPT) should be considered in older patients if feasible, because of hemorrhagic complications. The risk of intracranial hemorrhage is significantly higher in patients >75 years of age and is associated with 60% mortality within the first 30 days [89]. About 42% of NSTE ACS patients receive excess parenteral antithrombotic drugs which increases bleeding, hospital length of stay, and mortality [90]. About 3 out of 20 major bleeding events in ACS patients are attributed to excessive antithrombotic agent dosing [90]. Factors associated with excess doing include older age, female sex, lower body weight, and renal insufficiency.

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Prophylaxis with a proton pump inhibitor should be administered in older patients on DAPT to minimize the risk of gastrointestinal bleeding [91]. STATIN therapy: (see dyslipidemia chapter): Patients presenting with ACS should be placed on high-intensity statin. Antianginal agents: B-blockade reduces myocardial demand and ischemic symptoms and should be initiated in acute MI patients without cardiogenic shock. Beta-blockers have beneficial benefit on early mortality after MI especially in patients with depressed left ventricular function. Calcium channel blockers can be used in patients who do not tolerate beta-blockers, but there is no mortality benefit. Care should be taken to avoid use in patients with ejection fraction less than 35%. Nitrates can be used to relive angina but have no survival benefit.

Coronary Revascularization Strategies in Older Adults Older adults with ACS benefit from coronary revascularization but have higher incidence of complications. Therefore, management decisions regarding revascularization should be patientcentered with particular attention to patient’s preference, underlying comorbidities, and functional and cognitive status as well as overall life expectancy [74]. Radial access for coronary angiography rather than a femoral approach should be routinely used as it is associated with less vascular complication, lower incidence of stroke, improved patient comfort, and overall reduction in mortality [92]. CABG may be preferential in elderly patients who have three-vessel CAD with diabetes or left main disease. Although CABG provides full complete revascularization, less invasive percutaneous revascularization (PCI) should be considered in frail elderly patients who are often prone to higher perioperative complication such as stroke and neurocognitive decline [62]. These variables should be discussed with patients and caregivers. Recovery care following acute coronary syndrome: Delirium occurs often in older patients hospitalized for acute cardiac event [93] and can predispose to high rates of urinary catheters use,

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sedative administration, physical restraints, and long immobilization, all of which are detrimental and prolong recovery. Comprehensive multidisciplinary team discharge planning should be initiated as early as possible in the hospitalization. A systematic program emphasizing medication adherence, health care literacy and education, physical activity, psychosocial support, and lifestyle modification reduces ACS readmission and improves outcomes [62]. Cardiac rehabilitation should be recommended for older ACS and SIHD patients because of its cardiovascular benefits (improved exercise capacity, body mass index, and lipid levels). Additionally, it is associated with lower mortality [94], and benefit is present regardless of comorbidity status [95]. Despite strong convincing evidence and class 1A recommendation, older patients and women are less likely to be referred for cardiac rehabilitation after myocardial infarction [96]. Case Study Mrs. S, a 90-year-old female with history of hypertension, and metastatic lung cancer, and a remote history of smoking, presented after 5 days of epigastric pain for which she was self-treating at home with Maalox. On presentation, she had no ST elevation on EKG and her troponin peaked at 16 ng/ml. She was admitted with a diagnosis of Non-ST elevation MI. Echocardiogram showed EF of 35% with wall motion abnormalities. She reported resolution of her epigastric pain and was pain free throughout the hospitalization. Code status was discussed on admission, and patient made herself DNR/DNI. Intervention/discussion: Mrs. S. was initially treated with ACS medication (ASA, statin, and heparin). Oncology was consulted, and discussion of benefit and risk of cardiac catheterization was presented to patient and her daughter. Her expected life expectancy was considered to be less than 1 year. Her risk of major bleeding and vascular complications was high if she were to undergo cardiac catheterization and be placed on dual antiplatelet therapy afterward. The patient and her daughter decided to pursue conservative management with medical therapy and palliative

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care. She was discharged home and died with home hospice 8 months later.

Dyslipidemia Introduction A number of studies have demonstrated a linear positive correlation between elevated concentrations of low-density lipoprotein (LDL-C), total cholesterol (TC), and low levels of high-density lipoprotein cholesterol (HDL-C) with cardiovascular disease in the elderly. A National Heart Lung and Blood review of cholesterol in older persons suggests that total cholesterol is linked with fatal cardiovascular heart disease in both men and women including older adult patients. Treatment with lipid-lowering medications, specifically statins, are associated with cardiovascular mortality benefit across age groups. However, with advanced age, the risk of dying from noncardiovascular related disease such as cancer also increases. Therefore, the relative risk of CV-related mortality associated with dyslipidemia becomes attenuated with aging, but the absolute risk remains high. Compared to younger patients, older patients derive higher absolute risk reduction with lipid-lowering therapy. The number of patients needed to be treated to prevent a coronary event is therefore less at elderly age due to a higher absolute risk. The term dyslipidemia reflects disorders of both lipid and lipoprotein transport associated with arterial disease, more appropriately than hyperlipidemia [97]. The usual lipid profile often demonstrates low levels of high-density cholesterol, elevated triglyceride, and elevated lipoprotein concentration with elevated or normal total cholesterol. For the past two decades, a strong impact has been made on the management of dyslipidemia. According to NHANES data, there has been a reduction in the mean total and LDL cholesterol by 10 mg/dl and 13 mg/dl, respectively, from 1988–1994 data to 2007–2010 data in the United States. At the same time, the mean HDL has increased by 1.8 mg/dl [98]. These changes have

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been due to widespread use of statins. Statin therapy lowers cardiovascular events by 25–45% depending on the LDL-c reduction. Statin therapy in the elderly reduces all-cause mortality by 22% and cardiovascular mortality by 30% [97, 99]. Despite this fact, the use of statin therapy in older adults is not as prevalent compared to their younger counterparts. In the 2011 Medicare population database, statin use was 58.8% for highrisk individuals [100] who translate to less than half of the older adult high-risk population who are candidates for statin therapy not being prescribed statins. Additionally, few clinical trials have been done in older adults, especially in age groups greater than 75 years of age. Consequently, clinicians are extrapolating RCT data from a younger patient cohort to guide lipid therapy in the older adult patients. The choice to initiate statin therapy in elderly patients is often affected by age-related renal dysfunction and hepatic dysfunction, reduced muscle mass, polypharmacy and drug-drug interaction, frailty, and cognitive impairment. Treatment should also take into consideration patient preferences and life expectancy.

Pathophysiology There is higher prevalence of metabolic syndrome (MeTS) with aging, 45–55% at age 70 years and 60–70% at age
70 years [101]. Groups with a higher incidence of metabolic syndrome are commonly older women and Mexican American ethnicity. Metabolic syndrome is associated with elevated total cholesterol, triglycerides, and small dense LDL-C levels with decreased levels of HDL-C level. This lipoprotein profile is highly atherogenic and is a powerful risk factor for coronary artery disease [102]. Possible explanations for increased metabolic syndrome in the elderly include less caloric energy expenditure as a result of physical impairments, causing higher body mass index rather than increased caloric intake. Another explanation for increased metabolic syndrome in the elderly is increased diabetes prevalence as diabetes is associated with metabolic syndrome and lipoprotein abnormalities.

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Dyslipidemia Interventions in Elderly Adults Lifestyle Modification Lifestyle modification should be the initial approach in dyslipidemia management even in the elderly. Dietary modification in addition to increase in physical activity plays a vital role. The 2013 ACC/AHA cholesterol guideline recommends adherence to a dietary pattern that includes adequate intake of vegetables, fruits, and whole grains, and less saturated fats, sweets, sugar-sweetened beverages, and red meats. The DASH (dietary approaches to stop hypertension) and Mediterranean diets demonstrate CV benefits among other positive attributes. Adherence to the Mediterranean diet is shown to increase gut microbiome and is positively associated with improved physical vigor, cognitive function, and lower inflammatory markers (CRP and interleukin-17) among frail older adult patients [103]. Red yeast rice used in certain Chinese dishes contains monacolins K, which has similar mechanism of action to statins and has demonstrated a direct LDL-C and high-sensitivity CRP-lowering effect. An estimated reduction of 15–25% of plasma LDL-c levels can be seen within 6–8 weeks if red yeast rice is used daily [104]. Its effectiveness is directly related to the amount of monacolin K present in red yeast rice; doses of 2400 mg twice a day have same comparable LDL-C reduction compared to pravastatin 20 mg twice daily with better tolerability [105] When discussing dietary approaches, recommendation needs to be individualized to each patient as some elderly persons may be prone to malnutrition if excessive dietary recommendations are put into place. Another important element is physical activity. Older age is associated with more physical aliment and increased frailty thereby resulting in a sedentary lifestyle. Regular physical activity reduces VLDL levels, raises HDL-c levels, and slightly lowers LDL-c levels. Moderate intensity exercise for a minimum of 20–30 min per day at least three to five times a week is important as well as muscle strengthening exercise to increase

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muscle mass. Cardiac rehabilitation in older patients is beneficial and is associated with lower risk of death [106], and improved exercise capacity and quality of life. Cardiac rehabilitation is also valuable to help regain mobility, and physical strength, and improve frailty symptoms. Obesity is an independent major risk factor for CHD. Obesity is commonly associated with metabolic syndrome. Weight loss should be recommended for individuals with a BMI >30 kg/m2. Involvement of a dietary specialist can help facilitate an appropriate balanced diet to aid in weight loss. Smoking cessation is arguably the most important lifestyle change for CVD risk modification and should be emphasized in elderly patients still using tobacco products. It is estimated that 2.7 million older US adults actively use tobacco [107]. The incidence is higher in older men, people of lower socioeconomic status, and ethnic minority groups. Smoking is associated with excess mortality in older adults. Smoking cessation benefit is present in all age groups including adults 80 years and older [108]. Overall, lifestyle changes should be the firstline treatment for dyslipidemia. Combination of lifestyle changes and pharmacologic agents is needed in many elderly patients.

Statin Therapy Statins (3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors) are the most studied lipidlowering medication for cardiovascular disease. ACC/AHA guidelines recommend statins as the first-line therapy for prevention and treatment of ASCVD in older adult patients based on numerous RCTs demonstrating cardiovascular mortality benefit. However, there is limited clinical trial evidence in the extremes of age affecting its applicability in the very old. Addition of nonstatin therapies is recommended if more aggressive LDL lowering is required. In addition to its direct LDL-lowering effect, statin therapy has pleiotropic effects. Its protective effects on the vascular endothelium include reduction of thrombosis and platelet adhesion to the vascular endothelium; this in turn reduces

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vascular arterial inflammation and stabilizes vulnerable plaques. There is conflicting data on whether statins lower the risk of neurocognitive dysfunction and dementia in the elderly. Some early trials were positive [109], but subsequent trials have been negative. High-intensity statin Daily dosage lowers LDL approximately >50% on average Atorvastatin (Lipitor) 40 mg, 80 mg Rosuvastatin (Crestor) 20 mg, 40 mg

Moderate intensity Daily dosage lowers LDL-C approximately 30–50% on average Atorvastatin 10 mg, 20 mg Rosuvastatin 5 mg, 10 mg Simvastatin (Zocor) 20 mg, 40 mg Pravastatin (Pravachol) 40 mg, 80 mg Lovastatin (mevacor) 40 mg

Low intensity Daily dosage lowers LDL-c 65–75 years as these groups have been well represented in primary prevention trials. The mortality reduction outcome is similar to what is achieved in younger cohorts. A meta-analysis of statin and primary prevention in at-risk elderly subjects demonstrated statin therapy Significant reduction of MI by 39.4% and stroke risk by 23.8%, but did not translate to improved mortality benefit in the short term (mean follow-up of 3.5 years) [110]. Per the authors, the finding of this meta-analysis supports statin therapy use for high at-risk elderly patients older than 65 years of age, who are at least able to be on long-term therapy. The number needed to be

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treated to prevent one myocardial infarction or stroke at 1 year was 24 and 42, respectively. However, the recent cholesterol meta-analysis from the CTT group revealed less direct benefit of statin among patients >75 years without evidence of occlusive vascular disease [99]. Even though the relative risk reduction in patients older than 75 years was lower, the absolute risk reduction in major vascular events was 0.5% per year for every mmol/l reduction in LDL-c. Therefore, it is reasonable to initiate statin for primary prevention in older patients >75 years of age with elevated LDL-c provided that the adverse risk of statin therapy is low and there is willingness to take long-term treatment. The ongoing STAREE trial evaluating atorvastatin 40 mg for primary prevention in patients aged 70 years or older may shed more light on the issue [111]. Overall, there is a beneficial role of statins in primary prevention of myocardial infarction and stroke in elderly patients especially age less than 75 years of age; however, the benefit of statins decreases as the risk of noncardiovascular related mortality increases [110, 112]. Adherence to daily statin may also be challenging, especially in older adults with cognitive impairment. In one study, adherence to daily CV medications dropped from 74% at discharge to 38% 1 year later among patients >75 years, demonstrating how difficult it may be to be compliant with poly pharmacy [113]. Moreover, evidenced-based justification for statin uses in primary prevention in the very elderly (>75 years) is sparse as that age group is not well represented in clinical trials. Therefore, the decision for statin initiation for primary prevention should be done cautiously considering polypharmacy, comorbidity, and life expectancy. The decision to start statin therapy in patients >75 years of age should be shared decisionmaking based on clinical assessment of benefit over potential harm from therapy. Evaluation and Risk Assessment In adults who are free from ASCVD, traditional ASCVD risk factors should be assessed every 4–6 years. Several risk assessment algorithms have been proposed for estimation of 10-year cardiovascular risk. The Pooled Cohort Equations

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is the most representative algorithm in the United States as it is derived from community observational data that includes women and African Americans. In 2013, the American College of Cardiology (ACC) and American Heart Association (AHA) recommended using this risk assessment tool to inform decisions about statin therapy initiation. Gender AGE Race Total cholesterol HDL Systolic blood pressure Receiving treatment for high blood pressure (if SBP >120 mmHg) Diabetes Smoker

Because of the strong impact of age on the estimated 10-year risk for ASCVD, a higher proportion of elderly patients will become statin eligible at
75 years of age. Different studies have demonstrated that the current prediction risk models including PCE overestimate cardiovascular events in adults without preexisting atherosclerotic CVD [114, 115], with resultant consequence of overprescription of Statin and aspirin therapy in certain patients. The PCE can also underestimate risks in mature native American Indians, Asian Americans, and Spanish Americans. Caution should be exercised in using this risk stratification in very elderly patients (defined as >75 years of age) as scores have not been validated in this age group. In addition, it is important to incorporate risk-enhancing factors such as prior history preeclampsia, chronic inflammatory disease, premature menopause, metabolic syndrome, and chronic kidney disease. Statins in Secondary Prevention For secondary prevention in elderly patients, the use of statin has also demonstrated reduction in all-cause mortality and cardiovascular mortality. Statins were associated with reduction in coronary artery disease event by 30% and nonfatal myocardial infarction by 26% [116]. In addition, the number needed to treat to save one life was 1 in

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28 persons. Therefore, in patients 75 years of age or younger with clinical ASCVD, high-intensity statin therapy should be initiated or continued with the aim of achieving a 50% or greater reduction in LDL-c levels. In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate or high-intensity statin therapy after evaluation of ASCVD risk reduction, adverse effects, and drug interactions incorporating each patient’s frailty and preferences. If they are already tolerating high-intensity statins, it is reasonable to continue therapy [117]. The 2016 ESC/EAS guidelines management of dyslipidemia recommend treatment with statin for older adults with established CVD in the same way as for younger patients [118]. High-Risk Group The American College of Cardiology/American Heart Association task force on treatment of blood cholesterol in 2018 identified four high-risk groups that would benefit from statin from 20–75 years of age [117]. For patients less than 75 years of age, statin therapy is recommended in patients with clinical ASCVD, patients with LDL
190 mg/dl, patients with diabetes with LDL
70 mg/dl, and patients without diabetes, LDL
70 mg/dl, and ASCVD risk of
7.5%. After 75 years of age, recommendations were to individualize statin therapy based on ASCVD risk reduction benefits, potential for adverse effects and drug interactions, and patient preferences given the paucity of data in patients greater than age 75 years. Side Effects Associated with Statin Although rare, elderly patients are at higher risk for myopathy including rhabdomyolysis with high-intensity statin compared to younger patients. The overall rate of rhabdomyolysis on statin therapy is around 0.1% or 1 in 10,000 patients [119]. Risk factors for myopathy are greatest among elderly patients with coexisting renal insufficiency. With the exception of pravastatin and rosuvastatin, all available statins are metabolized by cytochrome P450. Concomitant use of medications that inhibit cytochrome P450 increases the

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risk of myopathy and myositis. Medications such as verapamil, amiodarone, and diltiazem frequently prescribed in elderly patients are metabolized by cytochrome P450. The doses of these medications may need to be adjusted. Another culprit is grapefruit juice, which contains CYP isoenzyme inhibitor; one quart of grapefruit juice a day can significantly inhibit cytochrome P450. Combination of statin with fibrate or niacin may also predispose to myopathy. Normally, myopathy and myositis resolve with discontinuation of these offending drugs and/or statin medication. There is also higher risk of statin-induced diabetes in older patients with metabolic syndrome. The rate is about one new case of diabetes per 1000 person years of treatment [120]. This risk is highest in women, advanced age, and higher statin dose [120, 121]. The absolute risk of statininduced diabetes is low compared to absolute risk CV reduction. Nevertheless, the development of diabetes often requires an additional medication, which may be problematic in elderly patients already on multiple medications. Elderly patients are at risk for developing insomnia, bad or vivid dreams, or difficulty concentrating with lipophilic statins, because these statins cross the blood-brain barrier [122]. Statins that are lipophilic include atorvastatin, lovastatin, and simvastatin. Alternative statin therapy such as pravastatin, rosuvastatin, or fluvastatin can be substituted; another alternative is to switch statin administration to earlier in the day.

Other Lipid-Lowering Agents (Nonstatin Drugs) Ezetimibe reduces LDL-c 15–20% by selectively inhabiting cholesterol absorption at the intestinal border [123]. Ezetimibe is the most frequently prescribed nonstatin drug, recommended for use in addition to statin therapy to achieve further reduction in LDL. It is not as clinically efficacious as statins in reducing cardiovascular events and should not be used as first-line monotherapy therapy. In individuals with STATIN-adverse effect, ezetimibe can be considered for monotherapy. In the IMPROVE-IT trial, ezetimibe combined with simvastatin had a favorable safety profile in highrisk individuals over the age of 65 years [124]. In

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the EWTOPIA trial, ezetimibe plus diet in moderate- to high-risk older patients was associated with a 44% reduction in cardiovascular event compared to diet alone [125]. Proprotein Convertase Subtillisin/Kexin type 9 (PCSK9) inhibitors: These are the most powerful LDL-c-lowering agents currently available. The two agents available in the US market are Evolocumab and Alirocumab, both administered as subcutaneous injection every 2–4 weeks. These drugs are humanized monoclonal antibodies and inactivate PCSK9 protein, an important regulator of LDL receptor degradation. As result, more LDL receptors are displayed on the liver cells leading to increased clearance of bloodstream cholesterol. A reduction in LDL-C occurs in a dose-dependent manner with reduction by as much as 70% alone and by 60% in patients already on statin therapy. Post hoc analysis of evolocumab and alirocumab trials show at least 50% reduction in LDL-c without significant safety concerns. Evolocumab demonstrated reduction in cardiovascular events in patients on maximally tolerated statin with LDL-C levels >70 mg/ml. The number needed to be treated with evolocumab to prevent one CV death in 2 years was 67 [126]. However, there is no specific cardiovascular mortality benefit with these drugs. PCSK9 inhibitors are reserved for patients who need further LDL-C reduction on maximal dose of STATIN and ezetimibe. The major drawback is cost. Annual cost of alirocumab ranges from $4500 to 8000 compared to ezetimibe annual cost of $304. It is estimated that alirocumab needs to cost $1974 annually to be cost-effective at $100,000 per quality-adjusted life year (QALY) compared to ezetimibe [127]. Inclisiran is a novel agent that works to suppress PCSK9 translation in the liver by using double stranded small-interfering RNA agent (RNAi). The ORION trials demonstrated an average of 50% reduction in LDL lowering when used on patients with ASCVD on maximally tolerated statin with LDL-C >70 mg/dl [128]. It is given as a subcutaneous injection twice a year unlike PCSK9 inhibitors that require frequent dosing with sustained reductions in LDL-C; it was well tolerated except for self-limiting injection site

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reactions and higher occurrence of mild to moderate bronchitis. It is currently FAD approved for use in patients with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents. Fibrates and gemfibrozil: These drugs primarily work on TG lowering and are not routinely recommended for LDL lowering. Fibrates and gemfibrozil work on lowering TG levels and have small incremental effect on HDL-C. These medications have minimal effect in LDL lowering and, when combined with statin, have higher risk of myopathy. There are very limited RCT studies in patients >65 years and no large trials in patients >75 years of age. Therefore, these drugs are primary used for treatment of severe hypertriglyceridemia. For patients with severe hypertriglyceridemia (TG levels >500 mg/dl), fenofibrate (preferred over gemfibrozil) or icosapent ethyl (Vascepa) is recommended [129]. Omega-3 fatty acids/n-3 polyunsaturated fatty acids PUFA (EPA and DHA): Prior observational data supported cardiovascular benefit of regular consumption of marine n-3 polyunsaturated fatty acid (PUFAs). It is thought that the cardiovascular benefit is primarily through its triglyceride- and inflammation-lowering effect [130]. Prior research trials such as the ACCORD and FIELD, focused on triglyceride reduction, have not translated to reduction in cardiovascular events [129]. Trials using low-dose mixture of EPA and DHA did not translate to positive outcome. The OMEMI trial examined the use of omega-3 fatty acid in older adults aged 70–82 years with recent acute myocardial infarction (ASCVD) already on background standard ASCVD therapy to ascertain if an addition of omega-3 will lead to reduction of subsequent cardiovascular events. Individuals were randomized to 1.8 g omega-3 fatty acids (930 mg EPA and 660 mg DHA) versus corn oil; there was no statistical reduction in primary composite end point of nonfatal MI, revascularization, stroke, all cause death, and heart failure hospitalization between the two groups. Moreover, atrial fibrillation occurrence was much higher in older individuals on omega-3 fatty acid [131].

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The REDUCE-IT trial is only one of the two positive outcome trials using purified EPA alone to address secondary prevention in ASCVD patients with persistent elevated triglycerides level >135 mg/dl and the first trial to include US patients. The first trial was JELIS, and it demonstrated 19% reduction in major coronary events in hypercholesterolemic Japanese patients treated with purified EPA compared to this placebo [132]. The REDUCE-IT trial enrolled patients with prior ASCVD with elevated triglyceride levels despite controlled baseline LDL-C on stable STATIN treatment [133]. The median age was 64 years. It is unclear the number of older adults >75 years enrolled in the trial. Individuals were placed on high-dose icosapent ethyl (Vascepa) 2 g twice a day versus mineral oil placebo. Of note, baseline EPA levels were also low at 26 ug/ml, which increased in the icosapent ethyl group. Treatment with icosapent ethyl was associated with 25% relative reduction of cardiovascular events and 8% absolute reduction [130]. The risk of atrial fibrillation was significantly higher in icosapent ethyl group as well as bleeding-related serious adverse effects compared to mineral oil placebo group. The proposed mechanism for purified EPA-associated CVD risk reduction is not clear; it is likely in addition to its triglyceridelowering effect; and it also has pleotropic antiinflammatory properties similar to STATINs. In the REDUCE-IT trial, there was notable decrease in the high-sensitivity C-reactive protein (HsCRP) among purified EPA-treated individuals. As a result, icosapent ethyl (Vascepa) is approved as adjunctive therapy in patients with ASCVD on good background statin therapy with elevated fasting triglyceride level. Care should be exercised in prescribing omega-3 fatty acid or its component in the elderly population given higher burden of atrial fibrillation associated with this therapy. Moreover, elderly patients are more likely have atrial fibrillation and life-threatening AF-related complication. Bempedoic acid is a new class of non-STATIN LDL-lowering agents. It is an inhibitor of the ATP citrate lyase, which is two steps ahead of the HMG CoA reductase [134]. Since it is a prodrug, it is

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broken down by the liver rather than in the skeletal muscle. As a result, its active metabolite is only present in the liver; this may be a good option for patients who have statin-induced myopathy/ myositis. The efficacy of bempedoic acid was evaluated in the CLEAR trials and has been associated with 17.4% reduction in LDL-c [135] and, when combined with ezetimibe (Zetia) in statinintolerant patients with established ASCVD, has significant LDL-C-lowering effect of 38% [136]. How much this LDL-C reduction effect translates into cardiovascular outcomes is still pending and will be addressed in the CLEAR-OUTCOME trial. Bempedoic acid is associated with hyperuricemia and gout symptoms. In addition, there is a higher risk of tendon rupture in patients >60 years of age. Currently bempedoic acid is only approved for LDL lowering in patients with heterozygous familial hypercholesterolemia (HeFH) or as an adjunct treatment in patients with established ASCVD on maximal tolerated statin therapy who require additional LDL reduction.

Lipid-Lowering Therapy and Frailty There is a high prevalence of frailty among patients with advanced atherosclerosis. Sarcopenia, which correlates with frailty, is associated with a higher incidence of arterial and vascular calcification. It is unclear if statin benefits are present in frail elderly patients as they are less likely to be enrolled in clinical trials. There is also a CHOLESTEROL PARADOX seen in frail patients who usually have lower cholesterol levels due to malnutrition and wasting, implying that cholesterol lowering may not be beneficial. Further clinical trial data is needed to evaluate statin use in this scenario.

Clinical Management Consideration/ Implication The majority of ASCVD-related events in elderly patients are nonfatal MI and stroke, and less likely fatal cardiovascular events. When deciding to

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initiate statin therapy, the focus should not be on longevity and survival but rather on preventing potentially disabling stroke and MI, which can affect quality of life. Statin therapy should not be initiated in older adults with limited life expectancy. It is estimated that it takes 5 years to realize the full benefit of statin therapy in primary prevention [137]. There is also concern for overtreatment with statins in some older adults using only the riskbased calculators. Thus, the challenge lies in identifying and avoiding statin therapy in low-risk adult patient even if their age alone qualifies them for statin therapy. One approach termed de-risking involves using negative risk factors such as absence of coronary calcifications or carotid plaque to identify those at low risk for ASCVD events [138], and not recommending statin therapy in that group. Absence of coronary artery calcification is associated with exceptionally low ASCVD event rates even in the elderly population [139, 140]. Using hydrophilic statins in elderly patients may be beneficial in reducing the neurological side effect and myopathic adverse event since these statins are less likely to cross the bloodbrain barrier and penetrate muscle tissue. It is also reasonable to start at a lower dose of statin, and if it is well tolerated, continue gradual up-titration until target LDL-C is achieved. The highest dose of statin should be used with caution in the elderly. Statins are not significantly associated with progressive cognitive decline. Prior observational study had suggested protective effect of statin therapy on dementia. A pooled result of 23,443 patients on statin therapy showed no significant difference in cognitive function in the short term; however, there was a 29% reduction in incident dementia in statin-treated patients [141]. There are also cost issues given many elderly patients are on limited income and already taking other medications. Atorvastatin, rosuvastatin, simvastatin, lovastatin, and pravastatin are generic and may be an option for some patients if cost becomes an issue.

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Clinical Vignette Mr. J. is a 75-year-old Caucasian male with history of controlled hypertension on amlodipine of 10 mg daily; office systolic blood pressure was 120/80 and generally runs less than 120. He denied history of diabetes, ASCVD, or tobacco usage. He exercises 30 mins a day without limitation. He had a lipid panel at his primary care office part of routine visit, demonstrating total chol 200 mg/dl, HDL of 60 mg/dl, and LDL140 mg/dl. His ASCVD risk was 22.3% for developing heart disease or stroke over the next 10 years. His PCP recommended statin therapy, but he is very hesitant to initiate therapy after reading about the risk of diabetes and cognitive function decline on the Internet. He is in clinic for a second opinion regarding statin therapy. Discussion: Since the reason for statin therapy is for primary prevention and the PCE (pooled cohort) equation can overestimate risks in older at-risk patients, it is reasonable to refer him for a coronary calcium scan. In addition, Mr. J would like to avoid future stroke or MI events since he is extremely functional. He underwent coronary calcium scan, and his total coronary calcium score was 400. He was reassured his absolute risk of statin-induced diabetes is very low compared to CV reduction he would gain on statin therapy given high coronary calcium score. Mr. J. agreed to statin therapy and started a lower dose of rosuvastatin with plan to gradual titrate up to goal LDL-c and patient’s tolerability.

Heart Failure with Preserved Ejection Fraction Introduction Prevalence of heart failure has increased in the past decades. It is estimated that by 2030, 8 million Americans will have heart failure, a projected increase of 46% [52]. Multiple factors driving the increased incidence of heart failure include the aging population and increased incidence of traditional risk factors such as hypertension,

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diabetes, and chronic kidney disease. About 72 million US adults have traditional risk factors for heart failure [142]. As a result, heart failure will continue to be a substantial growing public health burden [143]. Heart failure correlates with advanced age. NHANES data show a prevalence of 6.9% and 4.8% in men and women, respectively, in the age group 60–79 years. However, the percentage of older adults with HF doubles in the >80 years age group to about 12.8% in men and 12.0% in women [52] (Fig. 1). HFpEF patients are more likely to be older, female, and have a greater prevalence of hypertension, obesity, and anemia [144]. Older women compromise about 80% of new diagnosis of HFpEF [145]. In hospital, mortality in HFpEF ranges from 2.4% to 4.9% in observational studies and increases up to 5% in 30 days and 9.5% in 60–90 days. At 1 year, mortality is 20–29% [143]. By 5 years, at least half of patients with HFpEF have died, with mortality ranging from 53% to 74%; survival is much worse compared to HFrEF which has effective therapies [145–147]. The risk of death increases with comorbidity burden. Renal dysfunction, chronic obstructive pulmonary

disease, impaired cognition, reduced mobility, and disability are common in HF patients and are associated with higher rates of mortality [148, 149]. Hospitalization is common in patients with HFpEF. Within 30 days of hospital discharge, 20% of HFpEF patients are readmitted, and within 1 year >50% [150]. The majority (60%) of hospitalizations are due to noncardiovascular reasons, with the most common reasons being respiratory etiology in some studies [147]. Patients with HFpEF have poorer quality of life and higher symptom burden than HFrEF. Almost half of the patients in the TOPCAT trial (spironolactone in HFpEF patients) reported poor quality of life [151]. Adults with low scores on health-related quality-of-life questionnaires often have limited functional capacity and multiple chronic conditions. Poor quality-of-life scores are associated with higher mortality [152].

Definition and Diagnosis Heart failure is defined as a complex clinical syndrome that arises from structural or functional

PREVALANCE OF AORTIC STENOSIS BASED ON AGE GROUP 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% 50-59 yrs.

60-69 yrs.

70-79 yrs.

Prevalance of aortic stenosis based on age group

Fig. 1 Age-stratified prevalence of Aortic Stenosis

80-89

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impairment of ventricular filling or ejection of blood [153]. Exertional dyspnea, fatigue, and poor exercise tolerance are the most common symptom presentations of HFpEF. Orthopnea and paroxysmal nocturnal dyspnea are not as frequent and may be seen in other nonheart failure disorders such as pulmonary disease, deconditioning, and depression [154]. Functional impairment because of arthritis or visual or hearing loss may mask the development of dyspnea or fatigue, delaying diagnosis. Even though the left ventricular ejection fraction for defining HFpEF has varied in the past, the ACC/AHA/HFSA established cutoff is EF to >50%. Patients with EF between 41% and 49% are classified as midrange EF [155]. Diagnosis is clinical, but cardiac imaging is an important part of the evaluation. Unlike in HFrEF patient where echocardiography is the definitive test, in HFpEF patients, it provides supportive findings. Supportive echocardiographic findings are largely based on evidence of diastolic dysfunction, i.e., concentric left ventricular hypertrophy, left atrial dilation, abnormal left ventricular filling pressures, or relaxation. Of note, diastolic abnormalities in the absence of heart failure are common; an estimated 70% of patients >75 years will have some diastolic dysfunction on cardiac imagining [156]. Hence, the ACC-/AHA-/HFSAproposed list of HFpEF syndrome criteria include a) presence of clinical signs or symptoms of HF; b) evidence of preserved or normal LVEF; and C) evidence of abnormal LV diastolic dysfunction [155]. Atrial natriuretic peptide such as B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) is often elevated in HFrEF patients but may be slightly elevated or normal in patients with HFpEF. Elevation of BNP or NT-ProBNP can also occur in patients without heart failure, largely due to renal dysfunction and poor renal clearance. Natriuretic peptide levels are inversely related to BMI; this is particularly important since obesity is very common among patients with HFpEF. A significant portion of obese patients admitted with acute decompensated HF have BNP/NT-pro BNP levels that are below or mildly higher than the diagnostic cutoff level [148, 157].

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In addition, aging affects BNP level independent of clinical heart failure symptoms. Exercise stress testing or provocative invasive hemodynamic testing may be needed in patients with only exertional symptoms but normal or indeterminate Doppler echocardiographic parameters at rest, since many patients with HFpEF only display elevated LV filling pressures during exercise [158].

HFpEF and Multimorbidity The typical phenotype for HFpEF patient includes older women with history of hypertension, diabetes, obesity, and/or obstructive sleep apnea. In general, HFpEF patients have five times more comorbidities compared to HFrEF patients [159]. Commonly associated comorbidities include obesity, HTN, COPD, anemia, diabetes, CKD, frailty, cognitive dysfunction, dementia, cerebrovascular disease, and peripheral arterial disease [145]. Hypertension is a major significant risk factor and present in a majority of HFpEF patients. Numerous trials have demonstrated that control of hypertension is beneficial in older patients. The SPRINT trial showed lowering of systolic blood pressure to less than 120 mmHg was associated with 38% reduction in heart failure development and 43% reduction in cardiovascular death [160]. This benefit was consistent across age groups including patients >75 years of age.

Treatment HFpEF is a heterogeneous syndrome with multiple etiologies and comorbidities. Consequently, there are no unifying pathophysiological alterations in patients with HFpEF, and therapeutic options have largely been based on treating specific underlying etiologies such as atrial fibrillation, CAD, obesity, CKD, sleep apnea, and diabetes. Until recently, no studies have demonstrated benefit in HFpEF patients. The general clinical management includes optimization of systolic blood pressure to less than 130 mmHg, diuresis for fluid removal and symptom relief, and dietary and lifestyle modifications.

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Pharmacological Treatment for Symptomatic HFpEF (See Update) Diuretics can be used for symptom relief due to volume overload. Lowest dose of diuretics should be utilized to minimize the risk of orthostatic hypotension, falls, and syncope because of impaired left ventricular filling and cardiac stroke volume. Nonsteroidal anti-inflammatory medications can increase diuretic resistance and should be discontinued if possible. Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: Candesartan is the only ARB with minimal benefit in reducing HF hospitalization among HFpEF patients. Of note, patients that benefited from reduced hospitalizations had elevated BNP or pro-BNP levels [161]. Aldosterone Antagonists: Spironolactone was studied in the TOPCAT trial, which enrolled 3445 symptomatic HFpEF patients (median age of 69 years). Spironolactone did not show significant reduction in CV death or HF hospitalization, although there was a slight trend toward lower HF hospitalization [151]. In the post hoc analysis of the North America cohort, which had similarly matched patient characteristics to prior HFpEF trials, these patients respond positively to spironolactone with an 18% reduction in the primary end point [162]. Another trial of spironolactone among predominantly older HFpEF patients (mean age 71 years and 80% female) did not demonstrate significant improvement in exercise capacity, quality of life, LV mass, or arterial stiffness [163]. Nevertheless, it is a class 2b recommendation to use an aldosterone receptor antagonist to decrease hospitalizations in select HFpEF patients with elevated BNP levels or HF admission in the past year [153]. Aldosterone antagonists should only be initiated in patients with a GFR >30 ml/min and a normal serum potassium level. Angiotensin receptor-Neprilysin Inhibitor: In PARAGON-HF, Sacubitril-valsartan was studied in patients with LVEF >40% and elevated natriuretic peptides. The results demonstrated a small improvement but nonstatistically significant reduction in the primary composite end point of

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total heart failure hospitalization and cardiovascular death [164]. This effect was more evident in subgroups of patients with LVEF between 45% and 57%. Pooled analysis of PARADIGM and PARAGON-HF further divided patients into groups by LVEF; LVEF less than 42.5%, EF between 42.5% and 52.5% and greater than 52.5–62.5%, there was a modest reduction in heart failure hospitalization but not CV death among patients with midrange EF (40–49%) and no benefit in HFpEF patients with EF >50% [165]. Of note, women had sustained therapeutic effect of Sacubitril-valsartan at higher LVEF ranges compared to men. On Sacubitril-valsartan treatment, older women had lower rates of heart failure hospitalization compared to men; however, there was no difference in cardiovascular death between men and women [166]. As a result, in 2021, FDA extended the indication of Sacubitrilvalsartan to include patients with midrange EF and certain patients with LVEF >50%. Sodium glucose cotransporter 2 inhibitor (SGLT2i). In the EMPEROR-Preserved Trial (Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection), empagliflozin reduced the composite end point of cardiovascular death and heart failure hospitalization by 21% in patient with LVEF >40% with or without diabetes [167]. This was the first trial to establish unequivocal cardiovascular benefit of SGLT2i in patients with HFpEF. The EMPEROR-Preserved Trial enrolled patients with higher burden of symptomatic HF and natriuretic peptides and in addition enrolled patients who were much older (mean age of 71 years); these benefits were observed without significant adverse effect reinforcing the safety profile of SGLT2i. The effect of heart failure hospitalization reduction was seen across variable LVEF; however, benefit became more attenuated at LVEF >65% [168, 169]. In addition, SGLT2i was associated with symptom reduction, improvement in functional capacity, and quality of life [170, 171]. Perhaps in older adults especially ones with higher comorbidities, this is a more attainable goal than prolongation of life.

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Treatment of Underlying Comorbidities Coronary artery disease is frequent among HFpEF patients and revascularization should be considered in patients with angina or significant myocardial ischemia at stress testing. A meta-analysis of statin use in about 5000 HFpEF patients suggested possible mortality benefit with treatment [172] attributed to its pleomorphic antiinflammatory effects. Given limited RCT data, statin initiation is only indicated in HFpEF patients with atherosclerotic disease, not for treatment of HFpEF per se. Management and treatment of atrial fibrillation is paramount in symptomatic HFpEF patients. Tachycardia can impair LV filling because of shorter diastolic filling time and can precipitate decompensated heart failure. For this reason, sinus rhythm restoration or heart rate control if rhythm control is not feasible is recommended [173]. Catheter ablation has had limited longterm success in HFpEF. Prior trials of primary use of beta-blockers in HFpEf patients show no with mortality benefit or reduction in hospitalizations unlike in HFrEF [174]. But recent meta-analysis suggests a small cardiovascular mortality reduction with number needed to treat of 25 patients [175]. At the same time, its use for heart rate control and blood pressure control is acceptable. Hypertension and optimization of blood pressure may be the most significant intervention in HFpEF patients. The ACC/AHA/HFSA guideline recommends goal SBP of less than 130 mmHg and use of beta-blockers, angiotensin-converting enzyme (ACEI), and angiotensin receptor blockers (ARB) for hypertension [153]. Weight loss and exercise training: Exercise intolerance is a major complaint and is an independent predictor of morbidity and mortality in HFpEF [176]. Lifestyle changes including dietary modification, physical activity, and weight reduction can have beneficial effect on heart failure. Obesity increases the risk of incident HFpEF [177]. Intentional weight loss via caloric restriction improves exercise capacity in patients with HFpEF and is additive to exercise training [178]. Exercise training as a treatment for HFpEF patients was associated with significant

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improvement in cardiopulmonary fitness [179]; these effects were also seen in obese HFpEF patients [178]. A supervised maximal exercise test, monitoring for ischemia should be performed before patients begin an exercise program [173]. Even in older frail adults with decompensated HFpEF, cardiac rehabilitation can improve physical function and reduce hospitalization [180].

HFpEF Management Based on Clinical Phenotypes A key concept in HFpEF is the heterogeneity of this disease and the reason why “one size fits approach” is not working unlike HFrEF, highlighting the failure and lack of effective mortality benefit medications typically used in HFrEF. Shah et al. proposed using different clinical HFpEF presentation phenotypes as guide to clinical care [181]. Case Study An 80-year-old female with a history of poorly controlled hypertension and obesity presents with 5 months of shortness of breath and lower extremity edema. Shortness of breath is limiting her social activities where she volunteers for work at a senior citizen center. She can shop at her local grocery store but is unable to walk the whole store. Her current NYHA functional class is 3. Current medication includes Lisinopril 20 mg, metoprolol 25 mg BID, and pravastatin 20 mg. On presentation, SBP was 160/90, HR of 70 BPM, and weight 38 kg/m2. She had elevated JVP, mild crackles at the bases, and +2 pitting pedal edema. Electrocardiogram showed normal sinus rhythm with left ventricular hypertrophy and left atrial abnormality. The echocardiogram showed preserved LVEF of 60%, small LV cavity, moderate concentric hypertrophy, grade 2 diastolic dysfunction, left atrial enlargement, and a dilated inferior vena cava. She had normal renal CR and potassium. She is very concerned about her symptoms and would like to return back to her previous activities. At a modified Bruce protocol exercise test, she achieved her target heart rate and EKG was negative for ischemia.

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Intervention Start lowest dose diuretics needed to achieve euvoluemia. Treat hypertension to goal less than 130 mmHg by increasing Lisinopril and consider adding empagliflozin and spironolactone at different interval visits. Caution against starting both medications at the same time. Refer patient to dietician for caloric restriction and recommend exercise training.

Aortic Stenosis Introduction Aortic stenosis is the most common valvular disease among people >75 years of age [182] with prevalence around 9.8% among octogenarians [183]. Hemodynamically aortic stenosis is associated with adverse outcomes and increased risk of cardiovascular morbidity and mortality [184]. As life expectancy improves with advances in medical therapy, clinicians will encounter elderly patients with significant aortic stenosis more frequently. Surgical aortic valve replacement was the choice therapy for symptomatic severe aortic stenosis for more than 50 years but carried high operative mortality, and often elderly patients were excluded due to prohibitive risk. The advent of transcatheter aortic valve replacement transformed the care of aortic stenosis and is now the treatment of choice for older patients with intermediate to prohibitive surgical risk [183]. In this chapter, we summarize the current knowledge and management of symptomatic severe aortic stenosis in older adult patients. Keyword: severe symptomatic aortic stenosis, transcatheter aortic valve replacement (TAVI), calcific aortic stenosis (AS), and surgical aortic valve replacement (SAVR)

Pathology and Epidemiology Aortic stenosis is the most common valvular disease in the elderly reaching a pooled prevalence of

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9.8–12% [183, 185]. There is an exponential increase in aortic stenosis with age (see Fig. 2). The prevalence of severe aortic stenosis is around 3.4% [186, 187]. The recent Icelandic cohort study showed severe AS prevalence to be around 4.3% in adults aged
70 years [188]. The number of elderly patients with calcific aortic stenosis is projected to double by 2050 in the United States [189]. The most common etiology is calcific aortic stenosis which is a degenerative process that occurs as a result of active valvulitis, chronic calcium deposition, and long-standing stress on the aortic cusps [183]. Calcific aortic stenosis becomes more apparent in later stages of life and is commonly diagnosed in the sixth, seventh, and eighth decades. Risk factors for aortic stenosis are similar to atherosclerosis with dyslipidemia, diabetes, and hypertension, the strongest predictors for development of aortic stenosis [185, 190]. Obese patients have a twofold risk of developing AS if BMI is >35.0 kg/m2 [191]. Frequently patients will have coexistent coronary artery disease (CAD) [192] requiring coronary intervention at the time of valve replacement. Moreover, patients with CAD tend to have higher cardiac event rates [193]. Patients with diabetes also have more rapid disease progression [194, 195]. Additionally, it has been shown that even asymptomatic older adults >70 years of age experience higher cardiac event rate compared to younger asymptomatic individuals. Aortic stenosis occurs equally in men and women, but women tend to present later in the disease process and are usually much older with greater comorbidities [196].

Clinical Manifestations Patients with aortic stenosis have a long latent asymptomatic period before progressing to symptomatic phase [197]. Onset of symptoms is associated with high mortality rate [198], and if untreated annual mortality rate is 25% with an average survival of only 2–3 years [199]. Symptoms occur as a result of compensatory left ventricular hypertrophy, resulting in reduction of

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Fig. 2 Prevalence of heart failure among US adults
20 years of age, by sex and age (NHANES, 2013–2016). NHANES indicates National Health and

Nutrition Examination Survey. (Source National Heart, Lung, and Blood Institute tabulation using NHANES, 2013–2016 [52])

coronary perfusion during ventricular diastole, impaired diastolic dysfunction, and concomitant elevation in left ventricular end-diastolic pressure. This leads to the classic triad of AS symptoms: heart failure, syncope, and angina [200]. Most patients with aortic stenosis are first diagnosed when cardiac auscultation elucidates a systolic murmur. Severe aortic stenosis murmur is usually loud, late-peaking, and radiates to the carotid arteries, associated with delayed carotid upstroke. However, carotid upstroke may be normal in elderly patients because of the effects of aging on the vasculature. AS murmur may be heard best only at the apex as compared to the base of heart in some older patients. Symptomatic severe AS symptoms such as dyspnea on exertion, angina, and poor exertional tolerance are similar to other geriatric syndromes common in older patients. Additionally, symptomatic status can be difficult to ascertain in elderly patients who frequently have impaired physical mobility or may

subconsciously curtail their activities [201]; this can make diagnosis clinically challenging.

Diagnostic Modalities Transthoracic echocardiography is the primary modality for diagnosis. Doppler findings of a maximum aortic jet velocity (AV-Vel)
4 m/s, mean transvalvular pressure gradient
40 mmHg, in addition to valve area of 1.0 cm2 or indexed to body surface area of 0.6 cm2 are consistent with severe aortic stenosis. Echo can also shed light on the degree of left ventricular hypertrophy, diastolic dysfunction, and elevated filling pressures and aortic valve morphology. Aortic peak velocity is of strong prognostic importance and is also an independent predictor of outcome in older adults; patients with very severe aortic stenosis defined as AV-Vel
5 m/s have low event-free survival rates [202].

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The paradoxical low-flow/low-gradient severe aortic stenosis entity is common in older female patients [196]. These patients have low transaortic volume rate and stroke volume due to small hypertrophic left ventricular cavity despite preserved LV EF. On echocardiogram, they have a low mean and peak gradients 40 mmHg and 4 m/s, respectively, with AVA of less than 1.0 cm2. In cases with discrepant findings between clinical evaluation and echocardiography data, invasive hemodynamics with cardiac catheterization can shed light on severity of aortic stenosis and is recommended. Transaortic pressure gradient is obtained based on simultaneous measurement of the left ventricular and aortic pressure. AVA can be calculated using Gorlin formula [203]. Cardiac computed tomographic angiography (CTA) is more useful for aortic valve calcium quantification, but it is less useful for evaluation of AS severity. Severe aortic calcification >1000 Agatston units is suggestive of significant aortic valve disease.

Treatment Indications and Aortic Stenosis Therapy Untreated symptomatic severe aortic stenosis carries poor prognosis [193, 204]. There is no medical treatment for symptomatic aortic stenosis; therefore, aortic valve replacement (AVR) is a class 1 indication for symptomatic elderly patients with severe aortic stenosis. Symptomatic older adults who underwent aortic valve replacement had improved quality of life and life expectancy [205]. Bioprosthetic valve is preferred over mechanical valve due to lower life expectancy and avoidance of anticoagulation required for mechanical valve. Patients with bioprosthetic valve require lifelong aspirin therapy with 75–100 mg daily unless there is atrial fibrillation, congestive heart failure, or hypercoagulable condition [202]. Still, many elderly patients do not undergo surgical aortic valve replacement even those at low surgical risk [206]. About 33% of the elderly patients are denied surgical aortic valve

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replacement due to advanced age [207]. A recent study demonstrated that one in five patients with severe symptomatic aortic stenosis are denied valve intervention, and reasons include advanced age and comorbidities [208]. It is estimated that 40% of patients undergoing surgical aortic valve replacement are over the age of 75 years; nonetheless, management of these patients can be complex and difficult [202, 209]. Additionally surgical aortic valve replacement (SAVR) carries an operative mortality risk of 4.1% and in-hospital stroke risk of 5.4% in elderly patients [210]. Older adults who have multiple comorbidities and frailty syndrome have higher prohibitive surgical risk. The advent of percutaneous transcatheter aortic valve implantation has revolutionized management in elderly patients with severe aortic stenosis. The first TAVR valve was performed in 2002 [211] and has emerged as a better alternative for older patients. Initially, TAVR valve was approved for prohibitive or high-risk patients to undergo surgical AVR. In the landmark PARTNER trial, 358 patients deemed to be at prohibitive risk for SAVR (mean age of 83 years); TAVR was superior to medical therapy alone [212]. Operative mortality and the risk of stroke was much lower in the TAVR compared to the SAVR in high surgical risk older adult patients at 1 and 5 years [213]. In the intermediate surgical risk patients, randomized trials have shown TAVR to be noninferior to SAVR [214]. Results are also comparable in low surgical risk patients except for higher aortic valve reintervention for valve thrombosis in TAVR than in SAVR [215]. TAVR has more favorable risk compared to SAVR in octogenarians regardless of their surgical risk [216]. Current expert consensus recommends TAVR in older adults >75–80 years of age regardless of surgical risk. There are complications associated with both TAVR and SAVR; TAVR was significantly associated with lower risk of acute kidney injury, new onset atrial fibrillation, and lifethreatening bleeding but carries a higher risk of recurrent valvular regurgitation and permanent pacemaker placement [217]. Whether to purse TAVR or SAVR should be individualized especially among patients 70 years of age.

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Venous Thromboembolism in the Elderly Introduction Venous thromboembolism (VTE) is manifested clinically as deep venous thrombosis (DVT) and pulmonary embolism (PE) and is associated with significant morbidity, mortality, health care costs, and utilizations. Aging is one of the strongest and most prevalent risk factors for venous thrombosis. The incidence of VTE increases sharply with age, being rare in young individuals (65 years with shortterm bed rest (65 years old, stroke is associated with 1.3–3.5-fold increased risk of VTE [9]. COPD is a known risk factor for both PE and DVT and has an associated 1.2–1.4 increased risk for PE in individuals
60 years [10, 11]. Obesity causes a two- to threefold higher risk of VTE in men and women. The risk associated with severe obesity (BMI above 40 kg/m2) is even higher [12]. A meta-analyses evaluating the prevalence of major cardiovascular risk factors in VTE patients and control subjects found the risk of VTE was 2.33 for obesity (95% CI, 1.68–3.24), 1.51 for hypertension (95% CI, 1.23–1.85), 1.42 for diabetes mellitus (95% CI, 1.12–1.77), 1.18 for smoking (95% CI, 0.95–1.46), and 1.16 for hypercholesterolemia (95% CI, 0.67–2.02) [13]. Elderly people with multiple morbidities are especially vulnerable to develop thrombosis due to the possible interaction of the individual effects of these risk factors.

I. Onuorah et al.

Hormone Replacement Therapy (HRT) HRT causes elevation in levels of factors VII, IX, X, XII, and XIII and decreased levels of the anticoagulant proteins antithrombin and protein S, thereby leading to a procoagulable state. It is associated with an increased risk of thrombosis in the middle-aged and elderly women. Genetic Risk Factors The prevalence of genetic risk factors such as factor V Leiden mutation and prothrombin 20210A mutation is similar in the young and elderly. In individuals >60 years of age, factor V Leiden mutation has been reported to cause fivefold increased risk of thrombosis [14]. Similar studies in carriers of PT20210A mutation have shown 1.5–4.5-fold increased risk of thrombosis as compared to wild-type carriers [15].

Age-Specific Risk Factors Age-specific risk factors are almost exclusive to the elderly population; however, they are not studied in great detail. They include: Frailty Frailty has been defined as “losses of physiologic reserve that increase the risk of disability” [16]. Some markers of frailty include restricted activity, impairment in general cognition and physical performance, comorbidities, and disability in activities of daily living. The percentage of individuals with frailty increases with age, reported as 45 min) Malignancy Confined to bed (>72 h) Immobilizing plaster cast Central venous access

3 Points Age
75 years History of VTE

5 Points Stroke (80 years of age with nonhigh clinical probability of VTE, elevated D- dimer levels were found in almost 95% [33, 34]. An age-adjusted D-dimer cutoff (age multiplied by 10 in patients >50 years) has been prospectively validated in outpatients with suspected PE, decreasing the rates of additional imaging in patients >75 years of age [34]. Other laboratory tests include arterial blood gas as a measure of hypoxemia, and cardiac biomarkers

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such as troponin and brain natriuretic peptide (BNP) or NT-proBNP to classify patients as submassive PE and further risk stratify them. Radiological Workup A chest radiograph does not exclude or confirm pulmonary embolism but aids in excluding alternative explanations for symptoms such as congestive heart failure and pneumonia. CT pulmonary angiography is the imaging test of choice with high sensitivity (80%) and specificity (>90%). Its diagnostic accuracy is not age dependent. Due to the higher incidence of preexisting kidney disease and other comorbidities, elderly patients have a higher risk of contrast agent-induced acute kidney injury [35]. In patients with kidney disease, ventilation perfusion scan is an alternative test. However, the probability of an inconclusive planar VQ scan increases with age and 58% of patients aged
80 years have an inconclusive result compared to 32% of patients aged 75 years at high risk of bleeding [36]. These guidelines stratify the patients with VTE as low-, moderate-, and high-bleeding risk categories on the basis of risk factors listed in

I. Onuorah et al. Table 6 Risk Factors to Stratify Patients with VTE Age > 65 years Age > 75 years Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Previous stroke

Diabetes Anemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery Frequent falls Alcohol abuse Nonsteroidal anti-inflammatory drugs

0 risk factors – low Risk; 1 risk factor – moderate risk;
2 risk factors – high risk

Table 6. Following are the major ACCP guidelines for high bleeding risk patients. • In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a high bleeding risk, 3 months of anticoagulant therapy over extended therapy is recommended (Grade 1B). • In patients with a second unprovoked VTE and high bleeding risk, 3 months of anticoagulant therapy over extended therapy is recommended (Grade 2B). • In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”) and who have a high bleeding risk, extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy is recommended (Grade 2B). • In patients with PE and hypotension (systolic blood pressure 80 years, weight < 60 kg, and serum creatinine >1.5 mg/dL. Elderly patients receiving systemic thrombolysis have a significantly higher major (13% vs. 3%) and intracranial bleeding risk (1.4% vs. 0.5%) than younger patients, and therefore age > 75 years is a relative contraindication to systemic thrombolysis in the ACCP guidelines [36, 38, 39]. Case Study An 84-year old lady with history of hypertension and chronic kidney disease (baseline creatinine 2 mg/dL) presents with unilateral lower extremity swelling worsening for 2 days. She performs her activities of daily living (ADLs) and denies recent falls. For the last 2 days, she is unable to walk, due to pain and swelling in right lower extremity. She seeks medical care and goes to the urgent care clinic to visit her geriatrician. Her vital signs are stable, and examination is remarkable for pain, tenderness, and swelling in the right calf. The

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clinical suspicion for DVT is high, and her Doppler ultrasound shows deep venous thrombosis of right popliteal vein. She is diagnosed with unprovoked DVT of the right lower extremity. The physician has a detailed discussion with her regarding the management. After a thorough risk-benefit assessment, she chooses to be on anticoagulation for 3 months as the guideline-directed management. After a review of the subgroup analysis of trials comparing DOAC and warfarin, the physician offers her apixaban as preferred choice of anticoagulant for her DVT. She starts apixaban 2.5 mg twice a day (half the usual dose) given her age and renal dysfunction. She notices significant symptomatic improvement and continues it for a total of 3 months.

Conclusion CVD frequently affects older adults and remains a major cause of morbidity and mortality. Agingrelated cardiovascular changes predispose to this higher burden of cardiovascular disease. Clinical management remains a challenge in this population.

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of heart failure with preserved ejection fraction. N Engl J Med. 2006;355:251–9. 147. Gerber Y, Weston S, Redfield MM, et al. A contemporary appraisal of the heart failure epidemic in Olmsted County, Minnesota, 2000 to 2010. JAMA Intern Med. 2015;175:996–1004. 148. Anjan VY, Loftus T, Burke MA, et al. Prevalence, clinical phenotype, and outcomes associated with normal B-type natriuretic peptide levels in heart failure with preserved ejection fraction. Am J Cardiol. 2012;6:870–6. 149. Afşin Oktay A, Shah SJ. Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Curr Cardiol Rev. 2015;11:42–52. 150. Cheng RK, Cox M, Neely ML, et al. Outcomes in patients with heart failure with preserved, borderline and reduced ejection fraction in the Medicare population. Am Heart J. 2014;168:721–30. 151. Pitt B, Pfeffer M, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383–92. 152. Hoekstra T, Jaarsma T, van Veldhuisen DJ, Hillege HL, Sanderman R, Lesman-Leegte I. Quality of life and survival in patients with heart failure. Eur J Heart Fail. 2013;15:94–102. 153. Yancy C, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the Management of Heart Failure. J Am Coll Cardiol. 2017;70:776–803. 154. Daniel F, FJaWN. Cardiovascular disease in the elderly. Cover of Braunwald’s heart disease: a textbook of cardiovascular medicine. Philadelphia: Elsevier; 2019. p. 1735–66. 155. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline for the Management of Heart Failure. J Am Coll Cardiol. 2013;62:e147–239. 156. Nishimura RA, Borlaug BA. Diastology for the clinician. J Cardiol. 2019;73:445–52. 157. Stavrakis S, Pakala A, Thomas J, Chaudhry MA, Thadani U. Obesity, brain natriuretic peptide levels and mortality in patients hospitalized with heart failure and preserved left ventricular systolic function. Am J Med Sci. 2013;345:211–7. 158. Maeder MT, Thompson B, Brunner-La Rocca HP, Kaye DM. Hemodynamic basis of exercise limitation in patients with heart failure and normal ejection fraction. J Am Coll Cardiol. 2010;56:855–63. 159. Ather S, Chan W, Bozkurt B, et al. Impact of non-cardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59:998–1005. 160. SPRINT Research Group, Wright J Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373: 2103–16. 161. Campbell RT, Jhund P, Castagno D, Hawkins NM, Petrie MC, McMurray JJ. What have we learned about patients with heart failure and preserved

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Hypertension John C. Landefeld, Sharad Jain, and Craig R. Keenan

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Evidence for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 Goals of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 Considerations for Determining Individual Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 Quality of Life in Hypertension Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonpharmacologic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Monitoring of Treatment and for Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . When to Consider Discontinuation/Deprescribing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Resistant Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Severe Asymptomatic Hypertension and Hypertensive Emergency . . . . . . . . . . . . . . . . . . . Therapies to Be Used with Caution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High-Value Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

391 391 391 393 394 395 395 395 396 396

Patient and Family Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Social Determinants of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Abstract J. C. Landefeld · S. Jain · C. R. Keenan (*) Davis School of Medicine, University of California, Sacramento, CA, USA e-mail: [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_26

Hypertension is very common in older adults and causes significant morbidity and mortality. Treatment is very effective at reducing stroke, cardiac events, and mortality, even in the very 385

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old. Hypertension is defined as a systolic blood pressure > 130 mmHg or a diastolic blood pressure > 80 mmHg. Due to changes in physiology, comorbid conditions, increased susceptibility to side effects, and socioeconomic factors, blood pressure goals and treatments must be individualized for each older adult. The blood pressure goal in robust patients is systolic blood pressure < 130 mmHg. Nursing home residents and patients with advanced frailty or advanced cognitive decline likely need higher goals. Nonpharmacologic therapy should be implemented in all patients. First-line antihypertensive agents are angiotensin-converting enzyme inhibitors, non-dihydropyridine calcium channel blockers, thiazide diuretics, and angiotensin II receptor blockers. Comorbid conditions may influence choice of agents. Therapy requires close monitoring for potentially serious side effects, including electrolyte abnormalities, renal function, and orthostatic hypotension. Deprescribing should regularly be considered as cognition declines, frailty increases, or there are serious side effects from treatment. Involving caregivers in the education and management of hypertension is often essential due to frailty and/or cognitive decline. Use of an interprofessional team and telehealth for monitoring can be very helpful in the longitudinal care of older adults with hypertension. Keywords

Hypertension · Elderly · Blood pressure · Antihypertensive · Cardiovascular · Orthostatic hypotension · White coat hypertension · Masked hypertension · Deprescribing

Introduction Hypertension is common and its prevalence increases with age. If using a threshold of 140/90 mmHg, from 2013 to 2016, the prevalence of hypertension among US adults was 32% [1]. Stratified by age, those 65 years of age or older had a prevalence of 78.2% versus those aged 20–44 years who had a prevalence of 26.1% [2].

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For the clinician caring for older adults, many patients with hypertension will have been diagnosed before the age of 60. As a result, the care of geriatric patients with hypertension will frequently involve managing a diagnosis made during a previous period in that person’s life, with the added complexity of advancing age and increasing frailty. Some patients 60 years or older will receive a new diagnosis of hypertension, a reflection of the fact that age is a major risk factor for the disease. Clinicians caring for older adults must strive to provide treatment that allows patients to maintain their current level of functional status, while also preventing or slowing the loss of functioning that may impede activities of daily living. Given the multisystem damage that unchecked hypertension can cause, treatment is consistent with this principle. When managing hypertension in older adults, the clinician must work to identify a management plan that balances the risks of untreated hypertension with comorbidities, other medications, and the goals and values of the patient. As with other chronic diseases, such an approach depends on a robust discussion of the consequences of longstanding hypertension, the relative benefits offered by different approaches to therapy, the potential adverse effects of various treatments, and the monitoring plan for the patient going forward. Although the prevalence of hypertension and its consequences become more severe with advancing age, so do the risks of adverse events associated with its treatment. In spite of this, hypertension remains, for both the general population and the geriatric population, woefully undertreated. The physiology of blood pressure changes as people age. Up until age 50 or 60 years, systolic (SBP) and diastolic (DBP) increase with age. After age 60 years, the SBP continues to rise, while DBP usually stays the same or even decreases, leading to larger pulse pressures (PP). SBP and PP are better indicators of cardiovascular risk in older patients, while DBP is a better indicator in younger subjects. This change in SBP and DBP association with advancing age is due to increasing arterial stiffness. These stiffer blood vessels are less effective at modulating the pressure gradients during the cardiac cycle. As a result, many older adults have a widened pulse pressure, with systolic hypertension but relatively low diastolic pressures. The

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baroreflex also becomes less sensitive with age, contributing to increased risk for orthostatic hypotension as well as more blood pressure variations. The taste buds of many older adults are less sensitive to salt, which can lead to increased salt consumption. Collectively, physiologic changes of aging contribute to both increased rates of hypertension and increased risk for medication-induced adverse events.

Diagnosis Adults aged 60 years and older should have blood pressure measured at each office visit and at least annually. Proper blood pressure measurement is paramount to accurate diagnosis and avoiding inappropriate treatment. The recommended method is to measure three seated blood pressure readings after the patient has rested for 5 min and average them. Proper blood pressure technique also includes using proper cuff size, good back and arm support during measurement, avoiding putting the cuff over clothing, avoiding talking during measurement, and avoiding measuring in paralyzed arms. It is important that persistent hypertension be present on two or more visits before diagnosing a patient with hypertension. Out-of-office blood pressure readings, either by home blood pressure monitoring (HBPM) or 24-hour ambulatory monitoring (ABPM), should be considered in most patients with concern for hypertension. There is increasing evidence that out-of-office measurements are more accurate. The white coat effect, where patients are hypertensive in-office, and normotensive out-of-office, is seen in 10–15% of older adults. If the white coat effect is suspected, more formal out-of-office measurements with HBPM or ABPM should be done to better assess true blood pressure. Most evidence indicates that white coat hypertension does not increase cardiovascular events or death, and therapy is not indicated. So its diagnosis may avoid unnecessary treatment. More recently, studies of ambulatory monitoring have found that about 10% or more of older adults have masked hypertension (MH), where they are normotensive in-office and hypertensive out-of-office. MH is associated with an increase in

387 Table 1 Stages and diagnosis of hypertension [1] SBP < 120 and DBP < 80 mmHg SBP 120–129 mmHg and DBP ¼300 mg/g albumin/creatinine ratio – ACEI (or ARB if ACEI not tolerated) If no albuminuria, all first-line classes acceptable – thiazide, ACEI, ARB, and CCB Avoid thiazide diuretics Avoid ACEI, ARB, and aldosterone antagonists Diuretics can exacerbate hyperuricemia, should be avoided if possible Losartan can lower uric acid levels which may help reduce flares

ACEI Angiotensin Converting Enzyme Inhibitor, ARB Angiotensin II Receptor Blocker, and CCB Calcium Channel Blocker.

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Thiazide diuretics include hydrochlorothiazide and chlorthalidone, both of which are dosed once daily. Chlorthalidone has a longer half-life, is more potent than hydrochlorothiazide, and has proven reduction in cardiovascular events, so it is usually the preferred agent. However, due to this potency, it is also associated with increased rates of side effects, most notably hypokalemia. ACE inhibitors are interchangeable, but drugs with long half-lives which can be used in once-daily regimens are preferred (e.g., lisinopril, benazepril). Closely related agents are the ARBs, which also have many once-daily agents (e.g., losartan, valsartan). Once-daily dihydropyridine calcium channel blockers include amlodipine, felodipine, and long-acting nifedipine. The dosing of these agents is shown in Table 4.

Combination Therapy Some patients require combination therapy with two agents of complimentary drug classes in order

to achieve their target blood pressure. Although therapeutic equivalence exists for monotherapy with chlorthalidone, amlodipine, and lisinopril, the ACCOMPLISH trial found that the combination of benazepril/amlodipine led to fewer cardiovascular events than the combination of benazepril/hydrochlorothiazide among patients aged 55 and older who needed two agents [24]. This finding held true on subgroup analyses of patients older than 65 and 70 years. Thus, for patients requiring two or more agents to achieve their target blood pressure, a combination of ACE inhibitor and dihydropyridine calcium channel blocker is preferred. Single-pill combination therapy is available, combining medications of complementary mechanisms of action into a single tablet or capsule. This can be particularly helpful for older adults who are taking many other medications and for whom pill burden and cost can be an impediment to chronic disease management. The benazepril/ amlodipine used in the ACCOMPLISH trial is available in a combination pill. Many other

Table 4 Common antihypertensive classes, medications, and doses Medication class Thiazide diuretics ACE inhibitors Angiotensin receptor blockers Dihydropyridine CCBs

Non-dihydropyridine CCBs Beta-blockers

Medication name Hydrochlorothiazide Chlorthalidone Lisinopril Benazepril Losartan Valsartan Amlodipine Felodipine Nifedipine sustained release Diltiazem Atenolol Labetalol Carvedilol Metoprolol

Aldosterone antagonists Sympatholytic agents

Spironolactone Eplerenone Clonidine oral Clonidine patch

Starting dose, maximum dose 12.5 mg/day, 25 mg/day 6.25 mg/day, 25 mg/day 2.5 mg/day, 40 mg/day 2.5 mg/day, 40 mg/day 25 mg/day, 100 mg/day 80 mg/day, 320 mg/day 2.5 mg/day, 10 mg/day 2.5 mg/day, 10 mg/day 30 mg/day, 90 mg/day 12-h formulation: 60 mg BID, 180 mg BID 24-h formulation: 120 mg/day, 360 mg/day 25 mg/day, 100 mg/day 100 mg BID, 400 mg TID Immediate release: 6.25 mg BID, 25 mg BID Extended release: 20 mg/day, 80 mg/day Immediate release: 12.5 mg BID, 100 mg BID Extended release: 25 mg/day, 200 mg/day 25 mg/day, 100 mg/day 25 mg BID, 50 mg BID 0.1 mg QHS, 0.3 mg BID 0.1 mg patch weekly, 0.3 mg patch weekly

ACE Angiotensin Converting Enzyme, CCB Calcium Channel Blocker, BID twice daily, TID Three times daily; QID Four times daily, and QHS At bedtime

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combinations are also available, including ACE inhibitor plus hydrochlorothiazide (HCTZ), ARB plus HCTZ, amlodipine plus ARB combinations, and amlodipine plus other ACE inhibitors.

Monitoring of Treatment and for Side Effects Side effects of hypertensive treatment can range from relatively mild to life-threatening, and the frequency of these unintended events increases with age. All antihypertensives have the potential to cause orthostatic hypotension, falls, and fatigue. Antihypertensive therapies can reduce patients’ cerebral perfusion and lead to confusion, can precipitate bradyarrhythmia, and can lead to dangerous electrolyte derangements. Thiazides can cause severe hyponatremia and hypercalcemia, while ACE inhibitors and ARBs may cause severe hyperkalemia and/or acute renal injury. Calcium channel blockers frequently cause pedal edema, which can mimic heart failure.

When starting any antihypertensive agent, or increasing its dose, it is important to measure orthostatic blood pressures before initiation, as the presence of orthostatic hypotension may affect treatment goals and choice of therapy (see below). Baseline electrolytes should be measured prior to starting any diuretic, ACE inhibitor, or ARB. Electrolytes should also be monitored 1 week after any initiation or dose adjustment of these agents. After initiation of therapy or after dose adjustments, patients should be seen within 1 month to assess response. Patients with blood pressures at goal should be seen every 3–6 months. Attention to the development of side effects (Table 5) and consideration of monitoring needs should be done at each visit. Patients should have electrolytes and renal function checked a minimum of twice per year, and more frequently with drug changes. Proper blood pressure readings (per above) should be done at each office visit. Patients who do homebased blood pressure monitoring with proper technique can certainly be monitored via telehealth

Table 5 Common antihypertensive medication side effects and monitoring Medication class Thiazide diuretics

Calcium channel blockers ACE-inhibitors/ angiotensin II receptor blockers Aldosterone antagonists

Beta-blockers

Vasodilators (hydralazine)

Sympatholytics (clonidine)

Side effects Hypovolemia, hypokalemia, hyponatremia, hyperglycemia, hyperuricemia, hypercalcemia, hyperlipidemia, metabolic alkalosis, and sulfa allergic reactions Headache, lightheadedness, flushing, peripheral edema, and gingival hyperplasia Acute kidney injury, hyperkalemia, dry cough (lower with ARBs), anemia, and angioedema Gynecomastia, Stevens-Johnson Syndrome/toxic epidermal necrolysis, hyperkalemia, diarrhea, nausea, vomiting, and erectile dysfunction Bradycardia, orthostatic hypotension, dizziness, fatigue, nausea, cardiovascular conduction dysfunction, and bronchospasm Orthostatic hypotension, headache, tachycardia, flushing, nausea, and druginduced lupus erythematosus Bradycardia, orthostatic hypotension, rebound hypertension, depression, confusion, delirium, somnolence, dry mouth, fatigue, and dizziness

Comments Monitor electrolytes closely during titration due to risks of hypokalemia and SIADH

Avoid use when CrCl < 30 mL/min due to increased risk of hyperkalemia and worsening renal function Avoid use when CrCl < 30 mL/min due to increased risk of hyperkalemia, avoid as first-line antihypertensive Avoid as first-line antihypertensive. Avoid abrupt cessation to prevent rebound hypertension Avoid as first-line antihypertensive Avoid as first-line antihypertensive If discontinuing, taper clonidine to prevent rebound hypertension

SIADH Syndrome of Inappropriate Anti-Diuretic Hormone, ACE Angiotensin Converting Enzyme, ARB Angiotensin II Receptor Blocker, and CrCl Creatinine Clearance

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visits in place of some in-person visits, which may be very beneficial in those with limited mobility, cost constraints, and transportation issues. Because orthostatic hypotension (OH) is often asymptomatic, orthostatic blood pressure (supine and standing) should be measured regularly in patients on therapy, even if they lack the concerning symptoms of dizziness, falls, or syncope. Patients with OH may need changes to their medication, including avoiding those more prone to cause OH, including diuretics, alpha-blockers, and clonidine. Medications other than the antihypertensive agents should be reviewed, as they can contribute to OH. Examples include trazadone, tricyclic antidepressants, and antiparkinsonian drugs. Sometimes, liberalizing salt intake and increasing physical activity can improve OH. Lastly, use of an interprofessional team can be very helpful in managing patients with hypertension. Pharmacists in particular can assist with education of the patient and family, assisting with enhancing adherence (e.g., pillboxes, reminder systems, and bubble packs), identifying the most economical medications for patients with financial challenges (e.g., evaluating Medicare Part D formularies, pharmaceutical company discount programs), and titrating and monitoring therapy. Nurse visits for blood pressure monitoring can be efficient as well. Lastly, nutritionists can assist with education on DASH, low sodium, or weight loss diets.

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nursing home residents or approach the end of life, as this may improve overall quality of life, reduce treatment burden for caregivers, and may actually improve outcomes, as discussed above.

Resistant Hypertension Resistant hypertension is defined as blood pressure that is not controlled with medications from three complementary mechanisms of action (ideally with one being a diuretic). One should be vigilant for pseudoresistance, which may be due to white coat hypertension, poor blood pressure measurement technique, or poor adherence to medications, particularly in situations of polypharmacy or cognitive decline. Also, a careful history should explore if the patient is taking other medications that interfere with blood pressure control (e.g., nonsteroidal antiinflammatory medications, decongestants) or has a high salt diet. Clinicians should also consider causes of secondary hypertension, including RAS, OSA, thyroid disorders, and primary hyperaldosteronism, especially when a patient does not respond to medical therapy as expected. Treatment in refractory cases should usually include a diuretic and may require a loop diuretic in patients with chronic kidney disease. Considerable evidence exists that adding a mineralocorticoid receptor antagonist (i.e., spironolactone or eplerenone) as a fourth agent is effective when not contraindicated.

When to Consider Discontinuation/ Deprescribing When medications cause serious side effects (e.g., severe OH, falls, syncope, severe electrolyte abnormalities, and cognitive changes), interact with other necessary medications, or lead to hypotension, they should be deprescribed or a therapeutic alternative should be substituted. Many older patients’ blood pressure will decrease as they age, and thus if blood pressures become too low (i.e., SBP < 120 mmHg) deprescribing should be done. Lastly, raising or eliminating blood pressure goals should be considered as patients develop advanced dementia, become

Severe Asymptomatic Hypertension and Hypertensive Emergency Just as the prevalence of hypertension is higher among older adults, the prevalence of severely elevated blood pressures (>180/120 mmHg) is also higher among older adults than the general population. Severely elevated blood pressure may present without evidence of end-organ damage (severe asymptomatic hypertension) or with evidence of end-organ damage (hypertensive emergency). Increasing data suggest that severe asymptomatic hypertension, previously termed

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“hypertensive urgency,” should not reflexively lead to referring a patient to the emergency room. In fact, some studies have found that patients with severe asymptomatic hypertension who were referred to the emergency room were more likely to be hospitalized but did not have improved outcomes [25]. Patients who do develop acute end organ injury with severely elevated blood pressures are more likely to be older, however [26]. This emphasizes the importance of diagnostic workup in the clinic to evaluate for end-organ damage. The workup for end-organ damage should begin with a thorough history, assessing for new headaches, confusion, agitation, visual changes, focal neurologic deficits, chest pain, dyspnea, or symptoms of heart failure. The physical exam should evaluate for papilledema, retinal hemorrhages, elevated jugular venous pressures, an S3 gallop, rales, or new dependent edema. Lab assessment should include a urinalysis, serum creatinine, troponin, and an electrocardiogram. If this workup suggests end organ damage, prompt referral to the emergency department for further evaluation and management is indicated. If a patient does not to have evidence of end-organ damage, consider whether secondary causes of acutely elevated blood pressure may explain the elevated pressure. Pharmacologic treatment of severe asymptomatic hypertension is the same as for other hypertensive patients. The approach should focus on maximizing doses of antihypertensive medications already prescribed and starting new agents of a complementary but distinct class in a stepwise fashion. Follow-up within 1–2 weeks for repeat blood pressure monitoring and any indicated lab work should be scheduled.

Therapies to Be Used with Caution Beta-blockers, while not absolutely contraindicated in older patients, should be used cautiously for the treatment of hypertension in this population. These medications pose an increased risk of falls, can lead to cardiac conduction dysfunction, and can exacerbate pulmonary dysfunction in patients with underlying bronchospastic

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disease. They must be used cautiously when prescribing alongside acetylcholinesterase inhibitors (used for dementia) as this combination can cause severe bradycardia in some patients. Despite these concerns, many older patients with comorbid conditions, such as prior myocardial infarction or atrial fibrillation, may require and benefit from beta-blocker therapy. Hydralazine, a vasodilator, can contribute to sodium and water retention and has an unpredictable antihypertensive effect leading to excessive falls in blood pressure. It can also cause reflex tachycardia. As a result, hydralazine should not be used as monotherapy, and it should be used cautiously as a second- or third-line agent. Centrally acting sympatholytic agents such as clonidine should only rarely be used to control hypertension in geriatric patients due to the unpredictability of their effect and their high risk of side effects. Due to increased arterial stiffness, geriatric patients are more likely to suffer from orthostatic hypotension and autonomic dysfunction; medications that further impair a patient’s ability to maintain cerebral perfusion when changing positions can increase the risk of falls. These medications also carry a high risk of delirium and confusion. Alpha-blocking agents (prazosin, terazosin, and doxazosin) should also generally be avoided due to their ability to cause orthostatic hypotension and potential increased risk of congestive heart failure.

High-Value Care Medication nonadherence is among the most frequent causes of persistent hypertension. Many older adults are on fixed incomes, and costs of medications play an important role in determining a patient’s adherence to therapy. Clinicians should ask patients about the out-of-pocket costs of their medications, and whether these costs are a financial hardship. Clinicians should align their medication recommendations with insurance drug formularies and can consult Internet-based prescription drug price trackers to advise their patients on where to purchase medications at

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lowest costs. In addition, clinicians should always prescribe generic medications, which have similar efficacy at reduced cost when compared to brandname medications.

Patient and Family Education It is critical that patients and their families understand what hypertension is and why blood pressure control is important to the health and wellbeing of the patient, even in the absence of symptoms. The provider must consider the health literacy of the patient and family and should use language that is clear and understandable to the patient. It may be necessary to utilize an interpreter if the patient has limited English proficiency and to utilize culturally appropriate terminology to explain these concepts. It is always helpful to employ the “teach back” method by which the patient is asked to recite information back to the provider as a way to confirm that they understood the concepts explained. It is also important to provide the patient and family members with written handouts that they can read after they leave the office to review the information covered. There are excellent websites and books to educate on the DASH diet and low sodium diets. In patients with significant cognitive impairment, the education of family members or other caregivers on these topics is paramount. Topics that may be relevant to the patient and family might include: • What is high blood pressure and how is it defined? • Why is high blood pressure important to me? • Are there ways by which I can lower my blood pressure through lifestyle changes? • What medicine do you recommend to reduce my blood pressure? • How should I take my medication and what are the potential side effects? • How should I monitor my blood pressure once I start a medication? • What is my goal blood pressure? • Will I need more than one medication to treat my high blood pressure?

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Social Determinants of Health There are numerous barriers that affect the ability of providers and patients to adhere to recommended hypertension guidelines, especially for patients from vulnerable and marginalized groups. First and foremost is limited access to affordable care. A significant number of patients are either uninsured or underinsured and thereby have limited and inconsistent access to healthcare services; many of these patients only access services for urgent care and emergency services, making it challenging to identify and treat a chronic condition. Many of these patients have low health literacy, and health education resources may not be presented in ways that address cultural needs. In addition, information may not be accessible for patients with limited English proficiency if there is a lack of robust interpreter services. Costs for services, such as copays for visits or medications, may discourage patients from following recommended instructions. Finally, logistical issues, such as transportation challenges in attending appointments, and competing priorities, such as the need to focus on housing and employment, may make it difficult for patients to engage in appropriate care. Health systems must make efforts to mitigate these barriers by utilizing principles of chronic disease management, minimizing out-of-pocket costs for patients, ensuring adequate interpreter services, and utilizing open access scheduling models. In addition, providers should advocate for expanding telehealth visits together with remote monitoring as a way to reduce barriers for engaging with healthcare services [27].

Case Studies Case 1: Mr. Williams, 73 M with Multiple CVD Risk Factors, with New DX of HTN Part 1: Lee Williams is a 73-year-old man presenting to primary care for follow-up. Mr. Williams has a past medical history of class 1 obesity, hypercholesterolemia, bilateral knee osteoarthritis, tobacco use, and major depressive disorder. He takes

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atorvastatin for hypercholesterolemia, acetaminophen as needed for knee pain, and citalopram for his depression. Today he tells you he is feeling well; however, you notice that his initial blood pressure reading was 163/80 mmHg. At his most recent visit, 3 months previously, his blood pressure was documented as 158/84 mmHg. How do you approach Mr. Williams’ elevated blood pressure? Part 2: You diagnose Mr. Williams with hypertension. He is not taking any medications that might increase his blood pressure (e.g., NSAIDs, corticosteroids, and tricyclic antidepressants). His weight has been unchanged recently, with a BMI of 32 kg/m^2. He continues to smoke half a pack of cigarettes daily, adheres to no particular diet, and drinks minimal alcohol. Initial workup with a basic metabolic panel, TSH, urinalysis, and urine albumin:creatinine found normal renal function, no evidence of thyroid disease, and microalbuminuria. He lives at home and is able to do all of his IADLs as well as regularly do moderate levels of yardwork without difficulty. How do you approach treatment for Mr. Williams’ hypertension? Part 3: After discussing with Mr. Williams the natural history of hypertension, and his relatively high risk for cardiovascular events (by age, BMI, hypercholesterolemia, tobacco use, and hypertension), he made several nonpharmacologic changes to his health. He began walking for 45–60 min daily and adopted the DASH diet. With the assistance of varenicline, he has stopped smoking. He started taking amlodipine 5 mg daily. Despite titration of his amlodipine, his blood pressure was not at goal, and benazepril was added to his regimen. He now is at goal (most recent blood pressure of 125/78) on a combination medication with amlodipine 10 mg/benazepril 20 mg daily. Case 2: Ms. Garcia, 84F with Resistant Hypertension Part 1: Jocelyn Garcia is an 84-year-old woman with a history of stroke and chronic left hemiplegia. She also has hypertension, early dementia, hyperlipidemia, and a history of hypertension. She is a longterm resident at a local skilled nursing facility. She

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is coming to see you for primary care needs and is accompanied by her son. Her medications include aspirin, atorvastatin 40 mg daily, amlodipine 10 mg daily, hydralazine 10 mg three times daily, and clonidine 0.2 mg twice daily. On questioning, she is not ambulatory but does pivot to her wheelchair regularly. She requires assistance with bathing and all IADLs. Her blood pressure is 156/88, and heart rate 64 beats per minute. Recent lab tests reveal a creatinine of 0.7 mg/dL and normal potassium levels. How would you characterize Ms. Garcia’s hypertension? What would be your goals of therapy? What would you do to manage her blood pressure? Part 2: Ms. Garcia has Stage 2 hypertension and a very high cardiovascular disease risk given her prior stroke, hypertension, and diabetes. She also is not a patient that would have been included in most trials of hypertension therapy. Dementia is often a concern for adherence to a medication regimen, but this is not an issue in her facility. Given her frail status and nursing home residence, she is likely more susceptible to adverse effects from treatment, and a higher blood pressure goal is reasonable, such as < SBP 150 mmHg. She is already on three agents and above this goal, but she is not on an optimal regimen. Hydralazine is a second- or third-line agent, and it is currently at a very low dose. Similarly, clonidine is not a firstline agent and can contribute to confusion. Thus, you decide to continue the amlodipine, discontinue the hydralazine and clonidine, and instead use lisinopril 10 mg daily, which is titrated up to 40 mg daily. A third agent, the diuretic chlorthalidone, is added at 12.5 mg daily. She tolerates this regimen well and achieves a blood pressure of 145/76 mmHg.

Conclusion Hypertension in the older adult is a challenging dilemma given comorbid conditions, frailty, cognitive decline, and increased susceptibility to side effects of therapy. Thus, blood pressure treatment in older adults requires careful assessment of risks and benefits. Treatment goals determined on an

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individual basis are often informed by a careful geriatric assessment. The choice of antihypertensive agent is often informed by underlying comorbid conditions. Careful monitoring is required once treatment is started. Deprescribing may be indicated as patients age and develop more advanced cognitive decline and frailty. But with thoughtful care, control of hypertension in older adults is a highly effective treatment.

References 1. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. J Am Coll Cardiol. 2018;71(19): e127–248. 2. Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics – 2019 update: a report from the American Heart Association. Circulation. 2019;139(10): e56–e528. 3. Agarwala A, Mehta A, Yang E, Parapid B. Older adults and hypertension: beyond the 2017 guideline for prevention, detection, evaluation, and management of high blood pressure in adults, American College of Cardiology. 2020. Access online on 20 Aug 2020: https://www.acc.org/latest-in-cardiology/arti cles/2020/02/26/06/24/older-adults-and-hypertension. 4. Kotliar C, et al. Improved identification of secondary hypertension: use of a systematic protocol. Ann Transl Med. 2018;6(15):293–302. 5. Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ 1992;304:405–12. [PMID: 1445513]. 6. SHEP Cooperative Research Group. Prevention of stroke by anitihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA. 1991;265:3255–64. 7. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887–98. 8. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, et al. Randomized double-blind comparison of placebo and active treatment of older patients with isolated systolic hypertension. Lancet. 1997;350:757–64. 9. Wright JT, Williamson JD, Whelton PK, et al. SPRINT Reseach Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2013–116. 10. Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, et al. Intensive vs

399 standard blood pressure control and cardiovascular disease outcomes in adults aged
75 years: a randomized controlled trial. JAMA. 2016;315(24):2673–82. 11. Weiss J, Freeman M, Low A, Fu R, Kerfoot A, Paynter R, et al. Benefits and harms of intensive blood pressure treatment in adults aged 60 years or older. A systematic review and meta-analysis. Ann Int Med. 2017;166:419–29. 12. McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst Rev. 2009;4: CD004034. 13. The SPRINT MIND Investigators. Effect of intensive vs standard blood pressure control on probable dementia. JAMA. 2019;321(6):553–61. 14. Benetos A, Petorvic M, Strandberg T. Hypertension management in older and Frail older patients. Circ Res. 2019;124:1045–60. 15. Rich MW, Ouslander JG. Hypertension in older adults in the wake of the systolic blood pressure intervention trial. JAGS. 2018;66:652–4. 16. Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA, Clinical Guidelines Committee of the American College of Physicians and the Commission on Health of the Public and Science of the American Academy of Family Physicians. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Int Med. 2017;166:430–7. 17. Williams B, Mancia G, Spiering W, Rosei E, Azizi M, Burnier M, Clement D, Coca A, Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen S, Kreutz R, Laurent S. 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104. 18. ACCORD Study Group. Effects of intensive bloodpressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85. 19. Mader SL. Identification and management of orthostatic hypotension in older and medically complex patients. Expert Rev Cardiovasc Ther. 2012;10(3):387–95. 20. Benetos A, Labat C, Rossignol P, et al. Treatment with multiple blood pressure medications, achieved blood pressure, and mortality in older nursing home residents. The PARTAGE study. JAMA Int Med. 2015;175(6):989–95. 21. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med. 1997;336: 1117–24. 22. Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH Jr, Kostis JB, Kumanyika S, Lacy CR, Johnson KC, Folmar S, Cutler JA. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of

400 nonpharmacologic interventions in the elderly (TONE). JAMA. 1998;279(11):839–46. 23. The ALLHAT OFFICERS. Major outcomes in highrisk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA. 2002;288:2981–97. 24. Jamerson K, Weber MA, Bakris GL, Dahhlof B, Pitt B, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359:2417–28. 25. Patel KK, Young L, Howell EH, et al. Characteristics and outcomes of patients presenting with hypertensive urgency in the office setting. JAMA Intern Med. 2016;176(7):981–8.

J. C. Landefeld et al. 26. Katz JN, Gore JM, Amin A, Anderson FA, Dasta JF, Ferguson JJ, Kleinschmidt K, Mayer SA, Multz AS, Peacock F, Peterson E, Pollack C, Sung GY, Shorr A, Varon J, Wyman A, et al. Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) Registry. Am Heart J. 2009;153(4):599–606. 27. Khatib R, Schwalm J-D, Yusuf S, Haynes RB, McKee M, Khan M, et al. Patient and healthcare provider barriers to hypertension awareness, treatment and follow up: a systematic review and meta-analysis of qualitative and quantitative studies. PLoS One. 2014;9(1):e84238.

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Gabriela Sauder

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Postprandial Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Orthostatic hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Postprandial Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Evaluation and Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 Postprandial Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonpharmacologic Treatment of Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic Treatment of Orthostatic Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nonpharmacological Treatment of Postpradial Hypotension . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic Management of PPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

405 405 406 406 406

Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

Abstract

G. Sauder (*) Geriatric Medicine, David Geffen School of Medicine, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_30

Older adults are at risk for developing orthostatic (postural) hypotension, which is a significant reduction in blood pressure upon standing, and postprandial hypotension, which is a drop in blood pressure after meals [1, 2]. It is recommended that the clinicians have an 401

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increased awareness about these geriatric hypotensive syndromes and perform both symptoms screening and serial measurements of blood pressure and heart rate to diagnose these conditions to decrease the significant morbidity and mortality associated with orthostatic and postprandial hypotension [8, 31, 56, 57]. Keywords

Orthostatic hypotension · Postprandial hypotension · Older adults

Introduction Older adults are at risk for having orthostatic (postural) hypotension (OH), which is a significant reduction in blood pressure of >20 mm Hg in systolic blood pressure or of >10 mm Hg in diastolic blood pressure within 1–3 min of standing [1, 2], and postprandial hypotension (PPH), which is a drop in blood pressure after meals of 20 mm Hg systolic blood pressure or a systolic blood pressure decrease to less than 90 mm Hg within 2 h after eating [3]. Both OH and PPH are significant causes of morbidity and mortality in the older and frail population. Postprandial hypotension (PPH) in older adults is largely under-recognized, and it occurs more frequently than OH [4], and there is clinical correlation with increase in mortality due to syncope, falls and TIA/stroke [5], and lack of effective management for this condition [6].

Epidemiology Orthostatic and postprandial hypotension are more common in older adults than in the younger population [7, 8]. Orthostatic hypotension can be found in about 20% of patients over age 65 and increases with age, and comorbidities, such as frailty, hypertension, diabetes mellitus, and major cognitive disorder [7–10]. In institutionalized older adults, the prevalence ranged from 18% in older adults living in nursing homes in Italy – the PARTAGE Study [11] – to 51.6% in older adults with Parkinson’s disease [12].

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Postprandial hypotension is recognized as a frequent and significant condition in older adults, with a reported prevalence of 24–48% in healthy older adults [13], and more prevalent in conditions associated with autonomic dysfunction such as diabetes mellitus (~40%) [13], Parkinson’s disease (PD) (40–100%) [4], and ESRD on hemodialysis [3]. Data from the geriatric wards show a 46% prevalence of postprandial hypotension, and a high rate of being asymptomatic in 60% of the patients [14]. The prevalence of PPH in older people receiving tube feeding was 75% [15].

Pathophysiology The normal response to changing position from lying down to upright, as a result of pooling of a significant volume of blood up to 1000 mL in the lower extremities, is a decrease in venous return to the heart, diminished cardiac output, and blood pressure. This triggers a compensatory reflex of the central and peripheral nervous systems that activates the sympathetic nervous system and reduces parasympathetic outflow (baroreceptor reflex), thus limiting the fall in blood pressure with standing. The sympathetic nervous system increase in vascular resistance occurs fast within 1–3 s [16, 17]. As a result of these compensatory mechanisms, the change to an erect posture produces a small fall in the systolic blood pressure (SBP) up to 10 mmHg, an increase in diastolic blood pressure (DBP) up to 10 mmHg, and an increase in heart rate (HR) up to 25 beats/min. Failure of these autonomic compensatory mechanisms may cause OH. The pathophysiology of postprandial hypotension is multifactorial. It involves the interaction between autonomic and neural mechanisms, and the release of gut hormones that are influenced by meal composition and gastric distension [6]. Other risk factors include polypharmacy, taking diuretics, and having hot meals [3]. In older adults, the postprandial baroreflex of increases in heart rate, peripheral vascular resistance, stroke volume, and cardiac output triggered by the increasing of the blood flow in the superior mesenteric artery blood flow is blunted. In these patients, the postprandial fall in BP is greater when gastric emptying is more rapid, such as when eating

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a meal with high content of carbohydrates. Data shows that gastric emptying is influenced by the meal composition, with carbohydrates inducing an earlier fall in BP compared to protein and fat. As such, in older adults, a meal with high content of glucose, fructose, and sucrose induces the highest decrease in PPH. As a result, interventions such as diet modifications by replacing high nutritive sweeteners like glucose, fructose, and sucrose with low nutritive sweeteners such as xylose, erythritol, maltose, or maltodextrine could help manage postprandial hypotension [3, 6].

Diagnosis The diagnosis of orthostatic hypotension is made when there is a drop of 20 or more mm Hg in SBP or 10 or more mm Hg in the DBP within 3 min of rising from lying to standing [2]. There are three types of orthostatic hypotension: the classic type, defined as a sustained reduction in systolic blood pressure (SBP) of at least 20 mmHg or diastolic blood pressure (DBP) of at least 10 mmHg within 3 min of standing or head uptilted to an angle of 60 with or without reproduction of symptoms, initial orthostatic hypotension which is a transient drop in either systole 40 mmHg or a diastole 20 mmHg within 15 s of standing, and delayed orthostatic hypotension, where the reduction in SBP and/or DBP occur after 3 min of standing [18]. Postprandial hypotension is defined as a decrease in SBP more than 20 mm Hg after eating, or a SBP decrease to less than 90 mm Hg within 2 h after eating (a fall in blood pressure occurring 15–90 min after meals) is also common in older subjects [3, 19].

Etiology Orthostatic Hypotension Orthostatic hypotension is classified as neurogenic and non-neurogenic. The neurogenic orthostatic hypotension is due to impairment of the baroreflex-mediated sympathetic activation and the vasoconstriction of the skeletal muscle and splanchnic circulation, and it stems in the lesions or

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dysfunction of central and/or peripheral sites of the baroreceptor efferent pathway. It is either related to autonomic dysregulation due to age-related impaired baroreceptor sensitivity [7, 20, 21], or impaired autonomic dysfunction secondary to neurodegenerative diseases, diabetes mellitus, and neuropathies. With autonomic dysregulation, the blood pressure falls with upright position because the gravitational pooling of blood in the lower extremities and in the splanchnic circulation cannot be compensated by sympathetic vasoconstriction. It is a dysfunction of the noradrenergic neurotransmission in which postganglionic sympathetic neurons do not release norepinephrine resulting in impaired vasoconstriction, reduced venous return, reduced intrathoracic vascular volume, and cardiac output. Dysautonomia is suggested by lack of compensatory rise in the heart rate with postural hypotension. In neurodegenerative diseases with autonomic dysfunction defined as synucleinopathies – Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy (MSA, Shy-Drager syndrome), and pure autonomic failure (PAF, Bradbury-Eggleston syndrome) – the pathology is determined by the cytoplasmic neuronal (Lewy bodies) and glial inclusions containing alpha synuclein which are located in the brain and peripheral autonomic nerves [22, 23]. In neuropathies, such as small fiber peripheral neuropathies associated with diabetes mellitus, the autonomic dysfunction is located at the postganglionic autonomic nerves, with length-dependent “dying back” axonopathy, involving the distal portions of the longest myelinated and unmyelinated sensory axons, with relative sparing of motor axons [24, 25]. In most of the cases, the complication of orthostatic hypotension develops along with sensory neuropathy, erectile dysfunction, and gastrointestinal symptoms, independent of the duration or severity of diabetes. Of note, research shows that the prevalence of orthostatic hypotension is greater with the disease progression, and as such, clinicians must be aware of the related consequences in the management of the patients with major neurocognitive impairment [26]. The non-neurogenic causes of orthostatic hypotension are related to low intravascular volume due to losses – diarrhea, vomiting, blood loss,

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or use of diuretic – or to inadequate intake which is common in older adults who have a diminished sensation of thirst, leading to poor oral intake and dehydration. Despite normal to increased ADH secretion, older adults have diminished sensitivity to ADH, which impairs the ability to concentrate the urine. Moreover, most older adults may have an impaired thirst mechanism that can result in inadequate fluid intake despite dehydration, resulting in chronically low intravascular volume [27]. Other causes are the use of medications that have vasodilator effects – such as antihypertensives, muscle relaxants, nitrates, opioids, and PDE5 inhibitors – or have a side effect on autonomic dysfunction such as antidepressants, antipsychotics, and antiparkinsonian drugs, or drugs that induce volume depletion, such as diuretics and SGLTs inhibitors. Moreover, polypharmacy could contribute to OH through drug-drug interactions and drug-disease interactions. Other possible culprits are alcohol use, prolonged bed rest, and deconditioning [18, 21].

Postprandial Hypotension The etiology of the postprandial hypotension lies in the interplay between comorbidities that involve autonomic dysfunction such as diabetes mellitus and Parkinson’s disease, and meals – such as more common with breakfast and lunch, more frequent with large meals, higher risk with high content of carbohydrates, and with warm meals with temperature over 50  C. Moreover, polypharmacy (more than five medications) and taking diuretics contribute to encountering postprandial hypotension [3].

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conditions, there could be symptom unawareness [28, 29]. When patients do not report these typical symptoms, assessment may end there, and the clinician may falsely conclude that OH is absent. However, a previous study found that only 43% of patients experienced typical symptoms of OH, and one-third were completely asymptomatic [28, 30]. The researchers believe that one explanation for symptoms unawareness in this situation could be the global cerebral hypoperfusion caused by drop in blood pressure below the required level to process neuronal afferent signals of hypoperfusion and to generate symptoms.

Postprandial Hypotension Postprandial hypotension can cause syncope and falls in older adults. Clinicians should have a high suspicion especially in older adults with Parkinson’s disease, diabetes mellitus, and ESRD [3]. The majority of patients with postprandial hypotension are asymptomatic, and the diagnosis is often missed [31]. In patients with Parkinson’s disease, postprandial hypotension is associated with anosmia, constipation, orthostatic hypotension, and preprandial hypertension at rest [32]. Symptoms of OH should be graded for assessment and to monitor progress by obtaining screening questionnaires. However, given the significant percentage of patients that are asymptomatic, serial measurement of the blood pressure and heart rate sitting and standing are important and should be a routine component of the clinical assessment [33].

Evaluation and Assessment Symptoms Orthostatic Hypotension Orthostatic hypotension Can cause lightheadedness, dizziness, wooziness, presyncope and syncope, blurred vision, and even angina or stroke. Many times, older patients may present with atypical symptoms such as confusion, fatigue, or coat hanger pain. However, in about 33–43% of older adults with neurodegenerative

The clinician needs to focus on identifying treatable conditions that may be causative or contributory, by reviewing a detailed medication list, prescription and nonprescription (the “brown bag” evaluation), obtaining a thorough medical history and identifying the presence of hypertension, congestive heart failure, dementia, frailty,

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malignancy, diabetes, alcoholism, and polypharmacy, and identifying causes of potential volume loss such as vomiting, diarrhea, fluid restriction, and dehydration. On physical exam, one should look for evidence of parkinsonism, ataxia, peripheral neuropathy with distal sensory loss and a positive monofilament test, and hypo/areflexia, or dysautonomia with abnormal pupillary response, signs of gastroparesis, constipation or erectile dysfunction, and positive orthostatic vital signs. Obtaining orthostatic vital signs is very important given the fact that up to 40% of older adults with neurodegenerative conditions might by asymptomatic. As the recommended frequency of BP measurements varies between guidelines [34, 35], once identified that the patient has orthostatic hypotension, the serial BP and HR measurements should occur at 30, 60 s, and every minute for 8–10 min. If the HR fails to increase by 10–15 bpm while blood pressure drops, it suggests neurogenic orthostatic hypotension [36, 37]. Laboratory tests should include a CBC, BMP, TSH, vitamin B12, and folic acid. If a cardiac cause is suspected, an ECG, echocardiogram, and event monitor should be performed. In patients with severe neurogenic dysautonomia, there can be variation of the R-R interval on resting electrocardiogram, beat-to-beat blood pressure, and blunted HR variability induced by Valsalva maneuver or other standardized stimuli [38]. For selected patients with postural hypotension or syncope, a tilt-table testing could be recommended; however, it may not be well tolerated in some older adults. There is evidence that ambulatory blood pressure monitoring is helpful in diagnosing nocturnal and supine hypertension, and postprandial hypotension, if recordings can be done during symptoms [18]. Detailed autonomic testing is not widely available but can be useful in documenting an underlying dysautonomia and establishing prognosis.

Postprandial Hypotension Symptomatic older adults, especially those with Parkinson’s disease, diabetes mellitus, and ESRD,

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should undergo ambulatory blood pressure monitoring, and meal documentation as to type, content, amount, and temperature. The postprandial blood pressure drop may occur within 35 min but can be as late as 2 h [3].

Management Management of OH and PPH consists of nonpharmacologic and pharmacologic interventions.

Nonpharmacologic Treatment of Orthostatic Hypotension Nonpharmacologic treatment of OH consists in teaching and educating patients and families or caregivers about avoiding triggers that could precipitate or exacerbate OH such as warm temperature, crowded places, hot showers, baths or sauna, prolonged physical exercise that results in lower extremity blood pooling on a stationary bike, treadmill, long plane, or car rides, with then sudden uprising from the sitting position, straining with breath holding (Valsalva maneuver), and ingestion of large meals with high content of carbohydrates. Also, education should target the physical maneuvers that could increase the peripheral vascular resistance and reduce the venous pooling, such as leg crossing, dorsiflexing the ankles, contracting the arms, legs muscles, and abdomen, making a fist, and tightening the buttocks before standing up. Also, bending forward while raising from sitting to supine position may help [39]. Patients should be advised to safely continue to exercise, to maintain/improve physical fitness, and to avoid deconditioning. The use of compressive garments such as compression stockings thigh high and an abdominal binder could help with reducing the venous pooling, mainly in the lower extremities, and in the splanchnic circulation which contains up to 25% of the blood volume at rest. However, patients with frailty and neurodegenerative conditions have difficulty putting these on, and/or tolerating these compressive garments. Some studies show lack of efficacy of the compression garments [40].

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Patients should be advised on proper intake of oral fluids 40–48 oz/day, and on sodium intake up to 6 g/day – caution for patients with cardiac and renal comorbid conditions [41]. If they have symptoms and significant drop in SBP, they should be advised to ingest rapidly a 500 ml oral bolus of water. The research shows that this intervention could increase the SBP by 30 mm Hg by stimulation norepinephrine and activating the sympathetic nervous system [41]. Patients should be recommended to sleep with the head of the bed elevated up to 20 , or up to 6–9 inch. Raising the head of the bed reduces supine hypertension and may decrease the nocturnal diuresis and increase orthostatic tolerance [42–44].

Pharmacologic Treatment of Orthostatic Hypotension After discontinuing hypotension-inducing medications, enhancing hydration, and adding dietary salt, patients with continued symptoms can be treated with medications. The therapeutic goal of the pharmacologic treatment is to ameliorate symptoms while avoiding side effects, and it is recommended to titrate according to symptoms rather than blood pressure values [45]. The treatment approach involves expanding intravascular volume with fludrocortisone 0.1 mg every other day to a maximum of 0.3 mg every day. Patients treated with fludrocortisone must be monitored for seated or supine hypertension, and edema. They should be educated to measure their blood pressure supine, sitting, and standing upon awakening; before and 1 h after lunch; and before going to bed. A home blood pressure diary is useful for identifying and avoiding supine hypertension and is useful for safe medication management. Another treatment approach is enhancement of vasoconstriction through direct activation of alpha adrenergic receptor or by increasing peripheral norepinephrine release with sympathomimetic agents such as midodrine (starting at 2.5 mg two or three times daily increasing to 10 mg three times daily as needed) and droxidopa, up-titrated as tolerated starting at 100–600 mg three times

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daily. Midodrine and droxidopa should be avoided within 5 h of bedtime in order to limit supine hypertension [45]. However, indirect comparisons suggest that the risk of supine hypertension appears to be lower with droxidopa than with midodrine [46]. There are supplementary agents that have been proposed in combination with firstor second-line agents in patients with persistent symptoms, such as caffeine, pyridostigmine, and low-dose atomoxetine, with limited evidence of their efficacy [47, 48].

Nonpharmacological Treatment of Postpradial Hypotension Strategies for the treatment of postprandial hypotension should be directed at (1) meal composition, particularly carbohydrate type and content, (2) slowing gastric emptying and/or small intestinal carbohydrate absorption by medications such as acarbose and guar, and/or (3) increasing postprandial gastric distension by drinking water before the meal [49, 50]. Nonpharmacologic measures of PPH include the following: drink a large volume (500 mL) of water before a meal [51], decrease carbohydrate intake, eat frequent, smaller meals, assume a recumbent or sitting position after a meal [3], and drink caffeinated beverages with meals [52]. Patients should avoid diuretics and eating during their hemodialysis sessions.

Pharmacologic Management of PPH Caffeine trial preprandial in doses of 60 up to 200 mg may be recommended in symptomatic patients. However, there is a lack of randomized controlled trials to definitively recommend this intervention. Use of alpha glucosidase inhibitors such as acarbose and voglibose improves the postprandial hypotension by reducing the absorption of the carbohydrates in the small intestine and postprandial hyperglycemia, improves abnormal splanchnic pooling, modulates the rate of gastric emptying, and increases the GLP-1 levels

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inducing satiety. Using of these agents might be limited by adverse gastrointestinal adverse reactions such as diarrhea and flatulence [53, 54]. Guar gum, which is derived from the guar bean, acts as a bulking agent and has a role in slowing glucose absorption, and it may prevent postprandial hypotension [3]. Using of guar might be limited by gastrointestinal adverse reactions such as diarrhea, abdominal pain, and flatulence. Octreotide, a somatostatin analog which acts by increasing splanchnic and peripheral vascular resistance, has been studied in the treatment of postprandial hypotension. Its use is limited by cost, and potential QT prolongation.

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OH and PPH should be considered in any older adult with dizziness, recurrent falls, near-syncope or syncope episodes, or cerebral ischemic symptoms [52]. Physicians should have an increased awareness about these geriatric hypotensive syndromes and play an active role in timely diagnosis and management of these conditions in an effort to decrease the morbidity and mortality associated with orthostatic and postprandial hypotension. Treatment always requires education of the patient and/or family and caregivers regarding triggering situations and physiological countermaneuvers, along with other appropriate nonpharmacologic interventions, as well as pharmacologic management.

Prognosis References Orthostatic hypotension is a risk factor for cardiovascular and all-cause mortality [55]; when symptomatic, postural hypotension can cause falling, which has significant associated morbidity in a frail older population [8]. Several studies have demonstrated that older patients with OH have an approximately 2.5 times greater risk of recurrent falls compared with their elderly counterparts without OH, thus increasing the likelihood of fractures, head injury, and other trauma that may shorten the life span [56]. OH has been correlated to cognitive decline in the absence of an associated neurodegenerative condition by neuronal injury from chronic or repeated episodes of cerebral hypoperfusion [57]. Postprandial hypotension has been associated with increased risk of syncope, falls, stroke, angina, and increased mortality [31].

Conclusions Orthostatic and postprandial hypotension are common conditions in older adults and can be asymptomatic in a significant number of patients. Therefore, symptom screening without serial measurement of blood pressure and heart rate leads to false negative detection of these conditions in a substantial proportion of patients.

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37. Piha SJ. Age-related diminution of the cardiovascular autonomic responses: diagnostic problems in the elderly. Clin Physiol. 1993;13:507–17. 38. Furukawa K, Suzuki T, Ishiguro H, et al. Prevention of postprandial hypotension-related syncope by caffeine in a patient with long-standing diabetes mellitus. Endocr J. 2020; https://doi.org/10.1507/endocrj.EJ19-0370. 39. Wieling W, van Dijk N, Thijs RD, de Lange FJ, Krediet CT, Halliwill JR. Physical countermeasures to increase orthostatic tolerance. J Intern Med. 2015;277:69–82. 40. Podoleanu C, Maggi R, Brignole M, Croci F, Incze A, Solano A, et al. Lower limb and abdominal compression bandages prevent progressive orthostatic hypotension in elderly persons: a randomized single-blind controlled study. J Am Coll Cardiol. 2006;48:1425–32. 41. Newton JL, Frith J. The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging. Neurology. 2018;91(7):e652–6. https:// doi.org/10.1212/WNL.0000000000005994. 42. Fan CW, Walsh C, Cunningham CJ. The effect of sleeping with the head of the bed elevated six inches on elderly patients with orthostatic hypotension: an open randomised controlled trial. Age Ageing. 2011;40: 187–92. 43. Wieling W, Raj SR, Thijs RD. Are small observational studies sufficient evidence for a recommendation of head-up sleeping in all patients with debilitating orthostatic hypotension? MacLean and Allen revisited after 70 years. Clin Auton Res. 2009;19:8–12. 44. Saladini F, Di Marco A, Palatini P. Autonomic dysfunction: how to identify and when to treat? High Blood Press Cardiovasc Prev. 2016;23:237–43. https://doi.org/10.1007/s40292-016-0162-3. 45. Sinn DI, Gibbons CH. Pathophysiology and treatment of orthostatic hypotension in parkinsonian disorders. Curr Treat Options Neurol. 2016;18(6):28. https://doi. org/10.1007/s11940-016-0410-9. 46. Chen JJ, Han Y, Tang J, Portillo I, Hauser RA, Dashtipour K. Standing and supine blood pressure outcomes associated with droxidopa and midodrine in patients with neurogenic orthostatic hypotension: a Bayesian metaanalysis and mixed treatment comparison of randomized trials. Ann Pharmacother. 2018;52(12):1182. 47. Byun JI, Moon J, Kim DY, et al. Efficacy of single or combined midodrine and pyridostigmine in orthostatic hypotension. Neurology. 2017;89(10):1078–86. https://doi.org/10.1212/WNL.0000000000004340.

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Syncope Andrea Ungar, Martina Rafanelli, Giulia Rivasi, and Irene Marozzi

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Pathophysiology of Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412 Syncope Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurally Mediated or Reflex Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Orthostatic Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiac Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

413 413 415 415

Diagnosing Syncope in the Older Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Initial Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Carotid Sinus Massage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additional Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tilt Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Pressure Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autonomic Function Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrocardiographic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

416 416 418 418 419 419 419 421

Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Treating Reflex Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Treating Orthostatic Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Special Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Syncope and Falls in the Older Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Syncope and Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 Male, 86 Years Old . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 Proximate Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424 Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

Abstract A. Ungar (*) · M. Rafanelli · G. Rivasi · I. Marozzi Syncope Unit, University of Florence and Azienda Ospedaliero-Universitaria Careggi Florence, Florence, Italy e-mail: andrea.ungar@unifi.it; martina.rafanelli@unifi.it © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_29

The prevalence of syncope increases with advancing age and is associated with significant morbidity and mortality. Age per se should not be considered a barrier to the assessment and 411

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treatment of syncope. On the contrary, older patients with syncope require an early and detailed investigation and management. The diagnosis within this population can be complex due to atypical presentations, amnesia for events, absence of witnesses, and overlap with other clinical presentations as falls. Falls unrelated to specific medical or accidental conditions are defined unexplained and may underlie a syncopal mechanism. A comprehensive assessment of comorbid conditions and drug regimen is necessary. A standardized guidelines-based approach on neurally mediated syncope, through active standing test, Carotid Sinus Massage and Tilt Testing, is well tolerated in older patients. Advances in cardiac monitoring devices have increased the diagnostic yield for cardiac syncope. Treatment of syncope ranges from simple conservative measures to permanent cardiac pacing.

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frequent cause at all ages [5]; cardiac syncope is the second most common cause [6]; orthostatic hypotension (OH) is a frequent cause of syncope in very old patients. In the elderly, multiple causes are often present, and the diagnosis within this population can be complex due to atypical presentations, amnesia for events, absence of witnesses, and overlap with other clinical presentations, as unexplained falls [6]. The older patient with syncope requires an early and detailed investigation and management through a comprehensive assessment of comorbid conditions and drug regimen and a standardized guidelines-based approach. The aim of this chapter is to shed light on the various causes of syncope, to help the clinician dealing with clinical presentation and initial evaluation, and to know when and how to perform and interpret the second-level evaluation and how to choose the best management for the various forms of syncope.

Keywords

Syncope · Neurally mediated syncope · Falls · Unexplained falls · Elderly · Older patient · Geriatric medicine

Introduction Syncope is a transient loss of consciousness (TLoC) due to a transient global cerebral hypoperfusion, characterized by a rapid onset, short duration, spontaneous, and complete recovery [1]. Despite its frequency in the general population [2], the real estimation of its incidence is challenging because different definitions have been used in existing epidemiological studies and because most of the patients with syncopal episodes do not seek medical assistance. The first-time incidence of syncope by age is bimodal with a very high prevalence between the age of 10 and 30 years, which peaks again above the age of 65 years [3]. From the age of 70, the incidence of syncope increases rapidly up to 81.2 per 1000 patient years 80 years of age [4]. The prevalence of the different causes of syncope changes by age: reflex syncope is the most

Pathophysiology of Syncope The global cerebral hypoperfusion is what differentiates syncope from others TLoC as epilepsy, hypoglycemia, and episodes of only apparent loss of consciousness, as falls [1]. A list of clinical conditions incorrectly diagnosed as syncope is provided in Table 1 [1]. Cerebral autoregulation maintains a constant blood flow within a wide range of pressures [systolic blood pressure (SBP) between 60 and 190 mmHg]. When SBP decreases below this threshold, the brain perfusion decreases slowly and progressively, and if this hemodynamic status lasts for 8–15 s, ischemia and ultimately loss of consciousness will follow [7]. Therefore, the main mechanism is a fall in systemic blood pressure (BP), which may depend on a reduction of vascular total peripheral resistance (TPR) and/or cardiac output (CO). Vascular TPR may be reduced by an inappropriate reflex activity causing vasodilatation through withdrawal of sympathetic vasoconstriction (vaso-depressive reflex syncope) or by functional and structural impairment of the autonomic nervous system. A reduction in CO may be

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Table 1 Conditions that may be incorrectly diagnosed as syncope, adapted from Brignole M. et al. [1] Generalized seizures Complex partial seizures PPS or “pseudocoma” Falls Cataplexy falls Intracerebral or subarachnoid hemorrhage Vertebrobasilar TIA Carotid TIA Subclavian steal syndrome Metabolic disorders including hypoglycemia, hypoxia, and hyperventilation with hypocapnia Intoxication Cardiac arrest Coma PPS psychogenic pseudosyncope, TIA transient ischemic attack

caused by reflex bradycardia (cardio-inhibitory reflex syncope), by cardiovascular causes (arrhythmia, structural disease including pulmonary embolism and pulmonary hypertension), by inadequate venous return due to volume depletion or venous pooling, and by chronotropic and inotropic incompetence, through autonomic failure. An interaction between different mechanisms is also possible; thus, a low TPR may cause venous pooling of blood in the abdomen and lower limbs, which in turn decreases venous return and consequently CO [8]. Blood pressure adjustments on assuming the upright position in the older patient rely mostly on an increase in peripheral resistance [9], explaining the attributable role of vasoactive drugs as precipitating factors for syncope in the elderly. On assuming the standing position, there is an abrupt HR increase toward a primary peak at around 3 s, a further increase to a secondary peak at around 12 s, and finally a decline to a relative bradycardia at around 20 s, with a gradual subsequent increase. The initial biphasic HR response on active standing decreases with age, and the primary peak at 3 s is no longer present [10]. Age-related physiologic impairments of heart rate (HR), blood pressure, and cerebral blood flow, in combination with comorbid conditions such as heart failure, diabetes, and chronic obstructive lung disease, concurrent medications,

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and neuro-humoral adjustments, contribute to increase the risk of cerebral hypoperfusion and susceptibility to syncope.

Syncope Etiology A classification of the principal causes of syncope is provided in Table 2 [11].

Neurally Mediated or Reflex Syncope Vasovagal Syncope Central triggers such as fear, pain, and instrumentation or peripheral triggers such as orthostatic stress or hot environment might induce vasovagal syncope (VVS), which in the elderly has often an atypical presentation with uncertain stimuli or even apparently without triggers. Nausea, blurred vision, and diaphoresis are the most common prodromal symptoms in VVS but may be short, and the loss of consciousness may start abruptly, leading to falls and injuries [12]. In this context, retrograde amnesia has been demonstrated in patients with syncope induced on tilt testing (TT); indeed, about 25% of patients fail to recall their prodromes and TLoC during tiltinduced syncope [13]. Myoclonic movements are less frequent in older subjects, as the cerebral hypoperfusion relies mostly on a slower blood pressure drop instead of an asystolic response, which is typical of younger patients. The frequency of autonomic symptoms during the recovery phase is lower in older subjects; thus, the clinical features of VVS are very similar to those of cardiac syncope [14]. Carotid Sinus Syncope Carotid sinus syncope is defined when symptomatic cerebral hypoperfusion due to cardioinhibition, vaso-depression, or both is induced by stimulation at the site of the neck where the common carotid artery bifurcates, in those individuals in whom the carotid sinus reflex carries an abnormal response [15]. The reproduction of BP drop and/or HR responses while performing the carotid sinus

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Table 2 Classification of syncope, adapted from Moya et al. [11] Reflex (neurally mediated) syncope Vasovagal (VVS) Orthostatic VVS: Standing or less common sitting Emotional: Fear, pain, instrumentation, blood phobia Pain triggers: Peripheral or visceral Situational Micturition Gastrointestinal stimulation (swallow, defecation) Cough, sneeze Others (e.g., laughing, brass instrument playing, weight lifting, post-exercise) Carotid sinus syncope Orthostatic syncope Drug-induced orthostatic hypotension (e.g., vasodilators, diuretics, phenothiazine, antidepressants) Volume depletion (e.g., hemorrhage, diarrhea, vomiting, etc.) Primary autonomic failure (pure autonomic failure, multiple system atrophy, Parkinson’s disease, dementia with Lewy bodies) Secondary autonomic failure (diabetes, amyloidosis, spinal cord injuries, autoimmune autonomic neuropathy, paraneoplastic autonomic neuropathy, kidney failure) Cardiac syncope Arrhythmia as primary cause: Bradycardia: Sinus node dysfunction (including bradycardia/tachycardia syndrome) Atrioventricular conduction system disease Implanted device malfunction Tachycardia: Supraventricular Ventricular (idiopathic, secondary to structural heart disease or to channelopathies) Structural disease: Cardiac valvular disease, acute myocardial infarction/ischemia, hypertrophic cardiomyopathy, cardiac masses (atrial myxoma, tumors, etc.), pericardial disease/tamponade, congenital anomalies of coronary arteries, prosthetic valve dysfunction Cardiopulmonary and great vessels Pulmonary embolus, acute aortic dissection, pulmonary hypertension

massage (CSM) is defined as carotid sinus hypersensitivity; can manifest as cardio-inhibitory (asystole 3 s during CSM), vaso-depressor (a fall in SBP 50 mmHg during CSM), or mixed; and represents a positive response to CSM in an asymptomatic patient [1]. CI-CSH, in patients with a clinical diagnosis of suspected neurally mediated syncope, has been related to a long asystolic reflex detected by an implantable loop recorder (ILR) at the time of the spontaneous syncope [16]. CSH is common in older males without history of syncope, especially when affected by cardiovascular diseases [17]. When CSH occurs in a patient who previously had syncope with reproduction of symptoms, it is defined as carotid sinus syndrome (CSS) [1]. The prevalence of CSS has been estimated to range

from 20 mmHg within 15 s of standing followed by a spontaneous recovery, which is detectable by beat-to-beat BP monitoring [8]. IOH may have implications in older adults on vasoactive drugs [22] and may exacerbate the risk of falling; the 15% of long-term care residents indeed fall right after standing [23]. • Classical OH, detected on active or passive standing on tilt of at least 60 , within 3 min of upright position [8]. • Delayed OH (DOH), defined as OH occurring beyond 3 min of active or passive standing on tilt and characterized by a slow and progressive decrease of SBP. Hypotension can manifest clinically up to 30 min after the achievement of the upright position, and passive TT is needed for the diagnosis [8]. DOH is common in older patients and depends on the impairment of compensatory reflexes and increased heart stiffness,

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which leads to a higher susceptibility to decrease in preload [24]. The leading cause of OH in the older patient is pharmacotherapy (Table 3) [25]. Alpha-receptor blockers, nitrates, or benzodiazepines predict OH in this age group [21]. Other causes of OH are represented by primary autonomic failure (e.g., idiopathic Parkinson’s disease and multiple system atrophy), secondary autonomic failure (e.g., diabetic and alcoholic autonomic neuropathy), and dehydration. Occasionally, OH may be the first manifestation of malignancy or anemia, which should be excluded particularly in the older population [26].

Cardiac Syncope Cardiac syncope is more represented in the older than in the young population [27]. A syncope with an abrupt onset, occurring in the supine position, during exercise, rather than after, which is associated with palpitations or chest pain, should prompt the exclusion or confirmation of a cardiac cause, until proven otherwise. Cardiac syncope must be excluded in patients with known or suspected left ventricular systolic dysfunction, valvulopathies, and left ventricular outflow tract obstruction and in those with an abnormal electrocardiogram (ECG) and where the clinical context and concomitant investigations suggest pulmonary embolism. Neurally mediated cause of symptoms must not be assumed in any patient with these clinical and diagnostic features until a cardiac cause has been effectively excluded. A history of heart disease is indeed an independent predictor of cardiac syncope with a sensitivity of 95% and a specificity of 45% [28]. Arrhythmias are the most common cardiac causes of syncope. Both brady- and tachyarrhythmias may predispose to syncope. Guidelines [1] and clinical scoring systems [28] for identifying high-risk patients include arrhythmias as a predictor of death and adverse events. Older adults often have multiple potential causes of syncope, as coexisting OH and VVS [20], and a definite diagnosis is not always

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Table 3 Drugs causing orthostatic blood pressure drop, adapted from Gibbons C.H. et al. [25] Class of drugs Dopaminergic agents Antidepressant (tricyclic agents) Anticholinergics Antihypertensive agents Preload reducers Diuretics Nitrates Phosphodiesterase E5 inhibitors Vasodilators Alpha-1 adrenergic antagonists Dihydropyridine calcium channel blockers Other direct vasodilators Negative inotropic/chronotropic agents Beta-adrenergic blockers Non-dihydropyridine calcium channel blockers Central sympatholytic agents Centrally acting alpha-2 agonists False neurotransmitters Renin-angiotensin system (RAS) antagonists ACE inhibitors ARB

Examples Levodopa, dopamine agonists Amitriptyline, nortriptyline, imipramine, desipramine Atropine, glycopyrrolate, hyoscyamine

Furosemide, torsemide, acetazolamide, spironolactone, hydrochlorothiazide Nitroprusside, isosorbide dinitrate, nitroglycerin Sildenafil, vardenafil, tadalafil Alfuzosin, doxazosin, tamsulosin Amlodipine, nifedipine, nicardipine Hydralazine, minoxidil Metoprolol, propranolol, atenolol, bisoprolol, etc. Verapamil, diltiazem

Clonidine Alpha-methyldopa Captopril, enalapril, perindopril Losartan, telmisartan, candesartan

ACE angiotensin-converting enzyme, ARB angiotensin receptor type II blockers

found. The most common contributing causes of syncope in older adults are orthostatic/postprandial hypotension, followed by cardiac disorders [29]. Each patient should undergo a comprehensive evaluation, without stopping at the apparently first etiological diagnosis.

Diagnosing Syncope in the Older Patient The European Society of Cardiology (ESC) guidelines [1] suggest a standardized approach to the assessment and management of syncope, which is easy to use at any age and allows the reduction of unexplained syncope [6] (Fig. 1) [11].

Initial Evaluation The initial evaluation should answer if the event was a TLoC or not, if the origin of TLoC was

syncopal or not, if there was a clear etiological diagnosis of the suspected syncope, and if there was evidence of high risk of cardiovascular events or death [1]. The initial syncope evaluation consists of the following: • A careful history taking of present and previous attacks should focus on the time of the day, season, relationship with meals, nocturnal micturition, supine or upright position, drugs, duration of treatment, and time-relationship between drug consumption and appearance of adverse effects. The physician should search for the presence or absence of prodromal symptoms, the length of the loss of consciousness, the characteristics of the recovery phase, consequent injuries, and the impact of the event on confidence and ability to carry out basal/instrumental activities of daily living independently. Eyewitness accounts, in person, through a telephone interview, or through a video

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History, physical examination, ECG

Possible diagnosis

Definite diagnosis

Absence of definite or possible diagnosis

Treatment Cerebrovascular Cause

Neuro -mediated cause

Carotid Doppler Ultrasonography EEG* CT scan* Carotid Massage Echocardiogram Stress test ECG - 24 hours* Lung scan* Coronary Angiography* – – Electrophysiological study –

Carotid Massage Head-up tilt ABPM*

Cardiac Cause

Arrhythmias

Low cardiac output

–

Stress test ECG-24 hours

MSC Head-up tilt

Head-up tilt

–

Psychiatric evaluation* –

–

Unexplained syncope Recurrent or malignant syncope Intermittent loop recorder

Fig. 1 Standardized algorithm for the diagnosis of transient loss of consciousness, adapted from Moya A. et al. [11]

recording of the episode, should be collected as retrograde amnesia is frequent in older patients with syncope. The history taking should also include comorbidities, aspects of physical frailty and locomotor disabilities, details of cognitive status, functional capacity, and social circumstances of the patient. Precise details of the drug regimen have to be collected as numerous drugs, as alphareceptor blockers, nitrates, or benzodiazepines, were found to be predictors of OH; therefore, attention should be paid on the reappraisal of the drug regimen in the presence of OH in order to reduce the syncope recurrence [25]. Clinical features of syncope suggesting the diagnosis on the initial evaluation are listed in Table 4 [1]. • The physical examination should include a comprehensive cardiovascular and neurological assessment, searching for Parkinson’s

disease or other neurodegenerative conditions related to autonomic dysfunction, coupled with a careful observation of gait and standing balance for the evaluation of the locomotor system and the consequent risk of falling. • The active standing test consists of the measurement of BP in the supine position and then immediately after changing from the supine to the upright position and after 1 and 3 min of orthostatic position. Given the age-related increase in OH, standing BP measurements are mandatory in the elderly and should be repeated, preferably in the morning and/or “promptly” after a syncope, as the standing fall in BP is not always reproducible, especially when related to drugs or predisposing conditions [11]. • 12-lead ECG can be considered diagnostic and permits no further evaluation and institution of treatment, in cases of persistent sinus bradycardia 3 s; Mobitz II second- or third-degree atrioventricular block, alternating left and right bundle branch block; ventricular tachycardia (VT) or rapid paroxysmal supra-ventricular tachycardia; nonsustained episodes of polymorphic VT and long or short QT interval; acute ischemia with or without myocardial infarction [11].

Carotid Sinus Massage Carotid sinus massage may be performed within the initial evaluation in older patients, when there is a high suspicion of CSS, which is frequently responsible for syncope and unexplained falls in this age group [1].

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Under continuous HR and beat-to-beat BP monitoring, the clinician exerts pressure on the carotid sinus for 10 s, bilaterally, first in the supine and then in the upright position, on tilt table at an angle of 60 . The added diagnostic value of repeating CSM in the upright position has been well documented [30]. In order to assess the contribution of the vasodepressive component, CSM may be repeated after intravenous administration of 0.02 mg/Kg of atropine, which eliminates vagally induced asystole, thereby unmasking the vasodepression [31]. This quantification of the vaso-depressive component is clinically relevant because it has been shown that pacemaker therapy is less effective when the vaso-depressive effect is large, compared with predominant cardio-inhibition [32]. Transient ischemic attack or stroke during the 3 months beforehand or critical carotid artery stenosis on Doppler ultrasounds performed in the presence of carotid bruits represents relative contraindications to CSM [33]. In these situations, a careful risk/benefit assessment must be undergone.

Additional Tests Clinical history and physical examination should guide the choice of performing additional test. Prioritizing less expensive and higher yield tests may enable a more informed and cost-effective approach to evaluating syncope in older adults. Routine blood tests (cardiac enzymes, electrolytes, complete blood count, lactate, blood cultures, D-dimer) uncover an etiology of syncope in only 2% of the patients [1]. Cardiac enzymes are of little value if drawn routinely on older adults with syncope. Cardiac enzymes should only be drawn if the patient has other signs or symptoms suggestive of myocardial ischemia by history, such as chest pain, dyspnea, a concerning ECG, and an ECG that is uninterpretable for ischemia [34]. The echocardiogram may give a diagnosis in 2–22% of the cases, most often from aortic stenosis. The echocardiogram should be performed when the physical examination reveals a cardiac murmur. However, in the absence of history of a

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murmur or an audible murmur on examination, a valvular etiology for the syncope is unlikely [35]. Head computed tomography (CT) scans should be limited to cases of syncope and either neurologic deficit, neurologic complaints, or concomitant signs of head trauma [36]. Intracranial bleedings without evidence of trauma may be present in the older patient; thus, neurological assessment and evaluation for changes in a patient’s baseline mental status are mandatory. Electroencephalography has a low diagnostic benefit and should not be performed routinely [37]. Device interrogation is performed almost universally in patients with implantable cardiac defibrillators or pacemakers to assess for malfunction or new arrhythmias [38].

Tilt Testing The clinical situation corresponding to tiltinduced syncope is the one triggered by prolonged standing. Tilt testing should be considered to confirm a diagnosis of reflex syncope in patients with a suspected but not certain diagnosis after the initial evaluation and for the assessment of autonomic failure, especially for the reproduction of delayed OH. The test could reveal a susceptibility to vertical posture stress, defined as “hypotensive susceptibility,” which could cause syncope irrespective of the etiology of syncope itself [39]. The identification of hypotensive susceptibility makes TT a risk stratification tool, rather than only a diagnostic one, for patients with recurrent, traumatic syncope and ECG documentation of spontaneous asystolic reflex syncope, as showed in the ISSUE 3 Study [40], who could greatly benefit from pacing, especially when TT is negative, because of a pure cardio-inhibition [41]. TT can also be useful in guiding the differential diagnosis between syncope and unexplained falls, given the high rate of coexistence and misdiagnosis of these two clinical conditions in the older patient. It has been confirmed that the positivity prevalence of TT and CSM was similar in patients who experienced syncope and/or unexplained falls, suggesting that a comprehensive evaluation should

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be routinely performed in older patients with history of undetermined falls [1, 42]. Syncope is frequently associated with abnormal movements such as myoclonic jerks, oral automatism, head-turning, and urinary incontinence, thus mimicking the clinical presentation of epileptic seizures [1]. Syncope and seizures may coexist in a patient, either by pure chance or by pathophysiology. In this clinical context, the application of a standardized and guidelines-based protocol, comprising a careful evaluation and tilt testing, is useful for the differential diagnosis [43]. The test should be performed in the morning, in fasting state, in a quiet and dimly lighted place. Briefly, the test consists of 20 min of passive orthostatic position at an angle of 60 that is potentiated, if syncope does not occur, on administration of sublingual nitroglycerin (400 μg) (Italian Protocol) with a further 15 min of observation at the same angle. The test is positive if symptoms reproducing those reported by the patient during the spontaneous syncope are associated with hypotension, bradycardia, or both [1]. TT showed a similar positivity rate and specificity in the older population compared to what observed in younger patients [44] and is safe and well tolerated even in octogenarians, without major complications (such as sustained ventricular tachycardia, ventricular fibrillation, transient ischemic attack, stroke, and death). Thus, the test can be safely performed at any age [45].

Blood Pressure Monitoring Ambulatory BP recordings may be helpful in identifying abnormal diurnal patterns, as orthostatic, postprandial, post-exercise, or post-drug hypotension. These recordings may also help identify supine or nocturnal hypertension in treated patients [1] (Fig. 2).

Autonomic Function Tests To assess the autonomic function in patients with suspected autonomic failure as the underlying

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Fig. 2 A pattern of nocturnal hypertension and postprandial hypotension on ambulatory blood pressure monitoring

mechanism of syncope, Valsalva maneuver and deep breathing test should be performed [8]. The Valsalva maneuver provides a potential measure of sympathetic, vagal, and baroreceptor function; the efferent baroreflex arc consists of sympathetic and parasympathetic pathways. The maneuver is typically performed in the supine position by blowing through a mouthpiece connected to a mercury manometer for 10–20 s. The mercury column of the manometer is maintained at 40 mmHg. An expiratory pressure of 40 mmHg appears to result in an optimal response; lower levels do not provide an adequate stimulus, while higher levels result in poor reproducibility. The hemodynamic response to the maneuver may be attenuated by the buffering effect of blood within the thoracic cavity. Thus, the patient position during and duration of rest preceding the maneuver significantly affect test results. The hemodynamic response to the increase in intrathoracic and intra-abdominal pressure in normal subjects may be divided into four phases. In phase 1, there is a transient rise in BP and a fall in HR due to compression of the aorta and

propulsion of blood into the peripheral circulation, mainly not accompanied by an increase in muscle sympathetic nerve activity (MSNA). In early phase 2, there is a fall in BP, followed by a recovery of BP in late phase 2. These BP changes are accompanied by an increase in HR. The fall in cardiac output due to impaired venous return to the heart results in compensatory increase of HR, MSNA, and peripheral resistance. In phase 3, there is a fall in BP and increase in HR that occurs with cessation of expiration due to the release of expiratory pressure. In phase 4, there is an increase in BP above the baseline value, so called overshoot, due to the residual vasoconstriction and now normal venous return. An indirect measure of the parasympathetic autonomic function is the ratio of the shortest RR interval (the tachycardia) during or after phase 2 of the maneuver to the longest RR interval (the bradycardia) in phase 4 of the maneuver, so called Valsalva ratio. Age- and gender-based norms should be taken into consideration for the Valsalva ratio [46].

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Respiratory mediated heart rate variability is the most widely used index of cardiac parasympathetic function. During the deep breathing test, the patient is asked to breathe deeply at six breaths per minute for 1 min. In healthy individuals, HR rises during inspiration and falls during expiration. Respiratory sinus arrhythmia is dependent on both the frequency and the depth of respiration and is attenuated with advancing age [46]. The hemodynamic changes during the maneuvers should be monitored using beat-to-beat continuous noninvasive BP measurement and ECG. Autonomic function tests require patients’ compliance and are not always reproducible in the older patient.

Electrocardiographic Monitoring The gold standard for the diagnosis of arrhythmic syncope is the correlation between symptoms and ECG recording. The absence of an arrhythmia during a syncopal episode allows exclusion of an arrhythmia as the mechanism of the syncope [1]. ECG monitoring is aimed at diagnosing intermittent brady- and tachyarrhythmia and is indicated when there is a high pre-test probability of identifying an arrhythmia associated with syncope. Duration and technology of monitoring may vary, and the choice between one kind and other should be selected according to the risk and the predicted recurrence rate of syncope [1]. In-hospital monitoring is indicated when the patient is at high risk of life-threatening arrhythmia, and although the diagnostic yield varies from 1.9% to 16%, it is justified by the need to avoid immediate risk to the patient [35, 47]. Holter ECG monitoring in syncope has higher diagnostic value if symptoms are very frequent, as daily episodes might increase the potential for a correlation between symptoms and ECG. However, since in most of the patients symptoms do not relapse during the monitoring period, the true yield of Holter ECG in syncope may be as low as 1–2% [1]. Loop recorders, external (ELR) or implantable (ILR), have a loop memory that continuously records and deletes ECG. When activated by the

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patient, typically after a symptom has occurred, 5–15 min of pre-activation ECG is stored and can be retrieved for analysis. ELR can be useful in patients with relatively frequent syncope, when used early after the last episode [1]. ILR is implanted subcutaneously and has a battery life of more than 36 months. Last generation devices have a reduced size, with the same memory and battery, allowing a minimally invasive implantation and a daily wireless transmission to a service center with warning reports for predefined events [48]. ILR can be used either at the beginning or at the end of the diagnostic workup of the patients with syncope, as it has showed similar diagnostic yield [49]. Despite a high initial cost, the analysis of the cost per symptom–ECG yield has shown that ILRs may be more cost-effective than a strategy using conventional investigation [1].

Treatment The treatment of patients with syncope is based on risk stratification and identification of specific mechanisms. The therapy to prevent syncope recurrence often differs from that for the underlying disease. Even if bradycardia is a frequent mechanism of syncope, cardiac pacing, which is the most effective treatment for bradycardia, is less powerful in case of coexisting hypotensive component, as hypotensive reflex or orthostatic syncope is more challenging to be treated. An arrhythmic syncope would benefit from cardiac pacing, implantable cardioverter-defibrillators, and/or catheter ablation; in case of structural cardiac or cardiopulmonary disease, the treatment would be best directed at amelioration of the specific structural lesion or its consequences [1].

Treating Reflex Syncope The cornerstone of management of reflex syncope is nonpharmacological treatment, as education and reassurance regarding the benign nature of the condition, lifestyle modification, and avoidance of triggering situations [1].

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The physician should consider and revise the drug regimen, aiming at achieving an average SBP values around 140 mmHg, or at least below 150 mmHg, as per current guidelines’ recommendations [50]. The recurrence of syncope and pre-syncope is safely reduced by discontinuing/ reducing vasoactive therapy, without increasing the risk of cardiovascular and neurological events [51]. A recent algorithm to guide blood pressure management in patients with hypertension and syncope has been proposed, according to age, frailty status, characteristics of syncope, and cardiovascular risk. In individuals who are frail and/or aged at least 70 years, an SBP of 130– 140 mmHg might then be recommended as a safer treatment target. A similar approach is also recommended in older people with a history or a high risk of falls. SBP values up to 160 mmHg can be accepted in individuals with severe frailty and/or disability, in view of the extremely high risk of syncope and falls and the limited evidence supporting BP lowering [52]. Syncope in older adults often manifests with brief, atypical, or even totally absent prodromal symptoms, which makes physical counterpressure maneuvers (leg crossing, arm tensing, or hand grip) hard to be applied in this age group. ESC guidelines on syncope recommend cardiac pacing in patients with dominant cardioinhibitory CSS (class 2a, level B) [1]. Cardiac pacing is effective in reducing the recurrence of syncope in patients aged 40 years with severe asystolic neurally mediated syncope, previously documented by an ILR [40]. Nevertheless, a coexisting hypotensive mechanism should be considered as a possible cause of syncopal relapses in paced patients with positive TT [41]. A guidelines-based diagnostic algorithm was proposed to assess the efficacy of cardiac pacing in patients aged >40 years, with severe unpredictable, recurrent reflex syncope, who underwent CSM, followed by TT if CSM was negative, followed by implantation of an ILR if TT was negative. Those who had an asystolic response to one of these tests received a dualchamber pacemaker [53]. The recurrence rate was similar in CSM+, TT+, and ILR+ patients and highly reduced in the year following implantation, compared to year before. The recurrence rate was

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also significantly lower than that observed in the group of patients with nondiagnostic test who had received an ILR, instead of a pacemaker. The guidelines-based diagnostic algorithm proposed proved a clinical utility for the selection of candidates to cardiac pacing in everyday clinical practice. The effectiveness of this algorithm and the benefit of cardiac pacing were maintained up to 3 years. The benefit of pacing was irrespective of the index diagnostic test but influenced by the results of TT. In patients with negative TT, the recurrence rate was very low, while in those with a positive TT, the probability of recurrence of syncope within 3 years was 23% in patients with asystolic tilt and 27% in patients with mixed or vaso-depressor tilt response [54].

Treating Orthostatic Syncope Nonpharmacological measures are important components of therapy for individuals with chronic OH and should be offered to all patients starting with education, removal or dosage adjustment of offending medications, and physical and dietary intervention. Avoidance of prolonged standing and exposure to high environmental temperatures (hot bath, shower, or sauna) will minimize venous pooling. Arising slowly, in stages, from supine or sitting to standing is particularly important in the morning, after meals and urination/defecation. Targeting a careful dosage regimen in patients with cardiac and renal disease, a volume expansion with dietary intake of 6–10 g of sodium per day in addition to hydration with a minimum of 1.25 to 2.50 liters of fluid, is beneficial in order to balance expected 24-hour urine losses. Avoiding large meals and preferring low carbohydrates and alcohol intake may reduce postprandial hypotension. Compression stockings and abdominal binders help minimize peripheral blood pooling and orthostatic intolerance [55]. In case of autonomic failure and supine hypertension, raising the head of the bed by 10–20 degrees at night reduced both hypertension and nocturnal diuresis and helped restore morning blood pressure upon standing [1].

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If behavioral measures do not attenuate symptoms sufficiently, pharmacological interventions may become necessary, considering the risk of worsening of supine hypertension. Fludrocortisone is a synthetic mineralocorticoid, which is indicated in order to increase plasma volume by renal sodium retention. Peripheral vascular resistance is the limiting factor of fludrocortisone treatment, resulting in dosedependent supine hypertension. Alpha-agonist midodrine has been used, achieving a proper vasoconstriction of the peripheral vessels. Nevertheless, its limitation is represented by a short half-life, which requires frequent dosing and limits a long-term compliance. Furthermore, its use is related to adverse effects on urinary outflow, which requires special caution in older males [1]. Pyridostigmine, a cholinesterase inhibitor, improves ganglionic transmission and vascular adrenergic tone in primarily upright position, mediating a slight increase in diastolic blood pressure during standing without worsening supine hypertension [1]. Droxidopa is an orally administered artificial amino acid converted both peripherally and centrally into norepinephrine. The enzyme responsible for the conversion, aromatic amino acid decarboxylase, is widely expressed, and so the administration of droxidopa increases norepinephrine even if postganglionic sympathetic neurons are not intact. The drug has received accelerated Food and Drug Administration (FDA) approval for the treatment of symptomatic OH. It has been recently demonstrated that droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP in patients with symptomatic OH due to different orthostatic intolerance syndromes, without worsening supine hypertension [56].

Special Population Syncope and Falls in the Older Patient Falling is a major geriatric syndrome, with an age-related prevalence as for syncope, affecting mortality, morbidity, and institutionalization [57].

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The lack of witnesses and the amnesia for the episode frequently lead to misdiagnoses, defining as “unexplained” those falls, which are not clearly related to accidental or medical condition or consequent to vasoactive drugs’ effect. Especially in older adults, a misdiagnosed syncope may underlie an unexplained fall. Those unexplained falls in which a final diagnosis of syncope is confirmed after a diagnostic workup have been recently defined as “syncopal falls” [58]. Postural blood pressure decreases could cause a falling event. Beat-to-beat measures of impaired orthostatic BP recovery as delayed recovery or sustained OH are independent risk factors for future falls, unexplained falls, and injurious falls. OH may also provoke falls through indirect mechanisms. In many cases, loss of consciousness is avoided, but increased fall’s susceptibility remains through pre-syncope and associated physiological impairments [59]. About 20% of cardiovascular syncope in patients older than 70 years old presents as a fall, especially in patients with CSS and OH. More than 20% of the older patients with CSS complain of falls as well as syncope [60]. Finally, the presence of comorbidity could worsen the prognosis, as older adults with Parkinson’s disease or diabetes mellitus and OH have poorer balance scores in comparison to those without OH.

Syncope and Dementia Blood pressure impairments including OH, hypertension, as well as acute and chronic cerebral hypoperfusion are associated with impaired cognitive performance in older adults [61]. The risk of falling is higher in older adults with dementia than in their cognitively intact counterparts and is frequently related to syncope [62]. Unexplained falls may indeed mask a diagnosis of syncope or pseudo-syncope in almost 50% of cases. Orthostatic syncope is more represented in this population compared to other causes of syncope and is more often related to the effect of vasoactive drugs, such as nitrates, diuretics, and ACE inhibitors alone or in combination [63, 64]. Precipitant factors in the clinical

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history (mainly including postural changes and neck movements) and a better cognitive function have been identified as independent predictors of syncopal falls in patients with cognitive impairment [65]. A guidelines-based diagnostic protocol can thus be used even in this special population of older adults, manifesting syncope or unexplained falls [62]. The identification of the causes of falls and of individuals with syncope-related falls may have important clinical and therapeutic implications that, in turn, may reduce the burden of fall-related morbidity and mortality in this subset of frequent fallers.

Case Study Male, 86 Years Old Comorbidities: Arterial hypertension, diabetes, and benign prostate hypertrophy. Drug regimen: Losartan, 100 mg, 1 pill in the morning; metformin, 850 mg, 1 pill twice a day; aspirin, 100 mg, 1 pill after lunch.

Picture 1 Clinical case, right tibia and fibula fracture

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Proximate Medical History June 2019: Two episodes of fall while walking, with a clear accidental dynamic and consequent upper limbs minor trauma. Few weeks after, the patient experienced a fall’s relapse while bike cycling, reporting right tibia and fibula fracture (Picture 1), and left shoulder fracture and dislocation. The patient was unable to recall the characteristic of the episode, and no witnesses’ account was available. The patient was admitted to ortho-geriatric ward. The physical examination revealed 2/6 L systolic aortic murmur; no other physical abnormalities were evident. The supine blood pressure was 130/70 mmHg. Given the inability of assuming the standing position autonomously, the active standing test was not performed. The 12-lead ECG was unremarkable. The supine right carotid sinus massage induced 14-s asystole, with reproduction of syncope (Picture 2). Right tibia and fibula external stabilization was performed (Picture 3), and the patient was

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Picture 2 Clinical case, supine right carotid sinus massage

Picture 3 Clinical case, right tibia and fibula external stabilization

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admitted to sub-intensive care unit for postsurgery clinical and electrocardiographic monitoring. Five days after, the patient underwent permanent bicameral pacemaker implantation. The long-term follow-up in syncope unit did not reveal syncopal or fall’s relapses.

Conclusion/Summary Diagnosing and managing syncope in the older patient may be complex due to confounding symptoms, atypical presentation, and comorbidities. Age should not be a barrier to assessment and treatment. Nevertheless, a guidelines-based approach may be performed even in the oldest old and in special population, as older patients with cognitive decline. A structured and comprehensive assessment, best performed within a specialized syncope service, can lead to diagnosis and appropriate management in the majority of the patients.

References 1. Brignole M, Moya A, de Lange FJ, et al. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39:1883–1948. 2. Soteriades ES, Evans JC, Larson MG, et al. Incidence and prognosis of Syncope. N Engl J Med. 2002;347: 878–85. 3. Ruwald MH, Hansen ML, Lamberts M, et al. The relation between age, sex, comorbidity, and pharmacotherapy and the risk of syncope: a Danish nationwide study. Europace. 2012;14:1506–14. 4. Olde Nordkamp LAR, van Dijk N, Ganzeboom KS, et al. Syncope prevalence in the ED compared to that in the general practice and population: a strong selection process. Am J Emerg Med. 2009;27:271–9. 5. Del Rosso A, Alboni P, Brignole M, et al. Relation of clinical presentation of syncope to the age of patients. Am J Cardiol. 2005;96:1431–5. 6. Ungar A, Mussi C, Del Rosso A, et al. Diagnosis and characteristics of syncope in older patients referred to geriatric departments. J Am Geriatr Soc. 2006;54: 1531–6. 7. Van Lieshout JJ, Wieling W, Karemaker JM, et al. Syncope, cerebral perfusion, and oxygenation. J Appl Physiol. 2003;94:833–48. 8. Brignole M, Moya A, de Lange FJ, et al. Practical instructions for the 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J. 2018;39:e43–80.

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24. Ricci F, De Caterina R, Fedorowski A. Orthostatic hypotension: epidemiology, prognosis, and treatment. J Am CollCardiol. 2015;66:848–60. 25. Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol. 2017;264:1567–82. 26. Marrison VK, Fletcher A, Parry SW. The older patient with syncope: practicalities and controversies. Int J Cardiol. 2012;155:9–13. 27. Brignole M, Menozzi C, Bartoletti A, et al. A new management of syncope: prospective systematic guideline-based evaluation of patients referred urgently to general hospitals. Eur Heart J. 2006;27:76–82. 28. Del Rosso A, Ungar A, Maggi R, et al. Clinical predictors of cardiac syncope at initial evaluation in patients referred urgently to general hospital: the EGSYS score. Heart. 2008;94:1620–6. 29. de Ruiter SC, Wold JFH, Germans T, et al. Multiple causes of syncope in the elderly: diagnostic outcomes of a Dutch multidisciplinary syncope pathway. Europace. 2017;0:1–6. 30. Parry SW, Richardson DA, O’Shea D, et al. Diagnosis of carotid sinus hypersensitivity in older adults:carotid sinus massage in the upright position is essential. Heart. 2000;83:22–3. 31. Solari D, Maggi R, Oddone D, et al. Assessment of the vasodepressor reflex in carotid sinus syndrome. Circ Arrhythm Electrophysiol. 2014;7:505–10. 32. Lopes R, Gonçalves A, Campos J, et al. The role of pacemaker in hypersensitive carotid sinus syndrome. Europace. 2011;13:572–5. 33. Davies AG, Kenny RA. Neurological complication following carotid sinus massage. Am J Cardiol. 1998;81:1256–7. 34. Grossman SA, Van Epp S, Arnold R, et al. The value of cardiac enzymes in elderly patients presenting to the emergency department with syncope. J Gerontol A Biol Sci Med Sci. 2003;58:1055–9. 35. Chiu DT, Shapiro NI, Sun BC, et al. Are echocardiography, telemetry, ambulatory electrocardiography monitoring and cardiac enzymes in emergency department patients presenting with syncope useful tests? A preliminary investigation. J Emerg Med. 2014;47:113–8. 36. Goyal N, Donnino MW, Vachhani R, et al. The utility of head computed tomography in the emergency department evaluation of syncope. Intern Emerg Med. 2006;1:148–50. 37. Sun BC, Costantino G, Barbic F, et al. Priorities for emergency department syncope research. Ann Emerg Med. 2014;64:649–55. 38. D’Angelo RN, Pickett CC. Diagnostic yield of device interrogation in the evaluation of syncope in an elderly population. Int J Cardiol. 2017;236:164–7. 39. Sutton R, Brignole M. Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J. https:// doi.org/10.1093/eurheartj/ehu255.

427 40. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neurally-mediated syncope and documented asystole. Third international study on syncope of unknown etiology (ISSUE-3): a randomized trial. Circulation. 2012;125:2566–71. 41. Brignole M, Donateo P, Tomaino M, et al. Benefit of pacemaker therapy in patients with presumed neurallymediated syncope and documented asystole is greater when tilt test is negative. An analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol. 2014;7:10–6. 42. Rafanelli M, Ruffolo E, Chisciotti VM, et al. Clinical aspects and diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls. Aging Clin Exp Res. 2014;26:33–7. 43. Ungar A, Ceccofiglio A, Pescini F, et al. Syncope and epilepsy coexist in ‘possible’ and ‘drug-resistant’ epilepsy (Overlap between Epilepsy and Syncope Study – OESYS). BMC Neurol. 2017;17:45. 44. Del Rosso A, Bartoletti A, Bartoli P, et al. Methodology of head-up tilt testing with sublingual nitroglycerin in unexplained syncope. Am J Cardiol. 2000;85: 1007–11. 45. Ungar A, Rivasi G, Rafanelli M, et al. Safety and tolerability of tilt testing and carotid sinus massage in the octogenarians. Age Ageing. 2016;45:242–8. 46. Low PA, Denq JC, Opfer-Gehrking TL, et al. Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects. Muscle Nerve. 1997;20:1561–8. 47. Benezet-Mazuecos J, Ibanez B, Rubio JM, et al. Utility of in-hospital cardiac remote telemetry in patients with unexplained syncope. Europace. 2007;9:1196–201. 48. Pürerfellner H, Sanders P, Pokushalov E, et al. Miniaturized reveal LINQ insertable cardiac monitoring system: first-in-human experience. Heart Rhythm. 2015;12:1113–9. 49. Brignole M, Vardas P, Hoffman E, et al. Indications for the use of diagnostic implantable and external ECG loop recorders. Europace. 2009;11:671–87. 50. William B, Mancia G, Spiering W, et al. ESH/ESC guidelines for the management of arterial hypertension. Eur Heart J. 2018;33:3021–104. 51. Solari D, Tesi F, Unterhuber M, et al. Stop vasodepressor drugs in reflex syncope: a randomised controlled trial. Heart. 2017;103:449–55. 52. Rivasi G, Brignole M, Rafanelli M. et al. Blood pressure management in hypertensive patients with syncope: how to balance hypotensive and cardiovascular risk. J Hypertens 2020;38:2356–2362. 53. Brignole M, Ammirati F, Arabia F, et al. Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes. Eur Heart J. 2015;36:1529–35. 54. Brignole M, Arabia F, Ammirati F, et al. Standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncope: 3-year insights from the Syncope Unit Project 2 (SUP 2) study. Europace. 2016;18:1427–33.

428 55. Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension A randomized, placebo-controlled, phase 3 trial. Neurology®. 2014;83: 328–35. 56. Malasana G, Brignole M, Daccarett M, et al. The prevalence and cost of the faint and fall problem in the state of Utah. PACE. 2011;34:278–83. 57. Alboni P, Coppola P, Stucci N, et al. Differential diagnosis between ‘unexplained’ fall and syncopal fall: a difficult or impossible task. J Cardiovasc Med (Hagerstown). 2015;16:82–9. 58. Finucane C, O’Connell MDL, Donoghue O, et al. Impaired orthostatic blood pressure recovery is associated with unexplained and injurious falls. J Am Geriatr Soc. 2017;65:474–82. 59. Wieling W, Thijs RD, van Dijk N, et al. Symptoms and signs of syncope: a review of the link between physiology and clinical clues. Brain. 2009;132: 2630–42. 60. Kenny RA, Richardson DA, Steen N, et al. Carotid sinus syndrome: a modifiable risk factor for non

A. Ungar et al. accidental falls in older adults (SAFE PACE). J Am Coll Cardiol. 2001;38:1491–6. 61. Frewen J, Savva GM, Boyle G, et al. Cognitive performance in orthostatic hypotension: findings from a nationally representative sample. J Am Geriatr Soc. 2014;62:117–22. 62. Allan LM, Ballard CG, Rowan EN, et al. Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One. 2009;4:e5521. 63. Ungar A, Mussi C, Ceccofiglio A, et al. Etiology of Syncope and unexplained falls in elderly adults with dementia: syncope and dementia (SYD) study. J Am Geriatr Soc. 2016;64:1567–73. 64. Testa G, Ceccofiglio A, Mussi C, et al. Hypotensive drugs and Syncope due to orthostatic hypotension in older adults with dementia (syncope and dementia study). J Am Geriatr Soc. 2018;66:1532–7. 65. Mossello E, Ceccofiglio A, Rafanelli M, et al. Differential diagnosis of unexplained falls in dementia: results of “Syncope & Dementia” registry. Eur J Intern Med. 2018;50:41–6.

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James Iannuzzi and Michael Conte

Contents Key Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430 Epidemiology, Anatomy, and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

431 431 431 431

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes, Hypertension, and Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tobacco Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Socioeconomic Status, Race, and Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brief Overview of Uncommon Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

432 432 432 433 433 434

Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ankle Brachial Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toe Brachial Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Measures of Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnostic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

434 434 434 435 435 436 436

Person-Centered Focus on Approach to Diagnosis, Treatment, and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asymptomatic PAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intermittent Claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Limb Threatening Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

437 437 437 438 438

J. Iannuzzi (*) · M. Conte Vascular Surgery, University of California San Francisco, San Francisco, CA, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_35

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J. Iannuzzi and M. Conte Treatment and Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Exercise Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Person-Centered Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

439 439 439 442

Multidisciplinary Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Patient and Family Education (Health Literacy) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Emergencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Quality and Safety Alerts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444 Social Determinants of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Ethical Dilemmas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445 Cost Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 Conclusion Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446

Abstract

Peripheral arterial disease is common yet underdiagnosed particularly in the aging population. Even when asymptomatic, PAD is associated with progressive functional decline and represents a coronary artery disease equivalent for major cardiovascular events. Diagnostic evaluation includes a thorough pulse exam and noninvasive studies (e.g., ankle brachial index) to establish the presence and severity of arterial occlusive disease. Treatment for PAD is focused on risk factor modification with medical therapy for cardiovascular risk factors, smoking cessation, diet, and exercise with an emphasis on walking. Further imaging is only necessary when vascular intervention is being considered. Surgical or interventional treatment is guided by symptoms and is tailored to individual goals and preferences. Specific tools have been developed to help guide treatment decisions that take into account clinical presentation, revascularization efficacy, likelihood of amputation, and functional reserve. Keywords

Peripheral arterial disease · Claudication · Pain with walking · Chronic limb threatening ischemia · Leg pain · Intermitten claudication · Tissue loss · Gangrene · Amputation

Key Points • Peripheral arterial disease (PAD) is common among older adults and is associated with significant functional disability, reduced quality of life, and morbidity. • The primary goal in all patients is cardiovascular risk factor modification to reduce overall cardiovascular events and disease progression. Optimal medical therapy for PAD includes smoking cessation, exercise, anti-thrombotic, and lipid-lowering medications. • Most patients with PAD are either asymptomatic or have atypical leg pain. However, even those with no or minimal symptoms exhibit progressive functional decline. • Intermittent claudication (IC) is the most common symptom in PAD. Initial treatment should include lifestyle modification and an exercise program, with revascularization reserved for major lifestyle-limiting symptoms. • Chronic limb-threatening ischemia (CLTI) including ischemic rest pain or gangrene is associated with increased risk for limb loss and death. Treatment involves urgent revascularization aimed at pain relief, wound healing, and maintaining function. Some patients with CLTI are best served by primary amputation or palliation.

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Epidemiology, Anatomy, and Pathophysiology Epidemiology Peripheral arterial disease (PAD) is a local manifestation of the systemic process of atherosclerosis [1]. While many individuals with PAD are asymptomatic, the most common presenting symptom is intermittent claudication (IC) or pain with ambulation in the calf, thigh, or buttocks [2]. PAD is common particularly in the aging population with over 200 million people afflicted worldwide [3]. PAD prevalence increases with age to greater than 20% for individuals 70 years of age and older, or 50–69 years with a risk factor such as smoking or diabetes [4]. Atherosclerosis worsens with age, and thus, PAD prevalence is projected to increase in parallel with the aging of the world’s population [5]. The increase in PAD prevalence is projected to be more pronounced in low-income countries based on global estimates from 2000 to 2010 where globally PAD prevalence increased by 23.5%. The increase in PAD prevalence was not uniform where low-income countries had a 29% increase during this time frame compared to high-income countries that had a 13% increase in PAD prevalence [4]. PAD contributes significantly to functional disability and is a major risk factor for other cardiovascular events [1]. Cardiovascular disease is the leading cause of morbidity and disability in the USA [6]. PAD itself is the third leading cause of atherosclerotic morbidity after ischemic heart disease and stroke accounting for 1–2% of deaths globally each year. [3] PAD diagnosed by ankle brachial index
0.9 was associated with a threefold increase in cardiovascular risk over 10 years [7]. Furthermore, PAD is costly accounting for $21 billion in the US healthcare spending in 2008, greater than both cerebrovascular disease and coronary artery disease [8].

Pathogenesis Atherosclerosis leads to plaque formation; however, plaques differ in consistency and 6 types

431

have been described using histopathology [9]. The precursor lesion is a fatty streak made of lipid, cholesterol, and cholesterol esters within macrophages and SMCs. As the lesion progresses, it becomes a fibrous plaque with extracellular lipid and fibrous connective tissue that appears white and can protrude into the lumen. A necrotic central core consists of amorphous lipid and cholesterol crystals. Inflammatory cells and SMCs aggregate near the necrotic core where it is susceptible to rupture. There are multiple hypotheses about atherosclerosis and plaque formation including the cholesterol, response to injury, monoclonal, and chronic inflammation hypotheses [10]. Calcification is a common finding in advanced atherosclerosis. Vascular calcification occurs because of a pathologic response from modified lipid accumulation, pro-inflammatory cytokines, and plaque induced osteogenic cell differentiation. The calcification process is initiated by formation of hydroxyapatite crystals that are deposited in the tissue. Vascular calcification can be intimal or in the media (Mönckeberg’s medial calcification). Intimal calcifications can result in luminal stenosis, whereas medial calcification usually does not, but decreases the vessel wall elasticity and compliance [11].

Anatomy The normal arterial structure includes three layers: the intima, media, and adventitia. The intima includes the endothelium, basement membrane, and subendothelial space. Endothelial dysfunction is the first sign of vessel injury [12]. The endothelium releases NO, prostaglandins, and other vasoactive substances and is the site for interaction with blood elements including adhesion molecules, thrombomodulin, and plasminogen activators. Within the subendothelial space, atherogenic particles accumulate, become modified, and are taken up by macrophages. The media is comprised of smooth muscle cells that are responsible for the vasomotor function of arteries and can contribute to intimal thickening as a result of increased migration, proliferation, and inflammatory activation. Age and lesion formation

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increase macrophage accumulation. The adventitia is made up of vasa vasorum and connective tissue. As plaque volume increases, there is an increase in vasa vasorum. Atherosclerotic vasa vasorum proliferate, leading to neovascularization that may increase leukocyte migration. This in turn promotes inflammation and friability causing intraplaque hemorrhage. Atherosclerosis is increased at branch sites secondary to changes in hemodynamics that increase turbulent flow. High shear stress has an anti-inflammatory, antioxidant, and anti-adhesion to leukocyte effect. Low laminar shear stress decreases endothelial nitrous oxide synthetase causing increased adhesion molecule expression and SMC migration [13]. Branch point bifurcations and major curvatures disrupt laminar flow. Disease presentation in PAD is based on level of the occlusive disease and symptoms generally occur a joint space below the level of disease. Aortoiliac occlusive disease often leads to proximal muscle symptoms and Leriche syndrome. Leriche syndrome is classically described in male smokers and presents as buttock claudication, reduced or absent femoral pulses, and impotence. Femoropopliteal disease is associated with symptoms of intermittent claudication in the calf. Disease in the tibial vessels, when severe, can lead to tissue loss and/or rest pain. Tibial disease is often associated with Mönckeberg’s arteriosclerosis. In contrast to atherosclerosis where the plaque develops in the intima, Mönckeberg’s arteriosclerosis is associated with calcium deposition in the medial layer. While Mönckeberg’s medial calcification does not usually cause luminal obstruction, it alters the vessel wall reducing elasticity and compliance and can lead to further atherosclerosis [11]. Mönckeberg’s arteriosclerosis is most often seen in association with chronic kidney disease or diabetes.

Risk Factors The risk factors for PAD mirror the risk factors for atherosclerosis in other vascular beds such as coronary artery disease (CAD) and cerebrovascular disease (CVD) [4]. PAD risk factor distribution

J. Iannuzzi and M. Conte

varies globally, and this distribution is associated with national income status where lower income countries have a higher prevalence of PAD risk factors.

Demographics Age is the greatest PAD risk factor with prevalence increasing in the sixth to eighth decades to greater than 25% in those 80 years of age and older [3, 4, 14]. This increase in prevalence is secondary to age-related alterations in vascular structure and function as well as accumulated exposure to other cardiovascular risk factors [15]. Gender plays a role in PAD development where women suffer atherosclerotic disease at a later age, indicating a change in protection after menopause. Estrogen plays a role in increasing HDL while decreasing LDL; however, estrogen replacement therapy has not been proven effective [16]. Furthermore, there are differences in distribution of disease and treatment outcomes associated with gender.

Diabetes, Hypertension, and Dyslipidemia Diabetes is a major risk factor for PAD with a 2–4 times increased risk of PAD for those with diabetes compared to those without. Hyperglycemia and hyperinsulinemia promote vessel wall stiffness, endothelial dysfunction, and intimal low-density lipid deposition. Hyperglycemia increases superoxide formation from the mitochondrial electron transport chain. Superoxide anion inactivates nitric oxide impairing endothelial-dependent vasodilation. Hyperglycemia decreases SMC vasomotor regulatory function and increases SMC migration into atherosclerotic plaque. Diabetes increases not only the incidence but the severity of limb ischemia and is the most common cause of nontraumatic lower extremity amputation in the United States accounting for 55% of amputation-related amputations [17]. Hypertension is another major risk factor for PAD where elevated systolic blood pressure is the

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result of age-related stiffening of the arterial wall in elastic arteries. The renal-angiotensin-aldosterone system also contributes to vascular wall stiffness. Angiotensin II stimulates collagen, matrix remodeling, vascular hypertrophy, reduces elastin synthesis, increases oxidant stress, and depresses NO directly in addition to acting as a peripheral vasoconstrictor. Aldosterone also stimulates SMC hypertrophy, resulting in increased vascular stiffness. Dyslipidemia is a major risk factor for atherosclerosis. There is an inverse relationship between plasma high-density lipid (HDL) and atherosclerosis. Similarly, low-density cholesterol elevation alone is sufficient to cause atherosclerosis, and data from lipid-lowering drug studies suggest that there is no threshold below which LDL levels are not associated with risk reduction. The total cholesterol to HDL ratio, otherwise known as the atherogenic index, has better predictive ability than isolated parameters [18]. The target ratio for primary prevention is 1.4 is nondiagnostic consistent with medial arterial wall calcification. An ABI 0.91–0.99 is considered borderline for PAD, while an ABI
0.9 is diagnostic for peripheral arterial disease. Mild peripheral arterial disease occurs at an ABI or 0.7–0.9 at which point intermittent claudication may be experienced. Moderate peripheral arterial disease occurs with an ABI 75 years, CAD, anemia Age, CAD, smoking, tissue loss, BMI, Bollinger score, serum creatinine concentration, AP (number measured and highest value), prior stroke/TIA Age > 75 years, prior amputation or revascularization, tissue loss, ESRD, recent MI/angina, emergency operation, functional dependence Age, BMI, nonambulatory status, ESRD, cerebrovascular disease, tissue loss, left ventricular ejection fraction Age, tissue loss, DM, CHF, serum creatinine concentration, ambulatory status, urgent operation, weight, bypass conduit used Age, CKD, ambulatory status, CAD, CHD, COPD, tissue loss, diabetes, smoking, beta-blocker use

Meltzer, 2013 [73] Soga, 2014 [74] Simons, 2016 [75] Simons, 2018 [65]

Adapted from Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia AFS amputation-free survival, AP ankle pressure, BASIL bypass vs angioplasty in severe ischemia of the leg, BMI body mass index, CAD coronary artery disease, CHF congestive heart failure, COPD chronic obstructive pulmonary disease, CRAB comprehensive risk assessment for bypass, DM diabetes mellitus, ESRD end-stage renal disease, MI myocardial infarction, PREVENT III Project of Ex-vivo Vein graft Engineering via Transfection III, TIA transient ischemic attack, VQI vascular quality initiative

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should be used to guide whether revascularization with either endovascular or open approaches should be employed. The differentiation between CLTI and intermittent claudication is critical to contextualize treatment as CLTI can be limb threatening, whereas intermittent claudication is a balance of quality life, and thus, different considerations and risk/benefit calculations are necessary depending on presenting symptoms. Patient risk estimation is then necessary to determine the patient’s candidacy for limb salvage and includes evaluating periprocedural risk, baseline functional status, and life expectancy [53]. Treatment goals include pain relief, wound healing, and preservation of limb function. Shared decision making in these patients is paramount and patient goals need to be discussed and addressed. Those who are at the end of life or demented may be appropriately treated with primary amputation or palliation. While functional limb salvage is the goal in all patients, revascularization may incur significant morbidity and mortality, requiring multiple hospitalizations and prolonged outpatient care [66]. In patient’s undergoing lower extremity bypass, 26% will require new postdischarge nursing care, and in high-risk patients, this increases to 66% [67]. In individuals already living at a nursing home at 1-year after surgery, few remain alive and ambulatory and in those who remain alive few gained any function [68]. Candidacy for limb salvage in CLTI should include assessment of patient perioperative risk, life expectancy, and anatomic consideration [53].

Multidisciplinary Approach The older person with PAD requires a multidisciplinary approach for adequate care. The care team often requires collaboration of the multiple specialties involved in the care of these complex patients including cardiology, nephrology, endocrinology, primary care, geriatrics, podiatry, and physical therapy. Podiatric care is especially important for limb salvage to be sure patients receive optimal wound care and are offered alternatives to below the knee amputation for tissue loss. The Geriatric Surgical Verification program, quality

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program developed by the American College of Surgeons, recommends a large multidisciplinary committee for evaluation, optimization, and treatment of elderly patients that includes Anesthesiology, Emergency Medicine, care coordinators, physical and occupational therapy, nutrition, pharmacy, palliative care, and a patient navigator to name a few. PAD can progress quickly and is often overlooked making a multidisciplinary team approach ideal. While primary care plays an important role in monitoring and diagnosing PAD, vascular surgeons should be involved early in the evaluation process. Vascular surgeons are trained and continually updated on cutting edge medical therapy and receive training in frailty assessment incorporating vascular medicine into their practices. Interventionalists with training across the spectrum of treatment options including longterm patient follow-up assessments are ideal, as inappropriate use of endovascular techniques can limit future open revascularization options. There are multiple risk stratification tools for assessment of perioperative mortality and morbidity among patients with CLTI (Table 3). Failed revascularization can lead to symptom recrudescence or even rapid disease progression, making surveillance, postprocedural risk factor management, and medical care paramount.

Patient and Family Education (Health Literacy) The fundamental approach to PAD management is risk factor modification and surveillance. Patients should be counseled about smoking cessation, blood pressure, diabetes, diet, and exercise. Specific counseling on an exercise program for claudicants is necessary and should include finding a safe place to walk for 15–30 min 3–4 times weekly. Foot hygiene is particularly important in those with diminished distal extremity perfusion and those with diabetes. Patients should be counseled to keep wearing socks and to keep their feet dry. They should pay careful attention to washing their feet with soap and water and be aware of any new wounds, cuts, or blisters. Those with diabetes benefit from having their

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toenails clipped by a podiatrist as part of regular preventive foot care. Toe care can be particularly difficult in those with peripheral arterial insufficiency due to thickened nails. Patients and their families should be counseled on signs and symptoms that should prompt immediate medical attention. These urgent signs include an acute worsening of their symptoms including progression to rest pain, development of new nonhealing ulcers or wounds, a cold or painful extremity especially if coupled with changes to sensation. For all patients, but particularly those with prior revascularization, it is important that any changes as listed above are dealt with quickly as they suggest thrombosis of the prior intervention which is best treated early before nerve damage or unsalvageable tissue damage occurs. Patients and families also need to be aware that routine surveillance is necessary to ensure that any problems with the prior revascularization are identified and treated before the original revascularization thromboses as patency loss may limit future revascularization options.

Emergencies Acute arterial occlusion from either embolism or disease progression with thrombosis can be one of the most urgent conditions associated with PAD. While acute limb ischemia may be secondary to embolism, it can also result due to thrombosis from arterial stenosis, graft/stent thrombosis, or plaque rupture. The degree of ischemia can be classified based on symptoms and physical exam using the Rutherford classification that can guide

whether the extremity is salvageable and immediacy of revascularization (Table 4). In those with claudication or with prior revascularization, the new development of rest pain is urgent as it represents a limb threatening condition that can quickly progress to tissue loss and infection. Graft infection or wound infection after lower extremity bypass can be medical emergencies. A graft infection in the setting of a prosthetic bypass can be limb threatening, and the infected graft must be removed. Similarly, a wound infection near a prosthetic implant requires further evaluation with imaging to determine whether surgical exploration and revision is necessary. Signs and symptoms of wound or graft infection include erythema, pain over the graft, purulent or foulsmelling drainage, and elevated white blood cell count and should be considered in the setting of bypass thrombosis.

Quality and Safety Alerts Paclitaxel drug coating technology for endovascular treatment using drug-coated balloons is drug eluting stents that were developed to address ongoing issues with restenosis in treatment of the femoropopliteal region [76]. Drug coating technology offered reduced reintervention and increased long-term patency [76]. However, a recent meta-analysis of prior randomized controlled trials suggested that the use of Paclitaxel may be associated with increased 5-year mortality (HR 1.52 confidence interval 1.12–2.07) [77]. This study led the FDA to issue a black box warning about paclitaxel use. However, follow-

Table 4 Rutherford classification for acute limb ischemia{Citation} Category I. Viable II. Threatened (a) Marginally

Description/prognosis Not immediately threatened

Sensory loss None

Salvageable if promptly treated

(b) Immediately

Salvageable with immediate revascularization Major tissue loss or permanent nerve damage inevitable

Minimal (toes) or none More than toes, associated rest pain Profound, anesthetic

III Irreversible

Muscle weakness None

Arterial Doppler Audible

Venous Doppler Audible

None

Inaudible

Audible

Mild, moderate Profound paralysis

Inaudible

Audible

Inaudible

Inaudible

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up studies have failed to demonstrate this result including a Swedish multicenter randomized clinical trial performed and improved follow-up from the original randomized controlled trials places doubt on these results [76, 78]. Regardless, when considering the use of paclitaxel, the potential increased risk for death should be discussed [79]. Overtreatment remains a major concern in older adults and is particularly relevant to patients with claudication. The Society of Vascular Surgery and the Choosing Wisely campaign recommends that peripheral vascular interventions be limited to claudication patients with lifestyle limiting symptoms only after failed medical and exercise therapy [80]. Despite these recommendations, early intervention still occurs estimated at 3.2% of peripheral arterial endovascular interventions [80]. Open revascularization is also potentially overused in older adults particularly for those already requiring nursing care. In a study of nursing home-dwelling older adults undergoing lower extremity bypass, few were alive and ambulatory 1 year after surgery, and those who were still alive derived little, if any, functional improvement [68].

Social Determinants of Health Social determinants of health play a major role in the development and natural history of PAD as outlined above. Food, housing, and financial security have all been linked to increased rates of cardiovascular risk factors which all contribute to PAD risk [81]. Even after adjusting for differences in cardiovascular risk factors, PAD is over twice as prevalent among Blacks and non-white Hispanics compared to whites [82, 83]. Black patients with PAD are more likely to develop a new mobility deficit and have difficulty completing a 6-min walking test [84]. Blacks also more frequently present with CLTI and are less likely to have received appropriate medical therapy such as statins or aspirin both prior to and after discharge after CLTI presentation [85]. Blacks are also more likely to undergo major amputation primarily without revascularization attempt compared to whites when presenting with CLTI [86–88]. Surgeon practice diversity may contribute to

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differences in primary amputation where surgeons with a more diverse practice in New York State had a lower odds of primary amputation for blacks compared to those with a less diverse patient population [25]. Similarly, Hispanics are more likely than white non-Hispanics to present with limb-threatening lower extremity ischemia. Blacks, Hispanics, Native Americans, and Pacific Islanders all have higher rates of amputation than non-Hispanic whites. [89, 90] Surgical outcomes are also worse for Blacks and Hispanics with decreased limb salvage, patency, and increased 30-day complications after lower-extremity bypass [91, 92]. Increasingly social determinants of health are being recognized as important preoperative risk factors. One such example is food access where patients with low food access undergoing lower extremity bypass for CLTI were found to have 2.7 times the odds for 30-day readmission and increased risk for wound complications [93]. While it is recognized that social determinants of health play a major role in PAD development and natural history, there is little guidance on how these factors may be mitigated to prevent PAD development, progression, and treatment efficacy. It remains unclear whether open versus endovascular first surgical strategies are more cost-effective, and the currently ongoing BEST-CLI trial aims to address which approach may be more efficacious [94, 95].

Ethical Dilemmas Caring for the older adults with PAD is challenging due to increased patient frailty and more complex anatomy [96]. With the advancement in endovascular techniques, an increasing proportion of older patients are candidates for revascularization, yet determining who should undergo revascularization remains challenging. In a study of nursing home residents undergoing revascularization, few were alive and ambulatory 1 year after surgery [68]. In a meta-analysis of octogenarians undergoing revascularization for CLTI, mortality at 1 year was estimated at 32%; however, those treated conservatively had 3 times the

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odds for mortality compared to those who underwent revascularization [97]. Palliative therapy should rarely include revascularization unless necessary to treat intractable pain or improve the chances for successful amputation [53].

Cost Implications The costs associated with PAD outpace both coronary artery disease and cerebrovascular disease in part because patients frequently require multiple revascularizations [8]. In 2004, the estimated annual PAD-related costs in the USA exceeded $21 billion and is projected to increase as PAD prevalence increases [8]. Cost-effectiveness of competing treatment strategies for PAD remains controversial in the USA with particular concerns about when to treat intermittent claudication and whether drug-coated technology which is expensive should be used. In individuals with PAD, supervised exercise programs have been demonstrated to be the most cost-effective treatment strategy compared to endovascular therapy; however, supervised exercise program availability in the USA is limited [98]. Revascularization using open or endovascular approaches in mild to moderate intermittent claudication is only costeffective compared to unsupervised exercise programs over 2 years, but this benefit is lost at 5 years [99]. Based on this data, the primary approach for intermittent claudication should include an unsupervised or supervised exercise program until symptoms become severe.

Conclusion Summary PAD is a common disease among the aging population that is often unrecognized. There are major implications to long-term cardiovascular health and functional outcomes even when patients are asymptomatic. PAD evaluation should include a thorough pulse examination and arterial brachial indices with referral to a vascular surgery specialist for further evaluation. Treatment for symptomatic, nonlimb threatening PAD is largely

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personalized to presenting symptoms, but most often includes risk factor modification and an exercise program. In a minority of patients, symptoms will progress to chronic limb threatening ischemia that requires urgent evaluation and treatment for limb salvage. Treatment approach is individualized based on currently available risk scoring tools that help determine an individual’s likelihood of success with revascularization. A multidisciplinary approach is necessary for the care of the frail and older adults where decision making is complicated by advanced pathophysiology and increased perioperative risk.

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449 Severe Ischaemia of the Leg (BASIL) trial: a survival prediction model to facilitate clinical decision making. J Vasc Surg. 2010;51(5, Supplement):52S–68S. 73. Meltzer AJ, Graham A, Connolly PH, Meltzer EC, Karwowski JK, Bush HL, et al. The Comprehensive Risk Assessment for Bypass (CRAB) facilitates efficient perioperative risk assessment for patients with critical limb ischemia. J Vasc Surg. 2013;57(5): 1186–95. 74. Soga Y, Iida O, Takahaera M, Hirano K, Suzuki K, Kawasaki D, et al. Two-year life expectancy in patients with critical limb ischemia. JACC Cardiovasc Interv. 2014;7(12):1444–9. 75. Simons JP, Goodney PP, Flahive J, Hoel AW, Hallett JW, Kraiss LW, et al. A comparative evaluation of riskadjustment models for benchmarking amputation-free survival after lower extremity bypass. J Vasc Surg. 2016;63(4):990–7. 76. Schneider PA, Varcoe RL, Secemsky E, Schermerhorn M, Holden A. Update on paclitaxel for femoral-popliteal occlusive disease in the 15 months following a summary level meta-analysis demonstrated increased risk of late mortality and dose response to paclitaxel. J Vasc Surg. 2020. 77. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M, Paraskevopoulos I, Karnabatidis D. Risk of death and amputation with use of paclitaxel-coated balloons in the Infrapopliteal arteries for treatment of critical limb ischemia: a systematic review and meta-analysis of randomized controlled trials. J Vasc Interv Radiol JVIR. 2020;31(2):202–12. 78. Nordanstig J, James S, Andersson M, Andersson M, Danielsson P, Gillgren P, et al. Mortality with paclitaxel-coated devices in peripheral artery disease. N Engl J Med. 2020;383(26):2538–46. 79. Health C for D and R. UPDATE: treatment of peripheral arterial disease with paclitaxel-coated balloons and paclitaxel-eluting stents potentially associated with increased mortality – letter to health care providers. FDA [Internet]. 2019 Dec 20 [cited 2020 Sep 7]; Available from: https://www.fda.gov/medical-devices/ letters-health-care-providers/update-treatment-periph eral-arterial-disease-paclitaxel-coated-balloons-andpaclitaxel-eluting 80. Hicks CW, Holscher CM, Wang P, Black JH, Abularrage CJ, Makary MA. Overuse of early peripheral vascular interventions for claudication. J Vasc Surg. 2020;71(1):121–130.e1. 81. Parekh T, Desai R, Pemmasani S, Cuellar A. Impact of social determinants of health on cardiovascular diseases. J Am Coll Cardiol. 2020;75(11 Supplement 2):1989. 82. Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO, et al. Ankle-arm index as a marker of atherosclerosis in the cardiovascular health study. Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation. 1993;88(3):837–45. 83. Criqui MH, Vargas V, Denenberg JO, Ho E, Allison M, Langer RD, et al. Ethnicity and peripheral arterial

450 disease: the San Diego opulation tudy. Circulation. 2005;112(17):2703–7. 84. Racial differences in functional decline in peripheral artery disease and associations with socioeconomic status and education. J Vasc Surg [Internet]. [cited 2020 Aug 31]. Available from: https://www. jvascsurg.org/article/S0741-5214(17)30912-6/fulltext 85. Soden PA, Zettervall SL, Deery SE, Hughes K, Stoner MC, Goodney PP, et al. Black patients present with more severe vascular disease and a greater burden of risk factors than white patients at time of major vascular intervention. J Vasc Surg. 2018;67(2):549–556.e3. 86. Holman KH, Henke PK, Dimick JB, Birkmeyer JD. Racial disparities in the use of revascularization before leg amputation in Medicare patients. J Vasc Surg. 2011;54(2):420–6, 426.e1. 87. Regenbogen SE, Gawande AA, Lipsitz SR, Greenberg CC, Jha AK. Do differences in hospital and surgeon quality explain racial disparities in lower-extremity vascular amputations? Ann Surg. 2009;250(3):424–31. 88. Durazzo TS, Frencher S, Gusberg R. Influence of race on the management of lower extremity ischemia: revascularization vs amputation. JAMA Surg. 2013;148(7): 617–23. 89. Morrissey NJ, Giacovelli J, Egorova N, Gelijns A, Moskowitz A, McKinsey J, et al. Disparities in the treatment and outcomes of vascular disease in Hispanic patients. J Vasc Surg. 2007;46(5):971–8. 90. Tan T-W, Shih C-D, Concha-Moore KC, Diri MM, Hu B, Marrero D, et al. Disparities in outcomes of patients admitted with diabetic foot infections. PLoS One. 2019;14(2):e0211481. 91. Chew DK, Nguyen LL, Owens CD, Conte MS, Whittemore AD, Gravereaux EC, et al. Comparative analysis of autogenous infrainguinal bypass grafts in African Americans and Caucasians: the association of race with graft function and limb salvage. J Vasc Surg. 2005;42(4):695–701. 92. Rowe VL, Kumar SR, Glass H, Hood DB, Weaver FA. Race independently impacts outcome of

J. Iannuzzi and M. Conte infrapopliteal bypass for symptomatic arterial insufficiency. Vasc Endovasc Surg. 2007;41(5):397–401. 93. Smith EJT, Ramirez JL, Wu B, Zarkowsky DS, Gasper WJ, Finlayson E, et al. Living in a Food Desert is associated with 30-day readmission after revascularization for chronic limb-threatening ischemia. Ann Vasc Surg. 2020. 94. Childers CP, Lamaina M, Liu C, Mak SS, Suttorp Booth M, Maggard Gibbons M, et al. Costeffectiveness of leg bypass versus endovascular therapy for critical limb ischemia: a systematic review [Internet]. Washington, DC: Department of Veterans Affairs (US); 2019 [cited 2020 Sep 3]. (VA Evidencebased Synthesis Program Reports). Available from: http://www.ncbi.nlm.nih.gov/books/NBK543445/ 95. Menard MT, Farber A, Assmann SF, Choudhry NK, Conte MS, Creager MA, et al. Design and rationale of the best endovascular versus best surgical therapy for patients with critical limb ischemia (BEST-CLI) Trial J Am Heart Assoc 2016;5(7). 96. Fereydooni A, Dahl N, Chaar CIO. Technical and ethical challenges in the care of an independent nonagenarian with critical limb ischemia. Arch Clin Med Case Rep. 2020;4(1):130–7. 97. Wübbeke LF, Naves CCLM, Daemen J-WHC, Jacobs MJ, Mees BME. Editor’s choice – mortality and major amputation after revascularisation in octogenarians versus non-octogenarians with chronic limb threatening Ischaemia: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2020;60(2):231–41. 98. van den Houten MML, Lauret GJ, Fakhry F, Fokkenrood HJP, van Asselt ADI, Hunink MGM, et al. Cost-effectiveness of supervised exercise therapy compared with endovascular revascularization for intermittent claudication. Br J Surg. 2016;103(12):1616–25. 99. Djerf H, Millinger J, Falkenberg M, Jivegård L, Svensson M, Nordanstig J. Absence of long-term benefit of revascularization in patients with intermittent claudication: five-year results from the IRONIC randomized controlled trial. Circ Cardiovasc Interv. 2020;13(1):e008450.

Diabetes

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Naushira Pandya and Meenakshi Patel

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452 Evaluation and Care of Older Adults with Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Features and Recognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Burden of Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Challenges of Managing Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

453 453 453 453 454 455

Optimal Care for Older Adults with Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Assessment of Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Person-Centered Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment Goals for Glycemia in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Control of Cardiovascular Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

455 456 458 458 460

Hyperglycemia Management: A Case-Based Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case Discussion with Concurrent CKD Stage 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetes Management in the COVID-19 Pandemic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reducing Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hospital Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

461 461 463 464 465 466 467

Improving Care Transitions: Appropriate Information Sharing and Integrated Communication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467 Care of Patients with Diabetes at the End of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 The Interprofessional Team and Key Supportive Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469

N. Pandya (*) Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA e-mail: [email protected] M. Patel Department of Geriatrics, Wright State University Boonshoft School of Medicine, Dayton, OH, USA © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_38

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N. Pandya and M. Patel Diabetes Technology in Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469 Clinical Pearls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470

Abstract

Older adults with diabetes are a heterogeneous population in terms of comorbidities, functional ability, mental health and psychosocial issues, support system, location of care, staff competencies, and practitioner preferences. Hence, the care of these individuals is challenging and requires an individualized, creative, and person-centered approach. A systematic and careful evaluation of their health and comorbidities, diabetes self-management skills, hypoglycemia risk, mobility, cognitive and functional status, and affordability of medications is recommended. Over time, medical complexity will increase, with the background of concurrent geriatric syndromes and frailty. Older adults with diabetes are likely to experience one or more care transitions and may eventually need thoughtful discussions for planning care at the end of life. The authors will also discuss a casebased approach to medication management, glycemic goals, avoidance of hypoglycemia, and improving care transitions. Keywords

Diabetes · Diabetes mellitus · Aging · Older adults · Long-term care · Glycemic control · Geriatric syndromes · Hypoglycemia · Complications

difficulties. In the United States, 34.2 million Americans are affected by diabetes, and about 88 million (approximately one in three) have pre-diabetes. Racial and ethnic minorities and older adults are disproportionately affected, and the estimated crude prevalence of diabetes in those 65 years is 21.4% [63]. In post-acute and long-term care facilities, 30% of patients have diabetes. The overall cost of diabetes care in the United States has increased by 26% from $245 billion in 2012 to $327 billion in 2017. Those over 65 years comprise 67% of physician office visits, 46% of emergency department visits, and 24% of home health visits [5]. The care of older adults needs to be individualized due to varied degrees of clinical complexity, personal trajectory of diabetes, frailty, functional and cognitive impairment, as well as care setting and support system. These individuals may have existing complications, hypoglycemia, infections, and cardiovascular events. They may be subject to polypharmacy, adverse drug events, and multiple transitions of care. Diabetes may be associated with increased mortality, functional disability, and increased risk of needing institutional care [47]. The situation is further complicated by a relative lack of evidence-based guidance, and research gaps remain in the areas of optimal management of this heterogeneous group that could potentially improve clinical outcomes. By reading this chapter, readers will be familiar with:

Introduction Diabetes mellitus affects 463 million individuals globally and is predicted to affect 578 million adults by 2030. The aging of the world’s population is a contributor to this epidemic. It has been called a global health emergency and is a major noncommunicable disease responsible for an increase in comorbidity due to medical complications, functional impairment, and psychosocial

1. The challenges of managing the care of older persons with diabetes in different care settings 2. The impact of diabetes on function and overall health 3. Selecting and implementing individualized treatment strategies by utilizing an interprofessional, person-centered approach 4. Strategies to simplify treatment regimens and reduce hypoglycemia

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5. A holistic approach to older adults with diabetes and concurrent geriatric syndromes 6. Simplifying diabetes management and enhancing comfort at the end of life

Evaluation and Care of Older Adults with Diabetes Pathogenesis Genetic predisposition has a strong role to play in the increased prevalence of diabetes in the elderly. It is higher in Native Americans, Hispanics, blacks, and Micronesians as well as elderly identical twins. Mean glucose levels increase with age due to altered carbohydrate metabolism (reduced glucose-induced insulin secretion and insulinmediated glucose uptake, and increased fasting hepatic glucose production), obesity with high saturated fats and low complex carbohydrate diets, and sedentary lifestyle. In addition, low testosterone levels in older men appear to be a risk factor for the development of diabetes although the mechanism is unclear. Higher levels of tumor necrosis factor (TNF-α) in obese older adults are strongly correlated with insulin resistance. It has also been demonstrated that noninsulin-mediated glucose uptake (NIMGU) by insulin-sensitive tissues (liver, muscle, and adipocytes), as well as non-insulin-sensitive tissues (brain, nerves, and blood cells), is also impaired in older patients with diabetes [57]. Lean patients

with diabetes may have features of type 1 diabetes with marked insulin deficiency and the presence of islet cell antibodies; it is important to correctly identify older patients with type 1diabetes in order to select appropriate pharmacological treatments.

Clinical Features and Recognition Typical symptoms of diabetes are rarely present in older patients. This may be related to an age-related increase in renal threshold for glucose when glycosuria is present at very high glucose levels, and impaired thirst is seen in normal aging even in hyperosmolar states. Symptoms may be absent in half of cases or be less specific such as an increase in fatigue. Additional unique syndromes are also recognized more commonly in older patients with diabetes [56]; see Table 1.

Diagnosis Currently, the criteria for the diagnosis of diabetes are the following: • FBG 126 mg/dL (7.0 mmol/L) OR • 2-h PG 200 mg/dL (11.1 mmol/L) during oral glucose tolerance test (OGTT) OR • A1C 6.5% (48 mmol/mol) OR • Classic symptoms of hyperglycemia, hyperglycemic crisis, and random PG 200 mg/L (11.1 mmol/L)

Table 1 Nonspecific symptoms and unique syndromes associated with diabetes in the elderly [23, 56] Nonspecific symptoms Failure to thrive Confusion New or worsening incontinence Infections Myocardial infarction or stroke when hospitalized Dehydration

Unique syndromes Diabetic neuropathic cachexia (painful peripheral neuropathy, anorexia, depression, and weight loss) Diabetic neuropathy (focal or symmetric) Papillary necrosis with pyelonephritis or UTI Diabetic amyotrophy Malignant otitis externa Diabetic bullae Shoulder pain with limitation of movement Osteoporosis Diabetic ketoacidosis (if severe stressors, or use of antipsychotics or SGLT2 inhibitors)

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It is unclear whether age-specific criteria should be utilized for frequency of screening and for the diagnosis of diabetes. In a study of 1690 subjects without known diabetes in the Health, Aging, and Body Composition Study, those with impaired fasting glucose (IFG, 100–125 mg/dL), or elevated HbA1c (5.7–6.4%) according to the American Diabetes Association guidelines, suggested that the combination of FPG and HbA1c increased the odds of predicting the development of diabetes over 7 years [51]. Relying on FPG or HbA1c alone would lead to a missed diagnosis of impaired glucose tolerance (IGT) or diabetes in a substantial proportion of patients. It is known that applying the WHO two-step strategy of follow-up testing with OGTT on only those with IFG would fail to detect 25.8% of patients with diabetes and 78.4% of those with IGT [3]. However, the clinical impact and costeffectiveness of this strategy are unclear. Screening for diabetes is important in older adults whether living independently in the community, in an assisted living setting, or in the nursing facility. The prevalence of diabetes in this age group is about 25%, and the American Diabetes Association recommends all asymptomatic adults should be screened after age 45 or at any age if overweight or obesity is present (BMI >25 kg/m2 or  23 kg/m2 in Asian Americans) with one or more risk factors for diabetes [6]. Screening should also be performed based on symptoms. The diagnosis may often become apparent during a hospitalization or acute illness, and elevated glucose levels must be followed up and not attributed to illness-related stress alone.

Factors that Affect A1C and Pitfalls in Its Interpretation The limitations of glycated hemoglobin in the elderly include situations that affect red blood cell lifespan such as anemia, bleeding, blood transfusions, renal disease, uremia, acidosis or infection, and acute illness, all of which occur frequently in older adults and may alter the HbA1c values [15]. Iron or vitamin B12 deficiency, decreased erythropoiesis, alcoholism, renal failure, splenectomy, high-dose aspirin, chronic opiate use, and hemoglobin variants can lead to inappropriately

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high values of HbA1c. On the other hand, administration of erythropoietin, iron, vitamin B12, and vitamins C and E, acute and chronic blood loss, hemolytic anemias, chronic liver disease, low-dose aspirin, rheumatoid arthritis, splenomegaly, and hypertriglyceridemia can lead to inappropriately low values of HbA1c [78].

Clinical Burden of Diabetes Diabetes is now the seventh leading cause of death in the elderly according to 2017 data from the National Vital Statistics Report [76]. The contribution of diabetes may be underrepresented since diabetes is not always listed as a contributing cause of death when patients die of cardiovascular diseases. Elderly persons with diabetes have twice the age-match mortality rate than those without, and the principal cause of death is cardiovascular disease. The clinical burden of diabetes varies in individuals. However, it can be attributable to comorbidities and the presence of geriatric syndromes, functional impairment, cognitive impairment, vision status, demographic characteristics, and unique logistic issues related to the patient’s support system and living status (such as home, assisted living centers, and skilled nursing facilities). These factors can be additive and limit the benefit of certain interventions to treat diabetes. Consensus has evolved around dividing older adults with diabetes into three health status subgroups: first, a relatively healthy group with no comorbidities (except hypertension or osteoarthritis) and with no impairments; second, a group with difficulty in diabetes self-management (DSM) with multiple comorbidities and/or moderate to severe cognitive impairment, poor vision, and two or more instrumental activities of daily living (IADL) impairments; and third, a limited benefit group with the poorest health status, dependency in two or more ADLs, and/or residence in a long-term care facility [17]. These subgroups were represented in all age groups studied from age 51 and older, including those over 75 years of age. Although older adults with medical complexity, poor health status, and functional

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and cognitive impairment would be expected to have limited survival, analysis of the 2004–2008 Health and Retirement Study and the 2003 Health and Retirement Diabetes Study suggests this assumption may not be accurate. The 5-year survival probability of the relatively healthy group was 90.8%; the self-management difficulty group, 79.4%; and the uncertain benefit group, 52.5% [25]. The substantial survival in the selfmanagement difficulty group (even in the oldest old) indicates that these individuals would benefit from interventions to prevent or delay the onset of microvascular and macrovascular complications; they would also need additional support from caregivers and their health care system to manifest these benefits. Frailty and sarcopenia are now being recognized as complications with potentially high impact in older adults with diabetes. Evidence now suggests that diabetes is directly associated with both loss of muscle strength and quality, leading to an increased risk of sarcopenia [44, 82]. International studies in older adult populations and Japan and Mexico show an increase in the likelihood of frailty in people with diabetes, chronic kidney disease, and hypertension [49]. Frailty predicts the coexistence of cardiovascular disease (CVD), and CVD is associated with manifestations of frailty [4]. The three main categories of complications – vascular, physical function and neuropathic, as well as cognitive/mental health – may act synergistically and lead to disability in the absence of timely clinical intervention [73].

Challenges of Managing Diabetes Diabetes can be difficult to manage in older adults due to a combination of age-related, complex health, and psychological as well as socioeconomic factors. The contribution of each of these factors may vary in everyone, and this underscores the need for a person-centered approach when managing the care of older adults with diabetes. Table 2 summarizes these challenges by examining age-related, health, and psychological and socioeconomic factors [22, 40, 71]

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Optimal Care for Older Adults with Type 1 Diabetes People with type 1 diabetes are living longer in the West, have a higher comorbidity burden, and often need institutional care. Life expectancy is nearing the population average due to family longevity, good glycemic control (A1C age 70

Health and psychological factors Cognitive impairment or dementia (leading to poor appetite, medication non-adherence, and refusal of care and glucose monitoring)

Decline in renal function

Depression and/or anxiety

Changes in hepatic drug metabolism

Multiple comorbidities including vascular complications, sensorimotor deficits, neuropathy, and vestibular dysfunction Polypharmacy (leading to overly complex treatment regimens and increased risk of hypoglycemia) Medication errors Frequent glucose checks Persistent use of sliding scale insulin

Functional limitations Sarcopenia and frailty Impaired mobility, balance, and falls Impaired hand dexterity Vision impairment Dependency

Socioeconomic factors Limited social support Difficulty in access to healthy food Fixed income Difficulty in managing complex diabetic treatments, monitoring, and injections Difficulties in access to care Health insurance issues Reliance on ED and hospitals Prescription expense Transportation Poor health literacy Limited numeracy Homelessness Differing care settings (community, group home, ALF, long-term setting) Clinical capacity of healthcare professionals in assisted living or group home settings Varied or infrequent patient contact Reliance on phone coordination of care Frequent ED visits or hospitalizations Transitions in care setting and fragmentation of care

for assessing older adults with diabetes in order to make individualized and goal-oriented decisions when managing diabetes and their overall care. This often occurs in the primary care or post-acute and long-term setting by one practitioner-led team, with intermittent specialty consultations and physical, occupational, or speech therapy evaluations. Evaluation of existing medical records and a detailed history from patients and family or informal caregivers is important to identify diabetes type, complications, comorbidities, medication history and related adverse events, and propensity for hypoglycemia. A practical and comprehensive way of assessing older adults with diabetes may be achieved by utilizing the 4Ms Framework of the Age-Friendly Health Systems (What Matters, Medication, Mentation, and Mobility) developed by the John A. Hartford Foundation and the Institute for Healthcare Improvement (IHI). This general approach to care in older adults is evidence-

based; is easy to incorporate in everyday practice; reduces adverse medication effects; preemptively screens for depression, dementia, or delirium; and identifies factors that would increase fall risk and compromise mobility, as well as being consistent with what matters most to the older adult and family [54]. It is being widely adopted by many health systems and communities. The following schematic utilizes the 4Ms framework for older adults with diabetes (Fig. 1).

Person-Centered Approach The key to approaching person-centered care in older adults with diabetes should be a consideration of quality of life and maintaining autonomy and functional independence to the extent possible, regardless of care setting, and including end-of-life care. Discussions regarding goals of care should be

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Fig. 1 Applying the 4M Age Friendly Framework to Diabetes

individualized and include formal and informal caregivers and nursing staff in post-acute settings and should be informed by existing medical records in order to formulate an acceptable plan of care [67]. The following is a list of relevant considerations that may be discussed with patients and families after a clinical assessment. They are also addressed in the Assessment of Patients section above. • Quality of life • Preferences and values (e.g., diet, injections, glucose monitoring) • Diabetes trajectory (duration, complexity of regimen, insulin use, HbA1c level) and presence of complications, especially vascular

• Risk of hypoglycemia or hypoglycemia unawareness • Polypharmacy • Presence of geriatric syndromes including cognitive impairment [59]. • Frailty or functional ability • Vision status • Undernutrition or swallowing impairment • Remaining life expectancy • Demographic status (age, gender, race, marital status, educational status, low net worth, undocumented) The major goals of treatment include treating hyperglycemia, minimizing hypoglycemia, and

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considering comorbid conditions, existing complications, and functional impairments when selecting treatment. In frail patients, especially those with cognitive impairment, particular care should be taken to avoid or minimize hypoglycemia, drug interactions, and hypotension. Hence, a creative and proactive approach is needed when recommending treatment and adaptability and flexibility during subsequent care encounters.

Treatment Goals for Glycemia in Older Adults The value of intensive diabetes control in older adults is unclear. In those in whom life expectancy is limited, intensive control offers little benefit since microvascular complications develop over time. Most clinical practice guidelines recommend a global assessment of older adults with diabetes encompassing comorbidities and complications, function, cognitive status, patient preferences, and social factors including the support system. This framework helps to guide the management but is not intended to be rigid or prescriptive. Guidelines for glycemic control in older adults are based on consensus and expert opinion due to lack of high-quality data in older adults, especially frail individuals residing in institutional settings. Results of observational studies suggest that there is a J-shaped relationship between A1C and mortality in older adults with higher rates observed if A1C is 7.5 to 10.0% (58–86 mmol/mol) and with higher A1C variability [29, 36, 42]. A secondary analysis of the ACCORD trail data showed a higher mortality risk for older adults on intensive treatment even with high A1C levels [2, 20]. Table 3 represents consensus recommendations for A1C and fasting and premeal and bedtime goals (where applicable) for older adults with varying health status and cognitive and functional impairment, as well as those in skilled nursing facilities (in whom the goal is discharge to the community), in long-term care facilities, and who are near the end of life. Experienced clinicians will appreciate that not every patient fits neatly into each category and that flexibility of

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approach and management is required to accommodate patient preferences, care transitions, and change in clinical status. It is important to consider the estimated average glucose corresponding to A1C values and the factors that can affect increase and decrease in this value. An A1C of 8.5% is equivalent to an estimated average glucose of 200 mg/dL. More lenient A1C targets would increase the risk of extreme hyperglycemia, glycosuria, dehydration, postoperative complications, and poor wound healing, as well as hyperglycemic, hyperosmolar state [47].

Management Both clinical consensus and practice guidelines regarding the management of diabetes in older adults recommend that pharmacological and nonpharmacological treatment should be individualized. Attempting to place a patient in a health status group and evaluating cognitive and functional status, hypoglycemia risk, preferences, and prognosis is important in order to minimize adverse events and reduce the risk of hypoglycemia (see sections “Clinical Burden of Diabetes” and “Person-Centered Approach”). Lifestyle changes to improve activity level and glucose metabolism are possible to varying degrees in older adults, even those in institutional settings. In addition to optimizing glycemic control, adequate nutrition and exercise training may reduce the deterioration of physical dysfunction and potentially delay the onset of disability. Those who are living independently may be more capable of doing exercise. A review of exercise interventions with combined resistance and endurance training in older adults with diabetes showed that physical exercise is an effective intervention to improve functional capacity and muscle strength [21]. The addition of balance exercises and gait retraining when indicated could also be effective in reducing falls and improving quality of life. Results of the European MID-Frail consortium study showed that older adults with diabetes (mean age, 78.4 years) who underwent structured exercise training and diabetes and nutrition education had an improvement in their Short Physical Performance Battery score [69].

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Table 3 Compiled consensus recommendations for glycemia based on health status and site of care [7, 61, 67] Patient health status/site of care Relatively healthy (few chronic conditions, intact cognition and function)

Reasonable glucose targets Fasting and pre-prandial, 80–130 mg/dL (4.4–7.2 mmol/L) Bedtime, 80–180 mg/dL (4.4–10.0 mmol/L)

Reasonable A1C goal 50 years with one other additional cardiovascular risk factor (e.g., hypertension, dyslipidemia, smoking, chronic kidney disease/microalbuminuria) and low bleeding risk. When utilized, there is no evidence that a higher dose is more effective than a 75 mg per day dose in those individuals who have known cardiovascular disease. Aspirin should be used if the expected life expectancy equals or exceeds the time frame of clinical trials. For adults 70 years and older, aspirin should be used with caution. The benefit in older adults with established and documented ASCVD

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outweighs the risk, and it is still recommended. Age, anemia, and renal insufficiency are risk factors for bleeding in older adults [26]. Hypertension: For an older adult with diabetes, the target blood pressure recommended is less than 140/90 mmHg if therapy is tolerated. A systolic blood pressure less than 130 mmHg is not associated with better composite rates of fatal and non-fatal cardiovascular outcomes than systolic blood pressures between 130 and 140 mmHg [19, 28, 30]. There is potential harm in lowering systolic blood pressure to less than 120 mmHg in older adults with type 2 diabetes mellitus. ACE inhibitors and angiotensin receptor blockers also have cardiovascular and renal benefit in older adults with diabetes and may be preferred as the initial choice for blood pressure management. The Systolic Blood Pressure Intervention Trial (SPRINT) showed that blood pressure targets 100,000 patient-years found lactic acid levels at the upper limit in 4.3 and 5.4 cases per 100,000 patient-years in metformin treated and untreated type 2 diabetes mellitus (DM) patients [70]. Older patients should be warned if they are undergoing iodine-containing contrast radiological studies. Metformin should be temporarily discontinued during such radiological studies and during most

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hospitalizations. The other issue with metformin includes gastrointestinal side effects such as nausea, vomiting, and diarrhea. These can be mitigated by taking metformin with food or using controlled release preparations. Another caveat with metformin is it association with reduced absorption of vitamin B12. Therefore, vitamin B12 level should be monitored periodically. Metformin is generic and therefore quite affordable. Pioglitazone: In this case, pioglitazone could be considered as a treatment option. Pioglitazone is a thiazolidinedione that activates peroxisome proliferator-activated receptors (PPAR agonist) and is effective in increasing insulin sensitivity and peripheral tissues, primarily skeletal muscle. It has a low risk of hypoglycemia and is well tolerated in older patients and in those with mild renal failure. It can be used as an adjunct to other oral agents or in patients requiring large doses of insulin. There was a significant reduction of nonfatal myocardial infarction (MI) and recurrent stroke in patients with type 2 diabetes and a high risk of vascular events as well as benefit in patients with non-alcoholic steatohepatitis (NASH). However, other end points such as heart failure showed a significant increase with pioglitazone [32]. Pioglitazone can cause anemia, weight gain, peripheral edema, worsening heart failure, and, in some studies, an increased risk of fractures. It is generic and therefore affordable. Sulfonylureas: Sulfonylureas are also another affordable class of drugs that could be used. They are insulin secretagogues and, when used as monotherapy, can lower the A1C by 1–2%. The use of glyburide (in the USA) is not recommended, but glipizide, glimepiride, and gliclazide are tolerated in older adults. There is a high risk of hypoglycemia as well as weight gain with sulfonylureas. Of concern is that sulfonylureas are also associated with increased risk of cardiovascular events and mortality [14]. Clinicians are now using oral medications from other classes when possible unless cost is a major issue. DPP-4 Inhibitors: The dipeptidyl peptidase-4 inhibitors are another class of oral agents available. They inhibit glucagon-like peptide 1 (GLP-1) degradation and promote glucosedependent insulin secretion. Most of the agents

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in this class lower hemoglobin A1c by 0.7–0.9%, are weight neutral, and do not cause hypoglycemia. The limitations of use are in patients with liver failure and moderate to severe renal failure. Renal dose adjustment is required except in the case of linagliptin. They can cause nausea, pancreatitis, headaches, dizziness, and arthralgia. Overall, however, they are quite well tolerated. Cardiovascular outcome data for this class of drugs shows noninferiority compared to placebo for the most part. Several studies are ongoing. There is a concern for increased risk of heart failure with saxagliptin [46]. Given the cost of these medications and the limited efficacy, if injectable therapy is an option, the GLP-1 RA class of drugs would be a better choice. SGLT2 Inhibitors: These are a preferred class of oral agents recommended by the ADA guidelines especially in those people with diabetes who also have known ASCVD or with increased risk factors for ASCVD. These agents work through promoting glycosuria through the inhibition of sodium-glucose cotransporter-2 in the kidney. The mechanism of action for SGLT2 inhibitors is insulin-dependent, and the rate of hypoglycemia is low unless these drugs are combined with insulin and/or sulfonylureas. The A1C lowering by this class of agents ranges from 0.4 to 1.2% depending on baseline A1C values and current medication combination. The glucose lowering ability of this class of drugs is not affected by age or duration of diabetes. However, renal dose adjustment is necessary, and they are not effective in patients who have a GFR below 30 ml/min per 1.73 m2. Because of glycosuria, the side effects include polyuria and possible volume depletion in patients who are not able to meet their fluid requirements. Weight loss (1.4–4 kg), slight hypotension (fall in systolic pressure between 2 and 5 mmHg), an increase in genital yeast infections and urinary tract infections, risk of bone fractures, and a slight risk of diabetic ketoacidosis are other potential adverse effects. This is generally a welltolerated class of drugs in appropriately selected older adults. Caution is suggested including adjustment of concomitant therapy such as insulin and antihypertensives because of fluid loss. In patients with heart failure, diuretic therapy may

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need to be adjusted. As a class, these drugs have been found to reduce major adverse cardiovascular events (MACE) and hospitalizations for heart failure and provide the benefit of renal protection. A small and transient decrease in GFR is observed at the beginning of treatment regardless of age. There was an increase (albeit small) in lower limb amputation events with canagliflozin. The FDA has removed the box warning for canagliflozin [31, 34]. Meglitinides and alpha-glucosidase inhibitors are other options. These are very rarely used in the elderly population due to poor efficacy, risk of hypoglycemia, and GI side effects.

Case Discussion In the case of the 68-year-old man undergoing rehabilitation following knee arthroplasty, the following interventions could be considered: • A good option would be to stop sliding scale insulin and initiate therapy with metformin soon after admission. As often occurs in skilled nursing facilities, premeal and bedtime glucose checks could be simplified to three to five checks a week. • If the patient is not able to tolerate metformin, he could be switched to a medication from any of the other therapeutic classes based on affordability and side effect profile. • If he has ASCVD or indicators for high risk for ASCVD, then the next recommended choice would be an SGLT2 inhibitor (unless he has chronic kidney disease (CKD) stage 4) or a glucagon-like peptide 1 receptor agonist (GLP-1 RA). • The sole or prolonged use of sliding scale insulin to control glycemia is not recommended in acute or post-acute, long-term settings due to the risk of hypoglycemia and glucose variability. It also increases patient discomfort and consumes a lot of nursing time and resources. This recommendation is also included in the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults [10, 11, 61].

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Case Discussion with Concurrent CKD Stage 4 We now consider the scenario of the same patient after he has developed acute kidney injury following an episode of Clostridium difficile colitis and volume depletion. This was corrected with IV fluids, but his GFR is currently 25 ml/min per 1.73 m2. In CKD stage 4 or higher, most of the oral agents discussed would not be a good choice including metformin. • In this case, the next choice of treatment would be an injectable agent. Current options are either a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or insulin. • The current recommendation by professional diabetes associations like the ADA is to start a long-acting GLP-1 RA if further glycemic control is required than can be obtained with oral agents. GLP-1 RAs are preferred as the next agent compared to insulin. This is regardless of whether renal function is impaired or not [8, 37]. This represents a significant change from prior treatment algorithms, in which basal insulin would have been the next additive step in treatment. • In patients with established cardiovascular disease including peripheral arterial disease, established renal disease, or heart failure, an SGLT2 inhibitor or a GLP-1 RA with data supporting cardiovascular benefit, are recommended regardless of A1C [8]. • In patients with an established diagnosis of heart failure, SGLT2 inhibitors are recommended if they can be used safely and are tolerated; however, in the case of the pateint in this case, an SGLT2 inhibitor would not be advisable because of CKD stage 4. GLP-1 RA: This class of agents has been a useful addition to the diabetes treatment armamentarium. They have potent A1C-lowering abilities (from 0.8 to 1.8%) and are associated with blood pressure and lipid-lowering properties. They reduce fluctuations in fasting and postprandial glucose levels by stimulating insulin release in a glucose-dependent manner, suppressing

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glucagon, and reducing gastric emptying and food intake. Although the glucose-lowering effect is like that of insulin, the risk of hypoglycemia is low [1]. Exenatide is not recommended if the creatinine clearance is 10%. As the acute illness improves and glucose toxicity resolves, it is often possible to resume oral agents and/or simplify the insulin regimen with frequent oversight. When initiating insulin, once daily basal insulin (U-100 glargine or detemir) is preferred in older adults and is associated with the least amount of side effects such as nocturnal and symptomatic hypoglycemia compared to NPH insulin. Longer-acting concentrated basal analogs (U-300 glargine or degludec 200 U/mL) with longer durations of actions are good options in those individuals requiring high doses of basal insulin or experiencing wide glucose excursions [22]. While other concentrated insulins such as U-500 regular insulin and the U-200 version of rapid-acting insulin lispro are available, their use in older adults must be carefully initiated and monitored by practitioners with experience in insulin dosing. If prandial insulin is required, attempt to use a single dose with the main meal of the day. Multiple daily injections of insulin may be too complex for the older patient with advanced diabetes complications, life-limiting coexisting chronic illnesses, or limited functional status. Even in the older adult living in the community, who is independent in their basic and instrumental activities of daily living, mealtime insulin can pose

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significant problems. Older adults have a difficult time counting the carbohydrates and estimating insulin needs. Therefore, most of them will require clear instructions for specific doses [7]. Hypoglycemia remains the biggest risk factor for insulin therapy. Other complications include headache, weight gain, lipodystrophy, injection site reaction, anaphylaxis, and hypokalemia. Rotation of insulin injection sites will help reduce the risk of lipodystrophy, and selection of appropriate needle length will reduce the risk of intramuscular injection and hypoglycemia in thin individuals. The high “out-of-pocket” cost of insulin for many patients increases the burden of disease management for many patients and contributes to non-adherence. In selected patients with cost concerns, higher A1C goals, and low risk of hypoglycemia, the use of NPH and regular insulin and 70/30 NPH/regular premixed insulin is acceptable. With these agents, a somewhat less stringent control of blood sugar is prudent to avoid the risk of hypoglycemia. Costs can be mitigated by programs that are available by almost all the pharmaceutical providers or by shopping around with programs like GoodRx for the pharmacies with the lowest price for that particular product. Older adults will need the assistance of family members or caregivers to navigate through these programs, fill out forms, and apply for lower cost medications.

Diabetes Management in the COVID-19 Pandemic Older adults with diabetes who do develop COVID-19 infection have a higher chance of developing serious complications. It is unclear, however, whether diabetes itself is a risk factor for COVID-19. Studies from several countries suggest that people with diabetes have higher requirement for intensive ventilation and mortality. A pro-inflammatory metabolic state promotes a viral surge with resulting insulin resistance and severe hyperglycemia. The use of glucocorticoids and vasopressors is felt to worsen the cytokine storm. These patients are more likely to be

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anorexic and develop dehydration, acute kidney injury, diabetic ketoacidosis, hypoglycemia, as well as hyperglycemia. Metformin and SGLT2 inhibitors would need to be discontinued and other agents dosed according to end organ involvement [38]. The importance of adequate hydration and nutrition cannot be overstated as well as the need for frequent monitoring of blood glucose and structured protocols for hyperglycemia in those who are clinically unstable. In stable patients who rely on outside caregivers or who reside in nursing facilities, this is also an opportunity to deprescribe by simplifying diabetes regimens, discontinue SSI, and reduce the number of glucose checks. Glucose targets should be individualized, negotiated with other practitioners, and remain consistent with those recommended by standard guidelines and based on the individual health status. During the pandemic with quarantine requirements and less support, it has been increasingly difficult for the older population to get their groceries, medications, and the social interaction that they require for their well-being. Interestingly, telehealth has helped to keep them in touch with their physicians. However, a lot of older adults do not have smartphones, nor do they know how to successfully navigate a telehealth visit using a computer. They depend on their family members or caregivers to assist them with these visits.

Reducing Hypoglycemia Older adults with diabetes are prone to hypoglycemia due to comorbidities, liver or renal disease, anorexia and weight loss, inconsistent meal consumption, alcohol use, slow adaptive hormonal counter-regulation, multiple daily doses of insulin, and gastrointestinal disorders affecting food absorption. The response to hypoglycemia (glucose level, 50–70 mg/dL or 2.8–3.9 mmol/L) in older adults is characterized by a decrease in glucagon, epinephrine, and acetylcholine/norepinephrine secretion and a loss of arterial elasticity resulting in compromised perfusion of cardiac and neural tissues [58, 62]. The risk is further increased due to improvement in diabetes management and pharmacotherapeutic options. In

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older adults, hypoglycemia has been associated with an increased risk of falls, fall-related fractures, seizure, coma, and cardiovascular events. Severe hypoglycemia, in which the patient experiences severe cognitive impairment and requires third-party assistance for recovery, can be particularly detrimental. Risk factors for this problem in community-dwelling older adults are age, black race, oral medications, insulin therapy, renal insufficiency, as well as functional and cognitive impairment [50]. There are few data on the prevalence of hypoglycemia in nursing homes. The Italian DIMORA study of 2258 patients in nursing homes showed that severe hypoglycemia was more prevalent in subjects with dementia and who were on a sulfonylurea or a metformin-sulfonylurea combination. A French study of 236 nursing home patients noted tight glycemic control in over 59% of patients, and hypoglycemia occurred in 18% of patients [67]. Hypoglycemia and cognitive impairment have a bidirectional relationship. Severe and frequent hypoglycemia episodes have been associated with cognitive impairment, and cognitive impairment has been associated with hypoglycemia since recognition and treatment of early hypoglycemia are impaired [35]. In dependent patients with dementia, neuroglycopenic symptoms due to hypoglycemia may be mistaken for delirium or attributed to behavioral and psychological symptoms of dementia. Minor hypoglycemic symptoms such as sweating, tachycardia, and dizziness may go unrecognized. Hence, it is essential for first-line caregivers and staff to check the blood glucose immediately when there is any acute change of condition or mentation. A proactive approach to prevent and reduce hypoglycemia is briefly outlined below. • Establish appropriate goals for glycemic control based on individual factors; U-shaped relationship between A1C and mortality risk [29], more hypoglycemia and higher mortality noted in intensive treatment group ACCORD [2]. • Avoid relying on A1C as a sole parameter of glycemia control in older adults; A1C levels only reflect glycemia over the past 90 days, are affected by comorbidities, and may miss

24

• • •

•

•

•

•

•

Diabetes

critical glucose variability. Even in older adults with A1C levels over 8–9% and greater, continuous glucose monitoring (CGM) studies show hypoglycemic episodes [60]. Assess for cognitive impairment and depression which may affect hypoglycemia management and diabetes self-care. Assess for fall risk, balance, and frailty since hypoglycemia increases the risk of fall-related fractures. Assess vision; diabetic retinopathy as well as cataracts and macular degeneration affect medication management, insulin injections, and glucose monitoring. Appropriate selection and dosing of glucoselowering medications; select doses for renally cleared medications based on estimated glomerular filtration rate (eGFR) and not serum creatinine. If a sulfonylurea (SU) is selected, avoid glyburide; use glipizide or glimepiride which primarily undergoes hepatic elimination. Linagliptin may be a reasonable choice as an add-on to oral medications or insulin because renal dose adjustment is not required [48]. Administer basal insulin in the morning rather than at night; avoid NPH which has been associated with a higher overall rate of hypoglycemia [62]. Simplify complex insulin regimens. Discontinue sliding scale insulin and titrate the basal dose to an FBG goal of 90–150 mg/dl. If prandial insulin doses are 10 units, decrease this dose by 50%, and add a non-insulin agent if necessary, depending on BG trends [61]. Consider second-generation basal insulins (deludec 200 units/mL or glargine 300 units/ mL) in patients requiring high doses of basal insulin with high glucose variability. These agents are effective and well tolerated, with lower rates of severe hypoglycemia [22]. Pharmacovigilance for drug-induced hypoglycemia by commonly used medications; these include ACE inhibitors (possible indirect increase in insulin sensitivity), alcohol (inhibition of gluconeogenesis, depletion of glycogen, it

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increases insulin secretion), allopurinol (which decreases SU excretion), beta-blockers (which inhibit glycogenolysis and attenuate hypoglycemia signs and symptoms), chloroquine (mechanism unknown), fluoroquinolones (unknown mechanism, possible enhanced insulin secretion), pentamidine (cytolytic release of insulin), and salicylates (which increase insulin secretion and sensitivity and alter SU elimination) [79]. • Review injection technique, site rotation, and appropriate needle length (3–5 mm) to avoid intramuscular injection of insulin [66]. • Diabetes technology (CGM) in some cases of unpredictable or nocturnal hypoglycemic and high glucose variability.

Hospital Care Older adults with diabetes are more likely to be hospitalized and have three times the prevalence of diabetes than younger adults. The leading causes are cardiovascular (angina, heart failure, stroke, coronary artery disease) and pulmonary diseases (chronic obstructive pulmonary disease (COPD) and pneumonia), followed by infections. Their lengths of stay may be longer, and mortality rate higher. Insulin is the preferred treatment, and although treatment regimens should be individualized, clinical guidelines recommend target glucose levels between 140 and 180 mg/dL (7.8 to 10 mmol/L) in the ICU and non-ICU settings [77]. Every attempt should be made to plan a smooth transition to home or other post-acute setting and medical care, with a treatment regimen that is feasible, affordable, and compatible with the patient’s support system.

Improving Care Transitions: Appropriate Information Sharing and Integrated Communication Transfer from one care site to another (e.g., hospital to home or to a group home or long-term setting) carries significant risk for older adults with diabetes due to change of providers, poor coordination of care, medication reconciliation

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errors, and inadequate access to medical records. These factors can lead to unnecessary rehospitalization, and in the post-acute and longterm setting, experience shows that medication errors, duplication of tests, delays on diagnosis, and lack of follow-through on tests or referrals are commonplace. Training on blood glucose selfmonitoring and administering injectable treatment should be implemented a few days prior to discharge for patients who are capable. Following a checklist as shown in Table 4 for important information to provide or review at the time of discharge from an acute care or long-term facility would help to standardize the process and close gaps [67]. Nursing facility leadership including medical directors and directors of nursing can develop and implement standardized discharge procedures. Increasingly, hospitals and health systems and skilled nursing facilities are developing preferred partnerships with interprofessional teams consisting of practitioners, nurses, physical therapists, wound care specialists, dietitians, and palliative care specialists to improve bidirectional care transitions.

Care of Patients with Diabetes at the End of Life Patients with diabetes who are receiving palliative care and those at the end of life need careful and ongoing evaluation and a treatment plan that is not burdensome, provides comfort and dignity, avoids hypoglycemia, and maintains quality of life to the extent possible. In order to accomplish this, the

practitioner and the interprofessional team will need to discuss overall care goals, glucose goals, and the intensity of treatment with the patient, family, and caregivers. The basis of recommendations for palliative diabetes care is derived from caregiver surveys and consensus reviews [12, 52]. The following concepts and interventions are important for clinicians to bear in mind [61]. • Identification of patients with diabetes who exhibit progressive medical and functional decline and need palliative care; discuss advance directives. • Consideration of other comorbidities and coexisting geriatric syndromes that contribute to the advanced stage of illness. • Selection of treatments that reduce the risk of hypoglycemia and relax glycemic targets (it is unclear what level of hyperglycemia leads to harm in patients at the end of life). • Remove any restrictions on food and fluids; avoid dehydration. • Patients can exercise the right to refuse treatment and monitoring and stop insulin. • Consider deprescribing or discontinuing treatment (especially injectable and metformin or GLP-1 RA which have gastrointestinal side effects). • Reduce the frequency of glucose checks, e.g., twice a week except in special circumstances. • Use of basal insulin alone or with an oral agent may be necessary. • Avoid unnecessary diagnostic tests, emergency room visits, or hospitalization.

Table 4 Suggested checklists for care transitions [67] Transferring from hospital to LTC History, physical exam, practitioner notes, and consultation reports Accurate updated diagnosis list Laboratory test and key imaging study results Current medication list reconciled before discharge (note brand changes) Time of last basal insulin Hypoglycemia episodes (specific symptoms) or hypoglycemia unawareness Provide information on self-management skills

Transferring from LTC to ALF or home Home health service referrals and details of follow-up appointments Accurate updated diagnosis list Medication list with written reason for each medication Instructions on how and when to use injectable medications for diabetes Instructions on blood glucose frequency and targets Education on hypoglycemia recognition and treatment and use of glucagon by caregivers Contact information for LTC facility and primary care practitioner (PCP); send medical summary to PCP

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• Provide palliative or hospice care in familiar home or care setting if possible. It may be helpful to stratify such patients in three ways: (1) stable patients in whom discussion of care goals and deintensification of treatment should begin, (2) patients with organ failure in whom avoidance of hypoglycemia is paramount as is closer attention to medication management, and (3) dying patients in whom oral agents and insulin should be withdrawn.

The Interprofessional Team and Key Supportive Services In addition to medical practitioners and specialists such as ophthalmologists, cardiologists, and palliative care specialists, patients with diabetes require the involvement of the interprofessional team to support them and manage their care. This is particularly important in older adults who have functional decline and are at risk for geriatric syndromes such as falls, frailty, depression, polypharmacy, and cognitive impairment. Studies have shown that older adults with diabetes have a faster rate of cognitive decline, mobility decline, more falls, and sensory impairment than individuals without diabetes [61]. Table 5 lists members of the interprofessional team and key supportive services.

Diabetes Technology in Older Adults The use of insulin pens with prefilled cartridges and push button injection has been increasingly

accepted by older adults (if cost is not a barrier), and individual pens for patients in skilled nursing and long-term care facilities reduce the risk of infection transmission and dosing errors. Continuous glucose monitoring (CGM) devices may be real time or intermittently scanned. CGM has been studied in people with type 2 diabetes (including those >60 years) and shown to have significant A1C lowering and time spent in the hypoglycemia range [9]. Older adults, especially those managed in outpatient settings who are eligible and capable, will require education, intensive training, and support in the use of CGM. It reduces the discomfort of multiple glucose checks, promotes engagement in self-care, reduces hypoglycemia, and increases time in range of blood glucose levels. Insulin pumps (or continuous subcutaneous insulin infusion, CSII) and continuous glucose monitoring technologies have been shown to be safe and efficacious in people with type 2 diabetes. As people with type 1 diabetes age, more clinicians practicing in eldercare settings will need to become familiar with these technologies and insulin dosing and adjustment. In 2014, results of the OpT2mize trial showed that insulin pump therapy was more effective in lowering A1C than multiple daily injections in participants aged 35–75 years independent of the duration of diabetes and cognitive scoring [13]. Medicare eligibility criteria for insulin pump therapy include MDI (at least three times a day) 6 months prior with frequent adjustments, glucose checks at least four times a day, and one or more of the following: A1C >7%, recurring hypoglycemia 2.5 mU/L [44]. The concern is that utilizing the current upper TSH limit around 4.0–5.0 mU/L in older adults does not imply that those with higher levels have age-related thyroid dysfunction; it may be normal and not associated with adverse clinical outcomes. It leads to overdiagnosis of hypothyroidism, with potentially unnecessary treatment. Currently there is insufficient evidence to use age-specific TSH references as a routine part of

Table 1 Risk factors for thyroid disorders [45] Risk factor Female sex Iodine deficiency Other autoimmune conditions Smoking

Hypothyroidism + +

Hyperthyroidism + +

+

+

_

+

Alcohol

_

NA

Selenium deficiency Drugs Syndromic conditions

+

+

+ +

+ NA

RA: rheumatoid arthritis

Comment Sex hormones suspected to be triggers Both hypo- and hyperthyroidism can result from severe iodine deficiency A second autoimmune condition is present in 10% of Grave’s disease patients and 15% of those with Hashimoto’s thyroiditis (RA most commonly) Smoking increases risk of Grave’s hyperthyroidism twofold, and that of Grave’s ophthalmopathy eightfold Moderate intake may be associated with decreased risk of hypothyroidism Lower selenium levels reported in one study; more pronounced in Grave’s disease Amiodarone, lithium, interferon gamma 25% of Down’s syndrome patients have thyroid disease (most commonly primary hypothyroidism); 13% of Turner’s syndrome have hypothyroidism

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479

Table 2 Interpretation of thyroid function tests Subclinical hypothyroidism Hypothyroidism Central hypothyroidism Subclinical hyperthyroidism Hyperthyroidism TSH-producing pituitary adenoma Thyroid hormone resistance Intermittent/poor medication adherence Sick euthyroid Thyroiditis/thyroid injury Persistent thyroid cancer

TSH " " # # # " " " or NL NL NL or # NL # "a

FT4 NL # # NL " " " " # NL or " NL " #b

TT3 NL NL # NL " " " " NL or # NL or "

Tg

Anti-Tg AB

" NL or "

NL or " NL or "

TSH thyrotropin stimulating hormone, FT4 free thyroid hormone, TT3 total triiodothyronine, Tg thyroglobulin, Tg-Ab anti-Tg antibody a TSH depends on degree of TSH suppression b FT4 depends on degree of thyroid supplementation

clinical practice. Table 2 provides a guide to the pattern of thyroid function abnormalities associated with common thyroid conditions. Ultrasound of the thyroid and the neck is recommended if a nodule or goiter is identified clinically or incidentally during other imaging studies, and the patient has a normal or high TSH level (see section “Medications that Interfere with Laboratory Tests of Thyroid Function in Euthyroid Individuals”, Fig. 1). In the case of hyperthyroidism, and suppressed TSH levels, a radioiodine scan is recommended to evaluate thyroid anatomy and identify the source of thyroid hormone overactivity. It is important to remember that certain medications can alter TSH secretion, as can the presence of pituitary disease and other clinical conditions. TSH secretion is also subject to intraindividual variability, as well as diurnal variation with a peak late at night and in the early morning hours. Drugs can affect thyroid hormone control, synthesis, transportation, metabolism, and excretion in the following ways [46] (Table 3): • • • • •

Hypothalamic-pituitary control of the thyroid Thyroid hormone synthesis or release Enhance thyroid autoimmunity Cause direct thyroid gland damage Affect protein binding of thyroid hormone

• Activation, metabolism, and excretion of thyroid hormone • Absorption of thyroid hormone preparations

Medications that Interfere with Laboratory Tests of Thyroid Function in Euthyroid Individuals Older adults often take multiple drugs and their regimen may be subject to change during transitions of care. Several drugs may cause spurious abnormalities in thyroid function tests in individuals who are euthyroid. Intake of usually over 300 mg of the common micronutrient biotin interferes with the TSH, T4, T3, and TSH receptor antibody assays, thus mimicking biochemical findings of Grave’s disease. Amiodarone in euthyroid individuals inhibits T4-to-T3 conversion, thereby causing a rise in TSH. This pattern can be misinterpreted as a thyrotropin producing tumor or thyroid hormone resistance. Heparin and low-molecular-weight heparins release endothelial lipoprotein lipase and the resulting rise in free fatty acids causes T4 and T3 displacement from binding proteins, leading to similar misinterpretation of thyroid function as with amiodarone. Phenytoin and carbamazepine accelerate thyroid hormone

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Physical Examination

Thyroid stimulating hormone (TSH), Thyroid ultrasound

TSH normal or elevated

TSH below normal

Radionucleotide scan Check FT4 and T3

Nonfunctional nodule

Functioning nodule

Ft4 and T3 normal

Ultrasound criteria for FNA met

Yes

No

FNA

Monitor

Subclinical hyperthyroidism

Observe unless treatment is warranted

Ft4 and/or T3 high

Overt hyperthyroidism

Treat

Fig. 1 Initial approach to a patient with a thyroid nodule

metabolism and also displace T4 from its binding proteins. However, the expected rise in freeT4 does not occur to a dilution problem with the assay, and its values are low or low normal, leading to a potential interpretation of central hypothyroidism [46].

Hypothyroidism Definitions It is useful to examine hypothyroidism in terms of etiologies causing thyroid gland failure or dysfunction (primary hypothyroidism) and hypothalamic pituitary causes of hypothyroidism (secondary

hypothyroidism). In case of the latter, it may be clinically relevant to detect dysfunction of other hypothalamic pituitary axes, such as secondary adrenal insufficiency. Primary hypothyroidism occurs in 2–6% of persons over the age of 60, more so in females than in males [1, 41]. Autoimmune thyroiditis is the most common cause of hypothyroidism in older adults, due to the increasing prevalence of antimicrosomal (anti-TPO) and antithyroglobulin antibodies [26]. Other causes include medical or surgical treatment of hyperthyroidism and medications which cause thyroid failure, such as iodine-containing substances (amiodarone, radioiodine contrast, antiseptics) and lithium [12].

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Table 3 Effects of medications on the thyroid by clinical indication and mode of action on the thyroid [46] Medication Hypothalamic-pituitary control Bexarotene

Clinical indication

Mode of action on the thyroid

Antineoplastic; treatment for cutaneous T cell lymphoma

TSH suppression and enhanced thyroid hormone sulfation; recovers after drug discontinuation Secondary hypothyroidism with subnormal FT4 levels, inappropriately normal TSH, and blunted response to TRH; effect may be permanent Destructive hypophysitis and secondary hypothyroidism

Mitotane

Adrenocortical carcinoma

Ipilimumab

Immune check-point inhibitor for advanced melanoma and renal cell carcinoma Critical care, immunosuppression Critical care, Parkinson’s disease Carcinoid tumors and growth hormone excess Type 2 diabetes

Glucocorticoids Dopamine agonists Somastatin analogues

Metformin Thyroid hormone synthesis or release Amiodarone Class III antiarrhythmic agent

Iodinated contrast agents Topical povidone iodine Supplements, expectorants, kelp Lithium Enhanced thyroid autoimmunity CTLA-4 and PD-1 inhibitors

Interleukin-2 and interferon alpha

Alemtuzumab

Direct thyroid gland damage Amiodarone

Tyrosine kinase inhibitors (e.g., sunitinib) Protein binding of thyroid hormone Oral estrogens, selective estrogenreceptor modulators, methadone, heroine, mitotane and fluorouracil Androgens, glucocorticoids, and niacin

Computed tomography and cholecystography

Metabolically insignificant TSH suppression with normal FT4 levels; may be confused with subclinical hyperthyroidism

Type I amiodarone-induced thyrotoxicosis; hypothyroidism in susceptible individuals Excess iodine leading to intrathyroidal inhibition of thyroid hormone synthesis (Wolff-Chaikof effect)

Bipolar disorder

Decreased thyroid hormone release; goiter and hypothyroidism

Immune system targeting of cancer cells

Painless thyroiditis, followed by hypothyroidism (common in patients with TPO and TG antibodies) Mild hyperthyroidism followed by hypothyroidism (risks are female gender, thyroid autoimmunity)

Immunostimulatory cytokines used in metastatic renal-cell carcinoma, melanoma, and hepatitis C Relapsing form of multiple sclerosis

Cardiac arrhythmias

Renal-cell carcinoma or gastrointestinal stromal tumors

Grave’s disease, subacute thyroiditis, hypothyroidism (hyper- and hypothyroidism may alternate) Destructive thyroiditis (type-2 amiodarone induced thyrotoxicosis; treated with glucocorticoids Ischemia leading to thyroiditis followed by hypothyroidism Increase in thyroid-binding globulin. Patients on oral estrogen, and receiving thyroxine will require dose increments. Reduction in protein binding; low clinical significance (continued)

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Table 3 (continued) Medication Clinical indication Phenytoin, carbamazepine, salsalate, other NSAIDS, high dose furosemide, and heparin Activation, metabolism, and excretion of thyroid hormone Amiodarone, dexamethasone and other glucocorticoids, high dose propranolol, ipodate, and propylthiouracil Phenytoin, phenobarbital, carbamazepine, and rifampin Tyrosine kinase inhibitors (e.g., Levothyroxine-dependent sorafanib) thyroid cancer Cholestyramine and colesevelam

Bile acid sequestrants

Absorption of thyroid hormone preparations Proton-pump inhibitors used daily

Ferrous sulfate, calcium carbonate, aluminum hydroxide, sucralfate, bile acid sequestrants, milk, coffee

Signs and Symptoms of Hypothyroidism in Older Adults Common signs and symptoms include fatigue, lack of appetite, cold intolerance, constipation, generalized weakness, alopecia, and dry skin. Hypothyroidism may also present with neuropathy, cerebellar dysfunction, or macrocytic anemia [1]. Older adults have a higher incidence of psychiatric symptoms related to hypothyroidism, such as depression and impaired cognitive domains, including memory, concentration, language, visuospatial perception, and executive function [22]. Some classical features of hypothyroidism may be missing in geriatric patients, such as weight gain and paresthesia [26] (Table 4). Hypothyroidism should be considered in the setting of persistent heart failure, macrocytic anemia, and/or hyperlipidemia [23]. Hypothyroidism may lead to insulin resistance and in turn diabetes. A high index of suspicion needs to be maintained when developing a differential diagnosis for older adults who are medically complex.

Mode of action on the thyroid Displacement of thyroid hormone form binding sites; low clinical importance but may alter thyroid function tests Inhibition of T4 to T3 conversion

Induce glucuronidation; may require increased dose of thyroxine Enhanced activity of type-3 deiodinase activity leading to accelerated inactivation of levothyroxine Reduce thyroxine levels in endogenous and iatrogenic thyrotoxicosis by interfering with enterohepatic recycling Reduction of acid milieu required for dissolution and transportation to the small intestine; may require higher doses of levothyroxine or use of a liquid preparation Interfere with gastrointestinal absorption; take levothyroxine 4 h before these medications, or at bedtime

Table 4 Symptoms and signs of hypothyroidism Symptoms of hypothyroidism in older adults Fatigue Cold intolerance Constipation Dysphagia Lack of concentration Memory loss Hearing loss Depression Generalized weakness or muscle cramps

Signs of hypothyroidism in older adults Alopecia Xerosis Hoarseness Weight gain Worsened congestive heart failure Anemia Hyperlipidemia Myxedema Neuropathy

Secondary Hypothyroidism This is defined as low TSH and low free T4 or inappropriately normal TSH with low free T4. Secondary hypothyroidism (caused by hypopituitarism) is an overlooked condition of older adults, as its presentation may be subtle and masked by concurrent chronic disease, geriatric syndromes,

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and age-related functional decline. Hypopituitarism is a rare condition with only 8–10 new adult cases per million people every year. With aging, the pituitary changes functionally, becoming more fibrotic and having altered vascular flow [3]. Hormonal feedback control in older adults may also become dysregulated due to the aging process [42]. The etiologies of hypopituitarism are numerous, including pituitary tumor, empty sella, pituitary surgery, radiation, Sheehan’s syndrome, stroke, hemorrhage, ischemia, trauma, infiltrative diseases, infections (e.g., HIV, tuberculosis), lymphocytic hypophysitis, chronic opioid use, and idiopathic processes. Some common clinical features in older adults with secondary hypothyroidism include anemia, alopecia, cachexia, cold intolerance, constipation, depression, falls, fatigue, hypotension, weakness, and weight loss. Practitioners may not be considering pituitary dysfunction leading to a delayed diagnosis by missing a normal TSH level in the presence of a low Free T4 [18]. In fewer cases, a Free T4 level was not ordered, and a TSH level alone was relied upon for diagnosis [18]. Several case series and case reports have highlighted idiopathic hypopituitarism in older adults [5, 11, 21]. Waise and Belchetz reported that a diagnosis of secondary hypothyroidism would have been missed if only TSH testing, or TSH first, had been utilized. All patients in their study had normal TSH and low free thyroxine. In addition, all of these patients had growth hormone, ACTH, and testosterone deficiency [37]. Secondary hypothyroidism may be a result of pituitary infarction, which can develop insidiously during coronary artery bypass grafting. Davies et al. reported two cases of a probable silent pituitary infarction following coronary bypass grafting. Hypopituitarism was suspected in these two patients who developed postoperative hyponatremia, fever, and hypotension. If left untreated, secondary hypothyroidism, as well as hypopituitarism, can have particularly serious consequences in frail older adults with multiple medical co-morbidities.

Diagnosis of Hypothyroidism When there is clinical suspicion for any form of hypothyroidism, a screening serum TSH and Free

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T4 level should be drawn. Antithyroid antibodies such as anti-TPO (anti microsomal) antibodies and antithyroglobulin antibodies are useful in diagnosis, with anti-TPO antibodies being more specific for autoimmune thyroid disease [1]. A low Free T4 with an elevated TSH suggests primary hypothyroidism. If the patient has had any recent critical nonthyroidial illness, laboratory results should be interpreted with caution and repeated once the patient has improved [1]. A thorough medication review should always be performed as part of the workup to rule out any iatrogenic causes, particularly in geriatric patients who tend to be exposed to polypharmacy. Diagnosis of thyroid nodules is discussed elsewhere in the chapter.

Management of Hypothyroidism Older adults with hypothyroidism should initially be treated with low doses of hormone replacement: 25–50 mcg levothyroxine daily. Dosing can be titrated up by 12–25 mcg daily every 3–6 weeks until a normal serum TSH level is obtained [3]. It may take extended time for TSH to normalize in geriatric patients, often due to longer latent periods prior to workup and diagnosis [1]. Patients should be closely monitored as dose adjustments are made, since older adults have increased sensitivity to hormone replacement and often have cardiac and pulmonary disease [34]. If there are significant cardiac co-morbidities, these older adults may be started on as low as 12.5 mcg daily of levothyroxine [1]. If the patient develops cardiac instability, dosing can be held for days to weeks and restarted at a lower dose once the patient improves [1]. If the patient remains stable from a cardiovascular standpoint, the dose may be titrated up at 12.5–25 mcg every 4 weeks as indicated by laboratory testing [1]. Patients over the age of 65 are often inappropriately dosed with levothyroxine according to a community survey of 339 persons: Only 43% were euthyroid, over 40% had low TSH, and over 15% had an elevated TSH [3]. Subnormal TSH was associated with low body weight, whereas elevated TSH was associated with diabetes in that study. If patients are started on medications that affect T4 absorption, the TSH should be checked in 4–6

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weeks. Serum TSH should be measured in 6–8 weeks after a change in dose or even the brand of levothyroxine. It is important to remember that a high TSH level in patients who are usually well controlled may indicate nonadherence with therapy. Due to a log-linear relationship between TSH and T4, a twofold change in FT4 can lead to a 100-fold alteration in circulating TSH [2]. In this situation, measurement of a FT4 level may be helpful.

Subclinical Hypothyroidism Definition Subclinical hypothyroidism is characterized by normal serum T4 and free T4 accompanied by an elevated serum TSH. This condition is seen in approximately 7–15% of adults over 60 years, making it the most common geriatric thyroid disorder [1, 26]. However, studies have shown that the upper limit of normal is higher with increasing age, so prevalence may be somewhat lower than these estimates [26]. Diagnosis The diagnosis of subclinical hypothyroidism is based upon biochemical testing alone. There has not been much success in purely clinical diagnosis; therefore, laboratory testing is required [6]. As in overt hypothyroidism, the first screening test is the serum TSH. If the TSH is elevated, it should be repeated and a serum-free T4 should be drawn. Some clinicians prefer concurrent measurement of TSH and Free T4 due to the possibility of secondary hypothyroidism in frail older adults. If the TSH is elevated and the free T4 is in normal range, the diagnosis of subclinical hypothyroidism is made. TSH can be transiently abnormal, so TSH measurement should be repeated after 1–3 months for confirmation of subclinical hypothyroidism [16]. AntiTPO antibodies are not usually performed unless the cause and/or treatment plan is unclear [16]. Most patients with subclinical hypothyroidism have autoimmune thyroiditis (Hashimoto’s). There is debate in the literature about what upper limits of normal are for older adults, particularly the oldest old; several studies have

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suggested that TSH physiologically increases with age and that normal range for these patients could be 6–8 mU/L, while others argue that cutoffs for normal should remain at 2.5–3 mU/L [8].

Signs and Symptoms Some patients with subclinical hypothyroidism may have nonspecific symptoms such as fatigue, constipation, and integumentary complaints, as in overt hypothyroidism. Others may be entirely asymptomatic. The level of suspicion needs to remain high in geriatric patients, as clinical presentation can mimic some of the physiologic changes of aging. Clinical Impact A large proportion of patients with subclinical hypothyroidism proceed to overt hypothyroidism according to many prospective studies, with 33–55% progression [41]. The risk of progression to overt hypothyroidism is related to the initial TSH serum concentration (over 12–15 mU/L) and the presence of anti-TPO antibodies. Many studies have associated a cluster of cardiovascular risk factors with subclinical hypothyroidism, such as hypertension, insulin resistance, diabetes mellitus, and hyperuricemia [26]. There is an increase in risk for cardiovascular diseases [coronary artery disease (CAD) and heart failure (HF)], especially if the TSH is above 10 mU/L [27]. The National Health and Nutrition Examination Survey (NHANES III) found higher mortality in patients with HF and subclinical hypothyroidism; however, there was no increased risk of death in patients without HF who had subclinical hypothyroidism [32]. Overall, there are controversial results regarding subclinical hypothyroidism and greater risk of cardiovascular and/or all-cause mortality. There is no definite association between stroke and subclinical hypothyroidism, particularly in adults over the age of 65; in younger adults with higher TSH levels, the relationship is less clear [9]. There may be neurologic effects of subclinical hypothyroidism, including memory loss and decreased executive functioning, due to decreased functioning of the hippocampus and overall slowed cognitive processing – both of which

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generally resolve with supplementation of thyroxine [35]. The Framingham Study associated subclinical hypothyroidism with increased risk of Alzheimer disease in females [38].

Management of Subclinical Hypothyroidism The American Association of Clinical Endocrinologists (AACE) recommend levothyroxine supplementation for older adults with TSH levels higher than 10 mU/L [4, 15]. Treatment of subclinical hypothyroidism in patients with TSH values between 4.5 and 10 mU/L is controversial. Initial dosing for older patients with or without cardiovascular disease is 25–50 mcg/day, which is low and helps to avoid over-replacement [4]. TSH monitoring and dose titration should be performed every 4–8 weeks until laboratory results stabilize [4]. The goal of treatment is to achieve a TSH of 3–6 mU/L (because of normal age-related increase of TSH level) for adults over 65 years with initial serum TSH levels above 7 mU/L. There is some controversy about treatment of subclinical hypothyroidism in older adults. Patients with a TSH level above 7 mU/L and patients with convincing symptoms of hypothyroidism are generally recommended for treatment, while in asymptomatic patients, observation is recommended [7, 16]. TSH and free T4 monitoring is initially recommended at 6 months and then yearly if laboratory values remain stable and the patient is clinically euthyroid [4, 15]. There is a lack of data for or against treatment of older adults with TSH levels of 4.5–10 mU/L, particularly in asymptomatic patients. Cardiovascular risk may be a valid reason to begin replacement with thyroxine and may improve the lipid profile [7, 17]. Multiple sources note that there are reasons to withhold treatment in older adults who are asymptomatic due to overall polypharmacy and pill burden, cost of medication and laboratory monitoring, and the potential risk of overtreatment and possible related new or worsened angina pectoris or arrhythmias [10, 37]. One study showed that just over 40% of patients over 65 years who take thyroid hormone replacement have a serum TSH level below normal range [10].

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If the patient is not treated, there is a consensus in the literature that regular follow-up and laboratory monitoring are indicated. A person-centered approach that takes into account overall life expectancy, disease burden, social supports and living situation, as well as goals of care needs to be employed in the management of subclinical disease in older adults.

Hyperthyroidism Definitions It is critical to diagnose hyperthyroidism in older adults, because if left undiagnosed, there is a potential for significant morbidity, mortality, and poor quality of life. Significant risks include cardiovascular impacts such as arrhythmias and osteoporosis with increased incidence of fracture [14]. Primary and subclinical hyperthyroidism occur more frequently in older adults, with incidence reported of 0.7–2% of persons over the age of 60 [14]. The most common causes of hyperthyroidism in geriatric patients include [14]: Endogenous: (40% toxic multinodular goiter, 30% toxic adenoma, 15% Graves’ disease, < 5% thyroiditis) Exogenous: (10% suppressive dosing of levothyroxine in setting of thyroid carcinoma, 5% excessive dosing of levothyroxine in setting of hypothyroidism) When there is low TSH and isolated elevation of T3, “T3 toxicosis” has occurred, which effects up to 10% of older adults [1]. This is generally due to T3 secretion from a nodule or goiter and is discussed elsewhere in the chapter. When there is isolated elevation of Free T4, this is known as “T4 toxicosis.” This condition is seen in patients with preexisting primary hyperthyroidism and concurrent nonthyroidal illness, and 50 deiodinase becomes inhibited by the acute illness state, leading to low or normal T3 [24]. Euthyroid hyperthyroxinemia results from a decrease in T4 to T3 conversion due to medications and altered protein binding, and this also needs to be ruled out [1].

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Amiodarone-related thyrotoxicosis occurs more frequently in older adults, who have a higher percentage of atrial fibrillation than younger patients. Prompt identification of clinical signs and diagnostic workup is essential. As mentioned above, amiodarone may cause a destructive thyroiditis (amiodarone-induced thyrotoxicosis type 2), resulting in hypothyroidism. Amiodarone use may also result in amiodaroneinduced thyrotoxicosis type 1, by inhibiting type 1 50 deiodinase and decreasing peripheral conversion of T4 to T3, therefore decreasing clearance of T4 and reverse T3 [20]. Entry of T4 and T3 into peripheral tissue is also inhibited by amiodarone, and elevation of serum T4 of up to 40% may be noted, which does not necessarily always cause overt hyperthyroidism [20].

Signs and Symptoms of Hyperthyroidism in Older Adults Signs and symptoms of hyperthyroidism in the elderly include [23]: • Atrial fibrillation (up to 20% of patients) or palpitations • Unintentional weight loss • Depression and cognitive decline, delirium, mania • Lethargy and fatigue • Heat intolerance • Sweating • Tremor • Diarrhea, vomiting, or constipation • Exophthalmia • Alopecia, coarse or thinning hair • Pretibial myxedema • Severe osteoporosis and increased fracture risk It is important to remember that some signs and symptoms of hyperthyroidism such as heat intolerance, anxiety, sinus tachycardia, and tremor may be missing in older adults due to effects of medications or physiologic changes of aging [40]. Older adults may present with atypical signs or symptoms of hyperthyroidism, including vomiting, constipation, depression, and fatigue [40]. Thyroid storm, which is less common in geriatric patients than in younger age groups, is

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decompensated thyrotoxicosis that presents with a severe hypermetabolic state, fever, neurocognitive changes, and possibly heart failure [1]. In older adults, the most common cause of thyroid storm is infection, rather than unprepared surgery or radioiodine therapy as in younger patients [19].

Subclinical Hyperthyroidism Subclinical hyperthyroidism is defined as subnormal TSH levels with normal levels of Free T4 and T3. Incidence is reported in 3–8% of the geriatric population [23]. There are reports of increased risk of coronary artery disease and cardiovascular associated mortality [29]. There is controversial evidence regarding the link between subclinical disease and osteoporotic fractures [1].

Diagnosis of Hyperthyroidism If there is clinical suspicion for hyperthyroidism, labs should be drawn. Of note, physical exam of the thyroid of older adults may not be as useful as in younger patients, due to atrophy of the gland [1]. Overt, primary hyperthyroidism is evidenced by low TSH and elevated total and free T4 levels. However, normal levels of total or Free T4 in the presence of low TSH point to subclinical hyperthyroidism or T3 toxicosis which should be confirmed. Presence of thyroid stimulating immunoglobulin (TSI) or other thyroid antibodies can help confirm a diagnosis of Graves’ disease. A medication review should always be performed to rule out iatrogenic causes, which occur more frequently in geriatric patients with high disease and medication burdens. Multinodular goiter, thyroid malignancies, and benign thyroid nodules will be discussed elsewhere in the chapter. Management of Hyperthyroidism Management of overt hyperthyroidism in older adults depends on the etiology, underlying co-morbidities of the geriatric patient, and person-centered goals of care. Treatment options include medical management or thyroid ablation, either by radioiodine therapy or by surgery. Subacute thyroiditis is generally self-limiting and is managed with supportive care.

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Hyperadrenergic symptoms may be treated with beta-blockers (as tolerated) by geriatric patients, and glucocorticoids if refractory, with close monitoring recommended [26]. Pain related to inflammation may be treated cautiously with nonsteroidal anti-inflammatory medications. Thyroid storm (severe thyrotoxicosis) is an emergency and requires inpatient care and rapid reduction of thyroid hormones. Treatment includes fluid and electrolyte stabilization, betablocking agents (e.g., propranolol 60-80 mg every 4-6 h), high doses of methimazole (20 mg every 4-6 h) or PTU (200 mg every 4 h), stress dose glucocorticoids, and Lugol’s iodine or potassium iodide at least one hour after starting antithyroid drugs [1]. Other agents that may be used in this type of multidrug approach to lower thyroid hormone levels include sodium iopadate, potassium perchlorate, and cholestyramine [1]. Radioiodine therapy is favored over surgical options or long-term medical management in older adults due to increased risk of associated morbidity, mortality, and adverse drug events [1]. Surgery is usually reserved for large obstructive goiters or when there is a high suspicion for malignancy [26]. Prompt control with radioiodine has shown increased benefits in reduction of mortality and symptoms in geriatric patients as compared to the younger population, and late complications of radioiodine are less of a concern in the elderly [36]. A short course of antithyroid medication is recommended as pretreatment in older adults who will receive radioiodine therapy, which has been shown to reduce the risk of iatrogenic thyroid crisis and tachyarrhythmias during ablation [36]. Antithyroid medications should be discontinued 3–5 days prior to radioiodine ablation and restarted 3–5 days postablation [1]. In older adults, the benefits of reducing potential thyroid and/or cardiac crisis afforded by these drugs are considered to outweigh the associated risk of increased radioiodine failure [1]. Patients should have monthly monitoring and follow-up as most will become hypothyroid and require replacement therapy [36]. Antithyroid medications may be used longterm to manage hyperthyroidism in older adults if radioiodine ablation is not considered the best option for the patient. These mediations include

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methimazole, propylthiouracil (PTU), and carbimazole. Older adults are at elevated risk for drug-induced agranulocytosis, particularly during the first 90 days of treatment with PTU [1]. Liver function may be altered with these medications and should be monitored regularly. The recommended choice for treating amiodarone-induced thyrotoxicosis type 1 (type 1 AIT) is thionamides, such as the above-mentioned medications, possibly with added potassium perchlorate to inhibit thyroid iodine uptake and enhance response to the antithyroid medication [26]. High doses of methimazole [40–60 mg/d] or propylthiouracil [600–800 mg/d]) are used to block thyroid hormone synthesis [31]. Type 2 AIT is treated with a relatively long course of glucocorticoids [31]. If thyrotoxicosis recurs after initial control, it is treated with glucocorticoids. In type 1 AIT, exacerbation may be due to mixed causes, which respond to addition of steroids. In type 2 AIT, relapse can occur after discontinuation of glucocorticoids, and treatment may need to be restarted [31]. Beta-adrenergic blocking medications can be used to manage cardiac and neurologic symptoms of hyperthyroidism and are contraindicated in patients with decompensated heart failure, asthma, and Raynaud’s disease [1]. Atrial fibrillation related to hyperthyroidism will often revert after antithyroid treatment reduces hormone levels, and anticoagulation is recommended until that occurs. Warfarin sensitivity has been noted in geriatric patients with hyperthyroidism, and lower doses with frequent monitoring are recommended [1]. Management of subclinical hyperthyroidism includes the same modalities as for overt hyperthyroidism. Subclinical disease in patients over 65 years of age is addressed by the American Thyroid Association (ATA) and recommends that patients should be treated when TSH levels are consistently below 0.1 mIU per L in patients 65 years or older [33]. The ATA recommends considering treatment for patients 65 years and older who have TSH levels of 0.1–0.4 mIU per L [33]. Association between low TSH levels and dementia is controversial, with no clear link of causality or cognitive benefit from treatment [13].

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Thyroid Nodules and Thyroid Cancer The thyroid becomes more nodular with age. Thyroid nodules are a common clinical or incidental radiological finding and are frequently nonfunctional. Thyroid nodules >1 cm detected by ultrasound may escape clinical detection. On the other hand, careful neck palpation has been shown to reveal solitary thyroid nodules in 6–10% of older adults [48], and in those over 65 years of age, ultrasonography can detect nodules in approximately 50% [51]. In adults, 5% of thyroid nodules have a malignant lesion, and this proportion increases in older adults in whom thyroid nodules are more prevalent. Peak occurrence of thyroid cancer is seen in two age groups: those between 20 and 29 years and those over 65 years of age, thus warranting a careful evaluation in order to exclude malignancies [56] if this is clinically appropriate in the light of patients’ comorbidities, functional and cognitive status, as well as preferences and values. Factors that have been identified with an increased risk of thyroid nodules and goiter include smoking (especially in areas of mild iodine deficiency), alcohol consumption more so in women, obesity and metabolic syndrome, and higher insulin-like growth factor-1 (IGF-1) levels. The main causes of thyroid nodules are listed in Table 5.

Diagnostic Approach to Thyroid Nodules The primary concern when a thyroid nodule is identified is whether it is malignant. The prevalence of thyroid cancer is higher in those over 60–65 years of age (as well as those under 30 years of age), in patients with a history of head and neck irradiation, and the presence of a family history of thyroid cancer, female gender, low iodine intake, and high body mass index. Additional features of the history that would suggest an increased likelihood of thyroid cancer are a history of total body irradiation for bone marrow transplantation, multiple endocrine neoplasia type 2 (MEN2), and familial adenomatous polyposis, or Cowden syndrome.

N. Pandya and E. Hames Table 5 Causes of thyroid nodules Benign causes Multinodular (sporadic) goiter (“colloid adenoma”) Hashimoto’s (chronic lymphocytic) thyroiditis Simple, colloid or hemorrhagic cyst Follicular adenoma Hürthle cell (oxyphil cell) adenoma Malignant causes Papillary carcinoma Follicular carcinoma (minimally or widely invasive, oxyphilic (Hürthle cell type), or noninvasive) Medullary carcinoma Anaplastic carcinoma Primary thyroid lymphoma Metastatic carcinoma (e.g., breast, renal cell)

The patient may discover a nodule, or it may be identified during a routine physical examination. It may also be reported incidentally during an imaging procedure such as computed tomography (CT) of the neck and chest, magnetic resonance imaging (MRI), or positron emission tomography (PET) scanning. Thyroid incidentalomas have the same risk of malignancy as palpable nodules, and a systematic diagnostic approach as outlined below is recommended for palpable and nonpalpable nodules [49] (Fig. 1). During the physical examination, the presence of a fixed hard mass, obstructive symptoms (e.g., stridor, or the presence of Pemberton’s sign), hoarseness, or the detection of cervical lymphadenopathy suggest the possibility of a malignancy. Thyroid ultrasound is recommended in all patients with a palpable thyroid nodule, goiter, or incidentaloma to assess the size and anatomy of the thyroid. It provides more information than the physical examination and can detect the presence of multiple nodules, posterior nodules, cysts, and any abnormalities of adjacent neck structures. It informs the clinician about which nodules should be selected for fine needle aspiration (FNA) biopsy.

Ultrasound Features of Malignancy It is important for clinicians to be familiar with ultrasonographic features of thyroid nodules

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when interpreting reports of thyroid and neck ultrasounds, or while looking at actual images, so that appropriate and informed referral of patients for fine needle aspiration biopsy can occur. These features include hypoechogenicity, microcalcifications, “twinkling” on B-flow imaging (a new sign), irregular margins, central vascularity, nodule that is taller than wider, absence or incomplete halo, documented enlargement of a nodule, and regional lymphadenopathy [55].

Thyroid Biopsy The usual technique is by fine-needle aspiration as an outpatient procedure. The majority of endocrinologists perform it under ultrasound guidance, as do radiologists. The overall accuracy of FNA is over 95%, with a false negative rate of 0–3%. This technique is highly feasible in older adults and helps to provide a more accurate diagnosis and selection of patients for surgical treatment [53]. Patients taking aspirin, nonsteroidal antiinflammatory drugs, or clopidogrel may discontinue them 5–7 days before FNA. However, it is recommended that in patients on systemic anticoagulation, the risk of stopping such drugs should be weighed against the risk of clotting and thrombosis. The risk of hematoma was 0.89% in a study of 336 of 803 patients undergoing FNA while on anticoagulants/antithrombotics including aspirin, clopidogrel, warfarin, rivoraxaban, or ticagrelor, and it was 0.49% in patients who were not on these therapies [50].

Evaluation and Management of Thyroid Nodules The most common thyroid cancer is papillary thyroid carcinoma (PTC) accounting for 85–90% of all thyroid cancers. Follicular thyroid carcinoma accounts for about 10% of thyroid cancers, whereas poorly differentiated or anaplastic cancers are rare and account for approximately 1–2% [54]. Although fine needle cytology is the primary diagnostic tool, inconclusive results present a diagnostic dilemma for which the application of

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molecular techniques to fine needle cytology has represented a significant advancement as a useful adjunctive tool in the evaluation of thyroid nodules in older adults. In large series utilizing the Bethesda System for reporting FNA cytology, 55–74% of the samples were reported as definitely benign and 2–5% as definitely malignant, with the remaining samples reported as cytologically indeterminate. The latter category comprises of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) reported in 2–18% of nodules, follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) reported in 2–25%, and suspicious for malignancy (SUSP) reported in 1–6% [52]. For nodules that are reported as nondiagnostic by FNA cytology, repeat FNA is recommended when feasible. Surgery is recommended for malignant lesions if clinically appropriate and aligned with the patient’s goals of care. However, for nodules reported as AUS/FLUS, FN/SFN, and suspicious, the use of molecular markers may be helpful in diagnosis to rule in or out the presence of thyroid cancer (risk can be between 10% and 40%) and thus inform the clinician about the need for surgery [49]. Important considerations in decision-making include the pretest probability of malignancy by risk factors, ultrasound findings and FNA cytology, feasibility of surgical treatment and follow-up, and importantly, patient preferences. It is also appropriate to refer such patients to endocrinologists familiar with thyroid neoplasms. If at the time of initial FNA cytology, an extra sample is collected should the cytology be indeterminate (AUS/FLUS or FN), it may be used for molecular testing. If such a sample is not available, repeat FNA with molecular testing is recommended. If molecular testing is not available, then diagnostic surgery (typically thyroid lobectomy) is recommended. Currently three approaches to molecular testing are commercially available in the United States. • Mutational analysis. The ThyroSeq v3 tests for a panel of molecular markers of malignancy such as BRAF and RAS. The sensitivity and specificity are high, including for Hürthle cell lesions.

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• Genomic sequencing classifier. The commercially available Afirma test utilizes thousands of genes to improve the discrimination of Hürthle cell neoplasms from non-neoplastic Hürthle cell lesions. It can also identify medullary thyroid cancer, parathyroid lesions, and BRAF V600E mutations. • Micro mRNA (miRNA) classifier combined with molecular markers of malignancy. The ThyraMIR and ThyGenX detect the presence of 10 miRNA genes and perform mutational analysis to detect the presence of eight oncogenes. Detection of the BRAFV600E mutation was successful in all 92 older adults with PTC despite concerns regarding the presence of lymphoplasmocytic infiltration and fibrous atrophy in older adults [47].

Thyroid Cancer Treatment Differentiated thyroid cancer is generally considered to be an indolent disease. However, this is not the case in older adults. A detailed review of the treatment of thyroid cancer is outside the scope of this chapter and is available from the 2015 American Thyroid Association publication on the Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer (2013 Am Thyroid Association . . .). Although there may be hesitation in treating thyroid cancer surgically in older adults, this is a relatively well-tolerated procedure. A retrospective study from the National Cancer Institute Epidemiology, and End Results (SEER) database of 424 patients aged 85 years and older on the characteristics and treatment of primary papillary or follicular thyroid cancers, reported the following. The size of the tumor and extent of disease were significantly related to the cause of death; those who did not have surgery were more likely to die of their thyroid cancer. Patients who underwent surgery had longer survival, although the type of surgery and radioactive iodine thyroid remnant ablation did not influence survival [57].

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The Safety of Thyroid Surgery in Older Adults Thyroid surgery in patients aged 70 years and older appears to be safe when indications for surgery are carefully considered regarding disease severity and optimizing postoperative outcome [58]. Indications for thyroid surgery include multinodular goiter with compressive symptoms, toxic goiter, suspicious or indeterminate thyroid nodule, and thyroid cancer. The relatively high rates of thyroid carcinoma and toxic goiter in this population may make surgery a justifiable approach. In a study of 320 Italian patients over age 70 years who had thyroid surgery, total thyroidectomy was performed in 283 patients. Although indeterminate or suspicious thyroid nodules were present in 60 cases preoperatively, the final histology revealed thyroid cancer in 86. The major complications included temporary hypocalcemia in 32.5%, temporary recurrent nerve palsy in 2.2%, and wound infection in 1.6%. Intensive care in the postoperative period was required in 7% of subjects with preexisting cardiovascular, pulmonary, or renal conditions.

Follow-Up of Patients with a History of Thyroid Cancer It is not uncommon in clinical practice to assume the care of new patients in the clinic or in the postacute long-term care setting, who may have had thyroid cancer in the past. Patients or family members may not report this problem, which may have been treated many years ago, and not noted in medical records during care transitions. Consequently it is always important to question why patients are on thyroid supplementation, to palpate the neck region for thyroid nodules, goiter, or lymphadenopathy, and to look carefully for neck scars, which may miss detection in older individuals with skin laxity and multiple skin folds. In patients who have unexplained hypocalcemia or who are on large doses of vitamin D or calcium supplementations, hypoparathyroidism should be suspected. This may be idiopathic, but may also

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be related to parathyroid damage during thyroid surgery. The presence of exophthalmos in patients on thyroid supplementation is a clue to prior treatment of Grave’s disease with radioiodine ablation or thyroidectomy. Patients who have been thought to be free of disease and treated by near-total or total thyroidectomy followed by radioiodine remnant ablation or treatment for recurrence, with 131I, At minimum, patients with a definite or suspected history of thyroid cancer should have the following studies: • TSH (identify appropriate goal – TSH suppression may not be necessary if the cancer was low risk without recurrence, or the patient has cardiac arrhythmias or low bone density). • Thyroglobulin should be undetectable with TSH stimulation (endogenous with thyroid hormone withdrawal or with recombinant human thyrotropin (rhTSH) administration). • Anti-Tg antibodies if these are present, the serum Tg level alone cannot be used as a marker for recurrent or persistent thyroid cancer. • Neck ultrasound identifies and characterizes malignant cervical lymph nodes (common site for PTC recurrence).

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• Patients with secondary hypothyroidism should be monitored and/or have supplementation adjusted based on Free T4 level alone. • When initiating levothyroxine replacement for older adults, monitor dose titrations closely at 4- to 6-week intervals. Starting doses of levothyroxine as low as 12.5 mcg daily should be considered for older adults with serious underlying cardiovascular co-morbidities. • Older adults with suppressed TSH levels, and normal free T4 levels, should have a T3 measurement to exclude the possibility of T3 toxicosis. • A systematic approach should be adopted for the evaluation of palpable and nonpalpable thyroid nodules utilizing TSH to assess thyroid status, followed by ultrasound, and radionucleotide scanning for those with hyperthyroidism. • Use of molecular markers is recommended when the results of the FNA cytology are indeterminate. • Identify the reason for thyroid supplementation and neck scars in all older individuals when assuming care.

Case Study Clinical Pearls • TSH and free T4 should both be measured in older adults. Primary and secondary hypothyroidism may have similar clinical presentations; therefore, suspicion for a pituitary cause needs to remain in the differential diagnosis when the TSH is in the low normal range or inappropriately normal in the face of a low free T4 level, and corresponding confirmatory laboratory analysis should be performed. Practitioners who may not be aware of a diagnosis of secondary hypothyroidism may reduce the dose of thyroxine in response to persistently low TSH levels, thus leading to worsening of symptoms. This can be problematic since longterm care patients can undergo multiple care transitions between acute and postacute longterm care settings.

A 79-year-old woman admitted to a skilled nursing facility from another state has an abnormal TSH of 0.15 μU/ml. She had a history of hypertension, diastolic heart failure, hypothyroidism, osteoporosis, L3 and L4 compression fractures, and mild cognitive impairment. Her vital signs were normal and physical examination was significant for slight pallor, alopecia, dry skin, generalized decrease in muscle strength, and delayed relaxation of her biceps reflexes. Her thyroid, cardiovascular, and abdominal examinations were normal; exophthalmos, neck scars, and tremor were absent. Her medication list at the time of admission was levothyroxine 88 mcg/d, nifedipine 10 mg/d, aspirin 81 mg/d, vitamin D 2000 U/d, alendronate 70 mg/week, and a multivitamin supplement daily.

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Management In view of her suppressed TSH, the dose of levothyroxine was reduced to 75 mcg daily. However, during a clinical evaluation 4 weeks later, she complained of increase in her fatigue and constipation. The facility staff also reported that she spent more time in bed and was reluctant to participate in any activities or exercise sessions. She was complaint with all medications administered to her. A repeat TSH level at that time was again suppressed at 0.12 μU/ml. A free T4 level was checked and reported to be 0.9 ng/dL (normal adult range 0.9–2.2 ng/dL). Her attending physician participated in a virtual care-planning meeting and asked the patient’s son about her thyroid history. Her son did not recall any history of goiter, hyperthyroidism, or thyroid cancer. He did remember that 2 years ago, following a fall in an assisted living center, a brain MRI had shown an empty sella. She was evaluated at that time by a neurologist and an endocrinologist with a final recommendation that she would always need thyroid supplementation and that her cortisol levels were normal. As a result, a diagnosis of secondary hypothyroidism was made and confirmed when her prior records were received. Her dose of levothyroxine was increased to 100 mcg/d and the dose was titrated to achieve a low normal free T4, since the TSH would not be expected to change with treatment.

Conclusion/Summary Thyroid disorders are common in older adults and can usually be evaluated utilizing a systematic diagnostic approach with targeted laboratory tests and imaging studies. It is important for clinicians to identify the cause of hypo or hyperthyroidism and individualize the need for and the intensity of treatment. Thyroid function tests should be interpreted in the light of the current clinical situation as well as medication and supplement regimen. Subclinical or overt hyperthyroidism is associated with adverse outcomes in older adults and should be treated. The intensity of thyroid supplementation

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needs to be individualized in older adults, who may have cardiovascular conditions or a prior history of thyroid cancer. Palpable thyroid nodules or incidentolamas in euthyroid or hypothyroid individuals should be examined by thyroid ultrasound and followed by FNA if biopsy criteria are met.

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Epidemiology 43. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and nutrition examination survey (NHANES III). J Clin Endocrinol Metab. 2002;87:489–99. https://doi.org/10.1210/jcem.87.2. 8182. 44. Leng O, Razvi S. Hypothyroidism in the older population. Thyroid Res. 2019;12:2. https://doi.org/10.1186/ s13044-019-0063-3. 45. Taylor PN, et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nat Rev Endocrinol. 2018;14: 301–16. https://doi.org/10.1038/nrendo.2018.18.

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Thyroid Surgery 57. Marvin K, Parham K. Differentiated thyroid cancer in people aged 85 and older. J Am Geriatr Soc. 2015;63: 932–7. 58. Raffaelli M, Bellantone R, Princi P, De Crea C, Rossi ED, Fadda G, Lombardi CP. Surgical treatment of thyroid diseases in elderly patients. Am J Surg. 2010;200: 467–72.

Infectious Diseases in Older Persons

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Dean Norman and Thomas Yoshikawa

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496 Aging and Host Defenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496 Clinical Features of Infection in Older Persons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 Pneumonia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

497 497 499 499 499 501 502

Urinary Tract Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis/Risk Factors for UTI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

503 503 503 504 504 505 506 506

Clostridioides difficile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506

D. Norman School of Medicine, San Diego VA Healthcare System, University of California, San Diego, California, USA e-mail: [email protected] T. Yoshikawa (*) Department of Veterans Affairs, Geriatrics & Extended Care, Charles R. Drew University of Medicine & Science, Los Angeles, CA, USA VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA David Geffen School of Medicine at UCLA, Los Angeles, CA, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_42

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D. Norman and T. Yoshikawa Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Coronavirus Disease 2019 (COVID-19) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508

Abstract

This chapter briefly reviews infections in older persons. Pneumonia and urinary tract infection are covered in some detail but other important infections also briefly reviewed. Keywords

Aging · Infectious diseases · Urinary tract infections · Pneumonia · Clostroides difficile · Coronavirus · Epidemiology · Infections · Clinical features

Introduction The specialized area of geriatric infectious diseases (GID) has evolved in tandem with the general field of aging, that is, geriatrics, gerontology, long-term care. With greater focus and intensity on epidemiology and public health of the older population, we now have narrowed which infections are most important in older adults, both in the community and long-term settings, be it institutional or noninstitutional. Although there are more than a dozen important topics on infections in older adults [1], for the purposes of this monograph, the authors will focus on the three most frequently encountered infections in older adults, that is, pneumonia, urinary tract infections, and Clostridioides difficile infection. In addition, a section on coronavirus infection 2019 (COVID-19), which has been and continues to be a major infectious disease in 2019–2020, will be discussed.

Aging and Host Defenses The aging of organs and physiology including immunosenescence (decline in immune function with aging) coupled with chronic disease,

iatrogenic and other factors weaken host defenses and increase the susceptibility to and severity of infections in older persons. The skin, a vital mechanical barrier, thins with age with loss of collagen and subcutaneous tissue and is easily damaged allowing pathogens to gain a foothold. Decreased saliva and antimicrobial protein content of saliva and reduced gastric acid and decreased gastric motility with age further diminish host defenses by allowing increased risk of colonization with pathogens and bacterial overgrowth, respectively. Blunting of cough and decreased mucociliary clearance with age diminish pulmonary host defenses. Common chronic diseases such as diabetes mellitus result in microvascular disease causing soft tissue damage which increases the risk of infection while chronic obstructive pulmonary disease accelerates age-related decline in pulmonary host defenses. The high prevalence of neurovascular disease in older adults increases the risk of stroke, which may impair swallowing resulting in increased aspiration, overwhelming already compromised pulmonary host defenses. Iatrogenic factors impacting host defenses in this vulnerable population include the failure to realize there are age-related changes in pharmacology and pharmacodynamics that may result in side effects of medications that compromise host defenses. For example, sedative hypnotic drugs and drugs that have anticholinergic effects increase the risk of sedation and aspiration. Nonjudicious use of antibiotics increases the risk of colonization and infection with multidrug resistant pathogens and Clostridioides difficile. Finally, the widespread use of catheters markedly compromises host defenses. Immunosenescence results in the degradation of both the innate and adaptive parts of the immune system. These two systems interact closely, and their decline increases the risk and severity of infection [2, 3]. The innate system does

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not need memory but relies on pattern recognition receptors such as Toll-like receptors (TLR). TLR embedded in sentinel cells such as macrophages, neutrophils, dendritic and natural killer cells recognize components of invading pathogens such as components of bacterial cell walls which in turn trigger an immediate cytokine response. The TLR-triggered cytokine response recruits neutrophils, another component of innate immunity as well as orchestrating the adaptive immune response. Aging appears to result in TLR dysregulation which then limits both innate and adaptive immune function [4]. Like the innate system, the adaptive system which is made up predominantly with B and T cells becomes dysregulated with age. Decreased T cell diversity, antigen responsiveness, cellular proliferation, and B cell functionality decline with age resulting in a decline in quantity and quality of antibody in response to antigens including components of some vaccines [5]. However, despite the decline in immune response to vaccines with age, vaccination is one of the clinician’s most important tools in preventing infections in the older population.

Clinical Features of Infection in Older Persons Atypical, nonclassical presentation of infections is common in older persons, particularly those who are frail, have cognitive impairment, and have multi-morbidities [6]. The clinician must be aware of how infections may present differently in seniors because diagnostic delays may lead to delays in the initiation of appropriate empiric antimicrobial therapy, increasing morbidity and mortality. On the other hand, loosely prescribing antibiotics for changes in a patient’s clinical status when infection is unlikely is potentially harmful. Never-the-less, acute, or subacute changes in cognition and behavior, new onset anorexia or incontinence, may indicate an infection is present and if otherwise unexplained a workup for infection should be included in the patient’s evaluation and empiric antimicrobial therapy considered.

497

It is also important to consider that fever and other signs of inflammation may be absent or blunted in older patients. Absent or minimal peritoneal findings may be present in cases of intraabdominal infection and cervical stiffness may not be present in meningitis cases. Bacteremia may be afebrile but present with other findings such as tachypnea or delirium. Finally, at times there may be a disconnect between the severity of infection and the clinical presentation in this population. The best example is a study of pyelonephritis in older versus younger women. Their presentation was similar, but bacteremia was present in nearly half of the old but none of the young women [7]. The specific presentations of pneumonia, urinary tract infection, and Clostridioides difficile infection are discussed in more detail elsewhere in this chapter. Fever is the cardinal sign of infection, but its absence may occur in nearly a third of infected older persons. Fever’s importance in prognosis and its’ important role in host defense has been reviewed elsewhere [6]. Recent studies confirming that baseline temperature declines with age and temperatures lower than the previous threshold of 101
F may indicate a fever is present and has led to changes in what temperature constitutes a fever in an older person. Taken together, these studies indicate that fever in this population, especially applicable to long-term care residents, can now be defined as a single oral temperature of 100
F or higher, repeated oral temperatures or 99.2
or higher or an increase of 2
F or more over baseline [6, 8].

Pneumonia Introduction In the past, a discussion of pneumonia which is defined as inflammation of the lung parenchyma due to infection would include four categories: community acquired pneumonia or CAP (pneumonia acquired outside of the hospital), hospital acquired pneumonia (HAP)(pneumonia developing 48 h after hospitalization), ventilator acquired

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pneumonia (VAP) (acquired 2 days after tracheal intubation), and healthcare-associated pneumonia (HCAP). HCAP included pneumonia acquired in long-term care facilities, dialysis patients, and others but is no longer considered a useful grouping of pneumonia patients as it resulted in too many instances of inappropriate use of broadspectrum antimicrobial therapy. HCAP patients are now considered as having CAP and the level of severity of the disease is used to determine whether or not there is a high probability of multidrug-resistant organisms [9]. HAP and VAP have distinct management methodology and will not be covered in this brief chapter section. Pneumonia is the leading infectious disease cause of hospitalization and death among adults and together, pneumonia and influenza are the eighth leading cause of death in the USA. Besides causing considerable morbidity and mortality in older adults, pneumonia places an enormous strain on our healthcare system. Insight into the impact of CAP on older persons (age 65 and older) can be gained by looking at prospective studies. First, based on their prospective epidemiologic study of CAP in adults requiring hospitalization done in 5 hospitals between 2010 and 2012, Jain et al. estimated that the incidences of hospitalization for those aged 65–79 and those over age 80 years were 9 and 25 times the rate for adults aged 18–49, respectively [10]. Another prospective study looked at the entire population of CAP cases in Louisville between the years of 2014 and 2016. The average age of the older pneumonia patient group was 78 years with nursing home residence and/or renal disease and/or congestive heart failure being associated with longer time to clinical stability, longer length of stays, and all-cause one-year mortality. Based on these study findings that were extrapolated to the population of the USA, it was estimated the incidence of hospitalization for pneumonia for older persons (age 65 years and older) in the USA translated to 942,437 individual cases per year. It was further estimated that 773,187 of those cases (82%) admitted to hospitals would be non-nursing home patients versus 18% coming from nursing homes. The Louisville study analysis also demonstrated the overall 30-day mortality rate for these

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patients to be 17%, the 6-month mortality rate to be 30% and the one-year mortality of 38%. The one-year mortality rate extrapolated to the entire older person population of the USA would suggest that there are nearly 360,000 CAP-related deaths per year in this population [11]. The one-year mortality rate predicted by the above study is consistent with a prior retrospective cohort review of 160,000 older hospitalized CAP patients versus 800,000 matched controls hospitalized for other causes. This study showed an 11% hospital mortality that was double the control population and a one-year mortality rate of 41% that was nearly twice that of control. Not surprisingly older age, male sex, and high pneumonia severity index scores correlated with higher long-term mortality [12]. The high one-year mortality rate for older persons hospitalized for CAP likely reflects more than just the detrimental effects of the pneumonia itself, but CAP in itself may indicate frailty. Readmission rates are unacceptably high for CAP and a large retrospective Medicare study looking at over three million hospital admissions for older persons with pneumonia between 2008 and 2016 determined the 30-day readmission rate to be 16.4%, which was only a slight improvement over earlier studies and reflected upon the results of efforts to reduce readmission rates. However, even that small gain in reducing the readmission rate was balanced out by increased emergency department visits and increased use of observation units [13]. As one would expect, mortality for nursing home residents hospitalized with pneumonia is higher than older persons living in the community at large. In one large study in Germany comparing the two groups, it was noted that nursing home residents hospitalized with CAP had a 27% 30-day mortality rate and a 44% 180-day mortality rate. Both these rates were three-fold higher than for non-nursing home residents hospitalized for CAP [14]. The precise healthcare cost for the care of hospitalized older pneumonia patients are difficult to determine but would be 10 billion dollars per year based on current data and is likely to be much higher.

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Pathogenesis The risk of and severity of infection is directly proportional to the size of the inoculum, the virulence of the pathogen, and inversely proportional to the integrity of the host’s defenses. In the vast majority of pneumonia cases, the infectious inoculum results from aspiration of the host’s own oropharyngeal flora that in turn overwhelms the host’s defenses. In a classic study done in persons age 65 an older, the risk of oropharyngeal colonization with potentially more virulent gramnegative bacilli increased with increasing level of care [15]. Poor dentition increases bacterial counts and there is some low-quality evidence that reducing dental bioburden by maintaining oral hygiene may reduce mortality from pneumonia compared to usual care [16]. Xerostomia that has a high prevalence in the elderly due predominantly to medications may also increase bacterial counts and the risk of colonization by virulent bacteria. Although adults of all ages aspirate small amounts of oropharyngeal secretions, older persons are more likely to aspirate larger volumes due to the high prevalence of swallowing dysfunction from cerebrovascular disease as well as neurodegenerative disorders such as Parkinson’s disease. The use of nasogastric tube feedings and sedative hypnotic and antipsychotic medications also increases the risk of aspiration. Finally, host defenses may be compromised by decreased mucociliary clearance, and although the protective cough and swallowing reflexes do not decline uniformly with aging, these reflexes have been found to be impaired in older patients with aspiration pneumonia [17]. Hence, there is the recommendation that older persons hospitalized with CAP have their swallowing function evaluated. Finally, chronic respiratory disease and its effect on pulmonary host defenses is a major risk factor for CAP and it has a high prevalence in the older population [18].

Etiology More recent studies of community acquired pneumonia suggest that isolation of an etiologic agent

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may not occur in most cases and that common respiratory viruses have become increasingly important as causes or co-factors in CAP. In a carefully designed prospective study of CAP requiring hospitalization, Jain et.al were only able to detect a pathogen in 38% of cases, with viruses being found in 23%, bacterial pathogens in 11%, and both in 3% [10]. A recent British prospective study using fast multiplex polymerase chain reaction (PCR) techniques to analyze sputum and or endobronchial aspirates in hospitalized CAP patients found PCR to be far superior to culture in finding a pathogen [19]. Bacterial pathogens were found in 87% of cases (usually Streptococcus pneumoniae or Haemophilus influenzae) and viral pathogens in 30% of cases (usually rhinovirus or influenza). The increasing availability of multiplex PCR technology may help clinicians to be better at determining the precise etiology of CAP. Another study determined risk factors that were independently associated with older CAP patients who were hospitalized and subsequently found to have multidrug-resistant pathogens (MDR) including MRSA. Two important factors were having been in a hospital in the previous 90 days (especially if they received antibiotics) or if they were residents in nursing homes [20].

Diagnosis Diagnosis requires an infiltrate to be present on chest imaging in a patient with a syndrome compatible with a respiratory infection. Computed tomography (CT) should not be done routinely because most often a good posteroanterior and lateral radiograph is enough to make the diagnosis. However, a CT is more accurate than a chest radiograph but even a “low dose” chest CT exposes the patient to over ten-fold the radiation from a chest radiograph. Moreover, there is a risk of incidental findings on CT such as pulmonary nodule(s) that have broad implications beyond the scope of this chapter. CT should be reserved for selected cases such as when there is a high suspicion for pneumonia but the initial chest radiograph and one done the next day after hydration

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do not demonstrate an infiltrate, or in complex cases such as where there is significant preexisting chest pathology making interpretation of the chest radiograph difficult. Pulmonary ultrasound is increasingly being used in emergency departments and shows promise in demonstrating pulmonary infiltrates while simultaneously excluding congestive heart failure as a cause of the infiltrates. Vital signs and pulse oximetry as well as a thorough physical examination should be routine. Unfortunately, fever and chest pain may be blunted or absent in older persons especially if they are frail. Looking at a large population of CAP cases age 65 and older that were hospitalized, Ewig et al. in the study mentioned above noted that while cough and dyspnea were present in over 80% of patients coming from the community at large or nursing homes, fever was present in only 57% of cases [14]. Confusion was present in nearly 50% of nursing home cases versus 15% of the non-nursing home patients. Chest pain was present in a third of non-nursing home patients versus only 16% of nursing home patients. Tachypnea was found in 18% of nursing home patients versus 13% of non-nursing home patients. Finally, severe hypotension was found in 39% of nursing home patients versus 21% of non-nursing home patients. (Table 1). Newly updated 2019 guidelines from the Infectious Diseases Society of America and the American Thoracic Society [9] recommend Table 1 Pneumonia signs/symptoms (Adapted from reference [14]) Community acquired pneumonia versus nursing home acquired pneumonia (NHAP) in older persons CAP (%) NHAP (%) N ¼ 2569 N ¼ 518 Cough* 88.5 83.3 Dyspnea 81.2 84.1 Confusion* 14.7 49.2 Chest pain* 33.2 16.4 Fever 56.9 56.8 Tachypnea 13.0 17.8 Severe hypotension* 21.2 30.3 *

Statistically significant difference

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pretreatment sputum Gram stain and culture and blood culture not be done for patients that are managed in the outpatient setting. However, these tests are recommended for those managed in the hospital setting or those that are either classified as severe or if there is suspicion the pneumonia is being caused by methicillinresistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa (see below). In frail older patients, it is often difficult to obtain sputum without an invasive procedure and culture and gram stain, and for that matter, molecular diagnostic testing may not be accomplished. Blood cultures may be positive in up to 15% of severe CAP cases. Similarly, urinary antigen testing for legionella antigen or nucleic acid and pneumococcal antigen should be done only in severe cases or, in the case of Legionella, if there are epidemiologic factors present, such as outbreaks. Infectious Diseases Society of America and the American Thoracic Society guidelines recommend rapid testing for influenza virus during periods of increased circulation of these viruses in the community for adults with CAP because antiviral therapy is available and the presence of influenza will have epidemiologic implications (e.g., isolation if admitted to the hospital). Multiplex PCR diagnostic testing is available for multiple respiratory viral pathogens, but its routine use in diagnosing the cause of pneumonia in older patients requires more research. Needless to say, all patients with suspected pneumonia should be tested for Coronavirus disease 2019. Finally, a nasal swab that is negative by PCR for MRSA makes MRSA pneumonia unlikely. A complete blood count with differential and renal panel should also be routine. Most important, the Infectious Diseases Society of America and the American Thoracic Society no longer recommend using serum procalcitonin solely to determine whether to begin antimicrobial therapy. Serum calcitonin is not a replacement for clinical judgment as it simply is not sensitive enough to detect bacterial pneumonia. However, exceptionally low or very high values may have some clinical utility in differentiating viral from bacterial infection, respectively.

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Management The first decision to make in caring for a senior with the diagnosis of community-acquired pneumonia is to determine whether the infection is severe because that will determine site of care, the need for further laboratory testing, and empiric antibiotic therapy. The Infectious Diseases Society of America and the American Thoracic Society CAP guidelines referred to above were first established in 2007 and updated in 2019 have been validated [9]. Severe pneumonia is presumed to be present in CAP patients if three or more minor criteria (respiratory rate greater than or equal to 30 breaths per minute); partial pressure of oxygen in arterial blood/ fraction of inspired oxygen (PA02/FI02) less than 250; multilobar infiltrates, confusion, blood urea nitrogen (BUN) greater than or equal to 20 milligrams/deciliter, while blood cell count of less than 4000 cells/ microliter (not due to chemotherapy), platelet count less than 100,000/microliter, temperature less than 36
C, hypotension requiring fluid resuscitation OR ONE major criteria (septic shock requiring pressor agents and respiratory failure requiring mechanical ventilation). The guidelines recommend using the Pneumonia Severity Index (PSI) over the CURB-65 to determine the appropriate level of care, the selection choices generally being treated either as an outpatient or on a general medical unit or a more intensive care unit. The PSI is more complex than the easy to remember CURB-65, but given clinicians are now equipped with smart phones, the PSI can be easily calculated. Neither prognostic model is a substitute for clinical judgment especially in geriatric medicine where psychosocial factors are often paramount. An older person with mild cognitive impairment and who lives alone with minimal assistance may not be an appropriate candidate for initial outpatient management even if either model predicts a low 30-day mortality rate/low risk class for this patient. The guidelines also recommend that for patients deemed to be safe to treat as outpatients and who are generally healthy with no risk factors for MRSA or Pseudomonas aeruginosa, oral agents may be used.

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Amoxicillin and doxycycline are the recommended first-line drugs. A macrolide (azithromycin or clarithromycin) can be used as an alternative if pneumococcal resistance is less than 25% in the community. Widespread resistance of pneumococcus to macrolides across the USA precludes the routine use of this drug as monotherapy in CAP. For outpatients with co-morbidities which would include most seniors, oral agents such as amoxicillin/clavulanate or a cephalosporin (cefpodoxime or cefuroxime) AND a macrolide or doxycycline are recommended. Single-drug therapy with a respiratory fluroquinolone (levofloxacin, moxifloxacin, or gemifloxacin) is an alternative, but clinicians should be aware that fluoroquinolones have significant side effects including increasing the risk for Clostridioides. For inpatients deemed nonsevere, a betalactam (ampicillin/sulbactam or ceftriaxone or ceftaroline) AND a macrolide or monotherapy with a respiratory fluroquinolone would be appropriate. Of note, clarithromycin is not available in parenteral form, limiting its utility in the initial inpatient setting. Doxycycline in combination with a betalactam may be used as an alternative for patients unable to tolerate a macrolide or fluroquinolone. Patients at high risk for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa would need expanded antibiotic coverage. We do not recommend expanding coverage routinely for patients admitted from nursing homes with CAP unless these organisms have been cultured in the past or if the patients have recently been in the hospital and received antibiotics. When laboratory results are known, more narrow spectrum drugs should be used based on antimicrobial resistance (de-escalation). (Table 2 summarizes these recommendations). For in-patients with severe pneumonia, a beta-lactam as noted above plus a macrolide or a beta-lactam plus a respiratory fluoroquinolone is recommended. Again, coverage for patients at risk for MRSA and or Pseudomonas aeruginosa would again require expanded antimicrobial therapy with de-escalation of therapy occurring when antimicrobial susceptibilities become known.

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Table 2 Summary of antibiotic recommendations for CAP. (Adapted from reference [9]) Outpatient: no comorbidity, low risk for MRSAa, Pseudomonas aeruginosaa Amoxicillin OR Doxycycline OR Macrolide (clarithromycin and azithromycin should not be used if pneumococcal resistance is over 25% in the community) Outpatient: comorbidities present Amoxicillin Clavulanate PLUS either a macrolide or doxycycline OR Cefpodoxime PLUS either a macrolide or doxycycline OR Cefuroxime PLUS either a macrolide or doxycycline OR Respiratory fluoroquinolone (levofloxacin or moxifloxacin or gemifloxacin) Inpatient: nonsevere Ampicillin/sulbactam and a macrolide OR Cefotaxime OR Ceftriaxone and a macrolide OR Ceftaroline and a macrolide OR Respiratory fluroquinolone Inpatient: severe Beta-lactam as noted above and either a macrolide OR respiratory quinolone a

Expanded coverage for MRSA and Pseudomonas is indicated as empiric therapy for CAP patients at high risk for these pathogens. Coverage should be narrowed if possible when antimicrobial sensitivities become available. Empiric MRSA coverage not necessary if nasal PCR swab for MRSA is negative

The Infectious Diseases Society of America and the American Thoracic Society guidelines recommend that the duration of therapy should be a minimum for 5 days and patients should be afebrile for 48–72 h and have no more than one sign of clinical instability (temperature greater than 37.8
C, heart rate greater than 100 beats per minute, systolic blood pressure less than 90 mm mercury, pulse arterial oxygen saturation less that 90%, or partial pressure of arterial oxygen less than 60 or continued change in mental status or inability to maintain oral intake). Finally, corticosteroids are no longer recommended as routine therapy in CAP. All geriatricians are familiar with the fact that early mobility is key to reduce hospital length of stay. The decision to treat CAP in a long-term care facility rather than transferring the patient to an acute care hospital will depend on the availability of laboratory testing, close monitoring, and the availability of clinicians. Advance directives should be obtained for all long-term care patients and therapy(s) adjusted to meet the individual patient’s treatment goals. Ceftriaxone may be given once per day and macrolides, doxycycline, amoxicillin/clavulanate, cefuroxime, cefpodoxime, and fluoroquinolones are all available as oral drugs.

Prevention Vaccinating children with the pneumococcal conjugate (Prevenar 13) vaccine has resulted in decreased invasive pneumococcal disease in both children and adults. Based on its effectiveness in creating herd immunity, the vaccine is no longer routinely recommended for all adults of any age. The decision to give Prevenar 13 to otherwise healthy seniors is currently recommended to be based on shared clinical decision-making. Pneumococcal polyvalent vaccination (pneumovax) is still routinely recommended and annual influenza vaccination is essential to reducing influenza cases and those complicated by bacterial pneumonia. Maintaining oral hygiene may have some role in reducing the risk of pneumonia [16] and reducing the use of sedating, and anticholinergic drugs will reduce the risk of aspiration. Reducing environmental and life style risk factors such as reducing smoking and exposure to second-hand smoke will reduce the burden of chronic respiratory disease and in turn reduce the risk of CAP. Reducing alcohol consumption, maintaining adequate nutrition, reducing multimorbidity, limiting contact with children with respiratory infections, and improving mobility may also reduce the risk of CAP [21, 22].

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Urinary Tract Infection Introduction Bacteriuria with or without pyuria is common in old age and frequently presents clinicians with a diagnostic conundrum. Clinicians must balance good antibiotic stewardship with potentially disastrous outcomes when trying to differentiate bacteriuria from true urinary tract infection. For this discussion, we will define asymptomatic bacteriuria (ASB) as per the Infectious Diseases Society of America (IDSA) criteria: The patient must be free of symptoms attributable to the urinary tract and second, if male, must have greater than or equal to 105 bacteria per milliliter of urine on a single clean catch voided urine or, for females, have two separate voided specimens that grow the same bacteria in the same numbers listed above. A single catheterized specimen that grows greater than or equal to 102 bacteria per milliliter of urine is also sufficient for either sex [23]. Urinary tract infection (UTI) is a clinical syndrome (e.g., cystitis, pyelonephritis) most often presenting with specific symptoms referable to the urinary tract. Diagnostic criteria will be discussed in more detail below but generally, bacteria are present in the numbers described above and so is pyuria. Pyuria is defined as greater than 10 white blood cells per unspun urine and is nearly always present with ASB or UTI but may occur without either of those conditions. The degree of pyuria does not distinguish asymptomatic bacteriuria from urinary tract infection. Asymptomatic bacteriuria in individuals may be dynamic, being present at different times with sterile intervals and periods where different pathogens can be cultured [24]. The prevalence of ASB increases with increasing age, increasing levels of debility, and dementia and with abnormalities of the genitourinary tract. Overall, the prevalence of ASB in the community in persons of age 70 or greater is 10.8–16% for women and 3.6–19% for men and as expected is much higher in residents of long-term care facilities (LTCF). In LTCF, the prevalence in women is 25–50% and men 15–50% [25]. Older persons not suspected of having symptomatic urinary tract infection should

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not routinely be screened for bacteriuria except as discussed below. Treatment of ASB outside of urologic surgery generally is of no benefit and has the potential to cause harm [23]. Urinary tract infection has an enormous impact on our healthcare system. It was estimated that there were 8.3 million ambulatory care visits, 24.3% of which were emergency department visits for UTI in 2007. A large percentage of these occurred in older persons [26]. It was estimated there were 188,360 hospitalizations for UTI in Medicare enrollees in 2008 and rates of UTI hospitalization for that year were estimated to be 266/100,000 enrollees between 65 and 74 years old, 895/100,000 for those between 75 and 84 and 2463/100,000 for those over 85 [27]. Although UTIs are the second most common infectious disease causing hospital admission for seniors, they are far less lethal than pneumonia, the leading cause: From 2000 to 2002, it was reported that urinary tract infections made up 15.5% of United States hospitalizations for infectious diseases in older persons versus 46% for pneumonia. However, UTIs only accounted for only 6.2% of all infectious diseases-related deaths versus 47.8% for pneumonia [28].

Pathogenesis/Risk Factors for UTI The urinary microbiome may change significantly with age [29], but its role in the pathogenesis of UTI is unclear. The first step in developing a UTI is periurethral colonization by fecal flora, which can then enter the bladder and cause infection and possibly ascend into the ureters and cause pyelonephritis. In the case of urinary catheters, pathogens eventually gain entrance into the bladder via the periurethral route or by colonizing the bladder catheter or collecting system. Any condition that interferes with the normal flow of urine will increase the risk of UTI. Unfortunately, some biologic changes with aging may interfere with normal urinary function and thus increase UTI risk. The increased postvoid residual seen in normal aging may play a role in the pathogenesis of ASB and UTI [30, 31], but reduced bladder

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capacity with aging has not been established as a risk factor. Whereas prostatic hypertrophy and prostatitis increase the incidence of UTI in men, atrophic vaginitis due to estrogen deficiency increases the incidence in women. Neurovascular complications of stroke and diabetes mellitus or other conditions that interfere with bladder emptying are substantial underlying factors for both ASB and UTI. Urinary catheters of any kind markedly predispose individuals to ASB and UTI. Intermittent bladder catheterization for an obstructed or neurogenic bladder is less likely to be complicated by UTI, and condom catheters used for incontinence and convenience have much less incidence of symptomatic UTI but risk for maceration of the penis does exist. Renal and bladder stones increase the risk of UTI as well as increase the chance of relapse and recurrence and may complicate treatment for UTI. Finally, the use of certain sodium-glucose co-transporter 2 inhibitors (SGLT2) for diabetes mellitus and heart failure is associated with a small but significant predisposition to UTI.

Etiology Escherichia coli, regardless of age, is the dominant pathogen for uncomplicated UTI where there is normal function of the urinary tract. Many older persons present with complicated UTI and in this case a variety of uropathogens are possible. Enterobacteriaceae sp. are the major pathogens and include Escherichia coli, Proteus mirabilis, and Klebsiella sp. and grampositive organisms, especially Enterococcus sp. are possible [32]. Patients with long-term indwelling catheter may have several pathogens isolated even when the sample is collected with a fresh catheter [33]. Older persons may have diminished host defenses and have increased exposure to antibiotics, be residents of LTCF, suffered recent hospitalizations, and have indwelling catheters or recent urologic procedures, all of which increase the risk of urinary tract infection, often with multidrug-resistant pathogens (MDR) [34].

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Diagnosis Urethritis and prostatitis will not be reviewed in this discussion. Uncomplicated urinary tract infection occurs much more frequently in women (here “uncomplicated” refers to bladder or kidney infection with normal genitourinary function). It presents similarly in otherwise healthy young and older women and is characterized by the acute onset of lower urinary tract irritative symptoms including dysuria, frequency, and in the case of cystitis, suprapubic pain may be present; fever (low grade) is generally absent. Nonobstructive pyelonephritis typically presents with fever, flank pain, costovertebral-angle tenderness, nausea, and vomiting; sepsis may be diagnosed. However, irritative lower urinary symptoms may or may not be present. Hematuria and urinary incontinence may also occur in both cystitis and uncomplicated pyelonephritis [35]. Complicated UTI in older adults occurs in both sexes and refers to UTI in persons with functional or structural abnormalities of the urinary tract that may increase the risk of treatment failure or poor outcomes [35, 36]. This usually includes any UTI in males because of possible infection of the prostate as well as possible obstructive uropathy from enlargement of the prostate. Conditions that increase the risk of complicated UTI also increase the risk of ASB and thus making distinguishing between true infection from ASB difficult. Complicated urinary tract infection may present with typical symptoms like uncomplicated infection. However, frail older persons, especially if demented or with chronic indwelling catheters, may present in a nonclassical fashion. Nonclassical presentation could include an otherwise unexplained change in functional status in the setting of bacteriuria or a fever with no localizing signs or symptoms. However, urinary tract infection generally should have symptoms referable to the urinary tract, and if these are not present, even with bacteriuria and pyuria, another cause of the patient’s decline should be vigorously sought before settling on the diagnosis of UTI. Otherwise, unnecessary or excessive prescribing of antibiotics will occur.

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IDSA strongly recommends not routinely treating functionally or cognitive impaired older patients with bacteriuria when localizing genitourinary or systemic signs of infection are not present, even when delirium is present or the patient has fallen [23, 25]. Moreover, the inappropriate treatment of ASB is so rampant that many hospitals have discouraged routine urinalysis when clinical UTI is not suspected and, as part of their antibiotic stewardship program, will not permit a culture and sensitivity in the absence of an abnormal urinalysis. In a well-designed prospective study of residents with advanced dementia in 25 nursing facilities between 2009 and 2011, the investigators studied 131 suspected UTI episodes. However, only 16% of these episodes met minimal criteria for treatment. For patients without catheters, minimal criteria presence meant there was evidence of dysuria or fever with one of the following: frequency, urgency, hematuria, costovertebral tenderness, pain, change in mental status, or rigors. For catheterized patients, minimal criteria included one of the following: fever, rigors, or change in mental status. In the case of fever, if there were no localizing findings but no other source of infection, then minimal requirement for a UTI was thought to be met. Surprisingly, 75% of the 110 episodes of suspected urinary tract infection that did not meet minimal criteria were still treated with antimicrobials [37]. For catheter infections, it is recommended the catheter be replaced and cultures obtained prior to treatment. This eliminates the possibility of the old catheter being obstructed or kinked and improves the accuracy of the urine culture (chronic catheters are often colonized with bacteria on the inner walls of the catheter, which may contaminate the urine for culture). An unpleasant odor or cloudiness of urine whether a catheter is present is not diagnostic of a urinary tract infection but could reflect dehydration, the presence of certain types of ammonia-producing bacteria or residual debris. A preliminary negative urine dipstick test for nitrites and leucocyte esterase makes the diagnosis of UTI unlikely. Given the variety of pathogens possible, it is strongly recommended that for seniors a culture be done with urinalysis prior to initiating treatment for this condition. Generally,

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for complicated urinary tract infection, localization of infection should be attempted. A digital rectal examination done in males may reveal prostatitis, and a postvoid residual test may alert the clinician to the possibility of obstructive uropathy. Ultrasound and computed tomography are helpful in diagnosing urinary tract pathology, and imaging should be considered in all patients hospitalized for UTI and in those with relapse.

Management Once it is determined that an older woman or man with cystitis can safely be treated as an outpatient, first-line drugs that can be prescribed include oral nitrofurantoin (5 days), fosfomycin (single dose), pivmecillinam (5 days), and trimethoprimsulfamethoxazole (TS) for 3 days. TS should be avoided if antibiotic susceptibility tests show a resistance rate of greater than 20% to this antibiotic [38]. Nitrofurantoin can safely be given with a creatinine clearance as low as 30 ml/min. Fluroquinolones, due to resistance and toxicity, are now considered second-line drugs for uncomplicated urinary tract infection. It should be mentioned that there are studies questioning the need for any antimicrobial therapy for simple cystitis [39]. Never-the-less, the current standard of care for this condition remains antibiotic therapy. When uncomplicated pyelonephritis is suspected and a urine culture has been obtained, an older patient who is able to take oral medication and is otherwise healthy and is reliable may be begun on an oral fluroquinolone (ciprofloxacin or levofloxacin). However, many older persons will require a prolonged observation period in the emergency department or urgent care setting after first receiving a short course of empiric parenteral antimicrobial therapy. This is done to ensure they can be safely discharged on an oral agent. Often, hospitalization and treatment with empiric parenteral therapy is required. Intravenous therapies could include a fluoroquinolone, an extended-spectrum cephalosporin such as ceftriaxone or a beta lactam/beta lactamase inhibitor such as piperacillin/tazobactam. Antibiotics are adjusted when culture results are known. When patients are hospitalized, treatment with

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parenteral therapy is usually 3–5 days with discharge on the appropriate oral antimicrobial therapy for a total antibiotic course of 10–14 days. Hospitalized patients should have blood cultures done, and if positive, parenteral therapy duration may need to be much longer and infectious diseases consultation should be considered. Urinary tract infections in older men are considered complicated and should involve a search for the site of infection. If it is clear cystitis or unobstructed pyelonephritis is present, each can be treated empirically similarly to older women. If symptoms suggest lower urinary tract infection, but the site is unclear, an oral quinolone may be given pending culture data. Bacterial prostatitis usually requires prolonged therapy, typically at least 30 days. Acute bacterial prostatitis may be severe and result in abscess, urinary obstruction, and urosepsis. The treatment of severe acute bacterial prostatitis with or without abscess is beyond the scope of this chapter, but empiric broad-spectrum antibiotic therapy will be necessary [32]. The management of acute complicated urinary tract infection presents more of a challenge. First, the severity of illness and advanced directives will determine where the patient should be treated. Second, patients who meet criteria for urosepsis will require additional measures apart from the prompt initiation of antimicrobial therapy. Acutely ill patients will be at risk for multidrugresistant (MDR) pathogens if they had a recent hospitalization or long-term care facility stay, recent antibiotic course, or recent urine culture demonstrating MDR pathogens. Those patients at risk for MDR will require empirical broadspectrum antibiotic therapy pending culture results. Apart from covering potentially resistant gram-negative pathogens, coverage of Enterococcus spp. and methicillin-resistant Staphylococcus aureus with vancomycin or another antibiotic active against these pathogens may be necessary.

Prevention Like other infectious diseases, minimizing risk factors, including multimorbidity, is an important

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strategy to reduce the impact of infection. In the specific case of UTI, reducing the use of urinary catheters as much as possible is important. The need for a catheter, even a condom catheter, should always be questioned. Frequently, indwelling bladder catheters are appropriately inserted during an acute illness episode but are “forgotten” and not removed despite the indication no longer being present. Vaginal estrogens may reduce recurrent urinary tract infections in postmenopausal female seniors. Cranberry juice or supplements do not appear to reduce the risk of UTI [40]. Prophylactic short-course preoperative antimicrobial therapy should be given for bacteriuric patients undergoing mucosal disrupting urologic procedures as well as certain major organ surgeries (e.g., heart, brain, and spine) and the antibiotic chosen to be based on the patient’s urine culture and sensitivity data.

Summary 1. Routine screening and treatment of ASB should be avoided except in special circumstances. 2. The presence and degree of pyuria does not distinguish ASB from UTI. 3. Minimal criteria for UTI should be met before initiating empiric antimicrobial therapy. 4. Empiric antimicrobial therapy should be based on the clinical situation and adjusted when the culture results are known. 5. The use of urinary catheters should be minimized, and their presence always questioned. Beware of the “forgotten catheter.”

Clostridioides difficile Introduction Clostridioides difficile, formerly called Clostridium difficile, is gram-positive bacilli (rod) that now has become the most important and leading etiology of healthcare-associated gastrointestinal infection and diarrhea in the United States,

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particularly in older adults. A relatively simple and easy method of remembering the key issues of C. difficile infection is the three “A’s”: Aging, Admission (to a healthcare institution), and Antibiotics [41]. Several reports supported the observation that the very old, institutionalized, and frail (functional deficits) are especially the high-risk population for C. difficile infection [42–44]. A variety of antimicrobial agents are associated with this infection with the most common drugs being clindamycin, penicillins, cephalosporins, fluoroquinolones, monobactams, and carbapenems [45].

Diagnosis Clinical manifestations generally range from mild (3 or more loose stools/day with no to mild abdominal pain); moderate (3 or more loose stools with moderate abdominal pain or tenderness, nausea, evidence of dehydration, and moderate leukocytosis); or severe (3 or more loose stools with blood, fever, severe abdominal pain, vomiting, ileus, may be hypotensive, altered renal function, low serum albumin); or severe complicated (add hypotension, respiratory distress, toxic megacolon, ileus, peritonitis [46]. Diagnosis of C. difficile infection should be suspected if a patient has a history of antimicrobial therapy within the past 14 days up to 3 months and unexplained diarrhea of 3 or more loose stools (see above). Stools should be tested for toxins A and B (a variety of test methods are available, but a multistep method involving glutamate dehydrogenase plus toxin, arbitrated by nucleic acid amplification test, has been recommended by the Infectious Diseases Society of America) [47].

Management Therapy for first-episode of C. difficile infection is now either vancomycin 125 mg orally 4 times/day for 10 days or fidaxomicin 200 mg orally 2 times/ day for 10 days [47]. If access to vancomycin or fidaxomicin is limited, an alternative drug is metronidazole for initial treatment of nonsevere

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C. difficile infection. For severe C. difficile infection, vancomycin 500 mg orally 4 times/day plus intravenous metronidazole 500 mg every 8 h are recommended. If ileus is present, the vancomycin administration should be by retention enema. If surgical management becomes imperative, subtotal colectomy with preservation of the rectum is recommended. For patients with recurrent C. difficile infection, a variety of treatment regimens have been proposed and are much too detailed for this review. Clinicians are recommended to consult with their local infectious disease consultant for suggestive regimens. Fecal microbiota transplantation has been recommended when multiple recurrences of C. difficile infections have failed standard antimicrobial therapeutic regimens [47]. Local availability and success of this intervention will determine prescribing of fecal microbiota therapy. The role of primary or secondary intervention of probiotics for prevention of C. difficile infection has had varied therapeutic results and will not be discussed in this review.

Coronavirus Disease 2019 (COVID-19) At no time in recent history since the great “Spanish Influenza (flu) of 1918” has the world experienced such a devastating infectious disease epidemic as the current coronavirus disease of 2019 (also called severe acute respiratory syndrome coronavirus 2 {SARS-COV-2}). Much like the flu, COVID-19 disproportionately attacks and kills older adults and those with chronic underlying disorders such as diabetes mellitus, heart disease, lung and renal disorders, cancers, and immunocompromised states [48]. Moreover, COVID-19 has caused havoc in long-term care facilities with rapid spread, severe illness, and deaths to the most vulnerable persons in society. As a result of this deadly disease, many long-term care facilities (nursing facilities, rehabilitation centers, and residential care housing) have had to make abrupt changes in daily care management such as more frequent daily patient observations and vital signs, testing all residents and staff for

508

coronavirus infection, wearing personal protective equipment for patient care, restricting admissions, limiting visitations, isolating residents with potential exposure or actual infections with COVID-19, ensuring and enforcing social distancing of residents and staff, regular washing of hands, and daily disinfecting of all equipment, objects, and surfaces to limit spread of the virus [48, 49]. The typical clinical manifestations of COVID-19 are headache, fever, cough, anorexia, myalgia, and dyspnea [50]. However, it is well known that older adults often do not have typical clinical symptoms and signs of infection such as fever or chills [6]. Moreover, many older adults suffer from cognitive impairment such as dementia, and consequently it is challenging to obtain any symptoms of this infection. Hence, it is essential to determine if an older adult exhibits any change from baseline in his/her clinical, mental, or functional status from baseline that is unexplainable on evaluation. Infection with COVID-19 may be causing this change. Such a resident should be placed in isolation and tested for coronavirus infection. If the resident is found to be positive for the virus, all residents and staff should be tested for this infection. Residents testing positive should be isolated and placed in quarantine for at least 14 days and remain in the nursing/residential facility if isolation care is available and the patient is clinically stable; otherwise, the resident should be transferred to an acute care facility for observation. Of course, all residents who become acutely ill, even without having a test performed, should be transferred to a hospital where (s)he can be assessed for COVID-19. The infected resident should not be allowed to return to the long-term care facility until (s)he has been symptom free for 14 days with two consecutive negative tests 24 h apart that are negative. All staff who appear ill and/or tested positive for COVID-19 should be sent home and have their healthcare provider evaluate the individual for this infection. If the staff is proven to be positive for the virus, the staff should not be allowed to return to work until they have been symptom free for at

D. Norman and T. Yoshikawa

least 7 days and have two tests negative for coronavirus 24 h apart. Staff and facility leadership are highly recommended to go to the Centers for Disease Control and Prevention (CDC) website for the most up-to-date recommendations because management and prevention strategies have constantly changed as more data and experiences on this infection become available. As of the writing of this chapter, there is no consistently proven treatment for this infection. The antiviral agent, remdesivir, and infusion of plasma containing antibodies against the virus obtained from previously infected persons preliminarily appear to be helpful in earlier recovery from this infection. These modalities have been approved for life-threatening therapy on an experimental basis and not for routine treatment at the time of this writing. Vaccine for COVID-19 is still in development and may not be readily available for the general public until the end of 2020. Until these treatment modalities are readily available, social distancing, washing with soap or use of alcohol-based sanitizers on hands, wearing a face covering, and limiting exposure to others, especially large crowds, are the most effective methods for prevention.

References 1. Yoshikawa TT, Norman DC. Infectious diseases in geriatric medicine. Clin Geriatr Med. 2016;32:xiii–xiv. 2. El Chakhtoura NG, Bonomo RA, Jump RLP. Influence of aging and environment on presentation of infection in older adults. Infect Dis Clin North Am. 2017;31(4): 593–608. 3. Meyer KC. Aging. Proc Am Thorac Soc. 2005;2: 433–9. 4. Bailey KL, Smith LM, Heires AJ, Atafiasz DM, Romberger DJ, LeVan TD. Aging leads to dysfunctional innate immune responses to TLR2 and TLR4 agonists. Aging Clin Exp Res. 2019;31:1185–93. 5. Coll PP, Costello VW, Kuchel GA, Bartley J, McElhaney JE. The prevention of infections in older adults: vaccination. J Am Geriatr Soc. 2020;68: 207–14. 6. Norman DC. Clinical features of infection in older adults. Clin Geriatr Med. 2016;32:433–41. 7. Gleckman R, Hibert D. Afebrile bacteremia. A phenomenon in geriatric patients. J Am Med Assoc. 1982;248:1478–81.

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8. Bradley SF, Gravenstein S, Mehr DR, Quagliarello VJ, Richards C, Yoshikawa TT. Clinical practice guideline for the evaluation of fever and infection in older adult residents of long-term care facilities: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(2):149–71. 9. Diagnosis and treatment of adults with communityacquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45–67. Published 10/1/2019. 10. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, Reed C, Grijalva CG, Anderson EJ, Courtney DM, Chappell JD, Qi C, Hart EM, Carroll F, Trabue C, Donnelly HK, Williams DJ, Zhu Y, Arnold SR, Ampofo K, Waterer GW, Levine M, Lindstrom S, Winchell JM, Katz JM, Erdman D, Schneider E, Hicks LA, McCullers JA, Pavia AT, Edwards KM, Finelli L. Communityacquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med. 2015;373(5):415–27. 11. Arnold FW, Reyes Vega AM, Salunkhe V, Furmanek S, Furman C, Morton L, Faul A, Yankeelov P, Ramirez JA. Older adults hospitalized for pneumonia in the United States: incidence, epidemiology, and outcomes. J Am Geriatr Soc. 2020;00:1–8. 12. Kaplan V, Clermont G, Griffin MF, Kasal J, Watson RS, Linde-Zwirble WT, Angus DC. Pneumonia: still the old man’s friend? Arch Intern Med. 2003;163(3): 317–23. 13. Khera R, Wang Y, Bernheim SM, Lin Z, Krumholz HM. Post-discharge acute care and outcomes following readmission reduction initiatives: national retrospective cohort study of Medicare beneficiaries in the United States. BMJ. 2020;368:l683–1695. 14. Ewig S, Klapdor B, Pletz MW, Rohde G, Schutte H, Schaberg T, Bauer TT, Welte T, for the CAPNETZ study group. Nursing-home-acquired pneumonia in Germany: an 8-year prospective multicentre study. Thorax. 2012;67:132–8. 15. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with gramnegative bacilli in the aged. N Engl J Med. 1978;298: 1108–11. 16. Liu C, Cao Y, Lin J, Ng L, Needleman I, Walsh T, Li C. Oral care measures for preventing nursing homeacquired pneumonia. Cochrane Database Syst Rev. 2018;2018(9):CD012416. Published online 2018 Sep 27. https://doi.org/10.1002/14651858.CD012416.pub2. 17. Ebihara S, Ebihara T, Kohzuki M. Effect of aging on cough and swallowing reflexes: implications for preventing aspiration pneumonia. Lung. 2012;190:29–33. 18. Cillóniz C, Polverino E, Ewig S, Aliberti S, Gabarrús A, Menéndez R, Mensa J, Blasi F, Torres A. Impact of age and comorbidity on cause and outcome in community-acquired pneumonia. Chest. 2013;144(3):999–1007. 19. Gadsby NJ, Russell CD, McHugh MP, Mark H, Morris AC, Laurenson IF, Hill AT, Templeton KE. Comprehensive molecular testing for respiratory

509 pathogens in community-acquired pneumonia. Clin Infect Dis. 2016;62(7):817–23. 20. Aliberti S, Di Pasquale M, Zanaboni AM, Cosentini R, Brambilla AM, Seghezzi S, Tarsia P, Mantero M, Blasi F. Stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia. Clin Infect Dis. 2012;54(4): 470–8. 21. Torres A, Peetermans WE, Viegi G, Blasi F. Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax. 2013;68:1057–65. 22. Loeb M, Neupane B, Walter SD, Hanning R, Carusone SC, Lewis D, Krueger P, Simor AE, Nicolle L, Marrie TJ. Environmental risk factors for community-acquired pneumonia hospitalization in older adults. J Am Geriatr Soc. 2009;57(6):1036–40. 23. Nicolle LE, Gupta K, Bradley SF, Colgan R, DeMuri GP, Drekonja D, Eckert LO, Geerlings SE, Köves B, Hooton TM, Juthani-Mehta M, Knight SL, Saint S, Schaeffer AJ, Trautner B, Wullt B, Siemieniuk R. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68(10):e83–75. 24. Mims AD, Norman DC, Yamamura RH, et al. Clinically apparent (asymptomatic) bacteriuria in ambulatory elderly me: epidemiological, clinical, and microbiological findings. J Am Geriatr Soc. 1990;38: 1209–14. 25. Nicolle LE, Bradley S, Colgan R, Rice JC, Schaeffer A, Hooton TM. Infectious Diseases Society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis. 2005;40: 643–54. 26. Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2007. U.S. Department of Health and Human Services. Centers for Diseases Control and Prevention, National Center for Health Statistics. Series 13, Number 169. 2011. 27. Jiang HJ, Wier LM, Potter DEB, Burgess J. Potentially preventable hospitalizations among medicaremedicaid dual eligibles, 2008. Agency for Healthcare Research and Quality, Division of Health Care Statistics statistical brief 96, September 2010. 28. Curns AT, Holman RC, Sejvar JJ, Owings MF, Schonberger LB. Infectious disease hospitalizations among older adults in the United States from 1990 through 2002. Arch Intern Med. 2005;165: 2514–25200. 29. Liu F, Ling Z, Xiao Y, Yang Q, Zheng L, Jiang P, Li L, Wang W. Characterization of the urinary microbiota of elderly women and the effects of type 2 diabetes and urinary tract infections on the microbiota. Oncotarget. 2017;8(59):100678–90. 30. Rowe TA, Juthani-Mehta M. Urinary tract infection in older adults. Aging Health. 2013;9(5) https://doi.org/ 10.2217/ahe.13.38. 31. Cortes-Penfield NW, Trautner BW, Jump R. Urinary tract infection and asymptomatic bacteriuria in older adults. Infect Dis Clin N Am. 2017;31(4):673–88.

510 32. Shaeffer AJ, Nicolle LE. Urinary tract infections in older men. N Engl J Med. 2016;374:562–71. 33. Grahn D, Norman DC, White ML, et al. Validity of urinary catheter specimen for the diagnosis of urinary tract infection in the elderly. Arch Inter Med. 1985;145: 1858–64. 34. Khawcharoenporn T, Vasoo S, Singh K. Urinary tract infections due to multidrug-resistant enterobacteriaceae: prevalence and risk factors in a Chicago Emergency Department; Emergency Medicine International. 2013:258517, 7 pages. https://doi.org/10.1155/ 2013/25851. 35. Hooten TM. Uncomplicated urinary tract infection. N Engl J Med. 2012;366:1028–37. 36. Nicolle LE. A practical guide to antimicrobial management of complicated urinary tract infection. Drugs Aging. 2001;18(4):243–54. 37. D’Agata E, Loeb MB, Mitchell SL. Challenges assessing nursing home residents with advanced dementia for suspected urinary tract infections. J Am Geriatr Soc. 2013;61(1):62–6. 38. Gupta K, Hooton TM, Naber KG, Wullt B, Colgan R, Miller LG, Moran GJ, Nicolle LE, Raz R, Schaeffer AJ, Soper DE. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52(5):e103–20. 39. Finucane TE. Urinary tract infection. Requiem for a heavyweight. J Am Geriatr Soc. 2017;65:1650–5. 40. Juthani-Mehta M, Van Ness PH, Bianco L, Rink A, Rubeck S, Ginter S, Argraves S, Charpentier P, Acampora D, Trentalange M, Quagliarello V, Peduzzi P. Effect of cranberry capsules on bacteriuria plus pyuria among older women in nursing homes: a randomized clinical trial. J Am Med Assoc. 2016;316(18): 1879–87.

D. Norman and T. Yoshikawa 41. White MB, Rajagoplan S, Yoshikawa TT. Infectious diarrhea. Norovirus and Clostridium difficile in older adults. Clin Geriatr Med. 2016;32:509–22. 42. Cober ED, Malani PN. Clostridium difficile infection in the “oldest” old: clinical outcomes in patients aged 80 and older. J Am Geriatr Soc. 2009;57:659–62. 43. Rao K, Micic D, Chenoweth E, Deng L, Galeck AT, Ring C, Young VB, Aronoff DM, Malani PN. Poor functional status as a risk factor for severe Clostridium difficile infection in hospitalized older adults. J Am Geriatr Soc. 2013;61:1738–42. 44. Mylotte JM, Russell S, Sackett B, Vallone M, Antalek M. Surveillance for Clostridium difficile infection in nursing homes. J Am Geriatr Soc. 2013;61:122–5. 45. Brown KA, Khanafer N, Daneman N. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57:2326–32. 46. Yoshikawa TT, Norman DC. Geriatric infectious diseases: current concepts on diagnosis and management. J Am Geriatr Soc. 2017;65:631–41. 47. McDonald C, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Sammons JS, Sandora TJ, Wilcox MH. Clostridium difficile. Clin Infect Dis. 2018;66:e1–e48. 48. D’Adamo H, Yoshikawa T, Ouslander JG. Coronavirus disease 2019 in geriatrics and long-term care: the ABCDs of COVID-19. J Am Geriatr Soc. 2019;68: 912–7. 49. Ouslander JG, D’Adamo H, Yoshikawa TT. Coronavirus disease 19 in geriatrics and longterm care: an update. J Am Geriatr Soc. 2019;68: 918–21. 50. Wang D, Hu B, Chang H, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020:E1–9. https://doi.org/10.1001/jama. 2020.1585.

Hematologic Disorders

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Shakira J. Grant and Debbie C. Jiang

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Anemias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Definition of Anemia in an Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology of Anemia in an Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis of Anemia in an Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Consequences of Anemia in an Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anemia of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Findings Associated with Anemia of Inflammation . . . . . . . . . . . . . . . . . . . . . . . Approach to Treatment of Anemia of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Erythropoiesis-Stimulating Agents to Treat Anemia of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Use of Iron in Patients with Anemia of Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

514 514 514 515 517 517 517 517

Anemia due to Vitamin B12 Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laboratory Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Vitamin B12 Deficiency Anemia and Pernicious Anemia . . . . . . . . . . . . Assessing and Monitoring Response to Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

520 520 521 521 522

519 519

Iron-Deficiency Anemia and the Older Adult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 Diagnosis of Iron-Deficiency Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 Management of Iron-Deficiency Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 Hematological Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525 Myelodysplastic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 525

S. J. Grant (*) Division of Hematology, The University of North Carolina at Chapel Hill, Chapel Hill, USA e-mail: [email protected] D. C. Jiang Department of Medicine, Division of HematologyOncology, University of Washington-Fred Hutchinson Cancer Research Center, Seattle, WA, USA Division of Hematology and Hematologic Malignancies, Beth Israel Deaconess Medical Center, Boston, USA © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_53

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S. J. Grant and D. C. Jiang Clinical Manifestations and Diagnosis of MDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Management of MDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526 Myeloproliferative Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Myelogenous Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and Diagnostic Features of CML . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of CML for Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

529 529 529 530

Polycythemia Vera . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Management of PV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531 Essential Thrombocythemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Management of ET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Primary Myelofibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533 Management of PMF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534 Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536 The Role of Geriatric Assessments and Frailty Scales in Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536 Developing a Personalized Approach for the Management of Adults with Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538

Abstract

Hematologic disorders are a diverse group of malignant and nonmalignant conditions arising from the blood and other hematopoietic sources. Many of the malignant disorders (myelodysplastic syndrome, multiple myeloma, and myeloproliferative neoplasms) are clonal in nature and occur with increasing frequency in older adults (aged
65 years). The prevalence of anemia also increases with advancing age. Importantly for older adults, the causes of anemia are many, resulting from chronic diseases, inflammatory conditions, and nutritional deficiencies, which may coexist therefore making the diagnosis difficult. As the global number of older adults continues to rapidly expand, the prevalence and incidence of hematologic disorders are also expected to increase. Thus, there is a need to refine the approaches to diagnosis and management of hematologic disorders to include strategies which account for the intersection of aging and hematology. Such an approach would involve assessment of patient fitness through the use of geriatric assessments, which may

then be used to tailor an appropriate individualized management plan for an older adult. Furthermore, such an approach accounts for the heterogeneity of aging while incorporating patient preferences. Use of a personalized approach for the management of hematologic disorders could improve disease-related outcomes, especially for those considered less fit or frail, while minimizing treatment-related toxicities and preserving quality-of-life. Keywords

Older adults · Multiple myeloma · Myelodysplastic syndromes · Myeloproliferative neoplasms · Anemia · Frailty · Geriatric assessments

Introduction Hematologic disorders comprise a diverse group of both malignant and nonmalignant conditions with heterogenous outcomes. These disorders are increasingly prevalent with advancing age, with those aged
65 years accounting for the greatest

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portion of all cases. Among the nonmalignant hematologic disorders, anemia is the most common disorder, posing several diagnostic and management challenges for older adults. The presence of anemia is associated with adverse outcomes such as increased mortality, cognitive impairment, cardiovascular diseases, functional disability including increased risk of falls and fractures [2– 5]. The health-related impacts of anemia are greatest for older adults, as multiple etiologies of anemia are likely to coexist. These include the higher prevalence of comorbid conditions including cancer seen with advancing age [6] in addition to nutritional deficiencies such as iron and vitamin B12 deficiency. With the anticipated doubling in the size of the population aged
65 years by 2050 [7], and improved diagnostic strategies, the prevalence and incidence of anemia will likely continue to increase. Thus, the approach to management will first require a working definition of anemia in older adults, a careful approach to identifying potential etiologies, and consideration of multidisciplinary input in some circumstances. Hematologic malignancies also disproportionately affect older adults. The clinical manifestations

and associated prognoses are highly variable, but are largely dependent on the clonal population from which they are derived. In the 2016 consensus-derived revision to the World Health Organization classification of hematological malignancies, cell of origin (lymphoid vs. myeloid) is used to classify these disorders [8] (Fig. 1). These malignancies develop from clonal expansions of hematopoietic cells, which lend to the unique phenotypic and genotypic differences observed across disease states. For older adults with hematologic disorders, the presence of additional age-related vulnerabilities may also shape clinical outcomes. These include age-related physiologic and pathologic conditions, which may alter the primary disease course and clinical outcomes among adults of the same chronologic age [9–11]. More recently, advances in tailoring therapy to older adults have been made. By developing personalized plans capable of addressing biologic, functional, and psychosocial factors, beyond that of chronological age, treatment plans that offer maximum efficacy while remaining tolerable for older adults with hematologic disorders may be developed.

Lymphoid

Lymphoid neoplasms with eosinophilia

#=

#B-lymphoblastic leukemia/lymphoma

Mature B-cell neoplasms

*T-lymphoblastic lymphoma/leukemia

Mature T-cell neoplasms

Hodgkin's lymphoma

PTLD

Immature B-cell neoplasm; * = Immature T-cell neoplasm; PTLD= posttransplant lymphoproliferative disorder

Myeloid

MDS

MPN

MDS/MPN

Myeloid neopplasms with eosinophilia

AML and related neoplasms

MDS= myelodysplastic syndrome; MPN= myeloproliferative neoplasms; AML= acute myeloid leukemia Fig. 1 Lymphoid and myeloid neoplasms. MDS myelodysplastic syndrome, MPN myeloproliferative neoplasms, AML acute myeloid leukemia

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More importantly, as new cancer therapeutics such as immunotherapy and molecular- and cellular-based therapies have improved the prognosis of many hematological malignancies, use of these global assessments is of critical importance. This chapter examines the anemias (chronic inflammation, iron deficiency, and B12 deficiency/pernicious anemia) and myelodysplastic syndromes that frequently evolve into leukemia. The most common myeloproliferative disorders and multiple myeloma are also discussed. We emphasize new therapy developments that may impact responses and survival while offering less toxic and more tolerable treatment for the older adult patient. Learning Objectives • Review commonly encountered hematologic disorders in clinical practice • Discuss important pathogenetic factors associated with hematologic disorders • Review the approach to the diagnosis of each of the highlighted hematologic disorders • Identify standard approaches to management of the identified hematologic disorders and unique challenges older adults may face • Understand the role of geriatric assessments in the global evaluation of an adult • Understand how a geriatric assessment may shape the care of an older adult with a hematologic disorder

Anemias Definition of Anemia in an Older Adult The diagnosis of anemia requires performance of a complete blood count with accompanying peripheral blood smear. Despite some interlaboratory variations in the hemoglobin thresholds used to define anemia, the World Health Organization’s (WHO) definition (hemoglobin 20% of years lived with disability [1]. While the incidence of low back pain is decreasing in high-income countries, it is increasing for OA, gout, and RA [2]. All of these bone and joint diseases may contribute to acute and chronic pain, dysmobility, and predispose to other health conditions such as depression or cardiovascular disease [3]. Despite the importance of musculoskeletal health for older adults’ well-being and independence, policymakers usually give little priority to bone and joint conditions. Likewise, many doctors including geriatricians neglect the clinical musculoskeletal examination. In spite of advances in imaging and laboratory testing, there is still no substitute for good history taking and locomotor system clinical examination. In patients with low back pain and a radiographic vertebral fracture for example, only the history and clinical examination can determine whether the pain corresponds to the fracture site. Polymyalgia rheumatica (PMR) causes sudden-onset stiffness and pain (mostly in the pelvic girdles, neck and shoulders) and muscle weakness. Giant cell arteritis (GCA) is an important diagnosis that should never be overlooked in

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older adults. About half of GCA patients present without PMR symptoms. Such patients have isolated jaw claudication and/or altered vision and raised inflammatory markers, which may rapidly progress to irreversible vision loss if not promptly treated with glucocorticoids. History and clinical examination alone suffice to diagnose this condition in typical cases, and treatment should not be delayed. Still, confirmatory testing is important given the potential side effects of glucocorticoid therapy, as well as to exclude important differential diagnoses such septic arthritis, spondylodiscitis, or malignant bone disease. In the past, geriatricians have also played a considerable role in treating older adults with glucocorticoids or methotrexate for RA. A basic knowledge on how to recognize RA and differentiate it from other forms of arthritis is still fundamental. However, there is an expanding armamentarium of biological and targeted disease-modifying anti-rheumatic drugs (e.g., tumor necrosis factor inhibitors, Janus-kinase inhibitors, tocilizumab, abatacept, rituximab, etc.) for the treatment of RA. Given the complexities as well as prescribing restrictions, the geriatrician is nowadays less likely to manage RA. Therefore, this chapter will only consider RA as an important differential diagnosis. It is still important though to keep abreast with the influence that RA medications may have, e.g., the need for proper vaccination, or specific side effects such as risk of infections, shingles, hematological and liver test abnormalities, gastrointestinal disturbances, venous thromboembolism, etc. The aim of this chapter is to provide geriatricians with the knowledge and skills needed to make individualized, patient-centered, and evidence-based diagnostic and treatment decisions related to osteoporosis, OA, gout, PMR, and GCA.

Osteoporosis Epidemiology The annual incidence of fractures due to osteoporosis has been estimated at almost nine million worldwide in the year 2000 [4]. In high-risk

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Caucasian populations, the lifetime risk of osteoporotic fractures may be as high as 45–55% in women and 20–25% in men [5, 6]. Hip fractures incur the most devastating consequences and the highest costs. Vertebral compression fractures often do not come to clinical attention but are still associated with acute and chronic back pain. Non-hip-non-vertebral fractures however represent >80% of fractures and >50% of associated healthcare expenditures, particularly in men and women younger than 80 years [7]. In general, most treatment options for osteoporosis have proven to reduce vertebral fractures, while only some have reduced hip fractures and very few individual randomized controlled trials (RCTs) have demonstrated prevention of non-hip-nonvertebral fractures. The key risk factors for fractures are older age, female sex, previous fractures, lower bone mineral density (BMD), and higher risk of falls. Fracture risk increases exponentially with age (Fig. 1), whereas BMD declines rather linearly with age. This underlines the importance of other risk factors for fractures such as an increasing risk of injurious falls in older adults [8]. Other important clinical risk factors include low body weight, height loss, hip fracture history in a first-degree relative, smoking, alcohol abuse (>3 units/day), and exposure to certain medications such as glucocorticoids, aromatase inhibitors, or chemotherapy. Men are about 1.6 times less likely to sustain an osteoporotic fracture in their lifetime and half as likely to suffer a hip fracture [5]. However, once men have osteoporosis, their relative risk of re-fracture is greater and their absolute risk of a second fracture similar as that of women of the same age. Similarly, the relative risk of mortality after fractures tends to be somewhat higher in men, with excess mortality 1 year after a hip fracture of around 33% in men and 20% in women [5]. BMD is measured by dual-energy X-ray absorptiometry (DXA) and expressed as standard deviations (T-score) above or below the average of white woman aged 20–30 years in the National Health and Nutrition Examination Survey III, or relative to age- and sex-matched individuals in that study (Z-scores). Each standard deviation

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Fig. 1 Annual fracture incidence/100,000 in men (black circles) and women (gray squares) by 5-year age bands in a population-based cohort study in Umeå, Sweden. (Adapted and reproduced from Bergström et al. [6], with permission from Springer)

BMD decrease approximately doubles the risk of fractures and triples the risk of hip fracture. However, BMD T-scores in the range of osteopenia (T-score between 1.0 and 2.5) are present in up to ~55% of post-menopausal women and ~70% of older men with typical osteoporotic hip fractures [9], and some may even have “normal BMD.” Therefore, DXA T-scores can be used to diagnose osteoporosis before the first fracture, but they cannot exclude osteoporosis in patients with typical low-energy fractures (see section “Diagnosis” below). In other words, DXA has high specificity but low sensitivity to diagnose patients at risk for fractures. In older adults aged 80 years, the predictive value of low BMD for fractures declines (because falls become much more common) while sensitivity increases (simply because low BMD becomes more universal). Yet even in older adults, BMD is an independent and highly modifiable fracture risk factor.

Pathophysiology Bone is a dynamic tissue composed of ordered calcium and phosphate crystals (hydroxyapatite) embedded in a collagen-based extracellular matrix. The mineral phase provides bone with rigidity (without it, bone would be pudding) but also makes it brittle. The matrix allows deformation, i.e., bending, like a tree in the wind. The term

“osteo-porosis” is not a misnomer: there is not a lack of mineral but rather a paucity of overall bone tissue, which manifests in cortical bone as excess porosity [10]. Contrary to common belief, bone loss in women does not decline after the menopausal transition but rather accelerates after the age of 65 years [10]. Osteoblasts and osteoclasts are chiefly responsible for bone formation and resorption, respectively. Osteocytes are however the most numerous, long-lived matrix-embedded “master” bone cells, which recruit and regulate osteoblasts (e.g., via wingless-type (Wnt) signaling inhibitors such as sclerostin) and osteoclasts (e.g., via inhibitors such as receptor activator of nuclear factor kappa-B ligand, RANKL). Bone formation and resorption are usually coupled (one triggers the other) and in healthy adults, balanced (equal volumes of bone resorbed and replaced). Bone remodeling serves to repair microdamage in old bone and to maintain mineral homeostasis. Around midlife however, osteoblastogenesis declines and the lifespan of osteoblasts decreases, resulting in shallower refilling of previously excavated resorption pits and net bone loss. Secondly, this deficit is amplified when bone turnover increases due to estrogen deficiency, which prolongs osteoclast lifespan and results in a greater number of bone remodeling sites. These changes may also be caused by aging via increased osteocyte apoptosis, altered reactive oxygen species

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metabolism, and distinct mechanisms of cellular senescence within bone [5]. In osteoporosis, adipogenesis is favored and bone marrow adipose tissue accumulates, although it remains unclear whether this unique fat depot contributes directly to age-related bone loss or not. The risk of fractures is determined by both bone strength and risk of falls and defense mechanisms, e.g., soft tissue padding around the hips [5]. Bone strength is not only determined by bone mass (i.e., bone mineral content) or BMD, but also by cortical bone geometry, cortical and trabecular bone microarchitecture, and bone (mineral and extracellular matrix) material properties. At the cellular level, bone mass is determined by the balance between bone formation and resorption. At the organ level, osteoporosis can develop when individuals fail to establish sufficient bone mass in early adulthood to midlife (i.e., peak bone mass), due to excessive bone loss, or both. Low peak bone mass before the onset of bone loss is a key contributor to lifetime osteoporosis risk. Regarding bone loss, a chief culprit is the failure of bone formation on the outer cortical bone surface (periosteal bone formation) to compensate for bone resorption at the endosteal side [7]. The key reason why men suffer less fractures is because they develop wider bones during puberty and midlife, which they consequently maintain better at older ages. A larger cortical bone diameter has important biomechanical advantages because it scales with bone strength to the sixth power. Men have greater periosteal bone formation from puberty throughout midlife. The former may be related at least partly to the direct actions of androgens on bone [5]. Bone resorption is due to estrogen deficiency after menopause, whereas older men usually maintain sufficient estrogen levels [5]. Additionally, older women have greater falls risk than older men.

Person-Centered Approach in Older Adults To Treat or Not to Treat Individualized treatment recommendations in osteoporosis require an assessment of fracture

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risk. Patients with prior hip or vertebral fractures are considered to be at very high risk of recurrent fractures and should generally be treated. Likewise, patients with a recent fracture are at imminent risk of recurrent fractures, because fractures tend to cluster in time [7]. However, osteoporosis medications need time to restore bone mass and strength. Several RCTs with antiresorptive drugs have shown fracture risk reduction after 12 months of treatment or earlier [11]. Patients at high/imminent fracture risk may benefit from bone anabolic drugs, which can improve BMD more quickly (see section “Bone Anabolic Drugs” below). In contrast, osteoporosis treatment may be foregone in older adults near the end of life (specifically, those with a life expectancy of less than 1 year), such as those with certain life-limiting comorbidities or very severe frailty. In some older RCTs, no benefit was shown in the subgroup of patients older than 80 years or those selected for increased fracture risk mainly due to an increased risk of falls. In the last two decades however, a myriad of other RCTs have demonstrated effectiveness in participants up to 90 years of age. Some studies even showed that because osteoporosis drugs appear to offer similar relative risk reduction, but older adults have increased absolute risk, the absolute risk reduction is even greater in the oldest old [12]. Of note, several pivotal trials showing fracture risk reduction with calcium and vitamin D supplements were performed in female nursing home residents (mean age 84 years) [13], and at least one RCT showed safety and efficacy on BMD with antiresorptive therapy in nursing home residents [14]. Thus, remaining life expectancy and very severe frailty are probably more appropriate reasons to consider not initiating osteoporosis treatment anymore, rather than age or place of residence. Some guidelines on fracture prevention in long-term care facilities are available [15]. Since treatment of osteoporosis equals fracture prevention, both fall prevention and bone strengthening should be considered simultaneously (applying both non-pharmacological and pharmacological measures). Still, osteoporosis drugs remain the easiest, most evidence-based,

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and most effective strategy to reduce fractures, on average by 40–60% for vertebral fractures and 20–40% for non-vertebral fractures [7]. Nevertheless, there remains a paucity of evidence on fracture prevention in patients with specific comorbidities and very high risk of falls, e.g., those with Parkinson’s disease, dementia, or prior stroke.

Individualized Fracture Risk Assessment Tools Most clinical trials in osteoporosis have shown efficacy in patients with BMD T-scores  2.5, previous hip or vertebral fractures, or both. Consequently, almost all guidelines consider these as clear treatment indications. However, most fractures occur in subjects without these risk factors [16]. Treatment based on clinical risk factors will therefore increase sensitivity but will also increase the proportion of the population eligible for treatment. Several tools are available for personalized fracture risk estimation. However, the predictive value of complex tools is often similar to that of simple tools, which incorporate basic information such as age, sex, and body weight.

Fig. 2 Graph showing assessment and treatment thresholds proposed by the UK National Osteoporosis Guidelines Group, according to age (X-axis) and 10-year probability of major osteoporotic fractures estimated by FRAX ®. The dotted line represents the intervention

M. R. Laurent

The most widely used fracture risk calculator is FRAX ®. Country-specific models are currently available for about 65 nations, with ethnic sub-tools available for the USA. Based on 11 clinical risk factors with or without BMD, FRAX ® estimates 10-year risk of hip and “major” osteoporotic fractures (hip, humerus, forearm, and clinical vertebral fractures). FRAX ® takes competing risk of mortality into account, i.e., the likelihood that the patient dies (based on the same risk factors entered in the model) before sustaining a fracture. The advantages of FRAX ® are that it is based on large population-based cohort studies, allows calculation with or without BMD, and is implemented in many guidelines, e.g., regarding cut-offs for treatment. In the UK, where access to DXA is limited, FRAX ® is first used without BMD, and BMD is measured only in those with intermediate probability (see Fig. 2 below). Disadvantages of FRAX ® also merit consideration. Firstly, the underlying country-specific models are often based on older hip fracture data and assumptions regarding other fractures. Only a 10-year time horizon is provided, which may underestimate 1-year risk in older adults. FRAX ® is only calibrated between ages 40 and

threshold. BMD measurement is recommended in those with intermediate probability as indicated by the amber area. (Reproduced from Compston et al. [18], with permission from Springer)

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90 years. Moreover, taking competing risk of mortality into account is controversial, because some evidence suggests that treatment of osteoporosis may reduce risk of mortality [17]. Some risk factors play no role independent of BMD, others are only available as categorical rather than dose-dependent variables (e.g., glucocorticoids, alcohol, smoking, fractures) while other important clinical risk factors such as falls are not incorporated. Finally, the underlying algorithm is not publicly available. Alternatives to FRAX® include the Garvan fracture risk calculator (developed in Australia) and QFracture in the UK. The Garvan nomogram calculates 5- and 10-year risk and is simpler with five risk factors (age, sex, BMD or body weight, number of falls in the last 12 months, and number of prior fractures since age 50). QFracture has much more risk factors but can be implemented in primary care electronic health records. Both Garvan and QFracture have been validated independently in other cohorts, although their value in ethnically very different populations remains uncertain. Based on cost-effectiveness estimates, the US National Osteoporosis Foundation suggests treatment for osteoporosis in patients with a FRAX ® fracture risk 20% for major osteoporotic fractures or 3% for hip fractures. The UK National Osteoporosis Guidelines Group suggests treatment in persons with a fracture risk that exceeds the FRAX ® score of a woman of similar age, an average body mass index (26 kg/m2), prior fracture history, but no other clinical risk factors. This approach results in a treatment threshold that is lower at younger ages but increases exponentially with age and has therefore been criticized as constituting ageism. In their most recent update however (Fig. 2) [18], the UK group proposes a hybrid model with a fixed 10-year major osteoporotic fracture risk intervention threshold after age 70 years at 20.3%, almost identical to the 20% cut-off proposed by US guidelines. No clinical trials have directly selected patients with an elevated fracture risk based on clinical risk factors but without prior hip or vertebral fractures and with osteopenia. However, a recent RCT in osteopenic older women showed that antiresorptive treatment over 6 years reduced

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vertebral, non-vertebral, clinical fractures, and height loss [16]. Moreover, a screening trial based on FRAX ® showed a significant reduction in hip fracture risk [19]. These findings provide growing support for treatment based on clinical risk factors in persons without prior hip or vertebral fractures or a T-score  2.5.

Shared Decision-Making Shared decision-making may improve compliance, a cornerstone for effective treatment in many chronic diseases. In patients at high or imminent fracture risk, physicians can recommend that effective and safe treatment options are available. In those at intermediate fracture risk, patient preference may strongly influence the choice between pharmacotherapy or careful monitoring and follow-up. FRAX ® and other risk estimation tools (see previous section “Individualized Fracture Risk Assessment Tools” above) may be used to convey number needed to treat and likelihood of benefit from treatment [20]. Some patients may have experienced painful fractures, remember a hyperkyphotic family member, or may limit their activities out of fear that their low T-score implies unavoidable fracture risk after minimal trauma. Such patients may attach great value to treatment effectiveness and fracture prevention. Others mainly want to ensure follow-up of their BMD with watchful waiting while avoiding medication use as long as possible. Many patients are concerned about potential side-effects such as osteonecrosis of the jaw and atypical femoral fractures. Thus, in practice, a lot of time is spent to reassure patients that – certainly compared to other chronic diseases – effective and safe drugs for osteoporosis are available.

Diagnosis The question of diagnosis in osteoporosis is secondary to the question “to treat or not to treat” (see previous section “Person-Centered Approach in Older Adults”). Indeed, treatment may not be necessary in all patients in whom osteoporosis can be diagnosed.

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Diagnostic Criteria When other metabolic bone diseases have been excluded (see section “Diagnostic Criteria” below), the diagnosis of osteoporosis can be made in post-menopausal women or men aged 50 years or older (in order of importance): – After a low-trauma clinical fracture, or – Following identification of asymptomatic vertebral fractures, or – Based on a DXA T-score of  2.5, or – Finally, even in the absence of the prior criteria, the US National Bone Health Alliance Working Group proposed that osteoporosis can be diagnosed based on an estimated fracture risk that exceeds the treatment threshold [21] Asymptomatic vertebral fractures can be screened using vertebral fracture assessment on lateral spine imaging with a DXA machine. This procedure has low radiation exposure and increases the diagnosis of vertebral fractures that would otherwise be missed. However, vertebral fracture assessment may have insufficient sensitivity for grade 1 fracture and should therefore not be used in patients with clinical suspicion of vertebral fractures, e.g., those with unexplained back pain. Furthermore, it increases operator time and may not be reimbursed. Vertebral fractures are most often graded using the Genant semi-quantitative method as follows: 20–25% height loss (grade 1), 25–40% height loss (grade 2), and >40% height loss (grade 3). The risk of subsequent fracture increases with the number and severity of vertebral fracture, although even asymptomatic grade 1 vertebral fractures increase the risk of subsequent fractures. In post-menopausal women or men aged 50 years and older, the diagnosis of osteoporosis can be made clinically after a fracture. DXA is not required in patients with hip or vertebral fractures, given that (1) the diagnosis is already clear and (2) the low sensitivity of DXA (see section “Epidemiology” above), although it may be considered in some patients for medication reimbursement purposes.

M. R. Laurent

Differential Diagnosis and Work-Up for Secondary Causes Before osteoporosis treatment is initiated, it is important to exclude other bone diseases, particularly metastatic bone disease or multiple myeloma. Alkaline phosphatase may be useful to distinguish these conditions: this test should always be within normal limits in osteoporosis. Slightly raised alkaline phosphatase in the absence of actively healing fractures or chronic renal insufficiency or markedly raised alkaline phosphatase should be further investigated. Paget’s disease of bone (osteitis deformans) is another common, underdiagnosed cause of raised alkaline phosphatase in older adults. The underlying cause of Paget’s disease remains unknown. Rare genetic forms have been identified, but the marked decline in incidence in the last few decades points to interaction with an environmental factor (possibly a viral trigger). Nowadays, Paget’s disease is most commonly an incidental biochemical or radiological/nuclear imaging diagnosis, which may be confused with osteoblastic bone metastases. Common symptoms include chronic bone pain, increased risk of OA in adjacent joints, and/or neural compression resulting in spinal stenosis or hearing loss. An enlarged skull or (varus) limb deformities (Fig. 3) are rarer nowadays. Pathological fractures are extremely rare and mostly seen in carriers of genetic mutations. A single dose of zoledronate i.v. is the treatment of choice for long-term suppression of bone turnover and stabilizing disease activity, which may also improve bone pain in some patients. However, RCTs have been underpowered to ascertain effects on bone deformity, nerve compression, or pathological fractures. Oral bisphosphonates may also be effective, while denosumab may be used if bisphosphonates are contraindicated. Osteomalacia (Greek, softness of bone), a condition of impaired skeletal mineralization, is another important differential diagnosis in older adults. Symptoms may include low BMD (sometimes very low) and sometimes fractures but also raised alkaline phosphatase, bone pain, and muscle weakness which distinguish it from osteoporosis. Osteomalacia is usually caused by severe vitamin D and/or calcium deficiency or long-

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Fig. 3 Panels 1–3: Classical drawings from the original publication by dr. Paget, of an older man with Paget’s disease, 6 months before death. Note lower limb and spine deformities, stooped posture, gait difficulties, and enlarged skull. Panel 4 (bottom): cap and hat of different sizes worn 32 years apart during adulthood, indicating skull enlargement. (Credit: Wellcome Library, London. Source: Paget [91]. Copyright: Creative Commons Attribution 4.0 License)

standing hypophosphatemia, e.g., in sun-deprived older adults, dark-skinned, or veiled persons. Other secondary causes include celiac disease, exocrine pancreatic insufficiency, ileostomies or urinary diversions, derivative bariatric surgeries, or certain drugs like enzyme-inducing anti-

epileptic or tuberculostatic drugs (which produce severe vitamin D deficiency) or tenofovir (or other causes of Fanconi syndrome). Older biopsy studies suggested that 2–5% of patients hospitalized on geriatric wards for other reasons may have unrecognized osteomalacia [22]. Treatment of

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osteomalacia is targeted at the underlying cause. Patients with nutritional deficiency may improve their symptoms dramatically with even low doses of calcium and vitamin D, whereas those with malabsorption or enzyme induction may require (very) large doses. Inadvertent treatment with antiresorptive or anabolic bone drugs may provoke profound, symptomatic hypocalcemia. Patients with a long-standing history of severe chronic renal insufficiency, particularly those on dialysis, may have one of five types of chronic kidney disease metabolic bone disease (formerly known as “renal osteodystrophy”). Emerging evidence suggests that the risk factors for fractures in these patients, e.g., age, gender, and low T-scores, are the same as in osteoporosis. However, these patients have not been included in osteoporosis RCTs. Hence, the benefit of antiosteoporosis drugs in this population is uncertain. Furthermore, they may be at increased risk of side effects such as hypocalcemia or cardiovascular adverse events. Osteoporosis should not be considered a final diagnosis: it may be a symptom of other, underlying secondary causes, which may require treatment, by themselves (Table 1). Some secondary causes of osteoporosis are so common, e.g., vitamin D deficiency, smoking, or alcohol abuse, that they merit systematic screening. Others are important but rarely diagnosed at older age. Some are exceedingly rare and should certainly not be tested for routinely but only if the history and clinical examination reveals other clues, e.g., mastocytosis or osteogenesis imperfecta. In summary, in addition to clinical history taking and examination, a minimal set of blood tests in osteoporosis may include calcium (which often requires adjustment for low albumin concentrations in older adults), phosphate and alkaline phosphatase (which should all be normal), 25-hydroxyvitamin D, creatinine and estimated glomerular filtration rate (which may inform treatment choices), serum protein electrophoresis, and thyroid-stimulating hormone. Some guidelines, e.g., from the US Endocrine Society, also suggest a complete blood count and liver function tests as non-specific screening for potential underlying conditions [23].

M. R. Laurent

Screening and Case Finding The US Preventive Services Task Force recommends DXA screening in women 65 years and older, whereas evidence in men remains inconclusive [24]. An RCT in women aged 70–85 years in UK primary care has suggested that screening based on risk factors and DXA in patients with intermediate clinical risk could reduce the risk of hip fracture by 28% [19]. Vertebral fracture assessment is also recommended in most osteoporosis guidelines. In clinical practice, a case finding strategy can be recommended, i.e., DXA and/or vertebral fracture assessment in patients with predisposing conditions. Given that osteoporosis and sarcopenia often coincide, osteoporosis case finding in patients with sarcopenia (and vice versa) merits consideration. Overweight and obesity on the other hand are associated with higher BMD and lower fracture risk, although not as much as would be expected for body weight. The protective effects of obesity is further attenuated in frail older adults [25]. Weight loss is associated with bone loss, which can be mitigated by physical exercise [26].

Treatment The aim of osteoporosis treatment is fracture prevention. This involves not only non-pharmacological and pharmacological osteoporosis treatments, but also fall prevention measures (see chapter “Falls and Fall Prevention”). There is a growing body of evidence for extra-skeletal benefits and risks of anti-osteoporosis drugs which may also be taken into account. Identification and treatment of underlying secondary causes, or stopping, reducing, or replacing drugs which increase the risk of bone loss, fractures, and/or falls (see section “Differential Diagnosis and Work-Up for Secondary Causes” above), are also part of the treatment of osteoporosis. Geriatricians should be familiar with guidelines for prevention of glucocorticoid-induced [27] or hormone deprivation therapy-induced bone loss, which are however beyond the scope of this chapter.

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Table 1 Selected list of secondary causes of osteoporosis and suggested testing Secondary cause or risk factor Smoking, alcohol abuse Disuse, lack of exercise Low body weight, weight loss, eating disorders Sarcopenia Low calcium, protein, energy intake Family history of fractures or osteoporosis Depression Vitamin D deficiency

Primary hyperparathyroidism Drug-induced osteoporosis: glucocorticoids, aromatase inhibitors, gonadotropin inhibition, chemotherapy, vitamin K-antagonists, proton pump inhibitors, antidepressants, anticonvulsants, immunosuppressants, etc. Hyperthyroidism Hypogonadism (incl. athlete’s triad, Klinefelter, Turner, late-onset hypogonadism, hyperprolactinemia) Cushing or Addison’s syndrome Diabetes mellitus type 1 and 2 Acromegaly

Rheumatic diseases (rheumatoid arthritis, ankylosing spondylitis, lupus, etc.) Gastrointestinal diseases (inflammatory bowel disease, cirrhosis, pancreatic diseases, bariatric surgery, celiac disease, etc.)

Table 1 (continued) Secondary cause or risk factor Hematological diseases, particularly monoclonal gammopathy of unknown significance Other comorbidities: chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, HIV, Parkinson’s disease, transplantation, epilepsy, sarcoidosis, mastocytosis, multiple sclerosis, Down syndrome, etc. Hemochromatosis

Suggested testing History History Body weight, body mass index, history Clinical examination History History History Calcium, 25-hydroxyvitamin D levels a Parathyroid hormone (if hypercalcemia) Medication history

Idiopathic hypercalciuria, kidney stones Osteogenesis imperfecta, connective tissue disease

Suggested testing Serum protein electrophoresis

History, clinical examination (abiochemical or genetic testing on indication)

a

Ferritin level, iron saturation a 24 h urine collection for calciuria Clinical examination, family history

a

Selective testing recommended, only when clinically indicated

Thyroid-stimulating hormone History (reproductive, sexual), clinical examination, atestosterone and sex hormone-binding globulin, prolactin History, clinical examination, acortisol History History, clinical examination (ainsulin-like growth factor-1) History

History, atissue transglutaminase antibodies and serum IgA (for celiac disease)

(continued)

Non-pharmacological Measures Healthy lifestyle and physical exercise should be promoted in all patients regardless of their fracture risk, given the myriad other health benefits. This includes smoking cessation, avoiding excessive alcohol intake, regular physical exercise, and a healthy diet. Fear of falling and fracturing may cause osteoporosis patients to limit their activities. This should be discussed with patients, who should instead be confident that with appropriate treatment, the disease can be modified to allow an active lifestyle instead of vice versa. Metaanalysis of exercise interventions in osteoporosis have consistently shown good safety without excess of exercise-related injuries. In general, three types of exercise are recommended in osteoporosis patients. First, weight-bearing exercises that cause direct impact on the skeleton may increase bone strength in the loaded bones, e.g., jogging or running, tennis, jumping exercises, etc. Secondly, exercise aimed at increasing muscle mass have shown increases in BMD, which attests to the importance of the so-called muscle-bone interactions. This however

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requires moderately intense training, e.g., weightlifting, whereas swimming or cycling, for example, are less likely to be effective (however, still better than remaining sedentary). However, most evidence from RCTs on this topic comes from structured exercise protocols, mostly supervised by a physiotherapist. Thirdly, Tai Chi (and possibly related exercises like yoga) has been shown to improve balance, may improve BMD, and reduce falls and fear of falling. Exercise trials have been underpowered for fracture outcomes, but this is not a reason not to strongly recommend exercise in osteoporosis patients. Healthy nutrition is also recommended in osteoporosis patients, with an emphasis on dietary calcium (mainly by encouraging dairy consumption) and sufficient protein intake (see ▶ Chap. 58, “Sarcopenia” and/or ▶ 16, “Nutrition in Older Adults”). Excessive salt intake, saturated fats and phosphate-rich beverages (e.g., fast food), and alcohol may detrimentally affect bone and calcium metabolism. Apart from the wellknown effects of vitamin D (see section “Calcium and Vitamin D” below), other vitamins (e.g., vitamin A, B12, C and K) also influence bone metabolism. Still, the evidence from RCTs is insufficient to recommend vitamin K supplements or restriction of dietary acid load.

Calcium and Vitamin D Physiology Calcium is essential not only for bone and mineral homeostasis but also for vital physiological processes such as coagulation and electrophysiology. Plasma calcium is controlled tightly by parathyroid hormone. Vitamin D exerts its positive influence on bone by stimulating intestinal calcium absorption and suppressing secondary hyperparathyroidism. When the body’s calcium balance threatens to become negative, secondary hyperparathyroidism maintains normocalcemia by stimulating bone resorption, renal calcium reabsorption, and synthesis of active 1,25dihydroxyvitamin D from circulating 25-hydroxyvitamin D. Like with any vitamin, correction of vitamin D deficiency is beneficial, but more is not better.

M. R. Laurent

Excess vitamin D may cause hypercalcemia and urolithiasis by stimulating not only intestinal calcium absorption but also bone resorption. Vitamin D also stimulates intestinal phosphate absorption while any form of hyperparathyroidism may cause hypophosphatemia. If calcium absorption becomes more severely impaired (e.g., due to very low vitamin D levels or bowel diseases), normocalcemia may be maintained at the expense of calcium and phosphate incorporation into bone, leading to osteomalacia. Recommended Calcium Intake and Vitamin D Levels The US Institute of Medicine and almost all guidelines in osteoporosis recommend daily nutritional calcium intakes between 1200 mg and 2000 mg for post-menopausal women or men 70 years. The average diet in Western societies contains ~300 mg of calcium from fruit and vegetables, bread, water, etc. Thus, at least ~900 mg would be required from calcium-rich foods, mainly dairy products. This equals about five standard portions of milk, yoghurt, or 2.5 portions of cheese. Some non-dairy foods are also rich in calcium (e.g., specific calcium-rich waters) but many are not typically consumed on a daily basis (e.g., canned fish with bones). The actual average dietary calcium intake lies around 700 mg/day but varies widely between individuals according to their dairy intake. The US Endocrine Society and many other osteoporosis guidelines recommend optimal calcium intake preferably from nutritional sources, with additional calcium supplements only if needed. While it was common practice in the past to prescribe 1000 mg calcium supplements to meet minimal requirements in every patient with osteoporosis, this is now replaced by a “personalized precision medicine” paradigm. Only a dietary history can determine the required dose of calcium supplements (plasma or urinary calcium concentrations are not informative). Vitamin D status can be monitored by measuring serum 25-hydroxyvitamin D concentrations, preferably using a reliable mass spectrometry method. Most guidelines recommend 25-hydroxyvitamin D levels in the range of

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50–150 nmol/L (20–60 ng/mL). Vitamin D intake from dietary sources is minimal, and sunshine exposure, skin complexion, mobility limitations, and wearing veils usually determine whether a person is at risk of vitamin D deficiency. Vitamin D intakes of 800–1000 IU/day are typically sufficient to obtain vitamin D levels in the desired range. However, the individual response to supplementation is quite variable, which supports a role for monitoring 25-hydroxyvitamin D levels during treatment. Calcium Supplements: Pharmacology Compliance with calcium supplements is generally poor, and poor compliance is associated with worse outcomes. Calcium supplements commonly cause abdominal pain and constipation, which may require trying different formulations, intake with food, or adding laxatives. Other reasons for poor adherence include out-of-pocket expenses, taste, aversion to medication, lack of patient education and awareness, pill burden, and true forgetfulness. Follow-up of osteoporosis patients should focus on these issues. Calcium supplements are most commonly prescribed as carbonate or citrate salts, which contain 40% and 21% elemental calcium, respectively. Close attention should be paid to prescribing the correct dose: capsules of 1250 mg calcium carbonate or 900 mg calcium citrate contain about 500 and 190 mg Ca2+, respectively. Commercial formulations usually indicate the dose of elemental calcium. Calcium carbonate is usually cheaper. Calcium citrate is equally well absorbed with or without food (while carbonate is better absorbed with food) and in patients taking gastric acid suppressants or those with achlorhydria (which is common in older adults). There is little evidence to support the contention that calcium citrate has better gastrointestinal tolerability. Because intestinal calcium absorption plateaus with doses above 500 mg Ca2+, larger doses are ideally spread throughout the day (but this increases pill burden and contributes to polypharmacy). Calcium competes for intestinal absorption with other divalent cations (iron, thyroid hormone, magnesium, antacids), bisphosphonates, and fluoroquinolones. Intake of

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any of these drugs should therefore be separated by a few hours. Calcium pills or capsules are often large and difficult to swallow for older adults; effervescent, chewable, or dispersible formulations may be more convenient but may taste badly. A common myth is that supplements should be taken at night, even though studies have long debunked this myth [28]. Pharmacology of Vitamin D Supplements Compared to vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol) has lower affinity to vitamin D-binding protein, a shorter half-life, and may be associated with lower total and higher free circulating 25-hydroxyvitamin D, which can however be overcome by using slightly higher doses. Thus, both can be effectively used to overcome vitamin D deficiency, and any difference have not been shown to result in clinically meaningful differences in outcomes. 25-hydroxyvitamin D (alfacalcidol) is available in some countries. As a more polar, watersoluble molecule, it has a shorter half-life, restores vitamin D deficiency more potently and quickly than vitamin D at the same dose (if loading doses are not used), and is useful in patients with malabsorption for fat-soluble vitamins. Obesity somewhat suppresses hepatic 25-hydroxylation of vitamin D, which however may simply be overcome by using higher vitamin D doses. Although alfacalcidol is favored in some countries or by some experts, it has insufficient evidence on clinically relevant outcomes, requires good compliance due to its short half-life, and may have a narrower therapeutic margin. Vitamin D is available in oral spray formulation in some countries, which can be useful for older adults with swallowing difficulties. Role of Calcium and Vitamin D Supplements in Osteoporosis One of the first RCTs ever to show fracture risk reduction( 43% hip fractures and 32% non-vertebral fractures) compared vitamin D and calcium supplements against placebo in women living in a nursing home (mean age 84 years) [13]. However, many subsequent RCTs in much younger, healthier, less calcium- and vitamin

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D-deficient post-menopausal women showed no effect on fracture risk, which could be explained at least partly by poor compliance [29]. Vitamin D supplements alone offer little benefit, which is not unexpected given the fact that their beneficial effect relies on intestinal calcium absorption. In general, calcium and vitamin D supplements by themselves have no effect on BMD or fracture outcomes ( 2.0, without fractures on treatment or baseline multiple vertebral fractures. High-risk patients should continue alendronate for up to 10 years or zoledronate up to 6 years. There is insufficient evidence regarding drug holidays in glucocorticoid-osteoporosis or in men (similar approach can reasonably be assumed in the latter but not in the former condition). Risedronate has a shorter half-life (but still, e.g., 6 months after 3 years of use) and thus can be used continuously. Ibandronate has both a short halflife and weak potency, has not been shown to reduce hip fracture risk, and is therefore not considered a first choice bisphosphonate in several guidelines. Denosumab Denosumab is a humanized monoclonal antibody against RANKL. RANKL is produced by osteoblasts and osteocytes and binds to its receptor RANK on osteoclasts and their precursors to act as a critical regulator of osteoclastogenesis as

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well as osteoclast activity and survival. Denosumab’s most common side effects include hypocalcemia and an increased risk of skin eruptions and soft tissue, respiratory, or urinary tract infections. In osteoporosis, denosumab is used as a 60 mg dose every 6 months. Compared to oral or i.v. bisphosphonates, denosumab is somewhat more potent at suppressing bone turnover and increasing BMD. However, RCTs powered to compare fracture efficacy are not available. Prolonged used of denosumab results in continuous BMD increases, whereas a plateau is often reached during bisphosphonate therapy. Thus, long-term denosumab therapy can often “cure” patients of their osteoporosis, with, e.g., 61% to 81% achieving a target T-score > 1.5 to 2.0, respectively, after 10 years of denosumab [33]. Regarding extraskeletal benefits, recent studies suggest that denosumab may reduce the risk of falls, increase muscle mass and strength, and improve glucose metabolism [34]. Importantly, the effect of denosumab is fully reversible 7–12 months after the last dose. During this time window, denosumab discontinuation has been associated with “rebound” increases in bone turnover above baseline levels and a transiently increased risk of multiple vertebral fractures. Delays in denosumab injections have also been associated with lower BMD gains and increased fracture risk. Given the benefits of continuing, the risks of stopping, and continued excellent safety profile of long-term denosumab use, it may be best to continue indefinitely (like most drugs in medicine except bisphosphonates). Should denosumab be stopped however, several recent RCTs have shown that follow-up treatment with bisphosphonates may partially maintain BMD gains achieved with denosumab. Switching from denosumab to teriparatide is not advised because this triggers transient to progressive BMD loss. Medication-Related Osteonecrosis of the Jaw (MRONJ) and Atypical Femoral Fractures Unfortunately, many patients and doctors believe that bisphosphonates and denosumab carry a high

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risk of medication-related osteonecrosis of the jaw (MRONJ) and atypical femoral fractures. In reality however, these risks are exceedingly low in osteoporosis patients. MRONJ is defined as jaw bone remaining exposed >8 weeks, usually following tooth extractions or other jaw bone surgery, in a patient treated with antiresorptives or an angiogenesis inhibitor, without prior radiotherapy or jaw bone metastases. Osteonecrosis of the jaw may also occur without medication exposure. The incidence of MRONJ is estimated at 1–10% of patients with metastatic bone disease (who are treated with antiresorptives at 10–12 times higher doses than in osteoporosis) vs. < 0.1%/year in osteoporosis. Most MRONJ in osteoporosis patients is grade 1 or 2 and can be treated without complications. Therefore, a dental check-up is recommended in cancer patients commencing high-dose antiresorptives, but this is not recommended in osteoporosis. Moreover, guidelines do not recommend discontinuation of bone drugs, neither before dentoalveolar surgery nor in those with active MRONJ. The existence of medication-related osteonecrosis in other bones, e.g., the external ear canal, remains uncertain. Atypical femoral fractures are defined as non-periprosthetic diaphyseal fractures (i.e., between the lesser trochanter and the supracondylar flare of the femur) occurring without or after a minimal trauma (fall from a standing height or less), originating from the lateral cortex, running horizontally but which may have a medial spike, and may show localized cortical thickening at the lateral cortex. However, the existence of periprosthetical atypical femoral fractures as well as atypical fractures in other long bones has been suggested. The pathophysiology remains enigmatic but has been proposed to involve altered bone material properties and stress fracture-like phenomena in combination with predisposing genetic factors, including Asian ancestry. The incidence is estimated at 80% relative risk reduction) and smaller benefits regarding non-vertebral fractures, although efficacy regarding hip fractures has not been demonstrated. Higher doses of teriparatide are available in some regions and exert greater effects on BMD but may also have more side effects. Compared to teriparatide, abaloparatide may be slightly more effective with less hypercalcemia. Adverse events include palpitations, flushing, and orthostatic hypotension shortly after the injection, whereas the risk of cardiovascular adverse events may be decreased [36]. Long-term teriparatide administration to rats has been associated with osteosarcomas, which is probably because rodents retain open growth plates throughout life. Extensive postmarketing surveillance has been completely reassuring that human osteosarcomas are not associated with teriparatide. Nevertheless, parathyroid hormone analogues are contraindicated in children with open growth plates and in cancer patients due to the theoretical risks of stimulation of bone turnover and stimulation of

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pre-existing cancer cells through the parathyroid hormone receptor. Combination therapy of teriparatide with denosumab or zoledronate has been shown to exert superior effects on BMD than either treatment alone. However, because combination therapy has not been shown to reduce fracture risk, it is not currently recommended [7]. The effect of teriparatide appears to be blunted in long-term bisphosphonate users compared to treatmentnaïve patients, supporting the up-front rather than second-line use of bone anabolic drugs. Romosozumab is a humanized monoclonal antibody against sclerostin, an osteocyte-derived inhibitor of Wnt signaling which stimulates modeling-based bone formation (i.e., transforms quiescent bone lining cells into osteoblasts) and suppresses bone resorption. It is administered as two s.c. injections every month for 12 months. This results in quick and pronounced increases in BMD and superior long-term fracture prevention through a “foundation effect.” However, increased cardiovascular risks have been noted compared to bisphosphonates. Nevertheless, initial short-term therapy with potent bone anabolic drugs followed by antiresorptive consolidation is a promising treatment avenue for patients with high/imminent fracture risk, most of whom are older adults.

Follow-Up The primary care provider plays a central role in osteoporosis follow-up, which should focus on compliance, the weakest link in osteoporosis treatment. Fracture and falls history should be regularly repeated to identify potential treatment failure. The latter can be defined as more than one fracture on treatment or one fracture plus lack of BMD or bone turnover marker response. Poor compliance, high baseline fracture risk, and risk of falls are the greatest predictors of treatment failure. Incident secondary causes of osteoporosis should also be excluded. There is some observational evidence that repeat DXA in clinical practice (and likely feedback of BMD responses) is associated with

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greater persistence and more switching of treatments [37]. BMD monitoring may indeed play a role in a treat-to-target strategy, to identify patients who may benefit from bisphosphonate drug holidays or switching to a more potent drug. BMD measurements are rarely useful at intervals hip) but also (to a lesser extent) increases the risk of hand OA. Whether, in addition to mechanical factors, metabolic factors are also involved remains unclear. Abnormal joint shape at birth and certain monogenic skeletal dysplasias (related to collagen or its processing in chondrocytes) predispose to premature OA, as do a family history of OA. A genetic cause such as Stickler syndrome should be suspected in early-onset OA or patients with severe myopia or other ophthalmological conditions or rheumatoid factor-negative RA. Women have a higher prevalence of knee and potentially hand, lumbar, and cervical OA [39, 40]. Genomewide meta-analyses have identified inflammationrelated genes associated with OA, as well as a complex genetic relationship of both increased height as well as short stature with OA [41]. Interleukin-1β inhibition has been associated with less need for large joint replacement surgery in a recent RCT [42].

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Common secondary causes of OA include prior avascular necrosis, intra-articular fractures or torn ligaments, and hemochromatosis. Diseases with diminished pain or sensory nerve function predispose to OA (e.g., Charcot foot or neuropathic spine), which may partly be due to increased risk of overload damage. Rare secondary causes include Paget’s disease, acromegaly, hyperlaxity disorders with or without joint dislocation (e.g., Ehlers-Danlos syndrome), high bone mass disorders, or mucopolysaccharidoses. Septic arthritis or uncontrolled inflammatory joint diseases like RA or crystal arthropathies may cause joint damage that may culminate in cartilage destruction like in late-stage OA.

Diagnosis Since radiographic OA is much more common than symptomatic OA, history taking and clinical examination are essential to confirm the clinical diagnosis of OA. Pain that worsens upon joint mobilization and loading in association with joint hypertrophy, instability, and deformity is the clinical hallmark of OA. Importantly, hip OA typically produces groin pain which may radiate to the knee, while lateral (trochanter) hip pain may be caused by bursitis and posterior hip or buttock pain is often due to lumbar OA. Joint space narrowing (reflecting loss of cartilage volume), enthesophytes, and malalignment are radiographic hallmarks of late-stage OA. Magnetic resonance imaging (MRI) may be more sensitive to detect cartilage defects in early OA and is less invasive than arthroscopy. The Kellgren-Lawrence scale is a simple, commonly used radiological scoring system, which may be used for OA in any joint, although mostly for research purposes: • Grade 0 (none): absence of OA radiographic signs • Grade 1 (doubtful): possible osteophytic lipping, joint space narrowing doubtful • Grade 2 (minimal OA): definite osteophytes and possible joint space narrowing

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• Grade 3 (moderate OA): moderate multiple osteophytes, definite joint space narrowing, some sclerosis, possible bone deformity • Grade 4 (severe OA): large osteophytes, marked joint space narrowing, severe sclerosis, definite bone deformity Severe hip OA may be associated with protrusio acetabuli, i.e., the protrusion of the femoral head beyond the usual margin of the acetabulum. Inflammatory flares are part of the natural history of OA. In these cases, joints become acutely swollen, warm, and painful upon mobilization (even without weight bearing), which hinders mobility. Bursitis, fractures, deep venous thrombosis, or ruptured Baker cysts may all mimic arthritis. Thus, X-rays and sometimes ultrasound are useful to confirm the diagnosis and/or assist in synovial puncture. Excruciating pain and/or severe sepsis, even when located nearby a joint, should raise clinical suspicion for a necrotizing soft tissue infection or compartment syndrome. Moderate fever and biochemically raised inflammatory markers may be present in severe OA flares. In such cases, the threshold for arthrocentesis and synovial fluid analysis should be low, to exclude other forms of acute monoarthritis including septic arthritis, gout, or calcium pyrophosphate deposition (CPPD) disease (pseudogout) (Table 2). Several biomarkers of altered cartilage metabolism are under investigation for the diagnosis and risk stratification of early OA, including C-terminal cross-linking telopeptide of type II collagen (CTX-II), cartilage oligomeric matrix protein (COMP), matrix metalloproteinase-3, etc. However, they are currently not sufficiently validated for use in clinical practice.

Person-Centered Approach in Older Adults The treatment of OA can have several goals: (1) reduce pain, (2) improve mobility, (3) reduce inflammation, (4) treat complications (e.g., mood

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Table 2 Differential diagnosis of acute arthritis in older adults Differential diagnosis Osteoarthritis

Clinical features Acute monoarthritis (commonly knee, hip, shoulder, sometimes spine) Joint hypertrophy and deformity

Gout

Acute mono- or oligoarthritis (metatarsals, ankle, wrist, knee, elbow, sometimes other joints) Risk factors for gout (see text) Hyperuricemia (may be false-low in acute gout), tophi in advanced disease Acute mono- or oligoarthritis Risk factors for gout may be lacking Trauma, surgery (particularly parathyroidectomy), severe illness, or bisphosphonates may trigger attack Acute mono- (rarely oligo)-arthritis (commonly knee, hip, shoulder, spine) High fever and sepsis should raise suspicion, but fever may be absent Nearby wounds may be entry point

CPPD

Septic arthritis (incl. bacterial, mycobacteria, fungal)

Rheumatoid arthritis

Hemarthrosis

Lyme disease

Spondyloarthritis (reactive arthritis, psoriatic arthritis, inflammatory bowel disease)

Sarcoidosis Leukemia, myelodysplastic syndrome Synovial or juxta-articular tumor or metastasis Plant thorn (foreign body) synovitis Whipple’s disease

Symmetric polyarthritis involving predominantly distal joints of the hands and feet Following trauma, or spontaneously in patients with bleeding predisposition, e.g., on anticoagulants Mono- to oligoarthritis, mostly knee (s) > shoulder, elbow, ankle, wrist Prior erythema migrans or tick bite Occupational exposure or travel history to endemic area Usually symmetric lower-leg arthritis with enthesopathy Underlying psoriasis may be absent or inflammatory bowel disease yet undiagnosed Usually ankles Erythema nodosum Secondary autoimmune arthritis Treatment-refractory mono-arthritis Previous or occult cancer diagnosis Foreign body trauma (torn) Treatment-refractory mono-arthritis Migratory chronic oligo- to polyarthritis of large joints (wrist, knees, ankles) Joint destruction or deformity rare Later diarrhea, abdominal pain, weight loss, wasting  central nervous system abnormalities

Diagnostic tests Moderate to severe OA on X-ray In case of synovial fluid aspiration: sterile inflammatory synovial fluid without crystals In case of synovial fluid aspiration: sterile inflammatory synovial fluid with uric acid crystals

Crystal depositions on X-rays In case of synovial fluid aspiration: sterile inflammatory synovial fluid with calcium pyrophosphate crystals Positive blood cultures Synovial aspiration shows inflammatory fluid, sometimes with positive Gram stains. Culture allows definitive identification of pathogens and antibiotic sensitivities Rarely: intra-articular gas (pneumarthrosis) Mostly positive rheumatoid factor and anti-cyclic citrullinated peptide antibodies Sometimes family history In case of synovial fluid aspiration: evacuation of hematoma Serological testing, polymerase chain reaction testing

Clinical, sometimes family history

Hilar adenopathies on chest X-ray Raised kinase-II Complete blood count Imaging, microscopic analysis of synovial fluid, biopsy Imaging may be negative; high index of suspicion needed to surgically remove thorn High index of suspicion needed due to its rarity Mimics spondyloarthritis but doesn’t respond to immunosuppressants Periodic acid-Schiff staining of biopsies, polymerase chain reaction testing, immunohistochemistry for Tropheryma whipplei; small bowel endoscopy

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and sleep disturbances, sedentarity) and/or underlying diseases, and/or (5) halt disease progression and prevent further joint destruction (i.e., a disease-modifying OA drug, DMOAD). Radiographic OA and/or clinical joint deformity is common in geriatrics but often not symptomatic. However, musculoskeletal pain in older adults is also very common and should always be investigated (at least clinically) and treated. The main difficulty in clinical decisionmaking is when to refer an older patient for hip, knee, or shoulder prosthesis surgery. These types of orthopedic surgery are very successful in improving pain and reducing the need for painkillers in (usually older) patients with severe OA. However, they also carry a risk of severe adverse events [43]. Patients may believe that prosthetic implants need to be replaced often, which is not the case: modern prosthetic joints may last for decades to a lifetime. Waiting too long may cause unnecessary suffering and ultimately, the patient may no longer be eligible for surgery because the risk of perioperative complications outweighs the benefits. In contrast, too early surgery without a prior trial of conservative management may unnecessarily expose to patient to perioperative risks. The benefits and risks as well as the expected post-operative rehabilitation should always be discussed with the patient. In patients with advanced dementia, life-limiting comorbidities, very high perioperative risk, or those with concomitant mobility limitations from other causes however, surgery should be avoided. Since patients may directly consult an orthopedic surgeon requesting joint replacement surgery, a pre-operative screening for physical, cognitive, or social frailty followed by a comprehensive geriatric assessment and geriatric co-management program may help attain the best outcomes.

Treatment As with any chronic condition, patient education and coping skills are the cornerstones of effective self-management in OA [44].

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Treating Pain and Inflammatory Flares The source of pain in OA remains enigmatic although both peripheral and central pain sensitization play a role. Non-steroidal antiinflammatory drugs (NSAIDs) are the drugs of choice to improve pain, physical function, and quality of life in musculoskeletal pain in general, including in OA [45]. Topical NSAIDs may be effective, particularly for superficial joints like in hand OA, with less side effects than oral NSAIDs. Adverse effects include photosensitization for topical NSAIDs, and increased cardiovascular risk, kidney injury, heart failure, and gastrointestinal ulcerations in oral NSAIDs. Overall, there is little convincing evidence that coxibs or certain NSAIDs have superior efficacy and/or safety compared to others. Some experts suggest switching from one NSAID to another if symptomatic control is not achieved, but this is more expert opinion than evidence-based practice. Acetaminophen (paracetamol) may also be tried for acute, short-term pain relief in OA [46]. The use of tramadol or opiates is discouraged [47] or reserved for severe pain in refractory cases. Non-pharmacological strategies may include specific acupressure or transcutaneous electrical nerve stimulation [45]. Notably, given the high rate of placebo response in OA trials, physicians should be optimistic about the effects of treatment. Inflammatory flares may respond to topical and oral NSAIDs, but more severe flares may require glucocorticoid injections (with or without local analgesics), oral glucocorticoids, or colchicine therapy. Local injections may be the treatment of choice for monoarthritis, because they limit (but do not exclude) systemic side effects. However, since glucocorticoids have a detrimental effect on chondrocytes and are associated with increased OA risk upon long-term use [48], they should be used sparingly, e.g., for very painful and/or disabling hip, knee, shoulder, or other OA flares. Side effects of glucocorticoids are manifold (see section “Glucocorticoids” below). Only a few short-term RCTs have investigated the use of colchicine, however mostly in stable OA, with symptomatic benefit in some trials but

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not others. There may be a limited role for capsaicin in OA of superficial joint, although local side effects are very common and limit the use in older adults. Duloxetine may have some effectiveness in OA and may be useful for those with concomitant depression. However, it should be titrated slowly due to the risk of side effects such as dry mouth, dizziness, constipation, fatigue or nausea, as well as hyponatremia or severe skin reactions.

Physical and Occupational Therapy While overloading may contribute to joint destruction (e.g., following sports or occupational injury, after meniscectomy or anterior cruciate ligament injury, in obesity, etc.), biomechanical stimuli in general are considered trophic for joint cartilage. Studies in long-term runners suggest that they are not at increased risk of knee OA, in contrast to other more injury-prone sports like football or soccer. Physiotherapy and/or Tai Chi should highly be recommended since they effectively reduce pain and improve physical function in OA patients [44]. The mechanism of effect of exercise in OA is not clear: it may reduce pain independently, may stimulate chondrocyte, or could avoid secondary disuse and improve stability by strengthening the surrounding muscles and tendons. A recent RCT showed superior 1-year outcomes with physiotherapy compared to glucocorticoid injections for knee OA [49]. Some patients may require walking aids, particularly those with late-stage OA who are not candidates for joint replacement surgery. Splints may be useful in patients with symptomatic base of thumb OA. Some older adults with knee OA report a benefit from knee braces, although this should be considered an adjunctive treatment in combination with physical therapy. Local heat or cold are not evidence-based therapies but are preferred by many patients. Given the importance of overweight and obesity as risk factors for OA, weight loss is an important non-pharmacological strategy in OA highly recommended in guidelines. In contrast, insoles or special shoes are ineffective in knee or hip OA.

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Disease-Modifying OA Drugs DMOADs remain the Holy Grail for OA, particularly for polyarticular forms. For example, because subchondral bone is known to play a role, several osteoporosis drugs have been investigated in OA, while others continue to be investigated. Despite numerous trials however [42], no DMOADs have been definitively established. Both oral glucosaminoglycans and chondroitine sulfate are marketed for OA. In meta-analyses, they show some effectiveness, which remains however uncertain and requires confirmation in larger RCTs [50]. Many specialists including geriatricians do not recommend these drugs; since their proposed mechanism of action is slow-onset, they may be considered “green bananas” in geriatrics. Platelet-rich plasma is under investigation, mainly for knee OA, but the available studies are small and heterogeneous. Injectable hyaluronans on the other hand are very expensive and not more effective than injectable placebo. Likewise, autologous chondrocyte transplantation currently plays no role in managing OA in older adults. Joint Prosthesis Surgery Patients with severe symptoms refractory to medical management may be candidates for joint replacement surgery. Importantly, a differential diagnosis with other conditions should first be considered in cases refractory to medical management (see Table 2 above). Total hip and knee replacement and reversed delta shoulder prosthesis surgery are the most commonly performed prosthetic joint surgeries in older adults, although prostheses exist for almost any other joint too. Some older adults may be eligible for unicondylar knee replacement surgery, which is cheaper and less invasive. Hip hemiarthroplasty, resurfacing, or osteotomy are however not advised in older adults. These treatments are usually very effective in improving medically refractory pain, which should be the primary indication for surgery. Most older adults who are still fit for surgery achieve good functional outcomes; however, rehabilitation may require several months. The decision to proceed with surgery requires

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informed decision-making. Expectations should be discussed to ensure that they are realistic. In contrast, arthroscopic procedures such as cartilage “shaving,” partial meniscectomy, etc. are to be discouraged since they offer no evidence-based benefit but still increase the risk of severe adverse events [51].

Follow-Up Follow-up is clinical and should focus on patientcentered goals. Radiographic follow-up is discouraged unless for pre-operative planning or for differential diagnosis. Visual analogue scales can be useful for pain. Some functional tests such as the timed chair stands, timed up-and-go test, or 6-min walk test have been used to monitor physical functioning in lower extremity OA. Formal scoring systems or questionnaires such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), the Hip Disability and Osteoarthritis Outcome Score (HOOS), the Australian/Canadian Hand OA Index, or the Functional Index for Hand Osteoarthritis are used mostly for research purposes. The added value of handgrip strength in monitoring hand OA remains uncertain.

Gout Epidemiology Gout affects between 1% and 6.8% of adults in Western societies. In developing countries, it is less common, but the incidence is increasing [52]. The disease is overall threefold more common in men, although the sex difference is larger in midlife and declines after the age of menopause in women [53]. The prevalence in older adults aged 65 years and older may be up to 5–6% in men and 2–3% in women in primary care studies and as high as 20% in men and 15% in women in population-based studies (Fig. 4) [53]. Calcium pyrophosphate deposition (CPPD) refers to the presence of these crystals in tissues.

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When causing arthritis, this is called CPPD disease. The European League Against Rheumatism has categorized the CPPD spectrum as follows [54]: • Asymptomatic CPPD • Acute CPP crystal arthritis (formerly pseudogout) • Chronic CPP crystal arthritis (formerly pseudo-RA) • OA with CPPD, with or without flares (formerly pseudo-OA) • Severe joint degeneration (pseudo-neuropathic joint disease) • Spinal involvement The prevalence of cartilage calcifications (which highly suggests, but not entirely specific for CPPD) on plain radiographs may affect 4–7% of adults in Europe and the USA [55]. However, the prevalence of CPPD markedly increases with age from ~15% in those 65 years and older to up to ~50% in those 85 years and older. The mean age lies around 70–72 years, with no clear gender difference. Gout is typically associated with medical conditions causing hyperuricemia (Table 3). A prevalence of >10% has been reported in populations prone to obesity and metabolic syndrome like Maori or Taiwanese aboriginals [52]. Glucosuria in (poorly controlled) type 2 diabetes mellitus is believed to protect against gout, an effect which appears to extent to sodium-glucose cotransporter2 (SGLT2) inhibitors [56]. Nutritional factors, in particular red meat, seafood, alcohol, and soft drink consumption, are associated with increased risk of gout, whereas vegetarian or healthy diets are associated with lower risk of gout. Most hyperuricemic older adults remain asymptomatic. The cumulative risk of clinical gout in studies with >25 years of follow-up lies ~15% in older adults with hyperuricemia (serum urate 408 μmol/l or 6.8 mg/dL, the threshold for crystal nucleation in vitro). However, the risk increases proportionally to the degree of hyperuricemia to ~50% in those with urate levels >10 mg/dL (64-fold hazard ratio) [52].

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M. R. Laurent

Fig. 4 Age-specific prevalence (a) and incidence (b) of gout in a population-based study from Taiwan in 2010. Blue, men; red, women. Error bars represent 95%

confidence intervals. (Reproduced from Kuo et al. [53], with permission from Springer Nature)

Similarly, CPPD (i.e., chondrocalcinosis) often remains asymptomatic. Unfortunately, identification of pyrophosphate crystals (ideally, the golden

standard for diagnosis) is notoriously difficult and inaccurate in clinical practice. Furthermore, X-ray imaging has low sensitivity for CPPD, which may

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Table 3 Risk factors for hyperuricemia and gout Risk factor Renal insufficiency Obesity and metabolic syndrome Nutritional factors

Drugs

Comment Acute and/or chronic

Alcohol Red meat, seafood Non-diet soft drinks, fructose Protective: dairy products (milk, yoghurt) Thiazides and loop diuretics Aspirin, including low-dose Angiotensin converting enzyme inhibitors, non-losartan angiotensin II receptor blockers, β-blockers, ticagrelor Cyclosporin, ethambutol, pyrazinamide, ritonavir, tacrolimus *Protective: calcium channel blockers, losartan, statins, fenofibrate, menopausal hormone replacement therapy, sodiumglucose cotransporter-2 (SGLT2) inhibitors

Male sex Menopause in women Cell lysis

Primary or secondary polycythemia Leukemia or lymphoma, small cell lung cancer Tumor lysis syndrome (spontaneous or treatmentinduced) Hemolytic or sickle cell anemia Rhabdomyolysis (trauma, compartment syndrome, extreme exercise, statins, etc.) Genetic causes (rare) Lesch-Nyhan syndrome, numerous other genetic forms Lead exposure

be better for ultrasound (showing linear cartilage densities). Thus, the diagnosis of CPPD and its true prevalence remain challenging to establish. The association of gout with arterial hypertension, cardiovascular, and kidney disease has long be considered bidirectional. However, this remains controversial, since it has not been clearly established that urate-lowering therapies reduce

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the risk of subsequent cardiovascular disease or renal function decline. Furthermore, Mendelian randomization studies have been unable to show that genetically determined hyperuricemia contributes independently to arterial hypertension, renal function decline, or cardiovascular disease [57].

Pathophysiology Urate is produced by xanthine oxidase as the final breakdown product of purines (adenine and guanine) and excreted via the kidneys in humans, higher primates, and Dalmatian dogs. Most other mammals use uricase to convert urate to allantoin. Birds, reptiles, and some desert animals also excrete urate but do so as a dry mass in their feces (“guano”). Almost a dozen transports control urate transport, and mutations or genetic variants in these genes may predispose to gout. Urate is a strong antioxidant and higher urate levels have been associated with better cognitive function; however, this effect is very small and unlikely to be clinically meaningful [58]. Gout arises when hyperuricemia leads to local supersaturation of uric acid within joint soft tissues and precipitation of monosodium urate crystals. In CPPD, inorganic pyrophosphate accumulates and complexes with calcium to form calcium pyrophosphate crystals. CPP crystals deposit almost exclusively in cartilage, which has high inorganic pyrophosphate content. Risk factors for CPPD include previous trauma to the joint, e.g. after meniscectomy. CPPD disease may typically be triggered by parathyroidectomy or hip fracture surgery. Hyperparathyroidism, hemochromatosis, and hypomagnesemia are other secondary causes of CPPD. The inorganic pyrophosphate transport regulator ANKH (murine progressive ankylosis, human orthologue) is a crucial target in CPPD, which may be responsible for a rare, dominant familial form. Other rare genetic causes include mutations in tissue-non-specific alkaline phosphatase (hypophosphatasia). Crystals may precipitate asymptomatically or trigger macrophages to initiate an inflammatory

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response, which relies on interleukin-1β and the NLRP3 (nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3, a.k.a. cryopyrin) inflammasome [57]. Crystal accumulation may lead to the formation of tophi in some patients, which should be considered an advanced stage of long-standing (usually more than a decade), poorly controlled (and often still untreated) gout. Infiltration of tophi into bone may lead to erosive bone lesions and predispose to later OA. Hyperuricemia further predisposes to urate nephropathy and urolithiasis. In contrast, lowering urate levels to 20 mg daily for more than 2 weeks, as they may continue to be infectious [37].

Treatment Early in the pandemic, the FDA provided EUA in March 2020 for the use of hydroxychloroquine in hospitalized patients with COVID-19. Hydroxychloroquine is an antimalarial drug with immunomodulating and antiviral effects. Early studies showed potential efficacy of hydroxychloroquine with antiviral and antiinflammatory effects. However, subsequent data from the RECOVERY trial, a large randomizedcontrol trial, showed no difference in 28-day

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mortality between hydroxychloroquine and placebo [38]. Hydroxychloroquine also has a high side effect and toxicity profile making it a potentially inappropriate medication in older adults. In June 2020, the FDA revoked its emergency use authorization. Treatment guidelines are based on disease severity and whether patients require hospitalization. As of December 2021, remdesivir was the only FDA-approved antiviral in the treatment of COVID-19 [39]. Remdesivir, a nucleotide analogue that inhibits viral RNA-dependent RNA polymerase, is recommended for treatment in COVID-19 patients hospitalized with severe disease on supplemental oxygen. Intravenous remdesivir 200 mg followed by 100 mg daily for up to 10 days is recommended to reduce the median days to recovery in hospitalized COVID19 patients [40]. Patients’ liver and kidney function should be monitored while on treatment. Remdesivir is contraindicated in geriatric patients with kidney disease with an estimated GFR of less than 30 ml/min [41]. There have been mixed guidelines on the use of steroids in COVID-19 infections. Initially in March 2020, there was a weak recommendation for the use of steroids. In April 2020, the IDSA recommended against the use of steroids except in COVID-19 patients with acute respiratory distress syndrome in a clinical trial setting [42]. Clinicians struggled with these mixed guidelines until June 2020 when further research found corticosteroid use beneficial. In a meta-analysis of seven randomized controlled trials, the use of corticosteroids reduced mortality in critically ill COVID-19 infected patients [43]. Dexamethasone is recommended in the treatment of severe or critically ill COVID-19 hospitalized patients. Dexamethasone treatment of 6 mg daily for 10 days reduced the number of days on mechanical ventilation. Careful monitoring for side effects specifically of concern in older adults includes psychiatric effects, such as acute delirium, secondary infections, and hyperglycemia [44]. In November 2020, the FDA issued EUA for the use of anti-SARS-CoV-2 monoclonal antibodies, for the combination use of casirivimab and imdevimab [45]. These anti-SARS-CoV-2

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monoclonal antibodies bind to the receptorbinding domain of the spike protein which allows for viral fusion and entry into host cell via the host cell’s angiotensin-converting enzyme 2 receptor [46]. As of November 2021, three monoclonal antibodies of bamlanivimab/etesevimab, casirivimab/imdevimab, or sotrovimab were recommended for the treatment of nonhospitalized geriatric patients with mild to moderate severity COVID-19 infections [47]. Socially frail older adults should receive assistance in coordinating transportation to infusion centers. Patients receiving treatment should be observed for 1 h postinfusion to monitor for possible adverse effects including hypersensitivity reactions. Patients who have received monoclonal antibodies should defer COVID-19 vaccination 90 days after treatment [46]. Casirivimab/ imdevimab are recommended for postexposure treatment for patients who are at increased risk of progression to severe COVID-19 illness, including patients who are not fully vaccinated or have an immunocompromising condition or taking immunocompromising medications [47]. Convalescent plasma contains high neutralizing antibody titers that is thought to provide passive antibody-based immunity. Convalescent plasma received EUA by the FDA in August 2020. A study of older adults treated with convalescent plasma found reduced progression to severe disease when compared to placebo [48]. However, further studies are needed, and the IDSA guidelines recommend against its use in hospitalized COVID-19 patients and limited use to the clinical trial setting in the outpatient setting [49]. Tocilizumab is an interleukin-6 (IL-6) receptor monoclonal antibody used in the treatment of cytokine release syndrome. Tocilizumab gained interest as a treatment in hyperinflammation and elevated IL-6 state of COVID-19 [50]. The IDSA recommends the use of tocilizumab for hospitalized patients with progressive severe or critical COVID-19 who have elevated markers of systemic inflammation in addition to standard of care [51, 52]. Baricitnib, a janus kinase (JAK) inhibitor, is recommended by the IDSA for use in combination

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with standard of care for patients hospitalized with severe COVID-19 and elevated inflammatory markers. Baricitnib with remdesivir is recommended for patients in whom dexamethasone is contraindicated [53]. Two oral antiviral medications have received EUA by the FDA for the treatment of mild to moderate COVID-19 infection in December 2021. Molnupiravir, a nucleoside analogue which inhibits viral replication, has been shown to reduce hospitalizations and mortality [54]. The other oral medication, Paxlovid, a combination of protease inhibitors nirmatrelvir and ritonavir has also been shown to reduce hospitalization and mortality in COVID-19 infections [55]. Due to the high rate of thromboembolic events, hospitalized COVID-19 patients should be placed on thromboprophylaxis. Outpatients with COVID-19 infections should not be started on thromboprophylaxis based on current NIH guidelines. Patients should continue angiotensinconverting enzyme inhibitors and angiotensin receptor blockers if already on the medications but should not be started as there is a lack of evidence [46].

Vaccines Vaccine development began prior to the first laboratory-confirmed case of COVID-19 in the United States. On January 11, 2020, the genetic sequence of SARS-CoV-2 was released, and vaccine development quickly began [56]. Although the pathogen was a novel coronavirus, the vaccines were developed using existing development methods and technologies. Prior to COVID-19, vaccine development typically took years due to a variety of factors. The pandemic necessitated a more collaborative approach. Data sharing between the public and private sectors and among countries worldwide was unprecedented, allowing numerous vaccines to enter clinical trials by late spring of 2020. Prior to COVID-19, most vaccine clinical trial phases to assess safety and efficacy occurred in sequence. Due to the urgency of identifying safe, effective vaccines, these phases took place in parallel for COVID-19. For

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instance, some COVID-19 clinical trials are evaluating multiple vaccines simultaneously, whereas in the past, each vaccine had separate clinical trials. Global collaboration, streamlining of process both in the laboratory and in clinical trials, allowed multiple safe, effective vaccines to be developed by fall of 2020. The vaccine platforms vary: nucleic acid (mRNA), viral vector (adenovirus), and inactivated virus. The mRNA and viral vector vaccines target the spike protein to induce antibody production after vaccine administration [57]. As of December 2021, the WHO Emergency Use Listing has approved seven vaccines against COVID-19 based on their efficacy, safety profiles, and suitability for middle- and low-income countries [58]. Individual countries issued their own emergency use authorizations at their discretion. In the United States, three vaccines have received Emergency Use Authorization (EUA) from the Food and Drug Administration (FDA): Pfizer/ BioNTech (BNT162b2/Comirnaty), Moderna (mRNA 1273/SpikeVax), and Janssen/ Johnson&Johnson (AD26.COV 2.S). On December 2, 2020, the United Kingdom granted temporary approval to the Pfizer/ BioNTech (BNT162b2/Comirnaty) vaccine, becoming the first country to authorize a COVID-19 vaccine for widespread public use. On December 11, 2020, the US FDA granted EUA to the Pfizer/BioNTech vaccine and a week later to Moderna [57]. Both of the aforementioned vaccines use messenger RNA (mRNA) which instruct cells to make SARS-CoV-2’s spike protein which then elicits an immune response [59]. In the initial randomized, blinded placebo-control clinical trials, vaccination with two-dose series of Pfizer/BioNTech administered 3 weeks apart had an efficacy of 95% in preventing COVID-19 disease, with only one case in the vaccine group being classified as severe [60]; two doses of Moderna given 4 weeks apart were 94.1% effective in preventing disease with zero severe cases in the vaccine group [61]. Due to the anticipated public demand exceeding initial vaccine supply, the Center for Disease Control (CDC) Advisory Committee on Immunization Practices (ACIP) issued recommendations

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for vaccine eligibility, with health care workers and residents of long-term care facilities being offered vaccination first in Phase 1a, followed by Phase 1b which included individuals 75 or older and nonhealth care frontline essential personnel. Individuals 65–74 years old were included in Phase 1c [62]. The first COVID-19 vaccination in the United States outside of a clinical trial was administered on December 14, 2020, to a nurse in Queens, New York [63]. As expected, the demand for vaccine doses far exceeded supply in the first few weeks. Special equipment was required for vaccination sites as the nature of the mRNA technology required storage at temperatures below standard refrigerators, and the shelf life of the vaccines are only a few hours at room temperature. During the initial rollout, most vaccination sites required appointments to be made via the Internet, with open appointments filling within minutes, which was a barrier for many older adults [64]. Anticipating the demand for vaccination among older adults, the Pharmacy Partnership for Long-Term Care Program was created in December 2020 by the CDC to facilitate on-site vaccination at enrolled Skilled Nursing Facilities (SNFs). Over 11,000 SNFs held at least one vaccination clinic during the first month of the program (December 18, 2020, and January 17, 2021). During that time, an estimated median of over 75% of residents and 37.5% of staff received at least one dose of vaccine [65]. Vaccinating homebound patients and caregivers presented unique challenges. In contrast to vaccine sites where individuals preregistered and were given an appointment time, signifying their desire for vaccination, not all homebound patients and caregivers were amenable to vaccination. Additional time was invested in identifying homebound patients and caregivers who were eligible and desired vaccination to avoid wasting doses and streamline the vaccination process. In February 2021, the FDA issued an EUA for the Janssen/Johnson & Johnson vaccine. This vaccine uses an inactivated adenovirus to transmit DNA to instruct cells to make SARS-CoV-2’s spike protein [66]. In the initial clinical trials,

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one dose of this vaccine was approximately 77% effective 14 days postvaccination and 85% effective after 28 days postvaccination in preventing severe COVID-19 infection. While less effective than the Pfizer/BioNTech and Moderna vaccines, this vaccine had the benefits of only requiring one dose and remaining stable in the temperature range of standard medication refrigerators allowing for more widespread distribution, particularly for populations that may have difficulty completing a two-dose series. Various programs were developed to bring the vaccine to patients who had difficulty accessing vaccines sites, such as the homebound, undomiciled, and prison populations, and the Janssen/Johnson & Johnson one-dose vaccine with its favorable temperature stability further facilitated these efforts. Several health systems utilized their home-based primary care programs to identify and administer vaccines to this population. A New York City-based program vaccinated 530 patients with the Janssen/ Johnson&Johnson vaccine in March and April 2021 [67]. As with all new vaccines or medications, widespread safety surveillance continued once mass administration began under EUA through the Vaccine Adverse Event Reporting System (VAERS) in the United States, with similar programs in other countries. The most common side effects are injection site pain, lymphadenopathy, fatigue, and fever for 24–72 h after vaccine administration [68]. The high prevalence of lymphadenopathy prompted radiology recommendations for routine screening mammography to be scheduled at least 8 weeks after vaccination [69]. Rare serious complications have been reported [70]. When evaluated in the context of the millions of doses that have been given in the United States and worldwide, serious side effects are exceedingly rare and appear to be even less of a risk in the older adult population. The real-world efficacy of the vaccines in preventing COVID-19 infection are not as high as in the initial clinical trials. This is likely due to a combination of factors, such as fewer mask requirements, reopening of businesses, and the emergence of new variants. However, the vaccines continue to have high efficacy in preventing severe COVID-19 infections requiring

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hospitalization. A study in July 2021 showed that one dose of the Pfizer vaccine showed 70–80% effectiveness in preventing hospitalization in the UK [71]. Another study of patients over the age of 80 with cancer showed a substantial serological response to the Pfizer vaccine 1 month after completion of the two-dose series [72]. Evidence emerged in mid-2021 that antibody levels and immunity seemed to decrease starting around 4–6 months after the second dose of the Pfizer vaccine. This data prompted the recommendation for third doses of mRNA vaccines and a second vaccine dose for those who received Janssen/Johnson&Johnson, with recommendations for those individuals to receive an mRNA vaccine dose for improved protection. Studies published in The New England Journal of Medicine in December 2021 showed a 90% decrease in mortality, as well as significantly decreased rates of confirmed COVID-19 infection and severe illness in patients who received a third dose of Pfizer vaccine 5 months after the second dose when compared to those who had not [73]. These data also hold true for those individuals over age 60 [74]. The first year of widespread COVID-19 vaccination has demonstrated safety and efficacy in preventing severe COVID-19 infection and death, particularly in the older adult population who are among the most vulnerable to severe morbidity and mortality from COVID-19 infection.

Continuum of Care Challenges The outset of the COVID-19 pandemic was marked by confusion, fear, and disorganization. With little preparation and lack of adequate infrastructure to handle such large volumes of critically ill patients, new care models were quickly formed.

Acute Care Setting In hospitals, bed capacity increased with makeshift medicine units. Many hospitals quickly built new units in their lobbies or outdoors, with

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multiple field hospitals set up across the United States [75]. Some health systems organized a network of COVID-19 intensive care units that were staffed in a pyramid model [76]. Specialists were redeployed to assist with inpatient COVID-19 care teams [77]. These sometimes included a cardiology attending, internal medicine resident, and orthopedic fellow, for example, with a critical care attending providing consultative guidance for multiple teams. The majority of the patients hospitalized during the pandemic were older adults. There was an immense and unprecedented need for geriatricians to develop care protocols guiding patient assessments. Geriatricians were primed to step into a leadership void and advocate for vulnerable older adults [78]. Isolation restrictions and suspension of hospital visitation policies increased the risk for hazards of hospitalization, including delirium, deconditioning, and falls. Geriatricians led initiatives to train providers on strategies for delirium prevention and quick assessments to screen for delirium [79]. Geriatricians were instrumental in guiding goals of care discussions with patients and their families, and ensuring advanced directives were prioritized during the COVID-19 pandemic. Innovative consult services were developed to assist with goal-directed care conversations in the emergency rooms and through telemedicine [80]. Geriatricians advocated for increased completion of advanced directives in the outpatient setting, which allowed for more accurate alignment of interventions with patients’ goals for older adults hospitalized with COVID-19 [81].

Long-Term Care Facilities Long-term care facility (LTCF) residents suffered tremendously during the height of the pandemic, having some of the highest COVID-19-related mortality rates. Due to limited COVID-19 testing availability during the height of the pandemic, LTCF deaths may have been under counted. According to CMS nursing home data, as of June 2021, there have been 132,703 COVID-19 deaths within nursing homes [82].

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Hospitals were required to expand capacity for the rising wave of COVID-19 admissions. In March 2020, New York was the first state to mandate LTCFs to accept COVID-19-infected patients, only if the facility had the ability to properly administer care. This created a large debate on balancing the need to protect vulnerable residents from infection with the need for hospitals to ensure bed availability for new admissions [83]. LTCFs created dedicated COVID-19 units and designated staff to care for patients. Even with strict infection control measures in place, LTCFs continued to face challenges with transmission, shortages in staffing, and bed availability. The COVID-19 pandemic demanded the need for rapid development of new infection control policies within LTCFs and Assisted Living Facilities (ALFs). Not only was transmission among patients a concern, but interfacility transmission was prevalent, due to LTCF staff members working at multiple facilities [84]. Physical therapy was postponed, visitation was halted, and all social activities were canceled to combat transmission. New testing requirements quickly became evident. The CDC put forth testing guidelines for all LTCFs and ALFs to test all staff members, vendors, and private duty aides to be tested once to twice weekly and daily monitoring of residents for symptoms. The CDC further recommended facility-wide testing of residents regardless of the presence of symptoms if a single resident tested positive [85]. Unlike the typical clinical presentation for COVID-19, LTCF residents commonly presented with atypical symptoms such as changes in mentation or behavior, and changes in function, making detection of new cases even more difficult. Memory care units with dementia residents were especially challenging to control transmission with residents having poor adherence to social distancing and mask wearing. In the spring of 2021, over a year from the initial closure, visitation restrictions were partially lifted, allowing families to reunite with LTCF residents. The effects from extreme isolation of residents during the pandemic will likely have lasting impacts on the geriatric LTCF population.

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Outpatient The COVID-19 pandemic impacted care for chronic medical conditions. In many health systems, elective procedures were postponed, and ambulatory care centers were closed. Day programs for older adults with cognitive impairment were canceled. This had drastic effects on care for older adults, many of whom rely on monthly visits with their geriatrician primary care doctors and structured social interactions at community centers. Utilization rates of telemedicine quickly increased in the United States in response to outpatient office closures. During the early phase of the pandemic, over 30% of visits were conducted via telemedicine [86]. For older adults above the age of 65, 23.7% of their visits were done by telemedicine, as opposed to only 0.1% of visits before March of 2020. This shift was possible due to changes in reimbursement policy by the Center for Medicare and Medicaid (CMS), which increased payments for virtual visits [87]. As the pandemic progressed, care began to shift back toward in-person visits. However, telehealth provided opportunities to reimagine care delivery in the outpatient setting. For many older adults with functional limitations and lack of access to transportation, telemedicine allowed for continued access to their primary care doctors. Even as the pandemic recedes, telemedicine will likely continue to be utilized by geriatricians in the decades to come. COVID-19 accelerated its adoption and was responsible for many health systems updating their virtual infrastructure to accommodate telemedicine [88]. While telemedicine increased during the pandemic, routine healthcare, including screening and vaccination rates, plummeted. In the 20 weeks after March 11, 2020, when COVID19 was declared a pandemic, screening mammogram rates fell by 58% [89]. In mid-April, the height of the pandemic in the United States, screening mammogram rates fell by 99%. These effects may stretch into the future, as older adults try to catch up with delayed screenings. There are concerns for a surge in diagnosis of advanced cancers that could have potentially been detected

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earlier had screening rates not decreased in 2020 [90]. This could have continued public health implications for years after the COVID-19 pandemic, particularly for older adults.

Home Setting COVID-19 had profound effects on homebound older adults who never contracted the disease. Both formal caregivers and family members with COVID-19 were unable to visit older adults while they were quarantined. There was a caregiver crisis for some older adults. Social isolation restrictions put in place to reduce the spread of COVID-19 have contributed to worse functional decline, sarcopenia, and frailty due to physical inactivity [91]. The drastic COVID-19 restrictions not only adversely impacted physical function but also harmfully impacted mental health. Worsening rates of mental health conditions related to COVID-19, including anxiety, depression, post-traumatic stress disorder, increased substance use, and suicidal ideation, have been reported [92]. Social isolation has also been shown to be a risk factor for elder abuse [93]. Although literature is still growing in this area, it has become evident that social isolation portends worse outcomes for older adults with cognitive impairment [94]. In a study looking at the effect of restrictive measures during the COVID-19 pandemic on cognitively impaired geriatric patients, 60% of participant’s caretakers reported cognitive worsening [95]. Recognizing this impact is important to improve prevention, screening, and access to mental health care. Caregivers of older adults were also impacted by social isolation during the COVID-19 pandemic. Many community services were closed, such as adult day programs. Other families canceled their home health aide services in fear of increased COVID-19 exposure risk from outside caregivers. Some older adults who contracted COVID-19 lost their caregivers. Geriatric multidisciplinary teams were key in helping families locate agencies and caregivers that were able to provide care.

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Clinical Pearls • Atypical clinical presentations of COVID-19 are common in the elderly with increased rates of comorbidity, polypharmacy, frailty, and dementia. Atypical presentations include delirium, falls and gait impairment, vomiting and diarrhea, and poor oral intake with dehydration [16, 96, 97]. Clinicians must keep a high clinical index of suspicion for infection to avoid misdiagnosis, increased risk of spread, and delay in treatment. • The COVID-19 pandemic created unique challenges for patients with dementia. Cognitively impaired older adults are particularly at risk for poor infection control measures with worse adherence with mask wearing, social distancing, and hand hygiene. Further, many cognitively impaired individuals depend on caregivers, routines, and social interaction – all of which had drastic changes during the COVID-19 pandemic. • Special attention should be given to polypharmacy and balancing the benefit of treatments with potential side effects. Psychotropic medications are commonly used in geriatric patients to treat mood disorders and dementia-related behavioral disturbances. Continued use should be weighed with the risks as psychotropic medications have the potential to worsen respiratory suppression, and cause QTc prolongation, and hepatoxicity. Potentially hepatotoxic or nephrotoxic medications (antidepressants, antipsychotics, mood stabilizers, and lithium) should be dose adjusted or withheld based on the clinical scenario [98]. Treatment regimens should be simplified by deprescribing unnecessary medications to reduce polypharmacy. Nonessential medications should be held until after the acute illness to reduce pill burden and limit potential side effects [99]. • Many geriatric patients will experience a prolonged time to return to a state of their usual health after COVID-19 infection when compared to younger patients, highlighting the importance to establish coordinated care plans for follow-up including home services,

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rehabilitation, and management [100].

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Social Determinants of Health There have been clear ethical and age-related disparities during the COVID-19 pandemic. There have been higher rates of COVID-19-related deaths among certain racial and ethnic groups. The rate ratio of death of Hispanic or Latino persons were 2.3 times more compared to white, non-Hispanic persons according to the CDC. Black or African Americans have 1.9 times the rate ratio of death [101]. One study showed large differences in the average age of death between patients of different races infected with COVID19. Whites had a significantly higher average age of death of 79 years compared to Blacks at 71.2 years, and Latinos at 66.7 years. These disparities highlight the importance of identifying and addressing possible causes of the disparities such as underlying differences in access to healthcare and underlying medical conditions [102]. During the height of the pandemic, hospitals were overwhelmed with the influx of patients. The high demand for personal protective equipment (PPE) and intensive care unit beds overwhelmed the supply. This prompted difficult decisions with the rationing of care and resources that required the development of new policies into how these decisions were made [103]. One example includes the need for healthcare workers to start reusing N-95 masks due to limited supply. Physicians were faced with challenging decisions with the rationing of care with ventilators due to shortages. The highest priority was given to the ethical value of maximizing benefits for patients [104]. A new phenomenon of an info-demic, or an overabundance of information, around COVID19 made it difficult to determine the validity of information [105]. Inconsistent federal and state regulations, continually changing guidelines, and misinformation all contributed to painting a landscape of uncertainty. The info-demic around COVID-19 magnified Americas poor health literacy, or the ability to access, interpret, and apply

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health information [106]. Additionally, misinformation around COVID was particularly common through social media outlets [107]. Unreliable news information was especially dangerous for vulnerable populations with poor health literacy. As the world moves increasingly online, it has become more difficult for older adults to achieve the same level of awareness and participation as their younger peers. Studies show older adults are at risk of lower technology literacy [108]. This has been particularly harmful during the COVID-19 pandemic, since many critical services that were once in-person moved to a remote and online setting. For example, the increased use of telehealth visits for geriatric patients in their homes and within facilities presented a hurdle because many of these patients have difficulty accessing the Internet and operating computers and smart phones. Vaccine registrations, which have been critical in protecting this population, were also primarily conducted online. Lastly, programs implemented as a means of preventative care such as exercise classes, social gatherings for mental well-being, and interactions with family members have all moved to the virtual space, which has presented another barrier for older adults.

Case Studies Case Study 1 A 90 year-old man with a past medical history of moderate Alzheimer’s dementia, hypertension, and coronary artery disease presents to the emergency room from home with lethargy, altered mental status, and inability to walk. Initial evaluation reveals blood pressure of 103/62, heart rate of 100, respiratory rate of 20, and a pulse oximetry reading of 90%. He appears frail, unable to answer questions. Chest X-ray reveals bilateral patchy opacities. Lab work is significant for mild leukopenia, hypernatremia, elevated BUN/Cr of 56/1.25, and urinalysis without evidence of infection. His RT-PCR returns positive for SARS-CoV2 infection. He has no previous admissions and no

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advance directives on file. His next of kin is unknown. A geriatric social worker is consulted to assist in the case. The patient’s daughter is contacted who confirms the patient has a medical order for life-sustaining treatment (MOLST) form indicating do not resuscitate (DNR) and do not intubate (DNI) status. Within a few hours, the patient’s oxygen saturation drops, and he requires a nonrebreather to maintain his oxygenation at 88%. The geriatric and palliative care team is consulted. His daughter is notified of his worsening clinical status and poor prognosis. The physician retrieves the tablet shared among the hospital staff and holds it so the patient’s daughter can FaceTime with her father, as she virtually recites a prayer, knowing this will be the last time her father hears her voice. The patient dies within a few hours, alone in a hospital bed without his family physically beside him. This case highlights a typical COVID-19 case in older adults in the first phase of the pandemic, the challenges with documentation of advance care directives, and the beneficial impact of geriatric social workers, geriatricians, and palliative care teams for endof-life care management.

Case Study 2 We review the longitudinal case of an 87-year-old man with past medical history of hypertension, coronary artery disease, and mild Alzheimer’s dementia. At the outset of the pandemic, the patient lived in a one-story home with his daughter and son-in-law. He was independent in his ADLs and at least partially dependent on some IADLs, including managing his finances and medications. He participated in activities at his local community center and was enrolled in a day program for patients with cognitive impairment. His impairments had been relatively stable with minor progression in the preceding year. He ambulated without an assistive device with no gait abnormality. In March of 2020, his day program was shuttered. He did not leave his home until May of 2020. He reportedly spent most of his days sedentary, watching television or listening to

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music. He was unable to operate a smartphone or tablet and had limited communication with friends during that period. While he normally ambulated up to a mile daily, this decreased to no more than a few 100 steps around the house. He was seen for a telemedicine visit by his geriatrician in May of 2020. He seemed withdrawn, and notably his daughter provided much of the history. She noted he had two mechanical falls in early May without injury. He was now ambulating with a cane. The family declined a referral to physical therapy due to fear of contracting COVID-19. The patient came to the office in September of 2020 for his first in-person visit in 9 months. He notably ambulated with a cautious gait. He appeared visibly frailer, with a noted decrease in grip strength and increase in Timed Up and Go test. Cognitive evaluation was completed and noted a drop in Montreal Cognitive Assessment (MoCA) score from 21 to 13 over the course of 1 year. The patient and family met with social work. He was provided with resources for a virtual day program, which only met once per week. The prospect of a home health aide was discussed. The patient’s daughter lamented that they did not have adequate financial resources available. She noted she was now working from home but had changed to part-time in order to care for her father. She indicated significant caregiver stress on herself and her family. In December 2020, the patient had a mechanical fall in his home while trying to go to the bathroom in the middle of the night. He was diagnosed with a right hip fracture, requiring surgery and hospitalization. His course was complicated by delirium and agitation. He was started on Seroquel while inpatient. He was transferred to subacute rehab after his surgery, and he remained confused. The patient was unable to be discharged home due to increasing care needs. His gait remained limited, and he was unable to participate regularly in physical therapy sessions. His weight decreased. He had limited visitation from his family due to COVID-19 precautions. In January 2020, he was given the first dose of the Pfizer vaccine for COVID-19. During the pandemic, he had never contracted the disease. But

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his clinical course was notable for a precipitous decline in functional status and significant progression of his cognitive dysfunction. The case highlights “non-COVID COVID” pathology: those patients and families who never contracted the disease but were profoundly affected by the pandemic.

Case Study 3 A 79-year-old female with a past medical history of moderate Alzheimer’s dementia and hypertension develops increased confusion and decreased appetite after having an exposure to COVID-19 by her home health aide. The patient has a telehealth visit, and her vital signs are reported with a blood pressure of 138/74 and a pulse of 90. She is breathing comfortably without accessory muscle use. Her oral mucosa is dry, and she has poor hearing. She opens her eyes to voice but is unable to answer questions. She answers yes or no to the family’s questions. Her two main caregivers have been diagnosed with COVID-19, and she is currently being cared for by her other children who are struggling to provide care. The patient is referred to a home care program for COVID-19 patients who help arrange for an alternate home health aide. The patient is recommended to receive monoclonal antibody infusion treatment and tolerates the treatment without complications. Her respiratory status remains stable. Two weeks after her initial presentation, she experiences more difficulty with transfers and ambulation and is started on home physical therapy. During her four-week follow-up, she develops worse sleep disturbances, agitation, and a decline in her cognitive abilities. She now requires total assistance with her activities of daily living and has urinary and fecal incontinence. At her 3-month follow-up visit, she never returns to her previous functional status and remains in a wheelchair, has developed a stage 2 sacral pressure ulcer, and repeat cognitive testing shows progression to severe Alzheimer’s dementia. The family is having difficulty caring for the patient with worsening behavioral and sleep disturbances and is considering nursing home placement. Working closely with

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the family, the geriatric multidisciplinary medical team develops a comprehensive care plan including counseling on approaches to manage behavioral disturbances, caregiver support, and adjustment of antipsychotic medications which enables the family to keep the patient at home. Although this patient did not require hospitalization for the treatment of her COVID-19 infection, her infection created more challenges in the dynamic of her care plan with her caregivers, management of her progressive neurocognitive illness, and deterioration in her functional status. This case highlights the importance of caregiver support and outpatient resources for vulnerable older adults in the setting of COVID-19 infection.

Conclusion The COVID-19 pandemic has affected millions of older adults and has influenced the infrastructure of medicine across all specialties. Older adults are at higher risk for severe infections and death from COVID-19. Atypical presentations of disease are common in older adults with high rates of multimorbidity and frailty. The initial lag in testing and diagnostics along with a paucity of knowledge in treatment options posed a considerable challenge for the health system. The COVID-19 pandemic has highlighted the gaps and vulnerabilities in the healthcare system infrastructure. Drastic changes had to be put forth in unprecedented time frames. The strict measures for transmission reduction with social distancing put in place to protect vulnerable older adults contributed to the adverse effects of worsening functional decline and mental health illness. The pandemic accelerated the adoption and acceptance of telehealth as an instrumental means of delivering healthcare. It is imperative that we rely on emerging evidence to improve our strategy for managing COVID-19 in the future. As the global COVID-19 pandemic continues to evolve, there is optimism with the advancement of vaccinations and effective treatments that we will have the necessary tools to combat the pandemic.

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101. Hospitalization and Death by Race/Ethnicity [Internet]. cdc.gov [cited 2021 July 20]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/coviddata/investigations-discovery/hospitalization-deathby-race-ethnicity.html 102. Zelner J, Trangucci R, Naraharisetti R, Cao A, Malosh R, Broen K, et al. Racial disparities in coronavirus disease 2019 (COVID-19) mortality are driven by unequal infection risks. Clin Infect Dis. 2021;72(5): e88–95. https://doi.org/10.1093/cid/ciaa1723. 103. Supady A, Curtis JR, Abrams D, Lorusso R, Bein T, Boldt J, et al. Allocating scarce intensive care resources during the COVID-19 pandemic: practical challenges to theoretical frameworks. Lancet Respir Med. 2021;9(4): 430–4. https://doi.org/10.1016/S2213-2600(20)30580-4. 104. Emanuel EJ, Persad G, Upshur R, Thome B, Parker M, Glickman A, et al. Fair allocation of scarce

779 medical resources in the time of Covid-19. N Engl J Med. 2020;382(21):2049–55. https://doi.org/10. 1056/NEJMsb2005114. 105. Zarocostas J. How to fight an infodemic. Lancet. 2020;395(10225):676. https://doi.org/10.1016/ S0140-6736(20)30461-X. 106. Mian A, Khan S. Coronavirus: the spread of misinformation. BMC Med. 2020;18(1):89. https://doi. org/10.1186/s12916-020-01556-3. 107. Stokel-Walker C. Covid-19: the doctors turned YouTubers. BMJ. 2020;369:m1563. https://doi.org/ 10.1136/bmj.m1563. 108. Wang S, Bolling K, Mao W, Reichstadt J, Jeste D, Kim HC, et al. Technology to support aging in place: older adults’ perspectives. Healthcare (Basel). 2019;7(2):60. https://doi.org/10.3390/healthcare70 20060.

Part III Cancer in Older Adults: An Overview

Cancer and Older Adults: The Introduction

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Armin Shahrokni, Helen Pozdniakova, and Brandon Nightingale

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784 Global Aging, Global Geriatric Oncology, and Global Effort . . . . . . . . . . . . . . . . . . . . . . 785 Disparity in Cancer Outcomes Based on Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785 Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786 Assessing Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787 Frailty and Cancer Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789 Benefits of Frailty Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790 Interventions Following Frailty Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791 The Role of Geriatricians and Geriatric Care Providers in Geriatric Oncology . . . . . . . . 792 Quality Versus Quantity of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794 Digital Health Technologies and Geriatric Oncology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795 Electronic Patient Reported Solutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795 Handheld and Wearable Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795 A Case of an Older Patient with Colon Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797

Abstract

A. Shahrokni (*) · H. Pozdniakova · B. Nightingale Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA e-mail: [email protected]; [email protected]; [email protected]; [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_123

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of death among all malignancies. Despite advances in colorectal cancer screening, the number of deaths has increased. Given that the incidence of colorectal cancer increases with age, it’s important to tailor 783

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treatment to this population with special needs. Here we discuss how to incorporate frailty, rather than age, to assess perioperative outcomes. To this end, several useful scoring systems that can easily be incorporated into general practice have been developed. In addition, chemotherapy risk calculators such as CARG or G8 can help predict the likelihood of chemotherapy toxicity in older patients. Focused geriatric assessment in patients with colorectal cancer is associated with improved outcomes such as a decrease in the incidence of chemotherapy toxicity and decreased risk of falls. Overall, geriatricians are an important part of the oncological treatment course and can advocate for their patients to receive tailored treatments to their functional status rather than their age alone. Keywords

Geriatrics · Oncology · Elderly · Frailty · Cancer outcomes · Geriatrician · Quality of life

Introduction Colorectal cancer is extremely common worldwide with a high incidence and prevalence in older adults. These patients face multiple uphill challenges before starting treatment. Older adults are at higher risk for treatment related complications and are less likely to be offered certain treatments, particularly surgery, due to their age. This chapter encourages the reader to adopt a different framework for evaluating older adults that takes into account other risk factors and discusses several landmark risk stratification tools that improve patient outcomes.

Epidemiology Cancer is a global phenomenon that disproportionately affects older adults. Approximately 60% of all new cancer diagnoses occur in patients aged 65 and older. The demographic shift is due to the aging of the population and increased lifespan

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in both developing and developed countries. In 2012, approximately 6.7 million cancer diagnoses (47.5% of all cancers) were in adults aged 65 and older worldwide. By 2035, this number is projected to increase to 14 million [1]. Less developed countries will see a 144% increase in cancer incidence in their older populations, compared to a 54% increase in more developed countries. Specifically, the greatest increase in cancer incidence in older adults will be seen in the Middle East and North Africa (157% increase), and the smallest increase will be observed in Europe (47%). In absolute numbers, China will experience the greatest increase in the number of older adults diagnosed with cancer, with an additional 2.3 million cases by 2035. By that year, two out of three cancer diagnoses in North America, Europe, Oceania, and China will occur in older adults residing in those regions. Among older males, prostate cancer will remain the leading cancer diagnosis, except in Asia, where lung cancer will be the most common diagnosis among older male patients. Among older women, breast cancer will remain the most commonly diagnosed cancer. Overall, five cancers, prostate, breast, lung, colorectal, liver, and stomach, will account for two out of three cancer diagnoses in older adults worldwide [1]. Cancer treatment is costly and is expected to become more expensive with more older adults with complex medical problems being diagnosed with cancer and people living longer due to more effective cancer treatments [2]. In Europe, approximately 200 billion euros were spent on cancer care in 2018 [3]. Cancer also causes significant financial burden on patients and their families, and such burden has been evaluated by many investigators. For example, one study showed that approximately half of cancer survivors experienced significant financial toxicity during and after their cancer treatment [4]. Another study showed that cancer patients have nearly four times higher annual expenditures than those without cancer (16,000 dollars vs. 4000 dollars) [5]. A systematic review of 74 studies assessing financial toxicity of cancer care confirmed that approximately one out of two cancer patients residing in the USA experience financial toxicity

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[6]. Although older adults with cancer were at lower risk for financial toxicity compared to younger patients due to the availability of Medicare/ Medicaid and the higher possibility of being retired instead of being employed at the time of cancer diagnosis, they still faced financial challenges outside of Medicare/Medicaid coverage, such as assistance with their daily activities and transportation.

Global Aging, Global Geriatric Oncology, and Global Effort The International Society of Geriatric Oncology (SIOG) was established in 2000 to address the issue of global geriatric oncology by bringing together cancer and aging experts and raising awareness of the issue. With members from over 80 countries, SIOG focuses on four areas: education, research, clinical practice, and collaboration among experts from different countries [7]. However, SIOG’s efforts have highlighted that not all countries have the same level of resources for geriatric oncology. Countries like the USA and Canada have more robust geriatric oncology programs, particularly in their major and comprehensive cancer centers [8]. Geriatric oncology fellowship programs also exist in the USA. Europe is also known for its strong geriatric oncology programs for clinical care and research on older adults with cancer. Australia, Asia, and Latin America have also made significant strides in advancing geriatric oncology and improving the assessment and care of older adults with cancer [8–10].

Disparity in Cancer Outcomes Based on Age Over several decades, numerous investigators have examined the relationship between age and cancer outcomes, with mixed results. For example, a systematic review of 48 studies comparing outcomes of older and younger patients with rectal cancer found that although overall survival was lower among patients aged 70 and older compared

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to younger patients, cancer-specific survival did not change by age [11]. Another study of approximately 133,000 women with breast cancer showed that middle-aged women had better outcomes compared to younger or older women with breast cancer [12]. Despite advances in cancer care, a study that assessed the improvement in overall survival of cancer patients from 1990 to 2010 revealed that older patients, especially those older than 75 years of age, were less likely to experience the same degree of improvement in their overall survival, despite the overall improvement in survival of patients with breast, prostate, colorectal, lung, and liver cancer [13]. A study of approximately 20,000 patients with pancreatic cancer showed that patients older than age 70 had significantly worse overall survival compared to younger patients [14]. However, another study showed that despite older patients experiencing more complications following pancreatic cancer surgery, their hospital length of stay and postoperative survival were similar to younger patients [15]. Another study showed that for every 10 years increase in the age of patients, the 10-year survival following resection of colorectal liver metastases decreased by about 31% [16]. A study assessing the short-term outcomes of patients who underwent liver surgery due to primary liver cancer or liver metastases found that patients older than age 70 had a much higher 30-day mortality compared to younger patients (4% vs. 2%) [17]. By reviewing the literature on the association between cancer outcomes and age, several points are clear. First, the definition of older age is an ever-changing phenomenon. Some studies have compared outcomes of patients older than age 65 to those who are younger, while others have selected age 70 or higher as the cutoff for defining older age. Second, the association between age and cancer outcomes is mixed. Some studies have shown no relationship, while others have shown a strong relationship. Third, very few studies have explored the aging-related impairments of this patient population while assessing the relationship between age and cancer outcomes. Fourth, in the cancer setting, and especially for older patients, more attention should be paid to

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cancer-specific survival versus overall survival. For example, an older patient who has successfully undergone a hepatic resection to remove liver metastases due to colon cancer may die in the future due to heart failure, stroke, uncontrolled diabetes, or dementia. This patient did not die because of cancer, but because of comorbidities unrelated to their cancer. This is significant because the management of these non-cancer comorbidities is typically done by the patient’s primary care provider or geriatrician. Fifth, chronological age is a non-modifiable factor. As a result, there are limited interventions that can be done to reduce the negative association between age and cancer outcomes. In the next section, we will discuss how to convert the age of a patient into aging-related impairments. We will explore how to transform age, a non-modifiable factor, into aging-related impairments. By doing so, we can develop interventions to mitigate the negative impact of agingrelated impairments on cancer outcomes of older adults with cancer.

Frailty Frailty is defined as the reduced ability of the body to tolerate stress [18]. In other words, if you apply the same level of stress to two people of the same age, the person who is more physically fit will experience a much better outcome compared to the person who is more frail. However, the most important factor in determining frailty is chronological age. [19] As a patient becomes older, the likelihood and degree of frailty increase significantly. This could be the reason why many studies, especially those based on real-world datasets, have found that older age is associated with poorer cancer outcomes. Conversely, in randomized control trials with other restrictive exclusion criteria such as the patient’s performance status, kidney or liver function, the relationship between older age and poorer cancer outcomes is weaker. Population-based studies are studying an older age cohort of patients with a higher likelihood and degree of frailty than studies conducted in randomized control trial settings. Another

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important point about frailty is that it is dynamic rather than static [20]. Patients can experience improvements or worsening of their frailty over time, depending on medical events and/or other stressors. For example, a systematic review showed that among non-frail patients who survived at least 3 years, about 14% of them became frail during that time period [21]. The same study also showed a correlation between frailty and other factors such as gender and country income level. This is significant when assessing the relationship between, for example, gender, age, and cancer outcomes. Such a relationship should ideally be adjusted based on the frailty of these patients. The limitations of exploring the relationship between age and cancer outcomes alone are so significant that some have called for an end to “talking about age alone” [22]. Biological age is also associated with significant molecular and physiological changes [23]. No single factor or a single molecular change can explain the aging process in humans. Some have argued that a combination of eight factors, namely, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, could lead to the aging process and/or its acceleration [24]. With aging, telomeres, which are chromatin tips responsible for protecting against chromosomal degradation, shorten. Epigenetic alterations can impact cellular function and occur with aging. Proteostasis is responsible for maintaining the integrity of the proteome, and with aging, such protection could be lost. The nutrient-sensing system includes amino acid-sensing mammalian target of rapamycin (mTOR) as well as low-energy state detectors (AMP kinase and the sirtuins), which can contribute to the aging process. Mitochondrial dysfunction results in decreased ATP production, less energy, and accelerated aging process. Biomarkers of cellular senescence, P16 and P19, are associated with aging and its accelerated process. Aging is also associated with significant physiological changes [23]. Aging affects all organs, but its association is different from one patient to another, and in one patient, one organ may be

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affected more than others. An example of a major physiological change is decreased compliance of large vessels such as the aorta. Stiff arteries can lead to an increase in systolic blood pressure and a decrease in diastolic blood pressure, leading to widening of pulse pressure. In the same line, the left ventricle compliance decreases, and its relaxation is delayed. These and other changes predispose the heart to the aging process, leading to an increase in blood pressure, aortic stenosis, heart failure, and nerve conduction abnormalities. Decreased lung function remains one of the hallmarks of the aging process. Peak aerobic exercise capacity falls by about 20% for every 10 years after age 70. Respiratory compliance decreases and as result functional residual capacity decreases. Aging process is also associated with decreased ability of respiratory muscles in response to issues like hypoxia. Aging is also associated with diffuse glomerulosclerosis. While serum creatinine may remain constant during aging, the glomerular filtration rate will fall. As a result, cystatin C may be a more accurate maker of kidney function in older adults than creatinine. Immune system, both adaptive and innate, also declines with aging. As we age, our bone marrow is more infiltrated with fat, which results in decrease in bone marrow hematopoietic tissue. Other organs also experience changes with aging. For example, liver mass decreases by about 20–40%. Age-related muscle loss is a result of infiltration of muscles by fat and connective tissues. Table 1 describes some of these changes.

Assessing Frailty The gold standard for assessing frailty is the geriatric assessment, which is usually performed by geriatricians [25]. This is a comprehensive assessment of older adults that typically starts by assessing cognitive function through tools such as the Mini-Cog [26] or Mini-Mental State Exam [27]. It then proceeds to assess patients for the presence and severity of various comorbidities, nutritional status, polypharmacy, gait and balance, history of falls, social support and activity, and

787 Table 1 Physiological changes associated with aging Nervous system

Cardiovascular system

Autonomic nervous system Respiratory system

Renal function

Hepatic function

Gastrointestinal system Endocrine system Body composition

Decrease in cerebral blood flow Decrease in number of neurons Decrease in conduction velocity in peripheral nerves Increase in myocardial and vascular stiffness Decrease in beta-receptor responsiveness Increase in sympathetic activity Decrease in parasympathetic activity Decrease in mechanical function: decrease in elasticity of lung, decrease in lung compliance, decrease in gas exchange, decrease in upper airway reflexes Decrease in renal blood flow Decrease in renal mass Decrease in diluting ability Decrease in hepatic mass Decrease in hepatic blood flow Decrease in enzyme activity Decrease in gastric emptying Decrease in insulin release Decrease in total body water, increase in % of body fat, decrease in lean body mass

emotional wellbeing. Table 2 describes the components of geriatric assessment. However, a comprehensive geriatric assessment may take up to 60 min to complete, making it unfeasible in fast-paced oncology or primary care clinics. Despite this, many argue that the value of the geriatric assessment is so high that oncologists and healthcare institutions should make every effort to perform it routinely [28]. Alternatively, some have explored other solutions to increase the likelihood of this assessment being performed as routine care. For example, instead of using paper questionnaires and hiring personnel to administer the assessment, some have developed web-based geriatric assessment tools. These tools have been shown to be feasible in patients older than age 75 going for surgery, older patients who are receiving chemotherapy, and minority patients [29–32]. However, a web-based geriatric assessment is not without

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Table 2 Components of a comprehensive geriatric assessment Domain Functional status

Mood Nutritional status

Social support Cognitive function Polypharmacy

Comorbidities

Points to consider Basic activities of daily living (e.g., bathing, grooming, feeding) Instrumental activities of daily living (e.g., shopping, handling finances, medication preparation) History of fall Use of assistive device Distress Depression Recent weight loss Dysphagia Oral hygiene Ability to prepare meal Presence of the caregiver Living condition Corroboration of the signs and symptoms with caregiver, family members, or others Reviewing patients’ medications, deprescribing, potentially inappropriate medications Their status and potential for optimization

challenges. One study has shown that the degree of patient frailty is associated with their ability to complete these web-based tools [33]. The more frail the patients are, the more likely they need assistance from others to complete these online questionnaires. This means that those who do not have anyone to assist them (such as those with poor social support) or institutions with limited resources to help with the completion of these web-based assessments may be left behind. Moreover, the same study also showed that among patients who are independent in completing the online geriatric assessment, those who are more frail took longer to complete the assessment than those who are fit. This is significant because oncology clinics are fast-paced, and staff should be aware of the relationship between the degree of frailty of patients and the time that they take to complete the assessment. These clinics should provide additional support for these patients or be mindful that a slower pace of completing these assessments may be a surrogate for the patients’ frailty status. Nonetheless, to provide an alternative for patients whose frailty impedes

them from completing a web-based geriatric assessment, some have explored voice-assisted solutions [34]. These solutions, which some might be familiar with names like Alexa or Siri, automatically read the questions to the patients and then register patients’ responses without any involvement from personnel. One small study has proven the concept of these tools. There are various frailty assessment tools available for patients and healthcare providers who may not have the time, resources, or necessary skills to perform a full geriatric assessment. These tools can be categorized into two models: the phenotype model and the cumulative agingimpairment model. [35] The Fried Frailty Index [36] is one of the most commonly used frailty assessment tools based on the phenotype model. It assesses five factors: involuntary loss of 10 pounds or more in the past 6 months, reduced grip strength, difficulty initiating movements, reduced walking speed, and fatigue. Patients with no impairments are considered fit, those with one or two impairments are prefrail, and those with a higher number of impairments are considered frail. On the other hand, the cumulative aging-impairment model is based on the theory that as we age, we accumulate various aging-related impairments [37]. The more we accumulate these impairments, the more frail we become, and consequently, we become more susceptible to adverse outcomes during and after cancer treatment. In one study, researchers used a web-based geriatric assessment tool called electronic rapid fitness assessment to assess the frailty of cancer patients [38]. The study found that the number of aging-related impairments was associated with a 6-month survival rate following cancer surgery. Even after adjusting for factors such as age and American Society of AnesthesiologistsPhysical Status classification, each additional aging-related impairment was associated with a 14% increase in 6-month mortality following cancer surgery. Other studies have also shown that the accumulation of aging-related impairments is associated with mortality, chemotherapy toxicity, and the risk of institutionalization [39–43]. In addition to instruments based on frailty phenotype or cumulative deficits, there are also many

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frailty screening tools that are shorter and take much less time to complete. An umbrella review of frailty screening tools reviewed 26 questionnaires aimed at detecting frailty and eight frailty indicators [44]. Huisingh-Scheetz and colleague described some of these frailty screening tools and provided guidance on how to approach frailty (assessment) in older patients with cancer [45]. Based on their guidance, factors to consider in selecting a frailty instrument are: feasibility of implementing the frailty instrument and its sustainability, and specific clinical or research needs and considering limitations of the selected instrument. For example, if you are working in a busy clinic with limited number of personnel, who are busy with many other tasks, selecting a selfreported frailty instrument might be more feasible for your practice than an instrument that requires interaction and time commitment between your staff and the patient.

Frailty and Cancer Outcomes Numerous studies have established a relationship between frailty and cancer outcomes [46– 51]. Generally, cancer patients who are frail have a significantly higher risk of experiencing outcomes such as falls, disability, cognitive impairment, hospitalization, functional dependence, social withdrawal, and mortality. In the context of oncologic surgery, many studies have shown the association between frailty and surgical outcomes. A recent systematic review and metaanalysis of 71 studies demonstrated that frail patients are three times more likely, on average, to die within 30 days after surgery, and twice as likely to be discharged to locations other than their homes, experience postoperative complications, or have prolonged hospital stays [52]. They are also four times more likely to experience longer term mortality than fit patients. In the surgery setting, a significant number of studies have used the modified frailty index [53], which is an 11-item instrument that includes ten items related to a patient’s comorbidities and one item related to functional independence. Because the modified frailty index is applied to a large

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dataset of the National Surgical Quality Improvement Program, studies that utilize the index have the advantage of a robust sample size, which allows for proper assessment of the relationship between frailty and surgical outcomes. For example, one study assessed the relationship between frailty and outcomes following gastrointestinal cancer surgery. They found that among 41,455 patients who had gastrointestinal cancer, frail patients were more likely to experience postoperative complications, prolonged hospital stays, and 30-day mortality compared to fit patients [54]. Another study evaluated the relationship between frailty, assessed by the modified frailty index, and surgical outcomes following esophagectomy. Among approximately 2000 patients, a higher frailty score was associated with a higher likelihood of morbidity and mortality following the surgery [55]. A similar finding was confirmed in another study of older women with ovarian cancer who underwent cytoreductive surgery [56]. A systematic review that evaluated seven studies showed that geriatric assessment is also associated with oncologic surgery outcomes. It demonstrated that impairments in basic and instrumental activities of daily living, as well as cognitive impairment, are associated with postoperative complications [57]. Another study of approximately 1000 patients over the age of 75 found that geriatric assessment is associated with 6-month postoperative mortality [38]. Overall, these studies highlight the importance of considering frailty and conducting geriatric assessments in the context of oncologic surgery. They demonstrate that frailty is significantly associated with poor surgical outcomes, including postoperative complications, prolonged hospital stays, and mortality. By conducting proper assessments and taking appropriate precautions, healthcare professionals can better manage the care of frail cancer patients undergoing surgery. Frailty is associated with poorer outcomes during medical treatment of cancer. A systematic review of 20 studies with approximately 3000 patients showed that frail patients are almost five times more likely to experience treatment intolerance during their course of cancer treatment

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compared to fit patients [49]. Another study on 500 patients aged 65 and older showed that frailtybased cumulative geriatric impairment is associated with a higher likelihood of grade 3 or higher chemotherapy toxicity, treatment discontinuation, and hospitalization [39]. A study on 1280 women with breast cancer aged 65 and older showed that fit women were more likely to be offered and be compliant with hormonal treatment. It also showed that frail patients are almost three times more likely to experience mortality due to breast cancer compared to fit patients [58]. Furthermore, there are now statistical models based on geriatric assessment and frailty of older adults with cancer to predict their chemotherapy toxicity such as Cancer and Aging Research Group-Chemotherapy toxicity calculator [59], which is validated [60] and is also available for patients with breast cancer [61]. Another commonly used chemotherapy risk calculator is called CRASH. [62]. In radiation oncology, the relationship between frailty and cancer outcomes is less studied. A limited number of studies were further limited in their conclusions by a relatively small sample size [63]. Future studies with larger sample sizes and ideally limited to a specific cancer type (e.g., head and neck cancer) are needed. In summary, we can substitute age with frailty, and different instruments, depending on the available resources, can be used to assess frailty. Frailty has a strong correlation with cancer outcomes of older patients. Moreover, frailty assessment can positively impact our cancer care, which we will describe next.

Benefits of Frailty Assessment Frailty assessment can be helpful in a variety of ways, including improving patient-physician communication. In fact, one study showed that performing geriatric assessment and sharing it with the oncology team lead to an improvement in communication, more discussion of agingrelated issues in each encounter, and increased patient satisfaction with the care provided [64]. However, it is important to note that this improvement in communication only occurred

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when the results of the geriatric assessment (including frailty) were shared with the treating care provider. Therefore, in routine care, attention should be paid to closing the loop by not only performing frailty assessments but also reviewing them with older patients and caregivers. To achieve this, the oncology team should buy into the concept of frailty assessment, understand its value, and have at least basic knowledge of interpreting the results and discussing the findings with patients and their families. Studies have shown that geriatric oncology training programs can be helpful in increasing knowledge and selfefficacy of cancer care providers in aging-related issues [65]. Another benefit of performing frailty assessment is a more accurate assessment of a patient’s life expectancy, which can help in cancer treatment decision-making. For example, many studies have shown that preoperative frailty of cancer patients is associated with both short- and longterm postoperative mortality. After cancer surgery, many older patients will be referred to the medical oncology team to make decisions on the risk/benefit of adjuvant treatment. To make a decision on administering adjuvant treatment, the medical oncology team should have a reasonable prediction of the benefits and risks of the proposed treatment. In general, the benefit of adjuvant treatment is to delay or reduce the risk of cancer recurrence. Therefore, a patient’s life span plays an important role in this assessment. If a patient has a predicted life span shorter than the timing of cancer recurrence, administering adjuvant treatment will have limited benefit. Assessing frailty allows the oncology team to have a more accurate prediction of one’s life expectancy. There are various life expectancy calculators available for use [66], which are suitable for patients with possible life expectancy of weeks (palliative prognostic index), 1 year (Gagne Index), 4–10 years (Lee Index), or 10 years (Suemoto Index) [67]. All these calculators have components of frailty and aging-related impairments. For example, the Lee Index [68] includes items related to comorbidities, basic and instrumental activities of daily living, and walking ability. Moreover, frailty assessment can assist cancer care providers in predicting the

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risk associated with certain cancer treatment decisions. For example, many studies have shown that frailty and/or the results of geriatric assessment are associated with a higher likelihood of chemotherapy toxicity as mentioned above. By performing frailty assessments, cancer care providers can have more insight into a patient’s life expectancy and the likelihood of risk associated with different regimens for cancer treatment. This is clear in certain chemotherapy toxicity calculators that are developed for older adults with cancer. For example, in the Cancer and Aging Research Group- Chemotherapy Toxicity calculator, the cancer care providers can assess how the likelihood of grade 3 or higher chemotherapy toxicity increases by adding more chemotherapy agents to the cancer treatment regimen [59]. Finally, the last yet not the least benefit of frailty assessment is the conversion of age as a non-modifiable factor to frailty as a modifiable factor. Assessing a patient’s frailty enables the cancer provider to provide more holistic care and not anchor on chronological age when making therapeutic decisions. Having frailty indexing tools readily available can help establish more person-centered care for older adults with cancer.

Interventions Following Frailty Assessment Assessing frailty in older adults with cancer is just the first step in providing person-centered care for these individuals. It is important to note that the frailty of a patient is dynamic and can potentially be improved with proper and timely interventions [69]. Referring frail patients to geriatricians and geriatric care providers is ideal when possible for further assessment and management of their aging-related impairments [70]. However, even in the absence of geriatricians, other interventions can be helpful in improving frailty and outcomes for these patients. The American Society of Clinical Oncology has published a practical guideline for assessing and managing vulnerabilities of older adults with cancer [71]. According to the guideline, referring patients to physical or occupational therapy may be beneficial if they have

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fallen in the past or have impairment with basic and instrumental activities of daily living. Consultation with a pharmacist to assess for drug-drug interactions and possible de-prescribing may be helpful if the patient is taking too many medications. Active involvement by the patient’s primary care provider and/or other subspecialists may be beneficial if the patient has multiple and severe comorbidities. Consultation with a social worker may be necessary to find proper community supportive services if the patient lives alone, has poor social support, or has difficulty with transportation. These interventions, either as a single intervention or as a bundle, can improve patient outcomes. In a seminal study, Dr. Mohile and colleagues randomized 718 patients older than 70 with incurable solid tumors or lymphoma to either routine care or geriatric assessment followed by providing cancer care providers with a list of aging-related impairments and possible interventions aimed at managing those impairments [72]. On average, each patient had 4.5 aging-related impairments. Among patients in the intervention group, only 51% experienced grade 3+ chemotherapy toxicity compared to 71% in the routine care group. Only 12% of patients in the intervention group experienced a fall in the first 3 months of the study compared to 21% in the routine care group. Finally, patients in the intervention group were more likely to have non-cancer medications discontinued compared to patients in the routine care group. To improve perioperative outcomes of older adults with cancer, some have proposed a multiphase pathway that starts with frailty assessment and then proceeds to prehabilitation, collaboration with geriatricians, and interventions aimed at reducing the stress of surgery [73]. Over the past decade, prehabilitation has gained increasing attention as a potential strategy to address functional decline in older patients with cancer who undergo major surgeries. Such patients are often frail and may experience additional complications due to cancer and surgery. Some studies have explored whether prehabilitation – which involves improving patients’ physical condition before surgery – can be effective for older or frail adults. A systematic review of 33 studies,

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involving roughly 4000 patients who underwent elective abdominal cancer surgery, found that prehabilitation may lead to improvements in complication rates, hospital stays, and nutritional status [74]. However, additional studies are still needed, as some data remains mixed. For instance, a review of ten studies on patients who underwent urological cancer procedures did not find any evidence that prehabilitation is associated with reduced surgical complications, hospital length of stay, or readmissions [75]. Other studies have examined the effects of preoperative geriatric assessments and identified high levels of distress or poor social support among patients, which could lead to increased utilization of mental health services in the postoperative period [76]. In conclusion, research has shown that frailty assessment can help improve the care of older adults with cancer, as it can provide valuable information about their health status. Moreover, interventions such as prehabilitation can help improve frailty status in older adults with cancer. The next section will explore the role that geriatricians can play in comanaging the care of older adults with cancer alongside other cancer care providers.

The Role of Geriatricians and Geriatric Care Providers in Geriatric Oncology Geriatricians and geriatric care providers could play a crucial role in the care of older adults with cancer, given their expertise in assessing and managing aging-related impairments. In one care model, patients who screen positive for frailty by a short frailty instrument in the oncology clinic could be referred to a geriatric clinic for a more comprehensive assessment of aging-related impairments. Geriatricians can conduct a more thorough cognitive assessment, such as the MiniMental State Exam [27] or Montreal Cognitive Assessment [77], which is essential since several studies have indicated the possibility of cognitive decline during or after cancer treatment [78]. Having an accurate assessment of baseline cognitive function would enable the provision of support for those with cognitive impairment, as well as a more

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precise definition of the cognitive function trajectory during and after cancer treatment. Geriatricians and geriatric care providers could also be more cognizant of supportive services in the community and refer patients with various agingrelated impairments to the appropriate resources. In the hospital setting, geriatricians and geriatric care providers can assist in preventing, detecting early, and managing delirium. They can also engage in shared decision-making to assess the risk and benefit of treatment options based on the patient’s frailty and overall goals of care. They can review the patient’s medication list, particularly those dealing with polypharmacy, and assist cancer care providers in detecting drugdrug interactions, especially when one of the drugs is cancer-related treatment. Numerous studies have demonstrated that collaboration between geriatricians and other care providers improves outcomes for older adults, not only in cancer but also in other areas such as orthopedics. In the orthopedic setting, collaboration between geriatricians and orthopedic surgeons has resulted in significant improvements in postoperative outcomes for older adults. A systematic review of 18 studies with approximately 9000 patients who underwent hip surgery demonstrated that geriatric comanagement was associated with a significant reduction in shortand long-term mortality and hospital length of stay [79]. A Cochrane review that primarily examined studies on geriatric comanagement for patients with hip fracture showed that geriatric comanagement reduced the likelihood of discharge to an elevated level of care [80]. One study assessed the impact of different models of geriatric comanagement on the outcomes of patients with hip fracture and discovered that all models of geriatric comanagement were similar in improving the outcomes of these patients [81]. In oncologic surgery, data is also emerging on the benefits of geriatric comanagement. A small study on older women with advanced ovarian cancer who underwent cytoreductive surgery showed that none of those patients died within 6 months of surgery [82]. Subsequently, a large retrospective study on approximately 1900 patients aged 75 and older who were either

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comanaged by the geriatric service or managed by a non-geriatrician team showed that geriatric comanagement was associated with a significant reduction in 90-day postoperative mortality [83]. A secondary data analysis of this study indicated that the benefit provided by geriatric comanagement could be irrespective of patients’ frailty level in this relatively old age cohort of patients [84]. A pre-post geriatric comanagement implementation study demonstrated that geriatric comanagement was associated with a significant reduction in high-grade surgery complications and 1-year readmission [85]. One study assessed the feasibility of geriatric comanagement in a prospective manner and found that geriatric comanagement was feasible in patients aged 75 and older who underwent radical cystectomy, and more importantly, the surgery team expressed their high level of satisfaction with such collaboration [86]. Due to this evidence, the American College of Surgery and the American Geriatrics Society have launched the Geriatric Surgery Verification Program to further advance the expansion of such programs [87]. In the field of medical oncology, several studies have explored the potential benefits of collaboration between geriatricians and oncologists. Three randomized trials have thus far demonstrated the benefits of such collaboration. In the Geriatric-Assessment-Driven Intervention (GAIN) study, 613 patients aged 65 and older with solid tumors who were starting a new chemotherapy regimen were randomized to either routine care or the GAIN arm. While all patients underwent a geriatric assessment, only those in the GAIN arm received a multidisciplinary team of oncologists, geriatric nurse practitioners, social workers, physical and occupational therapists, nutritionists, and pharmacists. Patients in the GAIN arm were less likely to experience grade 3 or higher chemotherapy toxicities (50.5% vs. 60.6%), resulting in a 10% reduction in high-grade chemotherapy toxicities. However, this decrease did not translate into improved outcomes such as emergency department visits, unplanned hospitalizations, hospital length of stay, unplanned readmissions, chemotherapy dose modifications or discontinuations, or overall

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survival [88]. In the second study [72], titled “Evaluation of Geriatric Assessment and Management on the Toxic Effects of Cancer Treatment (GAP70+),” a cluster randomized study, 718 patients aged 70 and older with incurable solid tumors or lymphoma were randomized to either routine care or the intervention arm. The intervention involved providing the medical oncology team with the results of geriatric assessments and prepopulated interventions based on detected impairments. The intervention led to a significant reduction in high-grade chemotherapy toxicities. During the study, 51% of patients in the intervention arm experienced high-grade chemotherapy toxicity compared to 71% of patients who received routine care. Patients in the intervention arm also experienced fewer falls during the 3-month study period compared to patients in the routine care group (12% vs. 21%). Further analysis showed that overall survival did not differ between these two groups. Therefore, patients were able to experience less high-grade chemotherapy toxicity (which may mean a higher quality of life and/or less functional decline), and it did not negatively impact their overall survival. In the third study [89], Integrated Geriatric Assessment and Treatment Effectiveness (INTEGERATE), 154 patients aged 70 and older with solid tumors or lymphoma who were about to receive chemotherapy, targeted therapy, or immunotherapy were randomized to either routine care or the intervention arm. Once again, the intervention involved a geriatric assessment performed by a geriatric oncologist, and the results were reviewed by a multidisciplinary team, with recommendations shared with cancer care providers. The investigators showed that patients in the intervention arm were more likely to experience higher functional activity over the 6-month study period compared to those in the routine care arm. Patients in the intervention arm also experienced fewer unplanned hospital admissions during the study. Despite these positive results, there are also negative studies. One study of 135 patients with cancer, with a median age of 76, showed that providing geriatric assessment results to the inpatient treating providers of these patients did not impact actual referrals to recommended services

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[90]. Another study from Canada, titled “Impact of Geriatric Assessment and Management on Quality of Life, Unplanned Hospitalizations, Toxicity, and Survival for Older Adults With Cancer: The Randomized 5C Trial,” [91] randomized 350 patients aged 70 and older who were diagnosed with solid tumors, lymphoma, or melanoma and were referred to first or second line chemotherapy, immunotherapy, or targeted therapy to either routine care or the intervention arm. The intervention consisted of geriatric assessment, review of the results, and providing recommendations to the treating care providers by a multidisciplinary team. The investigators found no improvement in overall survival, unplanned hospitalization, treatment toxicity, or change in treatment plan between two groups. In another study, the investigators failed to show the benefit of geriatric comanagement among patients aged 65 and older who underwent gastrointestinal cancer surgery [92]. In summary, high-quality data is emerging on the benefit of geriatric assessment of older adults with cancer, reviewing the assessment, and providing the cancer care providers with the possible interventions that could be done to improve agingrelated impairments detected via geriatric assessment. However, more studies are still needed to assess the optimal context for this model of care. By developing an efficient model, institutions with limited resources will be able to obtain maximum benefit from these services. In the next sections, we will review some of the emerging concepts in the field of geriatric oncology.

Quality Versus Quantity of Life Being diagnosed with cancer can be challenging for many older adults as they are faced with many unknown questions and have to make difficult decisions at a relatively fast pace. Even decisions such as consenting to a “simple” procedure can be a daunting task. Unfortunately, older adults are usually underrepresented in clinical trials, and as a result, the results of those clinical trials may not be applicable to this patient population.

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Traditionally, oncologic studies have focused on outcomes such as overall survival or progressionfree survival, rather than maintaining or improving the quality of life or functional activity of cancer patients, especially older ones. As a result, many patients are asked to choose between quality or quantity of life. A systematic review of 30 studies showed that older age could be associated with a higher likelihood of preferring quality over quantity of life [93]. Moreover, the study found that patients with poorer physical status valued their quality of life significantly more than the quantity of their lives. This shows another benefit of frailty assessment, by which cancer care providers may be able to understand why an older frail adult with cancer prefers their quality of life over quantity of their lives and may refuse cancer treatment completely or ask for adjusting the cancer treatment regimen so that the likelihood of maintaining quality of life increases. Another systematic review focused on older adults’ preferences for their cancer treatment. After reviewing 28 studies that included approximately 4300 patients, the authors showed that in 79% of those studies, quality of life was the highest or secondhighest priority for patients [94]. Some have developed a framework for cancer decisionmaking in older adults with cancer [95]. Although treatment decision making is challenging in a cancer setting, it is not unique to the cancer setting. Many older adults are faced with multiple and at times severe and incurable non-cancer comorbidities that they need to balance their quality and quantity of life. A study [96] on 163 patients with a mean age of 77 explored goals that patients want to achieve. The most common goals were having meals and other activities with family and friends, shopping, and exercising. The most common barriers to achieving those goals were pain, fatigue, gait imbalance, and shortness of breath. It goes without saying that almost all of these symptoms could happen as a result of cancer and/or cancer treatment. In summary, it is crucial to consider the quality of life of an older adult with cancer, and not just the quantity of life, during every phase of cancer treatment decision making.

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Digital Health Technologies and Geriatric Oncology Digital health technology has seen tremendous growth in the past decade, providing innovative solutions that go beyond the traditional patient-physician encounter. These solutions include telemedicine, wearables for continuous patient monitoring, and web-based tools for remote symptom reporting. A framework has been proposed for the remote monitoring of older patients with cancer, incorporating various digital health technologies. This involves the transfer of patient data, such as symptom reports, from wearables and smartphone applications to a data warehouse. The data is then analyzed using machine learning or signal processing to identify abnormal signals, which are promptly communicated to cancer care providers. This novel model of perioperative care and cancer care in general is set to revolutionize cancer treatment for older adults in the near future. In summary, digital health technology has the potential to transform healthcare by providing solutions that enable remote monitoring, assessment, and care of patients. The proposed framework for remote monitoring of older cancer patients demonstrates the possibilities that these technologies offer. As the field of digital health technology continues to grow, we can expect to see even more innovative solutions that will significantly impact healthcare in the future.

Electronic Patient Reported Solutions Electronic patient-reported solutions (ePRS) involve patients reporting their symptoms or completing a geriatric assessment through web-based applications, which eliminates the need to physically visit the clinic or call their cancer care provider. In 2014, a systematic review identified 33 ePRS implemented across various cancer practices to gather patient data. The review found that clinicians lacked agreement on administering, integrating, and reporting the results of these systems. Additionally, patient acceptance of these solutions was a concern. A systematic review of

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33 studies that used ePRS and reported on patient acceptance revealed that acceptance was influenced by factors such as age, access to electronic devices, technology support, privacy concerns, and the patient’s overall physical and emotional status. Clinicians expressed concern about information overload, the need for additional documentation, and a lack of incentives to use ePRS solutions. Despite these challenges, studies have shown that ePRS can improve outcomes for cancer patients. For example, a seminal study randomized 766 patients receiving chemotherapy to either routine care or the intervention arm, which involved patients reporting their symptoms via a web-based tool to the treating team and receiving weekly prompts to report these symptoms. The study found that ePRS reduced the magnitude of change in quality of life, and patients in the intervention arm were less likely to be hospitalized or seen in the emergency room. Moreover, an analysis of this study found that patients in the intervention arm also experienced improved overall survival. However, it is important to note that age and frailty can be barriers to using these solutions properly and consistently. Further studies are necessary to evaluate how ePRS can be made more age-friendly, so that older frail patients with cancer can also experience the benefits of these solutions.

Handheld and Wearable Technologies Over the past years, handheld and wearable technologies such as smart phones and wearables such as smart watches have been studied in different patient populations and for different purposes. In the beginning, these devices were mainly able to monitor few simple parameters such as number of steps that a patient walks daily; however, now they can also measure parameters such as heart rate, blood pressure, or level of oxygenation. With additional advances, other innovators have tried to add additional capabilities to these devices. For example, older adults with cancer are at higher risk of fall due to their cancer and/or their cancer treatment. Many investigators and innovators are developing applications aimed at detecting falls

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and near falls and sending alerts to various family and medical team members [97]. These solutions are also being incorporated into cancer-related clinical trials as well. One systematic review on 25 studies showed that about half of the studies looked at the feasibility of using such solutions, while 10 were observational and only 3 were randomized clinical trials. All of these studies used a wearable with accelerometer. These solutions were used for a short period of time of between 8 and 30 days, and significant majority of these studies focused on physical activity assessment of cancer patients [98]. A systematic review assessed older adults’ experiences with using wearable devices. The study found that four key concepts are vital for acceptability of these devices by the older patients: being motivated to use these devices, patient’s characteristics, full integration into daily life, and device features [99]. As technology advances, it is foreseeable that more studies will be conducted in older patients with cancer by using these devices.

A Case of an Older Patient with Colon Cancer An 84-year-old male with past medical history significant for diabetes, myocardial infarction about 6 years which was treated with stent, and hypertension on three different medications, who lives with his wife, and is independent in basic activities of daily living, but relies on his wife for cooking and cleaning. He continues to drive, although less than before because of his mild vision impairment, presents to you because he had had rectal bleeding for the past 6 months, and following workup, it was found that he has localized colon cancer, which can be resected surgically. However, he is concerned about the impact of surgery on his body and would like to know your opinion. • This is one of the situations that a geriatrician can be extremely helpful to the patient and to the surgery team. You, as a geriatrician, should assess patient’s overall frailty status and explain to the patient the result of frailty status and what it means for decision making. You have to

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explain that frail patients may not be able to tolerate the surgery the same way that fit patients do. As patients and/or their caregivers may be focused on the patient’s age, it is important that you substitute patient’s age with his frailty (or fitness) status. You have to explain the challenges that may arise during perioperative care. For example, if your assessment shows that patient’s cognitive status is impaired, the patient could be at higher risk for delirium. And delirium may lead to additional cognitive decline in the future. You need to explain to the patient and/or his family about the interventions that can be done to reduce such risk and to what degree you think risk reduction is possible. You also need to discuss and share your findings with the patient’s surgeon. Because there might be alternatives to the first proposed treatment (here surgery) that might be discussed with the patient, if you think the first proposed treatment may cause more risk than benefit. It is also important that you explore patient’s wishes and what matters to him the most. Do not assume that you know what the patient wants. Engage with the patient and ask him. Finally, if the decision is made to proceed with the surgery, suggest interventions aimed at optimizing the patient’s status such as prehabilitation and/or optimizing their comorbidities. If resources are available, plan to comanage the patient in the postoperative period.

Conclusion We are facing an aging population that are at higher risk for cancer diagnosis. Treatment of an older patient with cancer is challenging. Those who are frail are at higher risk for adverse outcomes. Frailty assessment provides significant benefits for the patients, caregivers, and their cancer providers. Various interventions can be implemented with the aim of improving outcomes of these patients. High-quality data has emerged to support the benefit of frailty assessments and geriatric interventions, and it is very likely that in the near future, more data will emerge to further support this notion.

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70. Cesari M, et al. The geriatric management of frailty as paradigm of “The end of the disease era”. Eur J Intern Med. 2016;31:11–4. 71. Mohile SG, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36(22):2326–47. 72. Mohile SG, et al. Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study. Lancet. 2021;398(10314):1894–904. 73. Montroni I, et al. Surgical considerations for older adults with cancer: a multidimensional, multiphase pathway to improve care. J Clin Oncol. 2021;39(19):2090–101. 74. Hijazi Y, Gondal U, Aziz O. A systematic review of prehabilitation programs in abdominal cancer surgery. Int J Surg. 2017;39:156–62. 75. Briggs LG, et al. Prehabilitation exercise before urologic cancer surgery: a systematic and interdisciplinary review. Eur Urol. 2022;81(2):157–67. 76. Trevino KM, et al. Is screening for psychosocial risk factors associated with mental health care in older adults with cancer undergoing surgery? Cancer. 2020;126(3):602–10. 77. Nasreddine ZS, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9. 78. Joly F, et al. Impact of cancer and its treatments on cognitive function: advances in research from the paris international cognition and cancer task force symposium and update since 2012. J Pain Symptom Manag. 2015;50(6):830–41. 79. Grigoryan KV, Javedan H, Rudolph JL. Orthogeriatric care models and outcomes in hip fracture patients: a systematic review and meta-analysis. J Orthop Trauma. 2014;28(3):e49–55. 80. Eamer G, et al. Comprehensive geriatric assessment for older people admitted to a surgical service. Cochrane Database Syst Rev. 2018;1(1): CD012485. 81. Van Heghe A, et al. Effects of orthogeriatric care models on outcomes of hip fracture patients: a systematic review and meta-analysis. Calcif Tissue Int. 2022;110(2):162–84. 82. Filippova OT, et al. Geriatric co-management leads to safely performed cytoreductive surgery in older women with advanced stage ovarian cancer treated at a tertiary care cancer center. Gynecol Oncol. 2019;154(1):77–82. 83. Shahrokni A, et al. Association of geriatric comanagement and 90-day postoperative mortality among patients aged 75 years and older with cancer. JAMA Netw Open. 2020;3(8):e209265. 84. McMillan S, et al. Association of frailty with 90-day postoperative mortality & geriatric comanagement among older adults with cancer. Eur J Surg Oncol. 2022;48(4):903–8.

799 85. Giannotti C, et al. Effect of geriatric comanagement in older patients undergoing surgery for gastrointestinal cancer: a retrospective, before-and-after study. J Am Med Dir Assoc. 2022;23(11):1868.e9–1868.e16. 86. Letica-Kriegel AS, et al. Feasibility of a geriatric comanagement (GERICO) pilot program for patients 75 and older undergoing radical cystectomy. Eur J Surg Oncol. 2022;48(6):1427–32. 87. Cooper L, et al. Launching a geriatric surgery center: recommendations from the society for perioperative assessment and quality improvement. J Am Geriatr Soc. 2020;68(9):1941–6. 88. Li D, et al. Geriatric Assessment-Driven Intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial. JAMA Oncol. 2021;7(11):e214158. 89. Soo WK, et al. Integrated Geriatric Assessment and Treatment Effectiveness (INTEGERATE) in older people with cancer starting systemic anticancer treatment in Australia: a multicentre, open-label, randomised controlled trial. Lancet Healthy Longev. 2022;3(9): e617–27. 90. Jolly TA, et al. A randomized trial of real-time geriatric assessment reporting in nonelectively hospitalized older adults with cancer. Oncologist. 2020;25(6):488–96. 91. Puts M, et al. Impact of geriatric assessment and management on quality of life, unplanned hospitalizations, toxicity, and survival for older adults with cancer: the randomized 5C trial. J Clin Oncol. 2023;41(4):847–58. 92. Nipp RD, et al. Effects of a perioperative geriatric intervention for older adults with Cancer: a randomized clinical trial. J Geriatr Oncol. 2022;13(4):410–5. 93. Shrestha A, et al. Quality of life versus length of life considerations in cancer patients: A systematic literature review. Psychooncology. 2019;28(7):1367–80. 94. Seghers PALN, et al. Patient preferences for treatment outcomes in oncology with a focus on the older patienta systematic review. Cancers (Basel). 2022;14(5):1147. 95. DuMontier C, et al. Decision making in older adults with cancer. J Clin Oncol. 2021;39(19):2164–74. 96. Tinetti ME, et al. Outcome goals and health care preferences of older adults with multiple chronic conditions. JAMA Netw Open. 2021;4(3):e211271. 97. Torres-Guzman RA, et al. Smartphones and thresholdbased monitoring methods effectively detect falls remotely: a systematic review. Sensors (Basel). 2023;23(3):1323. 98. Beauchamp UL, Pappot H, Holländer-Mieritz C. The use of wearables in clinical trials during cancer treatment: systematic review. JMIR Mhealth Uhealth. 2020;8(11):e22006. 99. Moore K, et al. Older adults’ experiences with using wearable devices: qualitative systematic review and meta-synthesis. JMIR Mhealth Uhealth. 2021;9(6): e23832.

Cancer Screening in the Older Adult

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Koshy Alexander and Beatriz Korc-Grodzicki

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical Perspective on Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Emergence of Screening and Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Considerations for Screening: Balance Between Benefits and Risks . . . . . . . . . . . . . . . . . . Consideration in Older Adults- Individualized Decision-Making . . . . . . . . . . . . . . . . . . . . . .

802 802 802 803 804

Cancer Screening Guidelines for Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lung Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Colorectal Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cervical Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uterine Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vulvar and Vaginal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Skin Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820

Abstract

Cancer incidence increases with age. It is the second most common cause of death in older adults. Prevention and early detection of certain cancers helps preserve quality of life and offers the possibility of a cure with less

K. Alexander · B. Korc-Grodzicki (*) Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill Cornell Medical College, New York, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_76

aggressive treatments. Lifestyle modifications and healthy behaviors can mitigate the modifiable cancer risks. Screening tests must be effective, safe, and well tolerated with acceptably low rates of false positive and false negative results. Some people diagnosed with preclinical cancer will die from competing causes. Older patients require an individualized approach in decision-making. Estimation of life expectancy, comorbid disease burden, and status on the fit-frail spectrum are important steps. The risk benefits of cancer screening should be discussed with the older adult and 801

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family/caregivers to arrive at a decision whether to screen or not. In this chapter, we describe the current prevention and screening recommendations for some common cancers where they exist. Keywords

Cancer prevention · Cancer screening · Early cancer detection · Geriatric oncology · Cancer risk factors

Introduction Screening refers to tests and exams used to find a disease, such as cancer, in people who do not have any symptoms. The term “screening” derives from the practice of sieving gravel from a riverbed to remove most small particles so that larger nuggets of gold are more easily identified. In health screening, this implies testing a large number of asymptomatic individuals with a view to detecting a small number with early disease or risk of developing disease in order to improve the outcome [1]. The incidence of most cancers increases with age, and cancer is the second most common cause of death in older adults after cardiovascular disease [2]. Hence, cancer screening takes on relevance in the older populations. Prevention and early detection of cancers, for which treatments are available, helps preserve quality of life and offers the possibility of a cure with relatively less aggressive and extensive treatments than if it were discovered at a later stage. The time that exists between screendetected and symptom-detected diagnosis is called the lead time. Universal screening involves screening everyone and is usually based on age and sex. Selective screening differs from this in that it is recommended for groups of people who are at a higher risk (e.g., family history, carcinogen exposure) of developing certain cancers.

Historical Perspective on Cancer The world’s oldest description of cancer was discovered in Egypt in the Edwin Smith papyrus,

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dating back to about 3000 BC. It is part of an ancient Egyptian textbook on trauma surgery and describes eight cases of tumors or ulcers of the breast that were removed by cauterization with a tool called the fire drill. The writing says about the disease, “There is no treatment” [3]. While early modern medical terminology was often bafflingly complex, terms for cancerous disease shared one clear referent. The most common names for the malady – “cancer,” “canker,” “kanker,” and “chancre” – derive from the same etymological root: the Greek “karkinos” or “crab” [4]. Hippocrates believed that the body had four humors – blood, phlegm, yellow bile, and black bile. When the humors were balanced, a person was healthy. An excess of black bile in various body sites was thought to cause cancer. This theory was embraced by the physician philosopher Galen and remained unchallenged through the middle ages. The lymph theory took prominence in the 1700s that tumors grew from lymph. Other etiologic considerations included Blastema theory, chronic irritation theory, and the infectious disease theory [5]. Modern knowledge of cancer occurred in the twentieth century. In 1915, Yamagiwa and Ichikawa, at Tokyo University, induced cancer in lab animals for the first time by applying coal tar to rabbit skin. In 1911, Peyton Rous, at the Rockefeller Institute in New York, described a type of cancer (sarcoma) in chickens caused by what later became known as the Rous sarcoma virus. He was awarded the Nobel Prize for that work in 1968. Oncogenes were discovered in the 1970s.

Emergence of Screening and Prevention The first screening test to be widely used for cancer was the “Pap test.” The test was developed by George Papanicolaou as a research method in understanding the menstrual cycle. Papanicolaou soon recognized its potential for finding cervical cancer early and presented his findings in 1923 [6]. However, it was not until the American Cancer Society (ACS) promoted the test during the

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early 1960s that this test became widely used for cancer screening. Although cancer has plagued the world for centuries, it was not until the early 1900s that people came together to create prominent cancer advocacy associations worldwide. In 1937, Congress established the National Cancer Act of 1937 to provide additional support for cancer research. It was the first time Congress had appropriated funds toward a noncommunicable disease. The Act established the National Cancer Institute (NCI) as the federal government’s primary agency to address research and training needs for the cause, diagnosis, and treatment of cancer. The Public Health Service Act of 1944 made the NCI a direct operating division of the National Institute of Health (NIH) [7]. In 1971, President Richard M. Nixon signed the National Cancer Act, which authorized the NCI Director to coordinate all activities of the National Cancer Program, to establish national cancer research centers, and to establish national cancer control programs. In 1979, NCI announced that a balanced, low-fat diet can reduce the risk of roughly 30% of cancers. Diet recommendations included low alcohol intake and increased amounts of fiber. In the 1980s, NCI created the Division of Cancer Prevention and Control (DCPC) and began several clinical trials on cancer prevention. In 1987, working guidelines for cervical and breast cancer screenings were developed, and in 1988 The Medicare Catastrophic Coverage Act mandated Medicare coverage of Mammography screenings. In the 1990s, the goal of a smokefree society by 2000 (ASSIST) was set, and prevention and screening studies of cancers in other organs such as the prostate, lung, ovaries, and colon were initiated. In 1997, the NCI reorganized, dividing the DCPC into the Division of Cancer Prevention (DCP) and the Division of Cancer Control and Population Sciences (DCCPS). Through the recent decades, research on prevention and early detection of cancers have continued. The Early Detection Research Network (EDRN) awarded grants for biomarker discovery and validation. In 2016, the White House Announced $1 billion in Investments in the National Cancer Moonshot initiative aimed at

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prevention, including cancer vaccine development and early cancer detection [8].

Considerations for Screening: Balance Between Benefits and Risks Screening tests must be effective, safe, and well tolerated with acceptably low rates of false positive and false negative results. In the late 1960s, the World Health Organization published the Principles and Practice of Screening for Disease. It elaborated ten fundamental principles that were intended to guide decision-making regarding institution of a given screening test [9]. 1. The condition sought should be an important health problem. 2. There should be an accepted treatment for patients with recognized disease, and treatment should be better at an earlier stage. 3. Facilities for diagnosis and treatment should be available. 4. There should be a recognizable latent or early symptomatic stage. 5. There should be a suitable test or examination. 6. The test should be acceptable to the population. 7. The natural history of the condition, including development from latent to declared disease, should be adequately understood. 8. There should be an agreed-upon policy on whom to treat as patients. 9. The cost of case-finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole. 10. Case-finding should be a continuing process and not a “once and for all” project. The prevention and early identification of cancer is an important component of healthy aging. Efforts to prevent cancer and identify early cancers in older adults need to consider cancer epidemiology, the clinical significance of the cancer, and the effectiveness, drawbacks, and cost of cancer prevention and screening. It is important that

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clinicians have a clear understanding of the prognosis with and without cancer treatment when discussing cancer screening with older adults [10]. Several factors need to be considered in weighing out the benefits against the risks and costs of screening. All screening tests have the potential to produce false positive and false negative results, generally more of the former. This can lead to unnecessary workup including invasive procedures and distress to patients. A fundamental concept in cancer screening is overdiagnosis, which is the detection of lesions that would never have been detected in a person’s lifetime in the absence of screening. Cancer screening inevitably leads to overdiagnosis, because some people diagnosed with preclinical cancer will die from competing causes before the cancer would have been noticed clinically. Overdiagnosis is mostly caused by the detection of slow-growing and dormant tumors [11].

Consideration in Older AdultsIndividualized Decision-Making Life expectancy: For older adults with a limited life expectancy, a late-life cancer may not become clinically significant before they die. The term overscreening is applied to identifying such cancers. Traditional recommendations regarding when to stop cancer screening in older adults are based on the patient’s age. Over the last decade, practice guidelines increasingly use life expectancy to guide screening decisions. In addition to age and comorbid conditions, an older adult’s physical and cognitive function have a significant impact on life expectancy [12]. Various life expectancy calculators are available online which give individual patients’ probability of living for 1 to more than 10 years [13]. Cancer treatment tolerance: Tools exist that can evaluate patients’ risks for developing treatment-related toxicities. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) [14] and Cancer and Aging Research Group (CARG) [15] scores are two validated calculators.

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Comorbid conditions: Assess patients’ comorbid conditions, their severity, and the likelihood of the patient dying from these as opposed to a yet undiagnosed early stage cancer. Endstage lung, cardiac, hepatic, and renal disease are all considerations. The Charlson Comorbidity Index [16] with 19 weighted conditions was published in 1987. The NCI comorbidity index published in 2000 is cancer-specific and excludes solid tumors, leukemias, and lymphomas as comorbid conditions, given this was developed in a cohort of cancer patients [17]. Comprehensive Geriatric Assessment: CGA [18], a multidimensional assessment of older adults, or other frailty assessment tools, should be performed. This categorizes patients into fit, prefrail, and frail. Understanding a patient’s fitness status and overall survival are important in determining the potential benefits that may be derived from cancer screening. Finally, gathering all the information obtained using these above tools, the risk benefits of cancer screening should be discussed with the older adult and family/caregivers to arrive at a decision whether to screen or not that aligns with their goals and preferences.

Cancer Screening Guidelines for Older Adults Breast Cancer Breast cancer is the most common cancer in American women, except for skin cancers. Total 12.9% of women will be diagnosed with breast cancer at some point during their lifetime. Breast cancer research receives the most NCI and nonprofit funding [19]. Just over 50% are diagnosed among women aged 55–74. Total 44% of new cases are diagnosed in those 65 and older. In 2017, there were an estimated 3,577,264 women living with breast cancer in the United States; 276,480 new cases are estimated in 2020. The median age at diagnosis is 62, and the median age at death is 69. Female breast cancer is the fourth leading cause of cancer death in the United States [20]. Overall rates

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of breast cancer incidence are similar in black (f) Certain noncancerous breast diseases: Prolifand white women; however, death rates remain erative benign breast disease without (relative risk 1.76) or with (relative risk 3.93) atypia is higher for black women compared with white women [21]. These differences can be largely associated with a significant increase in risk of explained by disparities in access to care leading developing breast cancer [25]. to black women presenting with later stage dis- (g) Previous radiation therapy: Women who had ease. Black women are less likely to get routine radiation therapy to the chest or breasts before age 30 have a higher risk of getting breast mammography and therefore tend to present cancer later in life [26]. with later stage breast cancer compared to white women [22]. Although rare, men can develop breast cancer as well. The risk factor Modifiable and screening guidelines that follow are for (a) Reproductive history: Having the first pregfemale breast cancer. nancy after age 30, not breastfeeding, and never having a full-term pregnancy can raise breast cancer risk. Risk Factors (b) Obese after menopause: Older women who are overweight or obese have a higher risk of Nonmodifiable getting breast cancer than those at a normal (a) Age: The risk for breast cancer increases with age [20]. weight. (b) Family history of breast or ovarian cancer: A (c) Use of HRT: Both estrogen-only and estrogen plus progesterone users are at a higher risk of first-degree relative or multiple maternal or paternal family members who have had breast developing breast cancer, more so the lobular than ductal cancer [27]. or ovarian cancer increase the risk. A firstdegree male relative with breast cancer also (d) Cigarette smoking: The carcinogenic potential raises risk. of cigarette smoking is unarguable. Studies looking at the risk of breast cancer have (c) Genetic mutations: BRCA1 and BRCA2 are shown varying results including negative tumor suppressor genes that produce proteins that are involved in cell growth and repair of associations [28]. Generally, smoking is associated with a modest but significantly damaged DNA. Inherited variations in these increased risk of breast cancer, particularly increase the risk for breast and ovarian cancer. Women who inherit a deleterious BRCA1 or among women who started smoking at adolescent or peri-menarcheal ages [29]. BRCA2 mutation face substantially increased risks of developing breast cancer, which is estimated at 70% [23]. Primary Prevention (d) Race: As mentioned earlier, the risk of breast Behavior modification as well as greater awarecancer incidence is similar in black and white ness among women, regarding breast cancer, may women. Race indirectly plays a role in that significantly contribute toward reducing the inciBRCA mutations are more common in certain dence of this cancer [30]. groups such as Ashkenazi Jews and Icelandic Chemoprevention: Selective estrogen receppopulations. tor modulators (SERMs) and aromatase inhibitors (e) Personal history of breast cancer: Women with (AIs) are used for breast cancer risk reduction. a personal history of breast cancer have a The USPSTF recommended SERMs for breast sustained long-term risk of experiencing cancer prevention in 2013 and reaffirmed their another breast cancer diagnosis. This may be recommendation in 2019 with the addition of another primary or an in-breast (local) recur- AIs. Only SERMs have US FDA approval for rence in the treated conserved breast breast cancer risk reduction [31]. Numerous risk (an ipsilateral cancer), or a contralateral breast assessment tools, such as the National Cancer cancer [24]. Institute (NCI) Breast Cancer Risk Assessment

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Tool [32], can estimate a woman’s risk of developing breast cancer over the next 5 years. Women 35 years or older, at greater risk, such as those with at least a 3% risk for breast cancer in the next 5 years, are likely to derive more benefit than harm from risk-reducing medications and should be offered these medications if their risk of harms is low [33].

Screening Screening test: Mammography is an X-ray imaging method to evaluate the breasts. It was first introduced in Canada in 1988. It is both a screening and diagnostic tool. Breast self-exam and clinical breast exams by a healthcare provider are not generally recommended screening methods. This is not to say they are not useful, but there is insufficient data to support their use as screening tests. Breast cancer screening guidelines for the older adult with average risk are shown in Table 1. The USPSTF recommends that primary care clinicians assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer or who have an ancestry associated with breast cancer susceptibility 1 and 2 (BRCA1/2) gene mutations with an appropriate brief familial risk assessment tool. Women with a positive result on the risk assessment tool should receive genetic counseling and, if indicated after counseling, genetic testing [34]. Risks Associated with Screening: Overdiagnosis of breast cancer is the main harm of mammography screening. US estimates suggest that 15 women are overdiagnosed for every 1000 women who undergo biennial mammography screening for 20 years from age 50 [38].

Lung Cancer Lung cancer is the second most common cancer in both men and women and is the leading cause of cancer deaths in both sexes. Total 12.7% of all new cancers diagnosed are lung cancers. The median age at the time of diagnosis is 71, and median age at death is 72 [39]. The two main

K. Alexander and B. Korc-Grodzicki Table 1 Breast cancer screening guidelines for the older adult US Preventive Services Task Force [35] (USPSTF)

American Cancer Society (ACS) [36]

American Geriatrics Society (AGS) [37]

The USPSTF recommends biennial screening mammography for women aged 50–74 years The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years Women ages 40–44 should have the choice to start annual breast cancer screening with mammograms if they wish to do so Women age 45–54 should get mammograms every year Women 55 and older should switch to mammograms every 2 years or can continue yearly screening Screening should continue as long as a woman is in good health and is expected to live 10 more years or longer Do not recommend screening for breast cancer without considering life expectancy and the risks of testing, overdiagnosis, and overtreatment For breast cancer, 1000 older adults would need to be screened to prevent one death in 10 years

types of lung cancer are small cell lung cancer (SCLC) and non-SCLC (NSCLC). NSCLC accounts for approximately 85% of all cases of lung cancer [40]. The ACS estimates about 228,820 new cases of lung cancer (116,300 in men and 112,520 in women) and about 135,720 deaths from lung cancer (72,500 in men and 63,220 in women) in 2020 [41].

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diameter of less than 2.5 μm. The doseresponse relationship relating lung cancer and ambient particulate matter might be Nonmodifiable higher if only adenocarcinomas of the lung (a) Age: Advancing age is a risk factor for many individual cancer types, and lung cancer is no are considered [47]. exception. Over 70% of new cases are diag- (c) Radon: Radon-222 arises naturally from the decay of uranium-238, present throughout the nosed in people 65 years and older [39]. earth’s crust. It has a half-life of 4 days, allo(b) Sex: Men historically have had a much higher wing it to diffuse through soil and into the air incidence of lung cancer than women, and before decaying [48]. The average indoor rates in men declined dramatically in the late radon level in the United States is about 1.3 twentieth century in tandem with a proporpCi/L, and the average outdoor level is about tional decrease in the male smoking popula0.4 pCi/L [49]. More than 85% of radontion. Rates in women are rising. induced lung cancer deaths are among (c) Race: African American men have markedly smokers. Even among people who are aware higher rates of lung cancer than non-Hispanic of radon as a health hazard, only a small fracwhite men [42]. tion live in a home that has been tested [50]. (d) Family history of lung cancer: This increases the risk for the disease in both smokers and (d) Asbestos: Asbestos is a group of minerals that occur naturally in soil and rocks in many parts never-smokers [43]. of the world. Asbestos has been used as an (e) Genetics: Somatic mutations in the TP53, insulating material since ancient times. ExpoEGFR, and KRAS genes are common in lung sure to asbestos dust in the workplace was not cancers. The p53 is a protein in the cell controlled in the first half of the twentieth nucleus that regulates cell growth and division century. Exposure to asbestos and increased by monitoring DNA damage. EGFR and risks of developing mesothelioma and lung KRAS code cell membrane proteins promote cancer are well established [51]. cell proliferation [44].

Risk Factors

Modifiable Risk Factors (a) Tobacco smoking: Cigarette smoking is the number one risk factor for lung cancer. In the United States, it is linked to about 80–90% of lung cancer deaths. Cigars or pipes also increase the risk for lung cancer. People who smoke cigarettes are 15–30 times more likely to get lung cancer or die from lung cancer than people who do not smoke. The higher the pack-year, the greater the risk, but even occasional smoking increases risk. Secondhand smoke is also a risk, and about 7300 people who never smoked die from lung cancer every year due to this [45]. With societal changes and regulations that have decreased the prevalence of smoking, lung cancer has become more frequent among former than current smokers [40]. (b) Air Pollution: Lung cancer is associated with prolonged exposure to air pollution [46]. Mortality risks increase linearly with exposure to particulate matter, with a median aerodynamic

Primary Prevention Smoking cessation: People who quit smoking have a lower risk of lung cancer than if they had continued to smoke, but their risk is higher than the risk for people who never smoked. Smoking cessation at any age can lower the risk of lung cancer [45]. Current smokers should be informed of their continuing risk of lung cancer and referred to smoking-cessation programs; screening should not be viewed as an alternative to smoking cessation [52]. Environmental pollution: Air quality control measures such as the Clean Air Act, which requires EPA to set National Ambient Air Quality Standards, can be helpful. Since 1986, the EPA has mounted an aggressive campaign urging people to test their homes for radon. Both the US Surgeon General and EPA recommend fixing homes with radon levels at or above 4 pCi/L. Occupational risk avoidance: There has been a dramatic decrease in the use of asbestos in the United States since the mid-1970s, and exposure

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has dropped dramatically. Asbestos use has been banned in the European Union since 2005, although the ban did not require removal of asbestos that was already in place [53]. Secondhand smoking exposure is also a consideration at the worksite.

Screening Lung cancer screening guidelines for the older adult are listed in Table 2. The National Lung Screening Trial (NLST) results were published in 2011, providing the first evidence from a prospective randomized controlled trial that lung cancer screening in a high-risk population was effective in reducing lung cancer deaths. The participants aged 55–74 were asymptomatic and had at least 30 pack-years of smoking history. A 20% relative reduction in mortality from lung cancer was observed with low-dose CT (LDCT) screening [54]. There is universal consensus that screening should be offered to people with apparent high risk for lung cancer, and this risk is almost exclusively defined on the basis of tobacco use history [55]. Risks associated with LDCT lung cancer screening: There is a significant chance of a false-positive result, which will require additional periodic testing, in some instances invasive procedures. Fewer than 1 in 1000 patients with a false-positive result experiences a major complication resulting from a diagnostic workup [52]. In the general population, complications of CT-guided lung biopsy have been well documented and include pneumothorax (4–60%), pneumothorax requiring chest tube (5–10%), hemoptysis (10%), pain, air embolism, atrial fibrillation, tumor seeding of the biopsy tract, and, on rare occasions, death (0.5%) [60].

Colorectal Cancer Colorectal cancer (CRC) is one of the most common cancers in older adults with a median age at diagnosis of 67 years [61]. Although the mortality rate from CRC is declining, largely due to CRC screening and preventive measures, older patients still carry a higher mortality rate than younger

K. Alexander and B. Korc-Grodzicki

patients [62]. Higher rate of mortality is partly due to older adults being diagnosed at later stages and be less likely to be offered standard treatment based on CRC staging [63]. Primary care providers and/or geriatricians are faced with a difficult decision when recommending CRC preventative measures. On one side, CRC preventative measures and screening methods are the reason for decline in CRC-related mortality, and on the other side, these procedures and methods carry higher risk in older adults [64]. The decision becomes more complex when different societies, tasked with providing guidelines, either recommend a hard stop of CRC screening at a certain age or recommend engaging in a shared decisionmaking process with patients and their caregivers.

Risk Factors Nonmodifiable Genetic predisposition is the dominant risk factor for colon cancer: personal or family history of CRC or large, advanced adenomas, inflammatory bowel disease, and history of abdominal radiation. Previous negative colonoscopies reduce the risk of CRC. The National Cancer Institute has an online risk calculator for colorectal cancer (https://ccrisktool.cancer.gov). Modifiable Risk Factors Several potentially modifiable factors, including obesity, diabetes, tobacco use, excess consumption of alcohol, excess consumption of processed meat, low consumption of foods containing dietary fiber, and lack of physical activity, have been consistently identified as risk factors in observational studies, but at present, they do not alter screening recommendations [65].

Primary Prevention Lifestyle: Though the impact of life-style interventions on reducing CRC incidence, especially in older adults, are difficult to quantify, increase in physical activity, reduction or cessation of alcohol consumption, stopping cigarette smoking, increasing dietary fiber, and consuming a diet high in fresh fruits and vegetables promote overall good health and may reduce CRC risk. There are

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Cancer Screening in the Older Adult

Table 2 Lung cancer screening guidelines for the older adult USPSTF [56]

ACS [58]

National Cancer Care Network (NCCN) [59]

Recommends annual screening for lung cancer with LDCT in adults aged 55–80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery Online risk calculator tools [57] are available that give information on individual cancer risk and appropriateness LDCT screen based on USPSK recommendations Clinicians should ascertain the smoking status and smoking history of their patients aged 55–74 years Clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about lung cancer screening with these patients who have at least a 30–pack-year smoking history, currently smoke, or have quit within the past 15 years, and who are in relatively good health The mortality reduction benefit should be discussed with the limitation that not all cancers will be detected by LDCT Adults who choose to be screened should follow the NLST protocol of annual LDCT screening until they reach age 74 years Identifies two high risk groups and recommends yearly screening for both: Group1. 55–77 years of age, 30 or more pack years of smoking, and has quit within the past 14 years or is a (continued)

809 Table 2 (continued)

AGS [37]

current smoker Group 2. 50 years of age or older with 20 or more pack years of smoking and other risk factors (other than secondhand smoke) Do not recommend screening without considering life expectancy and the risks of testing, overdiagnosis, and overtreatment (much of the evidence for benefit from LDCT screening for smokers is from healthier, younger patients under age 65)

indications that consumption of milk and whole grains might also confer a protective role against CRC [65, 66]. Antiplatelet agents: Regular use of aspirin and other NSAIDs has been shown to decrease the risk of adenomatous polyps and colorectal cancer. Recent data from the Aspirin in Reducing Events in the Elderly (ASPREE) study indicated that 100 mg of enteric coated aspirin increased cancer-related mortality and especially colon cancer death in older adults [67, 68]. The US Preventive Services Task Force (USPSTF) recommends long-term daily low-dose aspirin for the primary prevention of colorectal cancer and cardiovascular disease for people aged 50–59 years who have a 10-year risk of cardiovascular disease of 10 percent or higher and who do not have an increased bleeding risk. For those aged 60–69 years with a 10-year risk of cardiovascular disease of 10 percent or higher, aspirin use may be appropriate, but the decision should be individualized [69].

Screening Options for CRC screening are Fecal Immunochemical Test (FIT); high-sensitivity, guaiac-based fecal occult blood testing (FOBT); multitarget stool DNA testing (FIT-DNA); colonoscopy; and capsule colonoscopy, computed tomography colonography, and flexible sigmoidoscopy [70, 71].

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Though evidence favors colon imaging studies as the best means of preventing CRC mortality, fecal testing, including fecal occult blood testing (FOBT), fecal immunochemical testing (FIT), and multitargeted DNA testing (FIT-DNA), may be used to screen for CRC [72]. When discussing fecal testing with older adults who are frail or have a limited life-expectancy, shared decisionmaking is important. There is little benefit in doing fecal testing if the patient is not willing or is not a candidate for a colonoscopy. The value of colonoscopy in reducing risk of and mortality from colorectal cancer is well-established [73]. Both colonoscopy and sigmoidoscopy have been demonstrated to be more effective at reducing CRC mortality than annual fecal immunochemical test (FIT) for patients 75–79 years of age [74]. The USPSTF [69] and American Cancer Society (ACS) recommendations [71] for CRC screening are listed in Table 3. The options for CRC screening recommended by the ACS are fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. A similar recommendation is made by the National Comprehensive Cancer Network (NCCN) [75]. The US Multi-Society Task Force of Colorectal Cancer (MSTF) represents the American College of Gastroenterology, the American Gastroenterological Association, and The American Society for Gastrointestinal Endoscopy. Their recommendations are shown in Table 3 [76]. The MSTF CRC screening tests are ranked in three tiers based on performance features, costs, and practical considerations. The first-tier tests are colonoscopy every 10 years and annual fecal immunochemical test (FIT). Colonoscopy and FIT are recommended as tests of choice when multiple options are presented as alternatives. The second-tier tests include CT colonography every 5 years, the FIT-fecal DNA test every 3 years, and flexible sigmoidoscopy every 5–10 years. These tests are appropriate screening tests, but each has disadvantages relative to the

K. Alexander and B. Korc-Grodzicki

tier 1 tests. Because of limited evidence and current obstacles to use, capsule colonoscopy every 5 years is a third-tier test [76].

Table 3 CRC screening guidelines for the older adult USPSTF [69]

ACS [71]

US MultiSociety Task Force of Colorectal Cancer (MSTF) [76]

1. The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation) 2. The decision to screen for colorectal cancer in adults aged 76–85 years should be an individual one, considering the patient’s overall health and prior screening history (C recommendation) • Adults in this age group who have never been screened for colorectal cancer are more likely to benefit • Screening would be most appropriate among adults who (a) are healthy enough to undergo treatment if colorectal cancer is detected and (b) do not have comorbid conditions that would significantly limit their life expectancy 3. The benefit of early detection of and intervention for colorectal cancer in adults 86 years and older is at most small 1. Average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years 2. Clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history 3. Clinicians discourage individuals older than 85 years from continuing CRC screening 1. Screening should begin at age 50 years, except in African Americans in whom limited evidence supports screening at 45 years 2. Discontinuation of screening should be considered when persons up-to-date with screening, who have prior negative screening (particularly colonoscopy), reach age 75 or have 80 years of age (perforation, postpolypectomy bleeding, and cardiopulmonary complications) [64]. A systematic review has shown that the cumulative gastrointestinal adverse events may occur in approximately one-third of octogenarians. Moreover, 1 out of 200 patients may die from colonoscopy and 2 out of 300 may have perforated bowel following colonoscopy.

Cervical Cancer Cervical cancer incidence in the USA has decreased by >50% in the past 30 years because of widespread screening [77, 78], and most cases are diagnosed in women not adequately screened [79]. However, both cervical cancer incidence and mortality remain high in older women.

Risk Factors The two major histologic types of cervical cancer, adenocarcinoma and squamous cell carcinoma, share many of the same risk factors [80]. A large body of consistent evidence implicates infection with high-risk types of human papillomavirus (hrHPV) as the causative agent in cervical cancer. These infections are common, occurring in the majority of sexually active women over their lifetime. While most infections resolve without clinical consequence over a period of several years, persistent infections can lead to high-grade precancerous cervical lesions (such as cervical intraepithelial neoplasia [CIN] grades 2 and 3) that can progress to cervical cancer [81]. HPV-related risk factors: Risk factors that are associated with HPV-related cancers include early onset of sexual activity, multiple sexual partners, a high-risk sexual partner (a partner with multiple

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sexual partners or known HPV infection), history of sexually transmitted infections such as chlamydia trachomatis or genital herpes, early age at first birth (younger than 20 years old) and increasing parity (three or more full-term births), vulvar or vaginal squamous intraepithelial neoplasia or cancer (HPV infection is also the etiology of most cases of these conditions), and a compromise immune system (such as secondary to HIV infection) [80]. Non-HPV-related risk factors: Risk factors not associated with HPV infection include low socioeconomic status [82], nonwhite race [83], oral contraceptive use [84], and cigarette smoking [85].

Primary Prevention The primary approach to prevention of cervical cancer is vaccination against oncogenic human papillomavirus (HPV) infection. However, HPV vaccination has not been recommended for older women. In the United States, the HPV vaccine is approved through age 45 [86]. Screening Current screening guidelines from the USPSTF [81] and American Cancer Society (ACS) are summarized in Table 4. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors [88]. Women Older Than 65 Years: Screening may be clinically indicated in older women with an inadequate or unknown screening history. Women with limited access to care, women from racial/ethnic minority groups, and women from countries where screening is not available may be less likely to meet criteria for adequate prior screening. Certain considerations may also support screening in women older than 65 years who are otherwise at high risk such as women with a history of high-grade precancerous lesions [89]. A Kaiser Permanente registry study found that the majority of cases of invasive cervical cancer among women older than 65 years occurred among those who had not met criteria for stopping

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Table 4 Cervical cancer screening guidelines for the older adult USPSTF [81] https://www. uspreventiveservicestaskforce.org/uspstf/ recommendation/cervical-cancer-screening

ACS [87] https://www.cancer.org/cancer/cervicalcancer/detection-diagnosis-staging/cervical-cancerscreening-guidelines.html

screening [90]. This suggests that the decision to stop screening at age 65 years should only be made after confirming that the patient has received prior adequate screening. Current guidelines define adequate screening as: three consecutive negative cytology results or two consecutive negative HPV results within 10 years before stopping screening, with the most recent test performed within 5 years [88]. Risks associated with screening with cervical cytology and hrHPV testing include anxiety regarding tests results, unnecessary surgeries, and associated complications. Screening can lead to more frequent follow-up testing and invasive diagnostic procedures (e.g., colposcopy and cervical biopsy), as well as unnecessary treatment in women with false-positive results. Evidence from

Age 21–29: The USPSTF recommends screening for cervical cancer every 3 years with cervical cytology alone. (A recommendation) Age 30–65: The USPSTF recommends screening every 3 years with cervical cytology alone, every 5 years with hrHPV testing alone, or every 5 years with hrHPV testing in combination with cytology (cotesting) (A recommendation) The USPSTF recommends against screening for cervical cancer in women younger than 21 years. (D recommendation) The USPSTF recommends against screening for cervical cancer in women older than 65 years who have had adequate prior screening and are not otherwise at high risk for cervical cancer. (D recommendation) The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and do not have a history of a highgrade precancerous lesion or cervical cancer. (D recommendation) [81] Individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred) If primary HPV testing is not available, then individuals aged 25–65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation) Individuals aged > 65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation)

randomized controlled trials (RCTs) and observational studies indicate that harms from diagnostic procedures include vaginal bleeding, pain, infection, and failure to diagnose (due to inadequate sampling) [81].

Uterine Cancer Endometrial cancer (EC) is the most common gynecologic malignancy, with a mean age of diagnosis of 63 years [91]. Most cancers of the uterus occur in the endometrium originating in the epithelium. The remainder are mesenchymal, originating in the myometrial muscle or, less commonly, the endometrial stroma [92]. Given the presence of early symptoms (postmenopausal

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Cancer Screening in the Older Adult

vaginal bleeding), approximately 75% of cases are diagnosed in stage I and have 5-year survival rates of 90% [93]. No universal screening for endometrial cancer is indicated. Women can be triaged after the initial episode of postmenopausal bleeding with a transvaginal ultrasound (TVUS). If the thickness of the endometrium is 4 mm or less, an endometrial biopsy can be omitted [94]. However, if the vaginal bleeding persists, an endometrial biopsy should be performed. Women with an endometrial thickness of greater than 4 mm should have a pathologic evaluation of their endometrium, either with an office endometrial biopsy or a dilation and curettage. It is also appropriate to forgo the TVUS and perform a biopsy for all women with postmenopausal bleeding.

Risk Factors There are two different types of endometrial cancer – types I and II with different clinicopathologic characteristics and risk factors. Type I EC is more frequent (80% of EC), is stimulated by estrogen, typically preceded by endometrial intraepithelial hyperplasia (EIN), usually presents at an early stage, and has a good prognosis. Prolonged exposure to unopposed estrogen is a major risk factor for type I. Such estrogen exposure can come from chronic anovulation (polycystic ovary syndrome), estrogen-producing tumors, and excessive conversion of androgens to estrogen in peripheral adipose tissue, such as in obese women. Women who retain their uterus and are taking hormone replacement therapy (HRT) for treatment of menopausal symptoms should be prescribed both estrogen and progesterone therapy as estrogen only HRT carries a higher risk of endometrial cancer. The use of tamoxifen is also associated with an increased risk of endometrial cancer [95]. However, these patients also present with vaginal bleeding; thus, no screening is needed for patients taking tamoxifen, yet prompt evaluation of vaginal bleeding is warranted. Lynch syndrome, an autosomal dominant condition, carries a cumulative risk of endometrial cancer up to 60% [96]. Type II EC is less frequent, however, has a worse prognosis, and is not related to prolonged

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unopposed estrogen exposure. The average age at diagnosis is older for type II disease in most studies. The older patients are more likely to have aggressive papillary serous histology, higher grade tumors, and advanced stage disease [97]. Women with Type II EC are more likely to be older at diagnosis of nonwhite race, have a history of additional primary tumors, and are less likely to be obese [98]. Fortunately, women still present with postmenopausal bleeding which leads to prompt evaluation and treatment. Women can also develop other cancers in the uterus aside from cancer of endometrium, such as sarcomas. There are no screening tests for these cancers, and not much is known regarding exposure and genetic risk factors. It is paramount that women with concern or diagnosis of such cancers be referred to a gynecologic oncologist, as surgery is an integral part of treatment.

Primary Prevention There is no evidence that lifestyle changes prevent the development of endometrial cancer. The addition of progesterone to hormone replacement therapy was shown to decrease the risk of endometrial cancer [99]. Screening There are no screening tests or exams to find endometrial cancer early in women who are at average endometrial cancer risk and have no symptoms. The American Cancer Society recommends that, at menopause, all women should be told about the risks and symptoms of endometrial cancer and strongly encouraged to report any vaginal bleeding, discharge, or spotting to their doctor [100].

Ovarian Cancer Unfortunately, ovarian cancer remains the deadliest gynecologic malignancy, mainly because 75% of women present with advanced stage disease at the time of diagnosis. More than 50% of women diagnosed are 65 or older. There is no effective screening test for ovarian cancer, and signs and symptoms can be vague – increased abdominal

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girth, early satiety, and abdominal pain. It is very important to refer women with a confirmed diagnosis or high suspicion of ovarian cancer to a gynecologic oncologist for treatment, as this improves outcomes [101].

Risk Factors The incidence of ovarian cancer increases with increasing age. An analysis of data from the Nurses’ Health Study found that the risk increased approximately 2 percent for each additional year of age in patients 65 years of age in the in the highest quintile of vigorous activity had a 77% lower risk of advanced prostate [116].

Primary Prevention Supplementation. Selenium, Vitamin E, Vitamin D, and multivitamins and have all been evaluated for their ability to prevent prostate cancer with mixed results. The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) [123] found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up provided further insight into the relationship of vitamin E and prostate cancer. The authors concluded that dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men [123]. Supplementation with vitamin D did not result in a lower incidence of invasive cancer when compared with placebo [124]. A large prevention trial of male physicians showed that daily multivitamin supplementation modestly but significantly reduced the risk of total cancer [125]. Screening Because prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related death in American men, a large

K. Alexander and B. Korc-Grodzicki

amount of effort and resources has been devoted to screening with PSA testing and digital rectal examinations (DRE). There are limited data on the value of DRE alone. Some RCTs evaluated DRE with PSA, but none evaluated DRE alone. Even in patients with elevated PSA levels, DRE, did not influence the chance of detecting prostate cancer after 8 years of follow-up [126]. The US Preventive Services Task Force (USPSTF) has dropped its opposition to routine prostate cancer screening in favor of a shared decision-making process between men aged 55–69 years and their physicians. Most prostate cancers identified by PSA screening are low grade and grow slowly. Randomized trial data indicate no difference in prostate cancer mortality at 10 years between active monitoring and treatment for men with low-risk prostate cancers [127]. On the other hand, with no known means of preventing prostate cancer or for curing metastatic disease, the sole hope for reducing suffering and death from prostate cancer is through early detection and appropriate and effective patient management [128]. Current USPSTF [129] and ACS [130] recommendations regarding the use of PSA to screen for prostate cancer are outlined in Table 5. Choosing Wisely identifies PSA-screening in men older than 75 years as low-value care [131]. Risks Associated with Prostate Cancer Tests and Treatments For men aged 55–69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be an individual one and should include discussion of the potential benefits and harms of screening with their clinician [115]. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. Overdiagnosis is also common and is increasingly likely with increasing age. Yet, many men over 75 years of age continue to have PSA screening ordered [132]. In determining whether this service is appropriate in individual

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Table 5 Screening recommendations for prostate cancer USPSTF [129] https://www. uspreventiveservicestaskforce. org/uspstf/recommendation/ prostate-cancer-screening

ACS [130] https://www.cancer.org/ cancer/prostate-cancer/ detection-diagnosis-staging/ acs-recommendations.html

a. Recommends individualized decisionmaking between patients and their healthcare providers for men between the ages of 55 and 69 regarding PSA testing b. Clinicians should not screen men who do not express a preference for screening. (C recommendation) c. Recommends against PSA-based screening for prostate cancer in men 70 years and older. (D recommendation) Beginning at age 50, men at average risk of prostate cancer, who are expected to live at least 10 years, have a chance to make an informed decision with their healthcare provider about whether to be screened for prostate cancer

cases, patients and clinicians should consider the balance of benefits and harms based on family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs.

Bladder Cancer

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Risk Factors Nonmodifiable Risk Factors (a) Age: Increasing age is one of the most important risk factors. As the population ages, the incidence and prevalence of the disease will increase enormously [133]. (b) Gender: Incidence is three times higher in men than women. In addition, women have higher mortality rates relative to the incidence [134]. (c) Genetic susceptibility: Several genetic alterations have been linked to BC occurrence, most relevant, N-acetyl transferase and GSTM-1 null genotypes [136]. (d) Socioeconomic status is inversely related to BC incidence and outcomes. Populations with a low education level were found to have a 20% higher chance of developing BC, even after adjustment for smoking. Adults from low-income households are more likely to maintain diets deficient in healthy foods and hold occupations with a higher likelihood of exposure to carcinogens [137]. (e) Medical conditions: Certain medical conditions are linked to BC occurrence. Conventional urinary tract infections and viral infections, specifically Human Papilloma Virus, are recognized contributors to the risk of developing BC [138]. The causality of radiation exposure upon BC incidence was established from long-term studies of World War II atomic bomb survivors [139]. Patients having undergone radiation therapy for prostate cancer have a latent risk as many as 10 years following treatment [140]. Of common chemotherapeutic agents, only cyclophosphamide has been demonstrated to be associated with BC [141].

Bladder cancer (BC) is mainly a disease of aging; its incidence and prevalence increase around the sixth decade and peak in the seventh to eighth decade of life. It is the ninth most common cancer, Modifiable Risk Factors and, on average, it is three to four times more (a) Tobacco smoking is the main risk factor, accounting for about 50% of cases. Smoking common in men than in women [133] [134]. Absolute incidence and prevalence of BC are cessation is, therefore, the most relevant recommendation in terms of prevention, as the expected to rise significantly during the next risk of developing BC drops almost 40% decades because of population aging. In the within 5 years of cessation [135]. When someUSA, approximately 74% of bladder cancers one has stopped smoking for more than occur in adults 65 years of age or older [135].

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10 years, their risk of developing bladder cancer is similar to nonsmokers [142, 143]. (b) Diet: A single meta-analysis demonstrated that increased fruit and vegetable intake was associated with a decreased risk of bladder cancer [144]. The impact of diet on bladder cancer incidence in older adults is not clear. (c) Occupational Exposures: Occupational exposures have been estimated to account for up to 20–27% of bladder cancers; changes in legislation over the past 30 years seem to have led to reduced risks in the Western countries. Aromatic amines, to which exposure occurs in the chemical and rubber industries, are major occupational carcinogens [133].

K. Alexander and B. Korc-Grodzicki

evidence is insufficient to assess the balance of benefits and harms of screening for bladder cancer in asymptomatic adults, including older adults [148]. Regardless of age, neither urinalysis nor cystoscopy is recommended as a means of screening for bladder cancer.

Skin Cancer Skin cancer is the most common cancer in the United States and worldwide. In fact, more people are diagnosed with skin cancer each year in the United States than all other cancers combined! One in five Americans will develop a skin cancer by the age of 70 [149]. Skin cancers are classified as cutaneous melanomas and keratinocytic-epithelial tumors, commonly defined as nonmelanoma skin cancers (NMSC). In the latter group, the most common types are Basal cell (BCC) and Squamous cell carcinomas (SCC). NMSC account for at least 80% of all skin cancer cases, with a large prevalence of BCC (70%) over SCC (20%) in the general population [150]. They rarely result in death or substantial morbidity with 10% Body mass index (BMI) 70 >1 impaired GA domain Incurable solid tumors or lymphoma Starting new treatment regimen N 5 154 76 intervention 78 control Inclusion criteria Age  70 Solid tumors and lymphoma Candidates for systemic therapy

Outcomes Decreased incidence of severe chemotherapy toxicity in intervention group (50 vs 60%, p ¼ 0.02). Increased advance directive completion (24 vs 10%, p < 0.01)

Decreased incidence of severe chemotherapy toxicity in intervention group (50 vs. 71%, p < 0.01) Intervention group more likely to receive reduced doses (49 vs. 35%, p ¼ 0.03) No differences in 6 month survival

Quality of life better in the intervention group at 6 months Reduced hospitalizations (41% less) and emergency room visits (39% less)

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Breast Cancer

Breast Cancer Screening in Older Adults Breast cancer screening with mammography is recommended for women aged 50 to 74 by most international guidelines [38]. However, while some endorse stopping screening at a specific chronological age, others recommend continuing as long as overall health is good and calculated life expectancy is of at least 10 years or more [39]. The reason behind those discrepancies is the limited understanding of the effect of screening mammography in older women. In that regard, most of the studies that have showed a benefit of screening mammography (approximately 20% reduction in breast cancer-related deaths) have included younger women [40]. The benefit of screening mammography has been calculated to be much lower (around 6%) in women aged 60–69 years, and thus, the number needed to screen is much higher to prevent a breast cancer-related death [41]. Most experts agree in recommending exploring comorbidities and overall life expectancy when considering breast cancer screening, in order to avoid the risk of harms (particularly overdiagnosis) in women who have a high risk of death from competing causes [42].

Approach to Palpable Breast Masses in Older Adults Early breast cancer is more commonly asymptomatic and detected through screening mammography. However, larger tumors may present as a painless lump, which is the most common symptom of breast cancer. In older women, a new lump is most likely to be malignant, as breast benign disease is less common [43]. Other signs and symptoms that indicate a possible breast cancer are changes in breast size or shape, skin changes, nipple discharge or nipple inversion, and axillary lumps. Postmenopausal women presenting with a palpable mass should have a complete evaluation including a physical examination, a diagnostic mammography, and breast ultrasound [44]. The breasts of older women are less nodular and dense, making physical exam and mammographic interpretation easier. If there is a suspicion of cancer, a core-needle biopsy is the

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preferred diagnostic method, since it allows for the complete evaluation of immunohistochemistry biomarkers. However, a fine needle biopsy may also be appropriate for initial diagnosis and is easier to perform across clinical settings [45]. In addition to a breast evaluation, all older women with a potential diagnosis of breast cancer should receive a comprehensive geriatric assessment in order to evaluate physical function, comorbidities, cognition, polypharmacy, nutrition, psychological status, financial considerations, and social support, since this may influence breast cancer diagnostic and therapeutic recommendations [46].

Breast Cancer Staging and Workup Once the diagnosis of breast cancer is confirmed, the next step is conducting a staging workup, which must include bilateral mammography and ultrasound looking for multicentric or bilateral disease as well as for enlarged axillary lymph nodes. The recommended staging in older adults is the same as in younger women, and it normally includes a complete blood count and liver function tests (LFTs) if the patient is considered for systemic therapy, plus systemic imaging only in patients with locally advanced disease (T3 N1–3) or in the presence of sign or symptoms of metastatic disease. Systemic imaging may include chest diagnostic computed tomography (CT) or x-ray in case of pulmonary symptoms; abdominal imaging using CT, magnetic resonance ultrasound in case of abnormal LFTs, or abdominal signs or symptoms; and bone scan in patients with bone pain or elevated alkaline phosphatase. PET-CT might be helpful only in cases that are equivocal or suspicious of metastatic disease after performing standard staging studies [20].

Therapeutic Approach to Breast Cancer in Older Women Surgery The surgical approach to an older woman with localized breast cancer should take into consideration life expectancy, comorbidities, and frailty. Standard breast cancer surgery is recommended

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for fit older women with either breast conserving surgery (BCS) or mastectomy. Both types of surgery are well tolerated in older women, with a mortality of less than 2% and wound complications of 8% [47]. However, frail women are at higher risk of death (8%) as well as of functional decline one year after breast cancer surgery, particularly among those with prior impairment in ADLs or cognitive impairment [48]. Therefore, for frail patients with limited life expectancy, primary endocrine therapy instead of surgery may be a less morbid therapy, since it can provide disease control for up to 3 years without detrimental effects on overall survival (OS) when compared to surgery plus endocrine therapy [49]. Regarding the management of the axilla, SIOG guidelines recommend to treat it similarly to younger women, either with axillary lymph node dissection (ALND) if clinically positive at the time of diagnosis or with sentinel lymph node (SLN) biopsy if clinically negative [50]. Some studies suggest SLN or ALND can be reasonably and safely omitted in older women to avoid morbidity. However, routine omission of axillary staging might increase local recurrence, and additional studies are needed before considering it as standard of care [51–53]. An alternative for ALND in patients with positive SLN is whole breast radiotherapy, which is supported by RCT, which showed fewer side effects when compared to ALND [54, 55]. However, despite the evidence showing that fit older women should be offered standard surgical breast treatment, older women are still more likely to receive a mastectomy instead of BCS, and less likely to undergo appropriate axillary staging [56, 57].

Radiotherapy Adjuvant radiotherapy after breast conserving surgery has shown to reduce local recurrence and is considered a standard therapy. In general, it is well tolerated among older women, with non-significant increases in toxicity. However, the benefit of radiotherapy on survival among older women seems to

G. Henríquez et al.

be reduced, and some groups have studied the avoidance of adjuvant radiotherapy in older patients. The Cancer and Leukemia Group B (CALGB) 9342 study was a randomized clinical trial (RCT), which included women 70 years and over with stage I ER-positive breast cancer treated with lumpectomy and showed that adjuvant radiotherapy did not improve OS, while providing an 8% reduction in the risk local recurrence at 10 years [58]. Similarly, the PRIME II trial included women aged 65 years and over with tumors 3 months Use of anthracyclines

Abnormal liver function

Geriatric domains Hearing impairment Number of falls Ability to take medications Limitations in walking a block Social activity limitations IADLs Cognitive impairment Malnutrition CARG score Limitation in walking a mile Lack of someone able to provide advice

CARG Cancer and Aging Research Group, CRASH Chemotherapy Risk Assessment Scale for High-Age Patients; ECOG PS Eastern Cooperative Oncology Group Performance Status, LDH lactate dehydrogenase, IADL Instrumental Activities of Daily Living.

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considered for chemotherapy [19]. The CARG investigators have also developed a tool specific for older patients with breast cancer, which expands the CARG tool taking into consideration further tumor-, patient’s, and chemotherapyrelated variables (Table 3) [78]. Therefore, a sequential combination of anthracyclines and taxanes can be considered in fit, older patients with high-risk breast cancer based on tumor size, nodal involvement, and/or receptor profile (TN or HER2-positive) in either the adjuvant or neoadjuvant setting. However, in the majority of older patients, a postoperative taxane-based regimen (such as docetaxel/cyclophosphamide [TC] or weekly paclitaxel) may be a safer option, also in the context of a better efficacy profile of TC compared with doxorubicin/cyclophosphamide (AC) [79, 80]. Likewise, fit older patients can be considered for standard neoadjuvant chemotherapy regimen, although less fit individuals whose breast cancer is already operable are best served by primary surgery potentially followed by a less intense chemotherapy regimen. Evidence on adjuvant treatment decision guided by pathological responses to preoperative chemotherapy is equally sparse. The CREATE-X study of postoperative capecitabine in case of residual invasive breast cancer following neoadjuvant chemotherapy enrolled only patients aged 74 years and over, which again suggests that this approach should be considered only in fit, older individuals with TN disease [81].

Neoadjuvant/Adjuvant Endocrine Therapy Postoperative endocrine therapy should be considered in all older patients with luminal breast cancer as its use is supported by robust evidence. Nonetheless, comorbidities, predicted life expectancy, and disease risk of recurrence should be taken into consideration to guide also endocrine treatment decisions as for individuals with very low-risk disease and competing risks, the benefit may be marginal [82]. Aromatase inhibitors (AIs) are the standard endocrine treatment option in view of better breast cancer recurrence and mortality outcomes compared with tamoxifen [83]. However, tamoxifen

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remains a reasonable alternative in case of side effects and following an initial course of AIs [84]. The choice of endocrine agents should be balanced with expected benefits, patients’ preferences, and the potential range of side effects, which may include osteoporosis, cardiovascular risk, metabolic problems, and cognitive impairment on AIs [85–88] and thromboembolism, endometrial cancer, and liver fatty disease on tamoxifen [83, 89]. Consequently, bisphosphonates represent an appropriate option in the adjuvant setting not only to address both the issue of osteoporosis for patients on AIs, but also in the context of a 2–3% benefit in breast cancer-mortality documented on these agents in postmenopausal patients at moderate to high risk of recurrence [90]. Calcium and vitamin D supplementation should also be considered to limit the impact of AIs on bone mineral density and the risk of hypocalcemia on bisphosphonates. The risk of atypical fractures and osteonecrosis of the jaw on these agents should also be taken into account. The duration of endocrine therapy may be extended beyond 5 years in fit, older patients with high-risk breast cancer. However, decision-making here should be individualized on the basis of expected benefits and side effects. In this regard, evidence is more robust on the use of AIs following initial tamoxifen with a documented 2–4.6% improvement in recurrence-free survival at 4 years [91–93]. When AIs are used upfront, the MA.17R and the NSABP B-42 study showed a benefit of an extended course for up to 10 years (with the MA.17R documenting a 4% improvement in fiveyear disease-free survival), whereas this was not confirmed by the IDEAL and DATA studies [94– 97]. On the other hand, all studies showed increased risk of side effects sometimes occurring on AIs and including bone fractures and pain, osteoporosis, arthralgia, and myalgia, which is confirmed also by two large meta-analyses [98, 99].

Neoadjuvant/Adjuvant Targeted Therapy Evidence on the use of anti-HER2 agents in older patients is limited [100]. Retrospective data suggest that more than 80% of older patients are able

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to complete one year of adjuvant trastuzumab, although comorbidities and increasing age correlate with earlier discontinuations [101]. Generally, older adults with small, node-negative tumors derive good disease control benefit and low rates of cardiac events [102]. Also, a large metaanalysis documented a 47% relative risk reduction in patients receiving trastuzumab plus chemotherapy compared with chemotherapy alone [103]. Therefore, older adults should be offered for trastuzumab regardless of age [50]. Nonetheless, age remains a risk factor for left ventricular ejection fraction impairment and congestive heart failure (CHF) on trastuzumab in the NSABP B-31 study and real-world experiences [104–106]. CHF occurred in almost 30% of patients aged 66 years and over with stage I–III breast cancer retrieved from the SEER dataset, with coronary artery disease, hypertension, and older age being predictors of increased risk [107]. Diabetes may also increase the risk of cardiotoxicity associated with trastuzumab [108]. Therefore, regular cardiac monitoring is a crucial aspect of the management of older patients on anti-HER2 therapy. A shorter duration of anti-HER2 therapy may be suitable for older patients in an attempt to reduce cardiac risks: The PERSEPHONE study recently demonstrated the non-inferiority of a six-month course of trastuzumab compared with 12 months [109], although two more studies failed to confirm similar findings [110, 111]. Also, anthracycline-free regimens may be an appealing chemotherapy option to combine with trastuzumab. TC is associated with encouraging survival outcomes and a 6% rate of cardiac dysfunction, which is usually reversible [112]. Weekly paclitaxel plus trastuzumab is also an attractive option for patients with small, nodenegative tumors [113]. Although the use of singleagent trastuzumab is not supported by trial data, it may be considered when chemotherapy is not appropriate, especially when given along endocrine therapy in case of luminal disease, in the context of the reasonable five-year relapse-free and OS outcomes seen in this setting (80% and 87%, respectively) [114].

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Evidence on the use of other anti-HER2 agents in older patients is lacking. Only 13.1% of the patients enrolled in the APHINITY study of adjuvant pertuzumab plus trastuzumab were aged 65 years [115] and over, and no age-specific details were reported in the neoadjuvant studies of dual anti-HER2 blockade [116, 117]. Similarly, the KATHERINE study enrolled few older patients although trastuzumab emtansine (T-DM1) improves disease-free survival for patients with residual disease after neoadjuvant systemic therapy [118] and may still be considered for fit, motivated older individuals. Finally, the high incidence of severe diarrhea reported in the adjuvant EXTENET study of the tyrosine kinase inhibitor neratinib suggests that it may be a challenging option for older patients [119].

Treatment Considerations in Older Women with Metastatic Disease Decision-making for older patients with advanced breast cancer should balance expected benefits in terms of responses and survival and potential side effects. Older patients with luminal breast cancer should be offered a combination of endocrine therapy plus cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors. They have substantially improved progression-free and OS outcomes compared with endocrine agents alone [120]. A recent FDA pooled analysis of trial data confirmed their efficacy regardless of age [121] in the absence of any new safety signals, similarly to subgroup analyses of their landmark studies [122, 123] and preliminary data from the CompLEEment-1 trial [124]. However, the use of the mammalian target of rapamycin (mTOR) inhibitor everolimus may be more challenging in older adults due to more frequent discontinuations and mortality [125, 126]. Fit, older patients with HER2-positive disease are suitable for trastuzumab and pertuzumab plus chemotherapy in the first-line setting [100, 127]. Since docetaxel may cause severe side effects in less fit patients, an alternative chemotherapy backbone may be metronomic cyclophosphamide aiming to spare the use of a taxane and based on the improved progression-free survival up to more

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than 12 months compared with targeted agents alone and its safety profile [128]. Endocrine therapy plus dual anti-HER2 blockade is also a reasonable alternative for older patients who are not suitable for chemotherapy [129]. Chemotherapy is indicated for patients with ER-negative breast cancer or upon progression on multiple endocrine and anti-HER2 agents. Single agents are favored to minimize side effects [130] and commonly used agents include capecitabine, taxanes, eribulin, and vinorelbine. Of note, age does not influence the efficacy of eribulin in the absence of any impact on geriatric parameters and quality of life in older individuals [131, 132], whereas nab-paclitaxel is attractive to spare the need for steroidal premedication [133].

Primary Endocrine Therapy Pooled trial data suggest that surgery attains better local disease control rate and progression-free survival outcomes compared with primary endocrine therapy in patients with luminal breast cancer and a life expectancy of more than 5 years [134, 135]. Also, breast surgery reduces the risk of local recurrence and associated morbidity and is usually well tolerated. Older patients may also be suitable for local anesthesia where general anesthesia is contraindicated. Nevertheless, the OS benefit with surgery versus endocrine therapy did not reach statistical significance in a 2006 meta-analysis [134]. Moreover, two subsequent trials and an epidemiologic analysis did not confirm any impact of surgery on OS in older patients [136–138]. Therefore, endocrine treatment alone is a reasonable option for frail patients with a shorter life expectancy and in the context of competing risks of death. AIs are able to provide better disease control rates compared with tamoxifen [135, 139], with a median time to progression of 5 years. Novel Therapeutic Options A growing list of biomarkers is available to guide treatment selection in breast cancer, and functional genomic and expression signatures may identify patients who may respond to novel targeted agents. For example, patients with metastatic breast cancer and mutations in BRCA genes

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are candidates to Poly ADP-Ribose Polymerase (PARP) inhibitors. Available evidence suggests that PARP inhibitors are well tolerated in older adults [140]. PIK3CA is another common mutation in HR-positive tumors, which may respond to PIK3CA inhibitors. Although the SOLAR-1 RCT of the PIK3CA inhibitor alpelisib did not have age as an inclusion criterion, the median age of participants was 62 years and limited experience exists with this medication in older women [141]. In TNBC, expression of PD-L1 by IHC also predicts response to immunotherapy. Atezolizumab and nab-paclitaxel in combination are approved as a first line for TNBC [142]. However, it is important to mention that older adults are under-represented in immunotherapy clinical trials in general, and few studies suggest that are at a higher risk of adverse events and treatment discontinuation [143]. Therefore, it is essential to identify patients that might have a benefit of novel treatments and, in this setting, undertaking a full geriatric assessment may be helpful.

Patient and Family Education Effective communication for patients with breast cancer and their family/caregivers can improve educational needs, provide relevant information, improve mental and physical health, and reduce caregiver burden [144]. However, while there is a significant amount of information regarding the educational needs and concerns of women with breast cancer, there is a lack of data specific to older women with breast cancer and their caregivers. Among older adults with all types of cancer, the most commonly expressed educational needs are those related with physical symptoms, dealing with the side effects of treatments and performing daily activities. Additionally, older adults are significantly less likely than their younger counterparts to seek for health-related information and a significant proportion prefer not knowing specific information regarding prognosis [145]. However, despite these differences in information-seeking behaviors, recent data suggests that older adults with breast cancer desire more information and have significant

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agency and input in decision-making processes than previously thought [146]. Since weighing the benefits and risks of proposed breast cancer treatment may be difficult for patients and their caregivers, the only way to actively engage them in shared-decision making is through a dynamic and continuous educational process. A first step is to assess the decision-making preferences of each individual: Some may prefer to make all their health-related decisions themselves, others may desire more input from their family and others will defer most decisions to the clinical expertise and knowledge of physicians [146]. A potential strategy to improve patient education and to enhance shared decision-making is the use of decision support interventions (DSI) and decision aids. Unfortunately, there is a lack of older adult-specific decision aids, and most DSI target a younger patient population. Recently, Schonberg et al developed an older adult breast cancer-specific decision aid, which includes information about treatment choices (such as surgery, endocrine therapy, and radiation), life expectancy, and patient preferences and values regarding treatment outcomes. This decision aid, which is written at a sixth grade reading level, was proven acceptable among a sample of older women with breast cancer and could be an effective option to improve shared decision-making [147]. Another potentially useful tool, developed in the United Kingdom, is the Age Gap Decision Tool. This tool, available online at https://agegap.shef.ac.uk/, uses a mathematic model based on information from women aged 70 years and over-diagnosed with localized breast cancer between 2002 and 2012 and allows for the comparison of various treatment outcomes, including surgery, primary endocrine therapy, and chemotherapy [148, 149]. Shared decision making may be more difficult among older women with low health-literacy, since they may be less likely to engage in activities related to their own health management. Various strategies aimed at improving breast cancer-related health literacy have been studied, including the use of basic information cards, group workshops, patient navigation, and

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entertainment-based education strategies (including survivor stories and soap-opera narrative structures) among others [150]. However, it is important to point out that most of these interventions have targeted ethnic and racial minority groups and that none have been specifically designed for older women with low health literacy.

Emergencies Patients with breast cancer frequently face medical emergencies associated with their underlying disease and treatment. Some emergency situations might be preventable through the performance of a geriatric assessment and the early implementation of supportive care strategies. Pain is common among older patients with cancer, particularly those with advanced disease. Pain is a complex symptom that affects physical function, emotional status, and social activities. Acute pain is often associated with the cancer and its treatment. However, some patients may develop a chronic pain syndrome long after active cancer treatment has ended. Pharmacotherapy for pain can have serious side effects in older adults, such as falls, delirium, constipation, and urinary retention. Given the complexity of pain and the potential toxicity of pain medications, especially opioids, the assessment and treatment of pain in older adults should include psychiatric support, physical therapy, and complimentary therapies as needed [151]. Cancer-related chronic fatigue is present in 70–100% of patients with cancer, especially during active treatment. Patients often report fatigue as a more distressing side effect of treatment than nausea or vomiting. It may be the manifestation of physiologic and psychological stresses associated with cancer and its treatment, and can significantly interfere with ADLs, and lead to an increase in mortality and morbidity [152]. The biologic mechanisms of cancer-related fatigue are still unclear, although several proposed mechanisms include serotonin dysregulation, endocrine dysfunction (including the hypothalamic-

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pituitary-adrenal axis), circadian rhythm disruption, and cytokine dysregulation, which may be at play at once [153]. Breast cancer-related lymphedema (BCRL) is an important issue for survivors. It is estimated that approximately 30% of breast cancer survivors have BCRL. The incidence and severity of BCRL increase with age and with the extent of regional therapy. No definitive cure or treatment exists for this; therefore, both primary and secondary prevention are important. Exercise, rehabilitation, and eliminating risk factors continue to remain as the mainstay treatment of BCRL [154]. Endocrine therapy has been associated with various toxic effects, including deep venous thrombosis (DVT). A careful evaluation of concomitant comorbidities and the different spectrum of toxicity of the various endocrine therapy options and their adverse events (cardiovascular events, lipid metabolism, preexistent osteoporosis, cognitive functions) must be taken into account when recommending adjuvant endocrine therapy for older patients with breast cancer [155]. AIs, for example, increase the odds of developing cardiovascular disease and bone fractures but have decreased risk of DVT and endometrial carcinoma when compared with tamoxifen. Hot flashes, arthralgia, myalgia, and alopecia are also known common side effects of treatment with an AI but seem to be better tolerated by older women than by their younger counterparts [156]. Because bone density decreases with age, older women are at higher risk of osteoporosis-related fractures, of which hip fractures in particular are associated with a high risk of long-term complications as well as excess mortality [157]. Finally, it is also important to consider the increased risk of hematological toxicity in patients who are frailer, have multiple comorbidities, and need assistance at home. Neutropenia in particular is a concern among older patients, since age has been identified as a risk factor for this complication [158]. Whenever possible, chemotherapy options known to cause less neutropenia should be preferred. However, in cases where more intensive regimens of chemotherapy are needed, white blood cell (WBC) growth factor support should be

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provided in accordance with published guidelines [158]. WBC growth factor use may reduce chemotherapy delays and seem to be as safe and effective among older adults as in their younger counterparts [159, 160]. There is also evidence of worsening functional impairment in older patients treated with radiotherapy. Some of the most concerning toxicities that older adults may have a higher vulnerability of experiencing are fatigue, mucositis, xerostomia, dehydration, infections, and cognitive defects.

Clinical Pearls Decisions regarding the treatment of older women with breast cancer need to take into account tumor, treatment, and patient-related factors and to be aligned with the patient’s preferences and values (Fig. 4). As we have discussed, the geriatric assessment identifies issues that are not detected in usual oncology visits, allows for the calculation of competitive risks and non-cancer-specific life expectancy, provides relevant data for predicting the risk of severe chemotherapy toxicity, and may lead to interventions aimed at improving the patient’s QoL and treatment tolerance. These data need to be balanced against tumor biology and stage, the presence of symptoms, and the predicted benefit of treatment. In patients with localized breast cancer, the use of clinical prediction tools can help estimate the benefit of providing systemic treatments. An example of this is Predict, an online breast cancer prognostication and treatment benefit tool (https://breast.predict. nhs.uk/) developed in the United Kingdom [161]. This tool takes into account clinical and treatment data to provide information regarding the estimated benefit of various therapies (including endocrine therapy, anti-HER2 agents, and chemotherapy) on survival at five and ten years [162]. Importantly, this tool has been shown to accurately predict 5 year overall survival among older patients with breast cancer, although it slightly overestimates survival at 10 years. The reports generated by this tool can be utilized during clinical discussions in order to illustrate the predicted benefits of various treatments [163].

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Fig. 4 Proposed steps for achieving shared decision making when considering treatment for an older adult with breast cancer Table 4 Sample calculations of life expectancy for two patients with the same chronological age but differing clinical and geriatric assessment characteristics using the Lee-Schonberg Index (obtained from eprognosis.org) Characteristic Age Gender BMI General health status Chronic lung disease Heart failure Diabetes Smoking status Problems walking several city blocks Hospitalizations over last year Needs help with household chores Difficulty managing money Difficulty bathing or showering Difficulty pushing objects Ten year mortality Median life expectancy

The predicted benefit of treatment must then be weighed against an estimation of non-breast-cancer-specific life expectancy, as recommended by ASCO guidelines [19]. In order to do this, clinicians can utilize the freely available geriatric assessment-based calculators available online at eprognosis.org. Among these, the Lee-Schonberg index has been recommended to estimate a patient’s four, five, ten and 14 year mortality (https:// eprognosis.ucsf.edu/leeschonberg.php) [37, 164].

Patient 1 72 Female 27 Good No No No Never smoked No None No No No No 15% 25 years

Patient 2 72 Female 24 Good No No Yes Former smoker Yes One Yes No No Yes 68% 9 years

The results of these calculations (Table 4) can help clinicians put the predicted benefit of interventions based on the tumor’s biological characteristics into the context of non-breast-cancer-specific life expectancy and to frame discussions with patients and their caregivers. In cases where there is a plan to administer cytotoxic chemotherapy, clinicians should use the information obtained through the geriatric assessment to calculate the patient’s risk of

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experiencing severe treatment-related toxicity. The aforementioned chemotherapy toxicity calculations, which are recommended by ASCO guidelines, can also be accessed online (the CARG tool can be accessed at http://www.mycarg.org/tools, while the CRASH tool is available at https:// moffitt.org/eforms/crashscoreform/). Both of these websites allow for the download of graphic report cards, which can be shown to patients when discussing the risk and benefits of cytotoxic chemotherapy (both in the adjuvant and in the metastatic setting). Once the risks and benefits of treatment have been adequately defined, it is essential to align final therapeutic decisions with the patient’s wishes and preferences. It is important to remember that older patients are less likely to see the additive survival gains provided by various therapies as worthwhile, particularly when such therapies are burdensome or lead to functional or cognitive decline [27, 165]. This shift in priorities and motivations must be taken into account, and evidence-based therapeutic decisions and options must be adjusted accordingly in order to maximize benefits while reducing risks [165]. Finally, regardless of whether treatment is administered or not, interventions aimed at mitigating the deficits found through the geriatric assessment should be implemented (Fig. 3). Ideally, these interventions should be multidisciplinary and delivered either through a geriatric oncology-specific team or with help from geriatricians, who should co-manage patients along with the oncologist during the course of treatment.

Social Determinants of Health Multiple types of determinants contribute to individual cancer risk and the likelihood of survival after a cancer diagnosis. These include biological/ genetic, environmental, behavioral, health care, and social determinants [166]. The World Health Organization defines social determinants as “the circumstances, in which people are born, grow up, live, work, and age and the systems put in place to deal with illness” that are shaped by the

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“distribution of money, power, and resources at global, national, and local levels.” Social determinants include housing and neighborhood conditions, educational and economic factors, transportation systems, social connections, and other social factors and reflect interconnected social structures and economic systems shaped by the inequitable distribution of power and resources [167, 168]. Social determinants of health which have been associated with an increased incidence of breast cancer, more advanced stage at diagnosis, and worse survival include socioeconomic status (income and education), neighborhood deprivation, unemployment, racial discrimination, poor social support, and the presence of limited social networks. Other social determinants of health which represent barriers to receive appropriate breast cancer care include medical distrust, immigration status, inadequate housing, food insecurity, and geographic factors such as neighborhood access to health services [168]. Socioeconomic and environmental factors modify breast cancer incidence. For all racial/ethnic groups, breast cancer incidence rates tend to be positively associated with having a lower socioeconomic status. On the other hand, low socioeconomic status is associated with increased risk of aggressive premenopausal breast cancers, as well as late stage of diagnosis and poorer survival among older patients [168, 169]. There are welldocumented disparities in breast cancer survival by socioeconomic status, race, education, censustract-level poverty, and access to health insurance and preventive care. Poverty is also related with other factors that have been associated to late stage at breast cancer diagnosis and worse survival such as inadequate health insurance, lack of a primary care physician, and poor access to health care. In addition, environmental factors that are associated with increased breast cancer incidence (such as alcohol consumption) are more prevalent in deprived areas. These factors may have direct effects, or they may act indirectly through mediators such as obesity or earlier puberty [169]. The growth of the older adult population, as well as the increase in its racial and ethnic

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diversity, will lead to an increase in the number and types of ethical challenges faced by geriatricians and oncologists alike. A better understanding of the social determinants of breast health can be effective in designing and applying of appropriate theories and models of education and intervention aimed at improving access to healthcare in order to achieve an early diagnosis and timely treatment of breast cancer, which in turn could lead to a reduction in complications and mortality [170].

Cost Implications The cost of new technologies used to treat breast cancer has been the subject of intense debate in recent years, leading to initiatives aimed at improving the cost-effectiveness evaluation of new therapies and to various proposals aimed at crafting broader policy initiatives in this area. Worryingly, the continuous increases in the price paid for many breast cancer treatments have created a new type of toxicity for patients: financial toxicity [171]. Financial toxicity, defined as adverse economic consequences resulting from medical treatment, is established as an important burden and source of distress in cancer care. Financial toxicity has been documented in multiple malignancies, as well as across cancer stages and income levels. This term is used with intent in cancer care, creating an equivalency with other toxic and devastating side effects of cancer diagnosis and treatment [172]. A conceptual framework created by the National Cancer Institute (2018) relates numerous factors to financial toxicity, including illness status, insurance, medical and non-medical costs, and treatment choices, which can eventually affect health and financial outcomes [172]. Additional factors influencing the financial toxicity of cancer include out-of-pocket costs, such as co-payments, over-the-counter medications and supplies, childcare, transportation, parking, and meals; loss of income may also occur as a result of cancer diagnosis and treatment. This cost sharing has serious implications for all patients with

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cancer but particularly for patients with progressive chronic illness treated during a long period of time, such as women living with metastatic breast cancer [173]. High health care costs exist across all aspects of the breast cancer treatment continuum, from diagnosis to treatment and follow-up. Even in early-stage disease, breast cancer care can be chronic and expensive, characterized by multiple types and rounds of treatment [174]. For women with metastatic cancer, treatment is often sequential and involves expensive chemotherapy or immunotherapy that lasts several months to years. During treatment and into survivorship, patients with cancer and their families are more vulnerable to financial problems and at higher risk for bankruptcy and financial distress than patients with other chronic illnesses. Older adults with advanced or metastatic cancer appear to be particularly susceptible due to a more limited social network and functional status [175]. In 2015, ASCO proposed a cost of cancer care framework that evaluates cancer treatments using three values: clinical benefit (efficacy), toxicity (safety), and cost (efficiency). Instead of focusing solely on the efficacy of cancer treatment, the framework theoretically empowers patients by integrating the cost and financial impact of cancer care into considerations of QoL, convenience, life circumstances, lifestyle, and personal finances [176]. This personalized approach is particularly compelling for women with metastatic breast cancer because of the myriad of subtype-specific treatment options available as they progress through the disease trajectory [176, 177]. To mitigate distress associated with financial toxicity, oncologists should be aware of the potential for financial toxicity and work within their clinical settings to implement proactive assessment for appropriate referral to financial counselors.

Case Study Vignette An 89-year-old woman with a past medical history of hormone receptor positive breast cancer (left breast) treated with mastectomy and adjuvant

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hormonal therapy at age 69 palpated a 1.5 cm lump in her right breast; biopsy showed an infiltrating ductal carcinoma, grade 3, ER-, PR-, HER2-tumor (triple negative). On the geriatric assessment, the patient is partially dependent in instrumental activities of daily living, independent in activities of daily living, has no weight loss (BMI 35), no history of falls (uses a walking aid), no cognitive complaints, and good social support. The patient underwent breast conserving surgery finding a 1.4 cm triple negative tumor, with 0/1 sentinel lymph nodes with metastatic disease. After surgery the patient stopped going outside alone and using public transportation. On her next clinical visit, her oncologist offered adjuvant chemotherapy with four cycles of docetaxel and cyclophosphamide (TC), followed by radiotherapy to the breast. She was very scared about receiving chemotherapy and worried about the adverse events of treatment. Her 10-year noncancer-specific life expectancy was estimated to be of approximately 34% (using the Lee-Schonberg index), while the overall survival benefit of adjuvant chemotherapy was calculated to be of 3% (according to the Predict model). The predicted probability of grade 3–5 toxicity, according to the CARG chemotherapy toxicity tool, was of 50%. After analyzing her options, the patient decided to forego chemotherapy due to the limited benefit in survival, but accepted to receive radiation. Three months after surgery, she had recovered from the deficits and was going alone again and using public transportation, without any sign of relapse.

Conclusions The approach to an older adult with breast cancer goes beyond traditional tumor-related factors and requires the collaboration of multidisciplinary teams with both geriatric and oncology expertise. Throughout the care continuum, the patient’s overall health, life expectancy, and geriatric assessment characteristics should always be taken into account when making decisions, since not doing this might lead to both over and under treatment. Although the inclusion of

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older adults in RCT of novel breast cancer therapies is limited, currently available data support treating fit older patients using standard treatments developed in younger populations. For more vulnerable or frail older adults, evidencebased treatment modifications can be implemented after discussing their risks and benefits. Fortunately for the practicing clinician, there are a growing number of freely available resources designed to help in shared decisionmaking, including tools for the calculation of treatment benefit, life expectancy, and treatment toxicity, which are easily accessible and practical. Furthermore, there is increasing evidence of the benefits of creating multidisciplinary teams with geriatric expertise in order to co-manage patients with cancer across the disease spectrum, both for cancer-specific outcomes and for the mitigation of geriatric deficits. Finally, it is important to acknowledge that the social and financial aspects of breast cancer are vastly understudied in older populations, particularly those from diverse ethnic/racial groups, and that this is an area for future investigation.

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852 123. Sonke GS, Hart LL, Campone M, Erdkamp F, Janni W, Verma S, et al. Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial. Breast Cancer Res Treat. 2018;167(3):659–69. 124. DeLaurentiis M, Borstnar S, Campone M, Warner E, Bofill S, Jacot W, et al. Interim results from the full population of the phase 3b CompLEEment-1 study of ribociclib (RIBO) plus letrozole (LET) in the treatment of HR+/HER2– advanced breast cancer (ABC). J Clin Oncol. 2019;37(suppl 15):1041. 125. Pritchard KI, Burris HA 3rd, Ito Y, Rugo HS, Dakhil S, Hortobagyi GN, et al. Safety and efficacy of everolimus with exemestane vs. exemestane alone in elderly patients with HER2-negative, hormone receptor-positive breast cancer in BOLERO-2. Clin Breast Cancer. 2013;13(6):421–32.e8. 126. Jerusalem G, Mariani G, Ciruelos EM, Martin M, Tjan-Heijnen VC, Neven P, et al. Safety of everolimus plus exemestane in patients with hormone-receptorpositive, HER2-negative locally advanced or metastatic breast cancer progressing on prior non-steroidal aromatase inhibitors: primary results of a phase IIIb, open-label, single-arm, expanded-access multicenter trial (BALLET). Ann Oncol. 2016;27(9):1719–25. 127. Brain E, Caillet P, de Glas N, Biganzoli L, Cheng K, Lago LD, et al. HER2-targeted treatment for older patients with breast cancer: an expert position paper from the International Society of Geriatric Oncology. J Geriatr Oncol. 2019;10(6):1003–13. 128. Wildiers H, Tryfonidis K, Dal Lago L, Vuylsteke P, Curigliano G, Waters S, et al. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the elderly task force/ breast cancer group. Lancet Oncol. 2018;19(3):323–36. 129. Rimawi M, Ferrero J-M, de la Haba-Rodriguez J, Poole C, De Placido S, Osborne CK, et al. First-line Trastuzumab plus an aromatase inhibitor, with or without Pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): a randomized, open-label phase II trial. J Clin Oncol Off J Am Soc Clin Oncol. 2018;36(28):2826–35. 130. Cardoso F, Bedard PL, Winer EP, Pagani O, SenkusKonefka E, Fallowfield LJ, et al. International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst. 2009;101(17):1174–81. 131. Muss H, Cortes J, Vahdat LT, Cardoso F, Twelves C, Wanders J, et al. Eribulin monotherapy in patients aged 70 years and older with metastatic breast cancer. Oncologist. 2014;19(4):318–27. 132. Leo S, Arnoldi E, Repetto L, Coccorullo Z, Cinieri S, Fedele P, et al. Eribulin Mesylate as third or subsequent line chemotherapy for elderly patients with locally recurrent or metastatic breast cancer: a

G. Henríquez et al. multicentric observational study of GIOGer (Italian Group of Geriatric Oncology)-ERIBE. Oncologist. 2019;24(6):e232–e40. 133. Aapro M, Tjulandin S, Bhar P, Gradishar W. Weekly nab-paclitaxel is safe and effective in 65 years old patients with metastatic breast cancer: a post-hoc analysis. Breast. 2011;20(5):468–74. 134. Hind D, Wyld L, Beverley CB, Reed MW. Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus). Cochrane Database Syst Rev. 2006;1: Cd004272. 135. Morgan JL, Reed MW, Wyld L. Primary endocrine therapy as a treatment for older women with operable breast cancer – a comparison of randomised controlled trial and cohort study findings. Eur J Surg Oncol. 2014;40(6):676–84. 136. Chakrabarti J, Kenny FS, Syed BM, Robertson JF, Blamey RW, Cheung KL. A randomised trial of mastectomy only versus tamoxifen for treating elderly patients with operable primary breast cancer-final results at 20-year follow-up. Crit Rev Oncol Hematol. 2011;78(3):260–4. 137. Johnston SJ, Kenny FS, Syed BM, Robertson JF, Pinder SE, Winterbottom L, et al. A randomised trial of primary tamoxifen versus mastectomy plus adjuvant tamoxifen in fit elderly women with invasive breast carcinoma of high oestrogen receptor content: long-term results at 20 years of follow-up. Ann Oncol. 2012;23(9):2296–300. 138. de Glas NA, Jonker JM, Bastiaannet E, de Craen AJ, van de Velde CJ, Siesling S, et al. Impact of omission of surgery on survival of older patients with breast cancer. Br J Surg. 2014;101(11):1397–404. 139. Syed BM, Parks RM, Cheung KL. Management of operable primary breast cancer in older women. Womens Health (Lond). 2014;10(4):405–22. 140. Liposits G, Loh KP, Soto-Perez-de-Celis E, Dumas L, Battisti NML, Kadambi S, et al. PARP inhibitors in older patients with ovarian and breast cancer: young International Society of Geriatric Oncology review paper. J Geriatr Oncol. 2019;10(2):337–45. 141. André F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, et al. Alpelisib for PIK3CAmutated, hormone receptor–positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–40. 142. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and Nab-Paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–21. 143. van Holstein Y, Kapiteijn E, Bastiaannet E, van den Bos F, Portielje J, de Glas NA. Efficacy and adverse events of immunotherapy with checkpoint inhibitors in older patients with cancer. Drugs Aging. 2019;36 (10):927–38. 144. Li J, Luo X, Cao Q, Lin Y, Xu Y, Li Q. Communication needs of cancer patients and/or caregivers: a critical literature review. J Oncol. 2020;2020: 7432849.

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145. Le Saux O, Lapotre-Aurelle S, Watelet S, CastelKremer E, Lecardonnel C, Murard-Reeman F, et al. Systematic review of care needs for older patients treated with anticancer drugs. J Geriatr Oncol. 2018;9(5):441–50. 146. Wang SY, Kelly G, Gross C, Killelea BK, Mougalian S, Presley C, et al. Information needs of older women with early-stage breast cancer when making radiation therapy decisions. Int J Radiat Oncol Biol Phys. 2017;98(4):733–40. 147. Schonberg MA, Freedman RA, Recht AR, Jacobson AR, Aliberti GM, Karamourtopoulos M, et al. Developing a patient decision aid for women aged 70 and older with early stage, estrogen receptor positive, HER2 negative, breast cancer. J Geriatr Oncol. 2019;10(6):980–6. 148. Lifford KJ, Edwards A, Burton M, Harder H, Armitage F, Morgan JL, et al. Efficient development and usability testing of decision support interventions for older women with breast cancer. Patient Prefer Adherence. 2019;13:131–43. 149. Burton M, Collins KA, Lifford KJ, Brain K, Wyld L, Caldon L, et al. The information and decision support needs of older women (>75 yrs) facing treatment choices for breast cancer: a qualitative study. Psychooncology. 2015;24(8):878–84. 150. Ulloa JG, Hemmelgarn M, Viveros L, Odele P, Feldman NR, Ganz PA, et al. Improving breast cancer survivors’ knowledge using a patient-centered intervention. Surgery. 2015;158(3):669–75. 151. Arati Rao HJC. Symptom management in the elderly cancer patient: fatigue, pain, and depression. JNCI Monographs. 2004;32:150–7. 152. Naeim A, Aapro M, Subbarao R, Balducci L. Supportive care considerations for older adults with cancer. J Clin Oncol. 2014;32(24):2627–34. 153. Gerber LH, Stout N, McGarvey C, Soballe P, Shieh CY, Diao G, et al. Factors predicting clinically significant fatigue in women following treatment for primary breast cancer. Support Care Cancer. 2011;19 (10):1581–91. 154. Fu MR, Rosedale M. Breast cancer survivors’ experiences of lymphedema-related symptoms. J Pain Symptom Manag. 2009;38(6):849–59. 155. Radice D, Redaelli A. Breast cancer management: quality-of-life and cost considerations. PharmacoEconomics. 2003;21(6):383–96. 156. Turner N, Zafarana E, Becheri D, Mottino G, Biganzoli L. Breast cancer in the elderly: which lessons have we learned? Future Oncol. 2013;9(12): 1871–81. 157. Crivellari D, Aapro M, Leonard R, von Minckwitz G, Brain E, Goldhirsch A, et al. Breast cancer in the elderly. J Clin Oncol. 2007;25(14):1882–90. 158. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2015;33(28):3199–212.

853 159. Laribi K, Badinand D, Janoray P, Benabed K, Mouysset J-L, Fabre E, et al. Filgrastim prophylaxis in elderly cancer patients in the real-life setting: a French multicenter observational study, the TULIP study. Support Care Cancer. 2019;27(11):4283–92. 160. Varghese F, Wong J. Breast cancer in the elderly. Surg Clin North Am. 2018;98(4):819–33. 161. Wishart GC, Azzato EM, Greenberg DC, Rashbass J, Kearins O, Lawrence G, et al. PREDICT: a new UK prognostic model that predicts survival following surgery for invasive breast cancer. Breast Cancer Res. 2010;12(1):R1. 162. Candido Dos Reis FJ, Wishart GC, Dicks EM, Greenberg D, Rashbass J, Schmidt MK, et al. An updated PREDICT breast cancer prognostication and treatment benefit prediction model with independent validation. Breast Cancer Res. 2017;19 (1):58. 163. de Glas NA, Bastiaannet E, Engels CC, de Craen AJ, Putter H, van de Velde CJ, et al. Validity of the online PREDICT tool in older patients with breast cancer: a population-based study. Br J Cancer. 2016;114(4): 395–400. 164. Verduzco-Aguirre HC, Gomez-Moreno C, ChavarriGuerra Y, Soto-Perez-de-Celis E. Predicting life expectancy for older adults with cancer in clinical practice: implications for shared decision-making. Curr Oncol Rep. 2019;21(8):68. 165. Lux MP, Bayer CM, Loehberg CR, Fasching PA, Schrauder MG, Bani MR, et al. Shared decisionmaking in metastatic breast cancer: discrepancy between the expected prolongation of life and treatment efficacy between patients and physicians, and influencing factors. Breast Cancer Res Treat. 2013;139(2):429–40. 166. Dean LT, Gehlert S, Neuhouser ML, Oh A, Zanetti K, Goodman M, et al. Social factors matter in cancer risk and survivorship. Cancer Causes Control. 2018;29 (7):611–8. 167. Organization WH. World conference on social determinants of health: case studies on social determinants. 2014. Available from: http://www.who.int/ sdhconference/resources/case_studies/en/. 168. Coughlin SS. Social determinants of breast cancer risk, stage, and survival. Breast Cancer Res Treat. 2019;177(3):537–48. 169. Montroni I, Rocchi M, Santini D, Ceccarelli C, Ghignone F, Zattoni D, et al. Has breast cancer in the elderly remained the same over recent decades? A comparison of two groups of patients 70years or older treated for breast cancer twenty years apart. J Geriatr Oncol. 2014;5(3):260–5. 170. Gosain R, Pollock Y, Jain D. Age-related disparity: breast cancer in the elderly. Curr Oncol Rep. 2016;18 (11):69. 171. Joyce DP, O’Neill C, Heneghan HM, Curran C, Barry K, Sweeney K, et al. The changing cost of breast cancer care: lessons from a centralised modern cancer centre. Ir J Med Sci. 2019;188(2):409–14.

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Colorectal Cancer in Older Adults

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Armin Shahrokni, Helen Pozdniakova, and Brandon Nightingale

Contents Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856 Transitioning from Age to Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857 Assessing Frailty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857 Borrowing From Frailty to Create Predictive Models for Outcomes of Older Adults with Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860 Frailty Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861 What Geriatricians Need to Know About Colorectal Cancer Treatment . . . . . . . . . 862 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

Abstract

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of death among all malignancies. Despite advances in colorectal cancer screening, the number of deaths has increased. Given that the incidence of colorectal cancer increases with age, it’s important to tailor treatment to this population with special needs. Here we discuss how to incorporate frailty, rather than age, to assess perioperative outcomes. To this end, several useful scoring systems that can easily be incorporated into

general practice have been developed. In addition, chemotherapy risk calculators such as CARG or G8 can help predict the likelihood of chemotherapy toxicity in older patients. Focused geriatric assessment in patients with colorectal cancer is associated with improved outcomes such as a decrease in the incidence of chemotherapy toxicity and decreased risk of falls. Overall, geriatricians are an important part of the oncological treatment course and can advocate for their patients to receive tailored treatments to their functional status rather than their age alone. Keywords

A. Shahrokni (*) · H. Pozdniakova · B. Nightingale Department of Medicine, Jersey Shore University Medical Center, Neptune, NJ, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_78

Colorectal cancer · Fraility · Geriatric oncology · CARG · Chemotherapy

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Epidemiology Colorectal cancer is the third most commonly diagnosed cancer. It is also the second leading cause of death among all malignancies. Despite advances in colorectal cancer screening, the number of deaths from colon and rectal cancer has increased by 71% as of the year 2023 [1]. The rate of diagnosis and death due to colorectal cancer differs per country, likely due to factors such as diet and lifestyle [2]. In general, the risk increases by consumption of more red and processed meat and/or alcohol intake and lack of physical activity [2]. Body weight is also associated with the incidence and outcomes of patients with colorectal cancer [3]. In the United States, approximately 147,000 and 53,000 patients were diagnosed and died from colorectal cancer, respectively, in the year 2020. Although the incidence of colorectal cancer dropped slightly for patients aged 65 and older from 2011 to 2016, the overwhelming majority of colorectal cancer diagnoses still occurred in this patient population [4]. The cost of colorectal cancer treatment differs significantly based on the country that the patient resides and characteristics of their healthcare system. One study assessed the economic burden of colorectal cancer in Europe. It found that the cost of colorectal cancer treatment reached approximately 19 billion euros (approximately 20 billion USD). Within this cost, approximately 11 billion euros were because of loss of productivity due to disability, early mortality, and the cost of formal and informal caregivers. An additional seven and a half billion euros were lost due to hospitalizations, outpatient care, primary care, and emergency care. However, even within Europe, there is a significant variation in cost within each country [5]. Within the United States, the cost of colorectal cancer treatment in the first year of diagnosis is approximately $63,000 dollars per patient, with the majority of cost being from treatment. In addition, the cost of colorectal cancer treatment increased significantly in the last 6 months of life, especially in the last month of life. Similar to the first year of diagnosis, a

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significant majority of cost in the last 6 months of life was associated with the cost of inpatient care [6]. In addition to the cost associated with inpatient care, the rise in the cost of novel drugs also creates more financial strain for the patients, families, and healthcare systems. A retrospective study among Medicare beneficiaries showed that the share of cancer costs to Medicare in relation to novel targeted therapies increased substantially from 2006 to 2015. In this study, the share of cost for the targeted therapies increased from approximately 12–22% within this time period [7]. Another study showed that the progression of colorectal cancer is associated with the progression of financial cost. In this retrospective study, authors used U.S. administrative claims data from commercial and Medicare Advantage healthcare enrollees from 2006 to 2014. They found that the cost of healthcare was approximately two times higher among those whose cancer progressed versus those who did not [8]. The trend in incidence and mortality of colorectal cancer is a tale of two cities both in age of the population, and socioeconomic status of different countries. One study looked at the incidence of and mortality from colorectal cancer in 36 different countries. It found that the incidence of colorectal cancer increased in 10 out of 36 studied countries from the mid-2000s to mid-2010s. All 10 of these countries had medium-to-high Human Development Index (HDI), while six countries experienced a decline in the incidence of colorectal cancer, and these countries had the highest HDI. Twenty-four countries (out of the total of 36 countries) reported a decrease in mortality from colorectal cancer [9]. Nonetheless, it is expected that, each year, thousands of older adults will be diagnosed with colorectal cancer either as they go through colorectal cancer diagnosis workup because they are symptomatic or through colorectal cancer screening. As a result, the role of geriatricians in assisting different cancer care providers and patients and/or their families is crucial. In the next sections, we will review different modalities of colorectal cancer treatment and how a geriatrician can be helpful.

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Transitioning from Age to Frailty One of the most important steps in improving care and outcomes of older adults with cancer is moving beyond age and transforming age into frailty. Frailty is defined as the body’s decreased ability to withstand stress [10]. This means that if two patients receive the same level of stress to their bodies, the one who is more frail is more likely to have a negative experience than a patient who is fit. Still, one of the most important factors in frailty is chronological age [11]. As a person’s age increases, the possibility of that person becoming frail or having worsening of frailty increases significantly. This could be the reason why many studies, especially those based on real-world datasets, have found that older age is associated with poorer cancer outcomes. A systematic review on 29 studies on outcomes of metastatic colorectal cancer following surgical and locoregional treatment showed that older patients undergoing liver surgery for metastatic colorectal cancer were 2.5 times more likely to experience postoperative mortality and also had shorter overall survival [12]. Another study compared outcomes of patients younger than age 65 to those older and found that compared to 710 patients younger than age 65, older patients, especially those who were older than age 75, were less likely to undergo resection of liver metastasis (65% vs. 42%), and even among those who underwent resection, the postoperative mortality was substantially higher in older patient population. While the 90-day postoperative mortality happened in only 2% of patients younger than age 65, that rate increased to 8% among patients older than age 75 [13]. To improve such outcomes, researchers have investigated the impact of laparoscopic resection of liver metastasis compared to open surgery. One study assessed outcomes of 775 patients older than age 70 following open versus laparoscopic surgery. They found that laparoscopic surgery leads to less blood loss, less overall morbidity (22% vs. 39%), and shorter hospital length of stay (5 vs. 8 days) but with the same overall survival (51 vs. 45 months) [14]. Another study looked at the difference in the outcomes of patients who underwent open versus laparoscopic hemi-

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colectomy and found that among approximately 80,000 hemi-colectomies, 40% were laparoscopic surgeries. They found that regardless of age, patients who underwent laparoscopic surgery had a 20% reduction in 30-day readmission rate, and patients had shorter length of stay [15]. These studies, whether those who studied the relationship between age and outcomes, or those who have tried to improve outcomes of older patients by using various novel techniques, are limited in various ways. First, age is a non-modifiable factor. There is no way that one can reverse the clock and make an “older” patient become younger. Second, although it provides an easy target for clinicians whether cancer care providers, primary care providers, or geriatricians to offer or not offer certain cancer treatments, it misses the point that age is just a number. In our daily clinic experience, we have seen “older” patients who run a marathon, or run a company, or happily participate in various vigorous activities, and we have seen “younger” patients who possibly due to non-fault of their own suffer from severe and multiple comorbidities and are unable to perform certain simple activities of daily living. Studies only look at the relationship between age and outcomes, bundle healthy, and active older adults with non-healthy and inactive older adults together and do the same for healthy and unhealthy younger adults. Third, there is no denying that the care of older adults with cancer is complex. They are in general more likely to suffer from different comorbidities and have aging-related syndromes, otherwise known as geriatric syndromes. However, by creating a narrative of relating poor outcomes to age of a patient, a non-modifiable factor, we reduce the incentives for the investigators to assess interventions that can be aimed at improving the care and outcomes of older adults with any cancer. That is why some have argued that the age of talking about age alone is over [16].

Assessing Frailty Geriatric assessment, an assessment performed by the geriatric care provider, is the gold standard for frailty assessment [17]. This is a comprehensive

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assessment of older adults that typically starts by assessing cognitive function through tools such as the Mini-Cog [18] or Mini-Mental State Exam [19]. Additionally, it covers issues such as presence and severity of various comorbidities, nutritional status, polypharmacy, gait and balance, history of falls, social support and activity, and emotional well-being. However, a comprehensive geriatric assessment may take up to 60 min to complete, making it infeasible in fast-paced oncology or primary care clinics. Despite this, many argue that the value of the geriatric assessment is so high that oncologists and healthcare institutions should make every effort to perform it routinely [20]. Geriatric assessment is associated with outcomes of patients with colorectal cancer. One study consisting of 178 patients aged 70 and older explored outcomes of these patients based on frailty assessed by geriatric assessment. Among these patients, 12% were fit, 46% were intermediate, and 43% were frail. Frailty was associated with a significant increase in the risk of postoperative morbidity and mortality. Among fit patients, only 33% of patients experienced severe complications while this risk increased to 62% among frail patients [21]. Another study assessed 182 patients with colorectal cancer with the median age of 80 and found that severe comorbidity was independently associated with severe postoperative complications and early mortality. Moreover, dependency in instrumental activities of daily living and depression were associated with any complication, and poor nutritional status predicted early mortality [22]. In a study of 240 patients with an average age of 77, approximately 40% of patients were deemed high risk based on geriatric assessment (high risk was defined as having impairments in two or more geriatric assessment domains). Being in the high-risk category was associated with two times higher likelihood of postoperative complications [23]. In another, very large study consisting of more than 1000 patients older than age 75 who underwent various oncologic surgeries, the authors found that for each aging-related impairment, the risk of 6-month postoperative mortality increases by about 14% despite adjustment for

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various strong confounding factors [24]. Another study on 193 patients with an average age of 77 who had colorectal cancer showed that geriatric assessment can identify issues that were not previously known to the cancer care team, and more importantly, baseline aging-related impairments were predictors of future functional decline in this patient population [25]. A systematic review included six studies with more than 1000 patients who underwent gastrointestinal cancer surgery and assessed whether geriatric assessment is associated with patient outcome. It found that more comorbidities, polypharmacy, and dependency for activities of daily living were associated with postoperative complications of patients with gastrointestinal cancer [26]. These are just a small sample of studies that have shown the value of geriatric assessment in predicting outcomes of older adults with colorectal cancer. Although geriatric assessment might be difficult to implement in a fast-paced surgery or oncology clinic or in a primary care clinic in which general practitioner may not be aware of geriatric assessment and its value, however, one can argue that geriatric assessment should be performed in the geriatric clinic where geriatric care providers are practicing. The evidence to support the value of geriatric assessment in different phases of cancer care is substantial, and as a result, the value of a geriatric care provider who performs geriatric assessment is also substantial for both patients, their families, and referring oncologic providers. In addition to the gold standard of frailty assessment and geriatric assessment, we also have shorter and easier-to-administer frailty assessments, which can more readily be implemented in routine care. These instruments are mainly categorized into two models: the phenotype model and the cumulative aging impairment model [27]. The Fried Frailty Index [28] is one of the most commonly used frailty assessment tools based on the phenotype model. It assesses five factors, including involuntary loss of 10 pounds or more in the past 6 months, reduced grip strength, difficulty initiating movements, reduced walking speed, and fatigue. Patients with no impairments are considered fit, those with one or two

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impairments are pre-frail, and those with a higher number of impairments are considered frail. One study included 48 patients with colorectal cancer with the mean age of 82 whose frailty was assessed by Fried Frailty Index. It found that frail patients, as determined by Fried Frailty Index, were at higher risk for functional decline in the future [29]. A systematic review that evaluated 17 studies on more than 123,000 patients for their findings on the impact of frailty on clinical outcomes of colorectal cancer surgery found that frailty was assessed by a very diverse group of instruments, ranging from the Fried Frailty Index to G8 and some other instruments. Nonetheless, the systematic review, once again, found that frailty is a predictor of poor surgical outcomes [30]. The second category is frailty instrument, the cumulative aging impairment model, which is based on the theory that, as we age, we accumulate various aging-related impairments [31]. The more of these impairments we accumulate, the more frail we become, and consequently, we become more susceptible to adverse outcomes during and after cancer treatment. In one study, researchers used a Web-based geriatric assessment tool called electronic rapid fitness assessment to assess the frailty of cancer patients [24]. The study found that the number of aging-related impairments was associated with a 6-month survival rate following cancer surgery. Even after adjusting for factors such as age and American Society of Anesthesiologists-Physical Status classification, each additional aging-related impairment was associated with a 14% increase in 6-month mortality following cancer surgery. Other studies have also shown that the accumulation of aging-related impairments is associated with mortality, chemotherapy toxicity, and the risk of institutionalization [32–36]. We also have evidence specific to patients with colorectal or gastrointestinal cancer. For example, one study assessed outcomes of 75 patients older than age 65 who underwent abdominal surgery because of solid cancer. It found that the number of agingrelated impairments is associated with 30-day postoperative morbidity [34]. Another study on 195 patients aged 75 and older with stage II and III colorectal cancer showed that the number of

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aging-related impairments is associated with survival and discriminating between causes for mortality (cancer vs. non-cancer) [37]. Researchers have also developed and studied other solutions to facilitate the use of frailty instruments in fast-paced routine oncology or primary care clinics. For example, most instruments need personnel and ask patients to complete the assessment on paper. Instead of using paper questionnaires and hiring personnel to administer the assessment, Web-based geriatric assessment tools have been developed. These tools have been shown to be feasible in patients older than age 75 going for surgery, older patients who are receiving chemotherapy, and minority patients [38–41]. However, a Web-based geriatric assessment is not without challenges. A study has shown that the degree of patient frailty is associated with their ability to complete these Web-based tools [42]. The more frail the patients are, the more likely they need assistance from others to complete these online questionnaires. This means that those who do not have anyone to assist them (such as those with poor social support) or institutions with limited resources may be left behind. Moreover, the same study also showed that among patients who are independent in completing the online geriatric assessment, those who are more frail took longer to complete the assessment than those who are fit. This is significant because oncology clinics are fast-paced, and staff should be aware of the relationship between the degree of frailty of patients and the time that they take to complete the assessment. These clinics should provide additional support for these patients or be mindful that a slower pace of completing these assessments may be a surrogate for the patients’ frailty status. Nonetheless, to provide an alternative for patients whose frailty impedes them from completing a Web-based geriatric assessment, some have explored voiceassisted solutions [43]. These solutions, which some might be familiar with names like Alexa or Siri, automatically read the questions to the patients and then register patients’ responses without any involvement from personnel. In summary, geriatricians and geriatric care providers as experts in assessing frailty in older individuals who suffer from cancer. In addition,

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they possess the knowledge on the relationship between frailty and various health-related outcomes. A collaborative approach between healthcare providers and geriatricians can help to improve overall patient outcome, especially in patients who are suffering from cancer.

Borrowing From Frailty to Create Predictive Models for Outcomes of Older Adults with Cancer Over the course of the past decade, investigators have developed predictive models for the outcomes of older adults with cancer. Cancer & Aging Research Group (CARG) developed a chemotherapy risk calculator for older adults with cancer [44]. In this study, the authors enrolled 500 patients older than age 65, with the average age of 73, who were receiving chemotherapy from seven institutions within the United States. Among these patients, lung cancer (29%) and gastrointestinal cancer (27%) were the most common types of cancer. Through the course of study, high-grade chemotherapy toxicity occurred in more than half of patients. In the initial analysis, factors such as age, cancer type, different chemotherapy protocols (standard vs. modified dosing, single vs. polychemotherapy), and factors related to geriatric assessment (such as falling more than once in the past 6 months) were associated with the development of chemotherapy toxicity. Following this, the authors developed a predictive model where each of the above variables is assigned a different point value as seen in Table 1. One point is assigned for the following criteria: if they need help or are unable to take their

medications and if they have decreased social activity. Two points are assigned for age above 71 years, gastrointestinal or genitourinary cancer, use of standard dose of chemotherapy, polychemotherapy, self-reported hearing as fair or worse, and their ability to walk one block is somewhat or very limited. Three points are assigned for a hemoglobin 70 years old) once docetaxel treatment has failed. The studied dose of cabazitaxel is 25 mg/m2 every 3 weeks + prednisone 10 mg daily, and it was initially compared to mitoxantrone + prednisone [150]. Almost 20% of the patients included were
75 years old (all with ECOG 0–2). The response rate was 14.4% (9.6–19.3), and OS was better for the cabazitaxel group at 15.1 vs. 12.7 months (HR 0.7, 95% CI 0.59–0.83, p < 0.0001); median progression-free

Negative characteristics - Risk of seizures 1–3% - Significant fatigue

Key aspects to monitor - Blood pressure - Risk factors for seizures

- Requires prednisone 5–10 mg daily - Metabolic syndrome - Risk of hypokalemia - Greater risk of cardiac side effects - Risk of seizures - Risk of hypothyroidism - Risk of rash - Limited “real world” experience

- Blood pressure - Metabolic syndrome - Serum electrolytes - Liver function testing

- Blood pressure - Risk factors for seizures - Thyroid function testing - Blood pressure

survival was also superior in the cabazitaxel-treated patients. Older patients do have oncological benefits, but toxicity was higher compared to younger patients. Grade
3 complications included neutropenia (82%), febrile neutropenia (8%), and diarrhea (6%), but interestingly, there were no grade
3 peripheral neuropathy cases (which can be seen in some patients with docetaxel). Age
65 years old was associated with a higher risk for development of neutropenia, and age > 75, first cycle, and a pre-cabazitaxel neutrophil count 4000/mm3 were all predictors of neutropenic complications such as febrile neutropenia and severe infections. The use of prophylactic granulocyte colony stimulating factor can diminish neutropenia-related complications in the geriatric population (30% less probability for each given cycle) [151], and it can be given on the same day as cabazitaxel [152]. Furthermore, the FIRSTANA trial showed that a lower dose (20 mg/m2 every 3 weeks) was also effective and had fewer side effects [153]. QoL has been shown to improve in symptomatic men with mCRPC who received prior docetaxel [154]. Recently, cabazitaxel was compared with an ARAT (abiraterone or enzalutamide) in an RCT as a third-line treatment in men with mCRPC who had already received docetaxel and another ARAT (abiraterone or enzalutamide). Interestingly, cabazitaxel was superior in terms of OS and disease progression by imaging. Time to disease progression evidenced by imaging was 8.0 months

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with cabazitaxel vs. 3.7 months with the ARAT. This provides some insights into the sequence in which treatments should be utilized [155]. Importantly, whenever considering the sequencing of agents, one needs to reassess the patient’s level of comorbidity and frailty, along with patient preferences, after each line of treatment.

Poly(adenosine diphosphate ribose) Polymerase Inhibitors Olaparib [156, 157], niraparib, rucaparib [158], and talazoparib are all poly(adenosine diphosphate [ADP] ribose) polymerase inhibitors (PARPi) that are being tested in mCRPC patients [159], proving to be an option for patients who have certain germline and/or somatic mutations. The phase 2 validation study for olaparib [156] obtained a 33% response rate. Interestingly, the benefit was seen when germline mutations were present (BRCA 1/2, ATM). The mean age was 67.5 years, and the study included patients with ECOG 0–2. They did include some patients >75 years old, but the sample was relatively small (total n ¼ 50) to do sub-analysis by age, so it is hard to make specific recommendations for older patients. OS was 13.8 months with Olaparib vs. 7.5 months with ADT (including abiraterone or enzalutamide) (HR 0.47, 95% CI 0.22–1.02, p ¼ 0.05). The benefit was corroborated in an open label Phase 3 study [157]. Relevant grade
3 side effects were anemia (21%), nausea (1%), fatigue (3%), and dyspnea (2%). QoL analyses in men with mCRPC were presented recently at the American Society of Clinical Oncology (ASCO) 2020 meeting, suggesting that men who received Olaparib did better than men who were treated with abiraterone or enzalutamide.

Metastasis-Directed Therapy When a patient is found to have PCa metastasis, we can further divide them into oligometastatic or polymetastatic. The definition of an oligometastatic state has varied significantly in the literature, and the concept is relatively recent. There is no consensus on the definitions used in the trials, ranging

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from 3 to 5 sites [160–162], and in some cases the authors restrict such definition to involvement of bones, but some authors accept the presence of visceral metastasis as part of their definitions [163, 164]. Treating oligometastatic sites with metastasis-targeted local therapy (typically radiation, less commonly surgical resection) has been shown to be successful in controlling the treated site, and seems to delay the use of ADT in these men [165, 166]. The benefit of such therapy in terms of survival remains to be proven. As previously mentioned, we have to be selective regarding the indications for these treatments, as not all patients will benefit from therapies to prolong an already limited life span, particularly older men with multiple comorbidities.

Emergency situations Acute Urinary Retention Patients with PCa can develop acute urinary retention (AUR), requiring urgent medical care. This complication can result from prostatic growth, prostatic inflammation following organ-preserving therapeutic treatments such as RT or focal therapies, or from treatment complications such as bladder neck contracture after RP or RT. Furthermore, some patients develop urethral strictures that could also result in AUR. Among men who have received any local treatment for PCa, the incidence of treatment-related urethral strictures is around 5.2% [167]. Imminent Fractures/Spinal Cord Compression As a complication from PCa metastases, patients can develop bone pain and pathologic fractures. The incidence varies based on the stage of the disease (5-year cumulative incidence of skeletalrelated events in localized PCa is 1%, in locally advanced disease is 6%, and in metastatic patients the incidence is 42.3%) [168]. In men with non-metastatic PCa who are undergoing ADT, denosumab has been proven to decrease the rate of vertebral fractures, and it is recommended given the bone loss associated with ADT [108]. Similarly, in men with high-risk PCa or with vertebral

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metastasis, it is recommended to either start ADT with gonadotropin-releasing hormone antagonists, or give a couple of weeks of treatment with an antiandrogen (i.e., bicalutamide) prior to starting treatment with a gonadotropinreleasing hormone agonist, given the initial flare of testosterone associated with the agonists, which could result in pathologic fractures. In mCRPC patients, the incidence of such events is related to the presence of bone pain, time from CRPC to the development of metastatic disease, time to develop CRPC, and the presence of visceral metastases [169]. In men with painful metastases, the recommendation is to use options such as palliative short-course radiation (one to five treatments) to the metastatic site, radium 233, or intravenous bisphosphonates [170]. Many spinal metastases are asymptomatic or mildly asymptomatic, so careful evaluation and monitoring of the patient should be in place. PSA rises, mild bone pain without a history of trauma or signs of cord compression should be carefully examined, and imaging studies should be done in case of suspicion. Prostate cancer metastases usually show up in bone scans or CT scans as blastic lesions [171].

Radiation Cystitis Radiation cystitis happens in 5% of patients who receive pelvic radiation [172]. The incidence can be acute (3–6 months after RT) or late (later than 6 months of RT). The usual presentation is hemorrhagic cystitis, with or without pain. Pain can be significant, and the cystitis can cause AUR secondary to the formation of clots. Initial treatment consists of the placement of a urinary catheter for bladder irrigation. If the bladder irrigation does not work, a three-way catheter can be placed for continuous irrigation of the bladder. Some patients may even need blood transfusions and intravenous fluid resuscitation. Urologic consultation is required as patients may need intravesical treatments, hyperbaric oxygen treatment, stopping anticoagulation in some anticoagulated patients, or even endoscopic laser treatments. As a last resort, men may require a cystectomy, but such treatment has a very high mortality rate (close to 50%) [172].

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Conclusions Prostate cancer is a very common disease in older adults that in most cases can be cured by surgery or radiation. We should strive to detect PCa in early stages in men, especially in men who could benefit from curative treatment (based on life expectancy, quality of life, and patient preferences). Given the slow progression of most PCa, careful decisionmaking should be done as part of a multidisciplinary evaluation, in order to select which patients will benefit from curative treatment, and which patients should be followed conservatively. Advanced PCa patients have a variety of systemic treatment options that, in most cases, are equally as effective and tolerable in older men and younger patients. We should give real expectations from treatments to patients and their relatives, and a geriatric evaluation is of utmost importance in order to achieve rational decision-making. Significant uncertainties remain about the management of more frail individuals with both early stage and advanced PCa.

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Gynecologic Oncology

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Sindhuja Kadambi and William P. Tew

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914 Overview of Gynecologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914 Symptoms at Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914 Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915 Disparities in Care of Older Adults with Gynecologic Malignancies . . . . . . . . . . . . . . 915 Individualized Care for Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916

Abstract

This chapter introduces key concepts and principals of diagnosis and management of gynecologic malignancies in older adults. It provides overview of the occurrence of different types of gynecologic cancers in older adults, general principals of diagnosis and treatment of these cancers, describes disparities in care for older adults with gynecologic cancers, and provides

S. Kadambi Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA e-mail: [email protected] W. P. Tew (*) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_81

recommendations to individualize their care. Symptoms at presentation vary by cancer type and stage, and screening is currently available and recommended only for cervical cancer. Treatment of gynecologic cancers also varies by cancer type and stage and can include surgery, radiation, and or systemic treatments such as chemotherapy. Older patients have worse outcomes than their younger counterparts and black and Latino women are less likely to receive standard of care and have worse outcomes compared to white women. The final section reviews available geriatric assessmentbased tools to be used during treatment decision-making to identify older women at high risk for adverse effects from cancer treatment.

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Keywords

Gynecologic cancers · Ovarian · Endometrial · Cervical · Vaginal · Vulvar · Disparities in care · Geriatric assessment

S. Kadambi and W. P. Tew Table 1 Risk factors for gynecologic malignancies Cancer type Vulvar Vaginal Cervical Endometrial

Introduction This chapter introduces key concepts and principals of diagnosis and management of gynecologic malignancies in older adults. It describes how gynecologic cancers disproportionately affect older women. It provides an overview of the occurrence of different types of gynecologic cancers in older adults and the principals of diagnosis and treatment of these cancers. The chapter also discusses disparities in care for older adults with gynecologic cancers, and recommendations to individualize their care.

Ovarian

Risk factors Human papilloma virus (HPV), sexually transmitted infection Immunodeficiency syndromes Oral contraceptive prolonged use Obesity Diabetes mellitus Early menarche Late menopause Nulliparity Postmenopausal unopposed estrogen use (oral, transdermal patch or vaginal ring) Tamoxifen therapy Polycystic ovary syndrome Familial history of endometrial, ovarian, breast, or colon cancer (i.e., lynch syndrome) Early menarche Last menopause Nulliparity Breast cancer gene (BRCA) 1/2 mutations Lynch syndrome Family history of endometrial, ovarian, breast, or colorectal cancer

Overview of Gynecologic Malignancies Gynecologic (GYN) cancers include ovarian, cervical, endometrial, vaginal, and vulvar cancers. In the USA, approximately 94,000 women are diagnosed with GYN cancers each year. GYN cancers disproportionately affect older women with 40–45% of new diagnoses and 65% of deaths occurring in women over the age of 65 [1]. The median age and the percentage of women diagnosed with these cancers who are over the age of 65 are as follows: ovarian 63 years, 46%; endometrial 63 years, 45%; vaginal 69 years, 58.7%; and vulvar cancer 69 years, 60%. As the population ages, the prevalence of these cancers are expected to increase [2]. The risk factors for these cancers are as listed in Table 1.

Symptoms at Presentation Symptoms at presentation of GYN malignancies vary by cancer type and stage. Vulvar cancer presents as an ulcer, plaque, or mass which may be associated with pruritus or bleeding. Vaginal cancers can present with postcoital or postmenopausal

bleeding and a vaginal mass on pelvic examination. Cervical cancer can present with postmenopausal or postcoital bleeding but is often incidentally found on pelvic examination or detected by PAP/HPV screening. Endometrial cancer will typically present with postmenopausal bleeding. Women with ovarian cancer will have nonspecific symptoms such as bloating, abdominal/pelvic pain, and increased urinary frequency and urgency. Abdominal distention and an adnexal mass may be detected on exam.

Screening There are currently no effective screening tools available for ovarian or endometrial cancer. Screening for cervical cancer is done with a Pap smear (cytology with HPV testing) every 5 years in women aged 30–65. Screening should be continued after age 65 in women with a history of carcinoma in situ (CIN) 2 or 3 or adenocarcinoma in situ and should be discontinued in women with an adequate screening history and no history of high-risk precancerous lesions.

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Gynecologic Oncology

Treatment Treatment for gynecologic malignancies differs by type and stage. Depending on histology and staging, treatment may involve surgery, radiation therapy, chemotherapy, and/or targeted therapies. Early stage, localized disease is generally treated with surgical resection. Radiation and/or chemotherapy are recommended postoperatively as adjuvant treatment or may be the primary modality of treatment for locally advanced stage diseases. The standard treatment for early stage cervical and endometrial cancer is a curative hysterectomy, which involves removal of the uterus, cervix, bilateral fallopian tubes, and ovaries. It can be performed via an open radical hysterectomy or using minimally invasive total laparoscopic approach. In older women, a laparoscopic approach compared to a laparotomy has been associated with decreased operative morbidity such wound infections, blood loss, and ileus [3]. Although it has been shown to be associated with similar disease-free and overall survival in early stage endometrial cancer, laparoscopic hysterectomy led to a higher risk of disease recurrence and death compared to radical hysterectomy for women with early stage cervical cancers [4–6]. In ovarian cancer, most cases are diagnosed at advanced stage, and standard treatment involves cytoreductive surgery and combination chemotherapy with a taxane-platinum combination. Surgical risk and outcomes worsen with increasing age and comorbidities. A SEER-Medicare analysis showed that of women aged 75+ with advanced ovarian cancer and at least one comorbidity undergoing cytoreductive surgery had a 30-day mortality of 12.7% [7]. Advancing age, increasing stage, and increasing comorbidity were all associated with increase in 30-day mortality. Other risk factors for poor outcomes with cytoreductive surgery include poor performance status and poor nutritional status [8]. Older women are more vulnerable to toxicities of chemotherapy. Compared to younger women with advanced stage ovarian cancer receiving standard platinum-taxane chemotherapy, women aged 70 years had lower completion rates, increased toxicities (neutropenia and neuropathy), and shorter

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median overall survival (OS, 37 vs. 45 months, p < 0.001) [9]. However, Falandry et al. found that in vulnerable older women with advanced stage ovarian cancer, carboplatin monotherapy was inferior to combination chemotherapy with carboplatin and paclitaxel either weekly or every 3 weeks in survival outcomes (OS 7.3, 17.3, and NR months, respectively, p < 0.001) [10]. Newer targeted agents such as Poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents such as bevacizumab are also increasingly used [11]. PAPR inhibitors although generally well tolerated are associated with side effects including fatigue, nausea, neutropenia, and anemia which can affect quality of life. Bevacizumab should be used with caution in older patients, particularly given risk of hypertension and thromboembolic events [12].

Disparities in Care of Older Adults with Gynecologic Malignancies Overall, older patients with GYN cancers have lower survival compared to their younger counterparts and survival decreases incrementally with advancing age [13]. Older women are more likely to present with higher grade tumors, advanced stage disease, have poorer performance status, and are less likely to receive standard treatment including cytoreductive surgery, chemotherapy, and radiation [9, 14, 15]. Studies also suggest that older black and Latino women are less likely than their white counterparts to receive standard treatment and have worse cancer-specific and overall survival [16, 17].

Individualized Care for Older Adults Treatment decision-making in older adults with gynecological malignancies is challenging. Older women are underrepresented in clinical trials that set the standard of care [18]. Age and performance status alone are insufficient to predict treatment tolerance. Older adults are more likely to have comorbidities, physical, cognitive, and functional impairments, polypharmacy, poor nutrition, and

916

limited social support [19]. In the gynecologic oncology population, the prevalence of frailty has been estimated to be 16–25%, and frail patients have increased risk of mortality, postoperative complications, and chemotherapy intolerance [1, 20]. To better inform decision-making, it is important to identify patients who can tolerate and benefit from standard aggressive treatment versus those who are at high risk for adverse effects of treatment. The comprehensive geriatric assessment (GA) is a multi-domain geriatric evaluation that has been utilized in cancer patients to stratify older adults based on fitness [21]. Currently, tools utilizing the GA and clinical and laboratory data exist to predict surgical outcomes (e.g., Perioperative Assessment in Elderly Cancer tool) [22] and chemotherapy tolerance (Cancer and Aging Research Group (CARG) tool and Chemotherapy Risk Assessment Scale for High-Age Patients score) [23, 24]. The CARG study included a small portion of women with ovarian cancer (50 patients, 10%), and retrospective subgroup analysis showed that grade 3–5 toxicities occurred in 19 patients (37%) [25]. There are limited tools, however, that are specific to GYN malignancies. Ahmed et al. have derived a preoperative GA-GYN score to evaluate postoperative risk in patients undergoing primary cytoreductive surgery and found a significant association between higher GA-GYN scores (indicating more vulnerable patients) and major postoperative complications in older women with advanced stage [26]. The Geriatric Vulnerability Score (GVS) was developed from chemotherapy trials in older women with ovarian cancer and is able to predict patients with lower rate of chemotherapy completion, higher rate of severe adverse events including unplanned hospitalizations, and worse overall survival [27]. Despite advances, there are significant unmet needs in treating older women with gynecologic malignancies. Much needed geriatric specific trials are currently underway to explore preoperative assessment, radiation, chemotherapy dosing and timing (neoadjuvant or postoperative), as well as targeted therapies that may be better tolerated. In the meantime, thoughtful discussions are required with older patients with gynecologic malignancies

S. Kadambi and W. P. Tew

as it pertains to risks and benefits of treatment. The GA can be utilized to identify patients who are at risk for worse outcomes and to develop supportive care interventions that may improve tolerability of surgery, radiation, and chemotherapy in this population.

Conclusions In conclusion, this chapter reviewed key concepts and principals of diagnosis and management of gynecologic malignancies in older adults. It discussed the incidence of gynecologic cancers in older adults, and symptoms at presentation. It provided an overview of the diagnosis and management of gynecologic cancers. Lastly, it discussed disparities in care and outcomes for older women with gynecologic cancers and reviewed how the geriatric assessment can assist in better treatment decision-making for these patients.

References 1. Hay CM, et al. Chemotherapy in older adult gynecologic oncology patients: can a phenotypic frailty score predict tolerance? Gynecol Oncol. 2019;152:304–9. https://doi.org/10.1016/j.ygyno.2018.11.031. 2. Howlader NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. SEER Cancer Statistics Review, 1975–2017, National Cancer Institute, https://seer. cancer.gov/csr/1975_2017/ (2020). 3. Scribner DR, et al. Surgical management of early-stage endometrial cancer in the elderly: is laparoscopy feasible? Gynecol Oncol. 2001;83:563–8. https://doi.org/ 10.1006/gyno.2001.6463. 4. Galaal K, Donkers H, Bryant A, Lopes AD. Laparoscopy versus laparotomy for the management of early stage endometrial cancer. Cochrane Database Syst Rev. 2018; https://doi.org/10.1002/ 14651858.CD006655.pub3. 5. Melamed A, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905–14. https://doi.org/10. 1056/NEJMoa1804923. 6. Ramirez PT, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895–904. https://doi.org/10.1056/ NEJMoa1806395. 7. Thrall MM, Goff BA, Symons RG, Flum DR, Gray HJ. Thirty-day mortality after primary cytoreductive

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surgery for advanced ovarian cancer in the elderly. Obstet Gynecol. 2011;118:537–47. https://doi.org/10. 1097/AOG.0b013e31822a6d56. 8. Aletti GD, et al. Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment. Gynecol Oncol. 2011;120:23–8. https://doi. org/10.1016/j.ygyno.2010.09.010. 9. Sia TY, et al. The effect of older age on treatment outcomes in women with advanced ovarian cancer receiving chemotherapy: An NRG-Oncology/ Gynecologic Oncology Group (GOG-0182-ICON5) ancillary study. Gynecol Oncol. 2023 Jun:173: 130-137. https://doi.org/10.1200/jco.2010.28.15_ suppl.5030. 10. Falandry C, et al. EWOC-1: a randomized trial to evaluate the feasibility of three different first-line chemotherapy regimens for vulnerable elderly women with ovarian cancer (OC): a GCIG-ENGOT-GINECO study. J Clin Oncol. 2019;37:5508–8. https://doi.org/ 10.1200/JCO.2019.37.15_suppl.5508. 11. Liposits G, et al. PARP inhibitors in older patients with ovarian and breast cancer: young International Society of Geriatric Oncology review paper. J Geriatr Oncol. 2019;10:337–45. https://doi.org/10.1016/j.jgo.2018. 10.008. 12. Venkatesulu BP, Mallick S, Rath GK. Patterns of care of cervical cancer in the elderly: a qualitative literature review. J Geriatr Oncol. 2017;8:108–16. https://doi. org/10.1016/j.jgo.2016.12.004. 13. Dumas L, et al. Improving outcomes for older women with gynaecological malignancies. Cancer Treat Rev. 2016;50:99–108. https://doi.org/10.1016/j.ctrv.2016. 08.007. 14. Sharma C, et al. Patterns of care and treatment outcomes for elderly women with cervical cancer. Cancer. 2012;118:3618–26. https://doi.org/10.1002/cncr. 26589. 15. Fairfield KM, et al. Completion of adjuvant chemotherapy and use of health Services for Older Women with Epithelial Ovarian Cancer. J Clin Oncol. 2011;29: 3921–6. https://doi.org/10.1200/jco.2010.34.1552. 16. Taylor JS, et al. Disparities in treatment and survival among elderly ovarian cancer patients. Gynecol Oncol. 2018;151:269–74. https://doi.org/10.1016/j.ygyno. 2018.08.041. 17. Rauh-Hain JA, et al. Racial disparities in treatment of high-grade endometrial cancer in the Medicare population. Obstet Gynecol. 2015;125:843–51. https://doi. org/10.1097/aog.0000000000000605.

917 18. Ludmir EB, et al. Factors associated with age disparities among cancer clinical trial participants. JAMA Oncol. 2019;5:1769–73. https://doi.org/10.1001/ jamaoncol.2019.2055. 19. Owusu C, Berger NA. Comprehensive geriatric assessment in the older cancer patient: coming of age in clinical cancer care. Clin Pract (Lond). 2014;11:749– 62. https://doi.org/10.2217/cpr.14.72. 20. Handforth C, et al. The prevalence and outcomes of frailty in older cancer patients: a systematic review. Ann Oncol. 2015;26:1091–101. https://doi.org/10. 1093/annonc/mdu540. 21. Mohile SG, et al. Practical assessment and Management of Vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J Clin Oncol. 2018;36:2326–47. https://doi.org/10. 1200/JCO.2018.78.8687. 22. PACE Participants, Audisio RA, Pope D, Ramesh HSJ, Gennari R, van Leeuwen BL, West C, Corsini G, Maffezzini M, Hoekstra HJ, Mobarak D, Bozzetti F, Colledan M, Wildiers H, Stotter A, Capewell A, Marshall E. Shall we operate? Preoperative assessment in elderly cancer patients (PACE) can help: a SIOG surgical task force prospective study. Crit Rev Oncol Hematol. 2008;65:156–63. https://doi.org/10.1016/j. critrevonc.2007.11.001. 23. Hurria A, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29:3457–65. https://doi.org/ 10.1200/jco.2011.34.7625. 24. Extermann M, et al. Predicting the risk of chemotherapy toxicity in older patients: the chemotherapy risk assessment scale for high-age patients (CRASH) score. Cancer. 2012;118:3377–86. https://doi.org/10.1002/cncr.26646. 25. Won E, et al. CA125 level association with chemotherapy toxicity and functional status in older women with ovarian cancer. Int J Gynecol Cancer. 2013;23:1022–8. https://doi.org/10.1097/IGC.0b013e318299438a. 26. Ahmed A, et al. Pre-operative assessment and postoperative outcomes of elderly women with gynecologic cancers, primary analysis of NRG CC-002: an NRG oncology group/gynecologic oncology group study. Gynecol Oncol. 2018;150:300–5. https://doi. org/10.1016/j.ygyno.2018.05.022. 27. Falandry C, et al. Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: a GINECO prospective trial. Ann Oncol. 2013;24:2808–13. https://doi.org/10.1093/annonc/mdt360.

Hematologic Malignancies

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Richard J. Lin

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920 Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920 Benign and Malignant Hematological Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Incidence, Etiology, and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Hematological Malignancies of Older Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Geriatric Assessment in Hematologic Malignancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk-Adapted Approaches to Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient Education, Communication, and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Integrated Care Delivery, Quality and Safety, Cost Implications . . . . . . . . . . . . . . . . . . . . . .

921 921 921 923 925 926 926

Case Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 1 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 2 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case 3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

927 927 927 928 928 928 928

Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929

Abstract

Older adults have increased incidence and prevalence of a variety of benign and malignant hematologic disorders. They range from common anemia and age-related clonal hematopoiesis to aggressive acute myeloid leukemia

R. J. Lin (*) Department of Medicine, Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_82

and high-grade lymphoma. Management of these patients can be challenging given highly prevalent, age-related comorbidities, functional impairment, and reduced physiologic reserve. Comprehensive geriatric assessment is increasingly incorporated into the clinical management of patients with hematologic malignancies, hematopoietic cell transplantation, and cellular therapy. Several geriatric assessment domains such as functional deficit, mobility impairment, cognitive dysfunction and multi-morbidity have been shown to be 919

920

prognostic of survival, treatment tolerance, toxicities, and healthcare resource utilization across many hematologic malignancies. Comprehensive geriatric assessment not only risk stratify but also help identify potentially remediable geriatric vulnerabilities and should be considered as the standard of care for older patients with advanced hematologic malignancies. In additional, treatment-related functional decline and quality of life are important considerations for older adults, and ideally are evaluated through comprehensive geriatric assessment, timely prognostic communication, and shared-decision making. While we await randomized evidence supporting a geriatric assessment-guided, risk-adapted treatment strategy for older patients with hematologic malignancies, it is perceivable that geriatric assessment-directed, targeted supportive care interventions will be crucial components in a longitudinal, integrated, collaborated model of care between hematologic oncologists and geriatricians/geriatric oncologists to improve older patient outcomes. Keywords

Older patients · Anemia · Clonal hematopoiesis · Hematologic malignancies · Geriatric assessment · Functional decline · Quality of life · Communication · Geriatric co-management · Geriatric hematology clinic

R. J. Lin

hallmarks, stem cell exhaustion, is characterized by the loss of regenerative potential in the hematopoietic compartment, i.e., hematopoiesis, and the diminished production of adaptive immune effector cells including T-cells and B-cells leading to age-related increase in the incidence of anemia and common hematologic malignancies [3]. Additional hallmarks of aging, such as telomere attrition and cellular senescence, may also contribute to the increased risk in hematologic disorders among older adults [2, 4]. These inter-connected aspects of “healthy” and “pathological” aging not only contribute to the development of a myriad of hematologic disorders in older people, they also present unique, specific challenges in the clinical management of these patients due to both increased vulnerabilities to treatment-related side effects and decreased resilience with regard to functional recovery [5]. Thus, hematologic malignancies at older age warrant a comprehensive, whole-person assessment and a risk-adapted therapeutic approach [6]. In addition, the reduced functional reserve in each individual organ system may have implications for how older people tolerate specific therapy in the short term and how quality of life and functional independence could be maintained long term [7]. This chapter summarizes the incidence, risk factors, clinical management, and unmet needs for important hematologic diseases in older adults and highlights potential research opportunities.

Learning Objectives Introduction Aging is the process of gradual accumulating biological, phenotypic, and functional changes in a person over time, typically manifesting as a gradual decline from one’s peak overall physiological performance and a reduction in functional reserve (resilience) [1]. In a landmark article, Lopez-Otin has described nine common biological hallmarks of aging that are important for both healthy aging and major human diseases including cancer [2]. One of the

1. To appreciate the incidence of hematologic diseases in older adults. 2. To understand the role of comprehensive geriatric assessment in evaluating older patients with hematologic malignancies. 3. To examine treatment outcomes in hematologic diseases for older patients. 4. To assess the impact of curative and palliative treatment approaches on the function and quality of life of older patients with hematologic diseases.

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Hematologic Malignancies

Benign and Malignant Hematological Diseases Incidence, Etiology, and Risk Factors World Health Organization (WHO) defines anemia as a hemoglobin level of 33%) of urine produced at night (nocturnal polyuria) [31]. Referral to a urological specialist may be indicated for men who desire a consultation after having failed to meet treatment goals with adequate attempts at behavioral and/or medication treatment to help the patient or caregiver meet their goals. An elevated post-void residual (there are no clear cutoffs for PVR, but likely for those with >250–400 mL) may indicate a need for a pressure flow urodynamic study or cystoscopy. A high PVR without evidence of BOO could indicate a poorly contractile bladder (detrusor hypocontractility), which would likely not respond to treatment for BPH. A high PVR and BOO (but not urinary retention) might merit surgical treatment. Incidental discoveries of an abnormal prostate examination on digital rectal examination or hematuria should prompt consultation.

Management Treatment for male LUTS/BPH can be instituted following a general history and physical examination. The general approach to treatment should be guided by the severity of symptoms, degree of

48

BPH and Male Lower Urinary Tract Symptoms

bother, and patient preference [10]. Generally speaking, treatment should start with behavioral therapy [1, 2] due to strong evidence that these approaches in men are efficacious [28, 32, 33] and have a low risk of side effects. Mr. Braun feels that he is bothered by his urinary symptoms, but he also feels that he already takes too many medications. Behavior and lifestyle changes include alterations to timing of fluid intake, trial of decreasing caffeine and alcohol, adjusting or avoiding diuretics, decongestants, antihistamines, and treatment of constipation [10]. Fluid intake prior to bedtime or before going out should be attempted. Reducing consumption of mild diuretics such as caffeine [34] and alcohol may be helpful with LUTS. Pelvic floor muscle training, including the use of biofeedback, may be particularly helpful for patients with urgency symptoms [18]. Many recognize the use of pelvic floor muscle exercises to be useful in women with stress urinary incontinence, but a growing literature has shown that urgency suppression strategies can be useful for women [35, 36] and men [28, 32, 33] with a variety of LUTS. Urge suppression strategies help the patient deal with the sudden and compelling sensation to void that is difficult to postpone. Instead of rushing to the toilet, which increases intra-abdominal pressure and exposure to visual cues that can trigger urgerelated symptoms and accidents, patients are asked to pause, sit down if possible, relax the entire body, and contract pelvic muscles repeatedly to diminish urgency and inhibit detrusor contraction [35]. This is often referred to as a freeze-and-squeeze technique. In a trial with 200 men with LUTS/BPH storage symptoms, behavioral therapy alone offered a better response at 6 weeks than did two-drug therapy [37]. Urge suppression strategies are likely NOT a useful strategy where patients have cognitive impairment to a sufficient degree such that they cannot practice PFME or implement urgency suppression strategies. In addition to a bladder diary being a useful diagnostic tool, it can also be a meaningful part of implementing behavioral therapy [1].

987

Mr. Navarro says that after starting tamsulosin 0.4 mg nightly that his symptoms were initially much better than when he first came in. But now they are about where they were previously. Medications are commonly used to treat BPH/male LUTS (Table 2), either as single drugs or combined, alone or in combination with behavioral therapy. Multiple categories of pharmacological agents are efficacious in managing BPH/male LUTS. These include alpha-adrenergic antagonists (“α-blocker”), antimuscarinic anticholinergic medications (“anticholinergics”), 5-alpha reductase inhibitors (“5ARIs,” which patients may refer to as prostate-shrinkers), betathree agonists (“β-3-agonists”), and phosphodiesterase-5 inhibitors (“PDE5i”). These medications are used widely in older persons [38]. There are special considerations for prescribing medications to older adults with BPH/male LUTS. While medication treatment is well established and common, it is also imperfect. Anticholinergic medications sometimes used for BPH/male LUTS and desmopressin, used specifically for nocturia with nocturnal polyuria, are Beers list drugs regarded as potentially inappropriate medications [39]. There is an overall low drug adherence, resulting in low persistence or duration of treatment of LUTS/BPH medication therapy at 1 year [40, 41]. While using more than one medication for BPH/Male LUTS is often more efficacious [8, 20], it is associated with more than double the rate (30% versus 65%) of discontinuation within 10 months’ time [41]. Careful patient-provider communication and a patient-centered approach should be used to make sure that the treatment aligns with the patient’s goals [40]. Patients focused on immediate relief of LUTS should have alpha-blocker therapy [8, 42], whereas those with a large prostate willing to accept long-term drug treatment in the hopes of reducing their lifetime risk of having BPH surgery should be treated with 5-alphareductase inhibitors [8, 41]. Decisions to adhere to drug treatment are strongly influenced by the patient’s perception of discomfort and inconvenience [40]. Understanding whether or not a patient is benefiting from the prescribed medication is crucially important (Table 3).

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T. M. Johnson II and A. Mirk

Table 2 Medications used in management of lower urinary tract symptoms likely due to BPH/male LUTS by category and in order of frequency of prescribing in Medicare Part D beneficiaries in 2018 [38] Dosage

Frequency

Avg $/dose

2018 beneficiaries

0.4–0.8 mg 10 mg 4–8 mg

At bedtime At bedtime At bedtime

$0.31 $0.42 $8.24

3,738,737 167,862 65,460

1–8 mg 1–10 mg

At bedtime At bedtime

$0.52 $0.19

555,575 432,722

5 mg 0.5 mg

Daily Daily

$0.28 $6.28

1,421,653 3335

25, 50 mg 5 mg 5 mg

Daily Daily Daily

$2.36 $16.51 $52.49

79,750 54,818 298

Daily Bid, tid Q 4 days

$1.03 $0.37 $74.91

724,539 670,964 1707

Branded Branded Generic/branded Generic/branded Generic/branded Generic/branded Branded Generic/branded

5–20 mg 2.5–5 mg 3.9 mg/ 24 hr. 3% gel 5–10 mg 2–4 mg 1–2 mg 20 mg 60 mg 4–8 mg 7.5–15 mg

Daily Daily Daily Bid Daily or bid Daily Daily Daily

$12.33 $11.83 $3.92 $1.71 $1.19 $4.02 $10.49 $6.52

1136 270,564 188,506 54,297 63,290 28,626 68,779 15,036

Branded Branded

25–50 mg 75 mg

Daily Daily

$11.85 $15.28

464,893 n/a

Brand Name Generic Name Alpha-adrenergic antagonists (selective) Tamsulosin HCl Generic/branded Alfuzosin HCl ER Generic/branded Silodosin Generic/branded Alpha-adrenergic antagonists (non-selective) Doxazosin Mesylate Generic/branded Terazosin HCl Generic/branded 5-Alpha reductase inhibitors Finasteride Generic/branded Dutasteride Branded Phosphodiesterase 5-inhibitors Sildenafil Citrate Generic/branded Tadalafil Branded Vardenafil Branded Anticholinergic medications Oxybutynin (extended release) Generic/branded Oxybutynin (immediate release) Generic Oxybutynin topical Generic/ also OTC Oxybutynin chloride topical-gel Solifenacin succinate Tolterodine tartrate ER Tolterodine tartrate Trospium chloride Trospium chloride ER Fesoterodine Darifenacin hydrobromide Beta-3 agonists Mirabegron Vibegron

Table 3 Checking in on adherence, effectiveness, and side effects Verify adherence and assess the benefit and side effects! • Lead in questions: Did you obtain/receive this medication? Were you able to take it? Are your symptoms no different, better, or worse? More common with lower dosages More common with higher dosages No effect Efficacy and safety Adverse side effects • Okay. I understand your • Okay. So your symptoms are better • Has this medication helped you symptoms are worse/no better. with this medication? A bit better, at all? • (adherence) What was the dose of better, or a lot better? • Are you bothered by the medication, and how often did • Are you having side effects with this lightheadedness or dizziness? you take it? dosage? • Are you having trouble with dry • (expected effect) For how many • Are you at your goal with this mouth? days or weeks have you been taking medication? • Would you prefer to try a the medication? different medication? Or try to manage the side effects?

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BPH and Male Lower Urinary Tract Symptoms

With so many medication choices, where does one start? Most men with BPH/male LUTS are started on an α-blocker as a first-line medication [2] as they are generally well-tolerated and require a short time for some benefit (2–4 weeks) or until maximum benefit (12 weeks). Men with small or normal-sized prostates ( 1.4–1.5, or prostate volume of >30 cc on imaging such as a transrectal ultrasound) [2]. Physical examination via digital rectal examination will be insensitive [2, 10]. Finasteride and dutasteride can be associated with erectile dysfunction, decreased libido, ejaculatory disorders, and rarely, gynecomastia. There is a very low risk (0.5–0.7% incidence) of high grade (Gleason 8–10) cancer for men treated with finastide, and men should be informed of this possibility. Men should be monitored while on finasteride, with periodic PSA testing. Those with a rising PSA after a PSA drop should be assessed for the possibility of a high-grade cancer (modified recommendation based upon high-quality evidence) [10]. Because men on either finasteride or dutasteride will experience a 50% decline in their PSA, this value should be doubled (2x) when being used as a prostate cancer screening test. Given that BPH is a progressive disease and BPH/male LUTS may deteriorate over time [56], reducing the future need for

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precipitous relief of acute urinary retention (AUR) or postponing the need for BPH-related surgery is also a relevant goal [57]. Overall, this category of medications has been regarded by an international panel of gerontologists as having proven or obvious efficacy in older adults with limited efficacy or safety concerns and therefore endorsed [46]. Some men may experience impotence or decreased volume of ejaculate and loss of libido starting within the first year (3–8%) with these symptoms decreasing over time, and rarely (1–2%) of men may experience breast enlargement or tenderness over time [58]. PDE5i’s are indicated for ED + BPH/male LUTS treatment by some medical societies [10] but not by all. They provide an option for men being treated with BPH/male LUTS who also have concerns about erectile dysfunction [59]. Of note, the hypotensive effects of even uroselective α-blockers and PDE5is are additive, and they should not be given, depending upon the specific agent, within the same 24-hour period. This often means giving the α-Blocker at bedtime and holding it when a PDE5i has been taken for ED that date. Overall, this category of medications for BPH/male LUTS has been regarded by gerontologists as having questionable or limited efficacy by a panel of gerontologists due to lack of proven or obvious efficacy in older adults with some efficacy or safety concerns [46]. Also, the US Department of Veterans Affairs limits daily use of this category of medications for BPH/male LUTS based upon reduced efficacy versus when compared to other categories of medications. Medication therapies can be combined with behavioral therapy and with each other [1, 2]. The combination of α-blockers with anticholinergics has demonstrated better 12-week outcomes for LUTS (esp. UUI, and urinary urgency) in men with BPH + OAB [1, 27]. Contemporary studies using these medications have shown low rates of urinary retention, but caution should be used for men with significant BOO or PVRs >250 mL, as there are few studies in this population [10]. α-Blockers can be effectively combined with 5ARIs in men over 50 years of age who have a larger prostate (PSA >1.4) [8]. There is decrease in urinary retention, but

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there are additive side effects (especially ejaculatory disorders). The 5ARIs do demonstrate better 4-year outcomes on progression of symptoms and reduced need for surgery [8] as well as better longterm symptom improvement for men with moderate to severe BPH symptoms [60]. B-3 agonists and anticholinergics: They may be combined in OAB, but this is less well studied in men with BPH (or BPH plus OAB) and the potential risk of an adverse event of urinary retention could be additive [1]. Mr. Bronson has been taking three medications and feels that he is no better. His AUA-7 SI score was 29/35 when he first came in, and now it is 28/35. He is willing to consider surgical therapy for his symptoms, but is concerned about having to stop his anticoagulation therapy. Surgery and minimally invasive surgical therapies (MIST) can be useful in the treatment of older men with BPH/male LUTS (Table 4). Indications for surgery for BPH/male LUTS include recurrent or refractory urinary retention, recurrent UTIs, bladder stones, BPH causing renal dysfunction, symptom deterioration despite medical and behavioral therapy, and patient preference [7, 10]. Cystoscopy or other imaging modality should be performed to determine prostate size as well as the presence of a significant median lobe [7]. Patients undergoing a urological procedure should be informed of the possibility of treatment failure and the need for additional treatment [7]. Chronological age should not be regarded as a contraindication to BPH surgery [3]. At the same time, it is important to recognize that frailty is associated with an increased rate of complications (above the baseline of 10–15%) from commonly performed urological procedures such as transurethral resection of the prostate. This held true even after adjustment for age, race, and method of anesthesia with greater frailty associated with greater risk of complications [62]. The monopolar transuretral resection of the prostate (TURP) remains the primary, standard reference surgical treatment for BPH/male LUTS and is generally accepted as the gold standard [7]. The procedure involves obstructing adenomatous tissue through a transurethral approach using a cystoscope. It is used for moderate to severe

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Table 4 Considerations for surgical treatments in the older male patient Less invasive surgeries Name Prostatic urethral lift (PUL)b

Water vapor thermal therapy Transurethral microwave therapy (TUMT)b Urethral stent More invasive surgeries Name Transurethral incision of the prostate (TUIP) Photo selective vaporization of the prostate (PVP) Monopolar transurethral resection of the prostate (TURP)

Comment Outpatient, no anesthesia. Prostate must be free of midline tissues. Outpatient, no anesthesia Outpatient, no anesthesia Outpatient, no anesthesia

Prostate Size 30–80 cc

Comment

Prostate size 80 cc 80 cca

a

Treatment of choice for prostates of this size Must exclude presence of a middle lobe Table modified from AUA 2010/2014 BPH guidelines overview of medications and surgeries, CUAJ 2018 Fig. 3 [61], and Urology Care Foundation (https://www.urologyhealth.org/urology-a-z/b/benign-prostatic-hyperplasia-(bph) accessed 12/15/2020)

b

BPH/male LUTS symptoms in patients with prostate volume of 30–80 cc (CUAJ, 2018, strong recommendation based upon high to moderate quality evidence) [10]. Bipolar TURP has advantages over monopolar TURP in that it reduces the requirement of a grounding pad and energy transmission through the body (the grounding is on the catheter) and allows the use of 0.9% NaCl solution instillation in the bladder [7]. In monopolar TURP, the use of iso-osmolar sorbitol, mannitol, or glycine solutions can result in acute dilutional hyponatremia if the procedure is prolonged. Both monopolar and bipolar TURP require regional or general anesthesia, a hospital stay, and discontinuation of anticoagulant therapy. The perioperative mortality is 3 new drugs, bladder catheter and iatrogenic events) [9]. Disability, depression, previous stroke, alcohol abuse, and multiple chronic illnesses have also been considered as predisposing [9], while electrolytes’ imbalance, urinary retention, constipation, trauma and surgical interventions as precipitating factors [9]. Drugs should also be potential causes of delirium, especially opioids and benzodiazepines, which are therefore not recommended as first choice for insomnia, agitation, or delirium by common clinical guidelines [17]. Pathophysiology of Delirium Although many neurotransmitter systems have been historically implicated in the pathophysiology of delirium, the most commonly reported alterations associated with delirium include a deficiency in acetylcholine and/or melatonin availability; an excess in dopamine, norepinephrine, and/or glutamate release; and variable alterations in 5-hydroxytryptamine or serotonin, histamine, and/or gamma-amino butyric acid [18]. However, delirium is not only a matter of neurotransmitter dysfunctions. Recently, Maldonado proposed a hypothesis (the System Integration Failure Hypothesis, SIFH) that delirium occurs as the result of the specific combination of

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neurotransmitter dysfunction and the variability in integration and appropriate processing of sensory information and motor responses, as well as the direct breakdown in cerebral network connectivity [18]. According to SIFH, there are a number of patient-specific factors that serve as substrate to the development of delirium, including a “neuronal aging,” a neuroinflammation of the brain, an excess of “oxidative stress,” a “neuroendocrine dysfunction,” and a “circadian rhythm or melatonin dysregulation” [18]. The “neuroinflammation of the brain” hypothesis is greatly supported by scientific evidences. According to this hypothesis, delirium represents the central nervous system manifestation (CNS) of a systemic disease that has reached the brain parenchyma. It has been demonstrated that peripheral infections or surgery may induce activation of brain parenchymal cells, cells, which express inflammatory cytokines and other inflammatory mediators in the CNS (e.g., C-reactive protein, interleukin-6, tumor necrosis factor alpha, and others) [19], leading to neuronal and synaptic dysfunction and subsequent neurobehavioral and cognitive symptoms of delirium. Importantly, it has demonstrated that the microglia (the CNS resident macrophages) can be primed by prior neurodegenerative processes, triggering an exaggerated response to systemic inflammatory signals [20]. This can explain why patients with pre-existing dementia are more susceptible to delirium in particular circumstances (like as surgery or infections) with respect to non-demented persons.

Delirium and Frailty: A Complex Relationship Frailty is a clinical syndrome defined by the age-related depletion of the individual’s homeostatic reserves, determining an increased susceptibility to stressors and disproportionate exposure to negative health changes [21]. The physiological systems that are involved in the determination of frailty are mutually interrelated, so that when decline starts in a given system, implications may also regard the other systems [21]. According to this definition, frailty may represent the ideal pabulum for the development of delirium, and delirium, on its side, may represent the clinical

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manifestation of underlying frailty in a patient suffering from an acute decompensation [22]. However, only few studies until now have specifically focused on the relationship between frailty and delirium in older people, and even less have assessed if frailty is a predictor of delirium. Recently, a systematic review and meta-analysis explored the existence of an independent relationship between frailty and delirium [23]. Among 1626 articles retrieved, only 20 were available for the systematic review and 8 for the metaanalysis. Although an association between frailty and delirium was found, there was huge heterogeneity among the criteria to select populations and also among the methods to assess both frailty and delirium. Furthermore, most data pertained to studies performed in surgical wards [23]. A more recent study explored the relationship between frailty and delirium in a cohort of older inpatients hospitalized in an acute geriatric unit [24]. The study found that frailty was associated with delirium, and also that frailty significantly influenced the attentional tests, which are commonly used to assess delirium [24]. However, the study was single-center, and thus data are not necessarily transferrable to other clinical settings. Therefore, there is urgent need to explore this field. A further point is whether delirium may predispose itself to frailty. Indeed, several studies have demonstrated that delirium is a risk factor for not only for dementia or a worsening of a preexisting dementia [13] but also for subsequent functional impairment [7]. Patients with persistent

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delirium are also less likely to regain activity of daily living function in comparison with non-delirious patients [25]. It can be therefore hypothesized that the persistent or residual effects of delirium may delay or even hamper cognitive and functional recovery, ultimately resulting in new or increasing frailty and long-term disability and institutionalization. Future studies should better clarify this point.

Diagnosis of Delirium Delirium has been recognized for at least two millennia with the term ‘delirium’ deriving from the Latin ‘lira’ meaning to wander from one’s furrow. Prior to Diagnostic and Statistical Manual of Mental Disorders (DSM)-III, acute generalized disturbances of brain function were described by a myriad of labels (e.g., acute organic brain syndrome, acute confusion, brain failure, toxic encephalopathy, and intensive care psychosis) [26]. However, these terms do not represent distinct scientific entities and should therefore avoided in clinical practice [26]. Delirium, instead, should be viewed as an umbrella term incorporating these multiple synonyms, allowing to improve the communication among clinicians and, consequently, delirium management. Currently, the DSM-5 edition criteria (Table 1) are considered the gold-standard reference for the diagnosis of delirium [2]. Key diagnostic features include inattention, an acute onset and fluctuating course of symptoms, impaired consciousness, and disturbance of cognition (e.g., disorientation, memory impairment, language changes) [2].

Table 1 The Diagnostic and Statistical Manual of Mental Disorders (DSM) -5 edition criteria A. A disturbance in attention (i.e., reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment). B. The disturbance develops over a short period of time (usually hours to a few days), represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day. C. An additional disturbance in cognition (e.g., memory deficit, disorientation, language, visuospatial ability, or perception). D. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma. E. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies. Specify whether: Substance intoxication delirium: This diagnosis should be made instead of substance intoxication when the symptoms in Criteria A and C predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention.

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Occasionally, disturbance in sleep–wake cycle, perceptual disturbances (hallucinations or illusions), delusions, inappropriate behavior, and emotional lability may also be part of delirium symptomatology [9]. Delirium may present in three different subtypes, i.e., hyperactive, hypoactive, or mixed. The hyperactive subtype is characterized by restlessness, agitation, and or aggressiveness; the hypoactive is characterized by a withdrawal from interaction with the outside world, sluggishness (or lethargy), and reduced psychomotor activity; and the mixed subtype is characterized by the transition from hyperactivity to hypoactivity. Recently, Meagher et al. [27] described a nonhyperactive-nonhypoactive subtype of delirium, which is characterized by normal level of psychomotor activity and no fluctuations between hyperactive and hypoactive subtypes. It is still unclear which of these subtypes may underlie different phenotypic forms of delirium. However, various studies suggest that the hypoactive and the mixed subtypes are more common in frail older individuals and are associated with a worse prognosis [28, 29]. Delirium is essentially a clinical diagnosis. Its recognition, in fact, requires cognitive screening, astute clinical observation, and accurate informant’s interview, i.e., a list of procedures and practices, which do not represent the routine approach of most clinicians in their everyday routine practice. As a result, delirium frequently goes undetected in clinical practice [30, 31]. Possible explanations for this include the presence of sensory impairment, dementia, old age, and the hypoactive subtype of delirium [17]. Furthermore, many clinicians confound acute confusion and/or patient’s unusual behavior with disorders dementia-related, even in the absence of a formal diagnosis (of dementia). This a mistake with potential serious implications in terms of patient’s pharmacological management and prognosis. Misrecognition of delirium, in fact, may lead to excessively liberal use of sedatives and inadequate searching of the underlying causes of delirium. When in doubt, thus, it would be prudent to rule out delirium first than to attribute confusion to

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dementia and fail to recognize the presence of delirium. There are many diagnostic tools for delirium; the most commonly used is the Confusion Assessment Method (CAM) [32]. The CAM has been validated in high-quality studies of more than 1000 patients, showing sensitivity of 94%, specificity of 89%, and high interrater reliability [9]. However, cognitive testing and training are recommended for optimum use, implying that lack of formal training and education may lead to unacceptable rates of underdiagnoses. A new tool, which has recently been validated in the screening for delirium of older patients, is the 4AT test [33] (Fig. 1). The 4AT is of particular interest because it is brief (generally 75 mg/day) resulted in significantly higher rates of hospitalization with encephalopathy, falls, fractures, or respiratory depression compared to initiating gabapentinoids at lower doses (gabapentin 300 mg/day or pregabalin 75 mg/day) [32]. Impaired renal function can exacerbate CNS adverse effects including altered mental status and sedation, which can precipitate falls and fractures in older adults. If used in older adults, gabapentin and pregabalin should be renally dose adjusted based on creatinine clearance [23, 33, 34]. Gabapentinoids increase the risk of suicidal ideation and should be used with caution in patients who have a history of self-harm. In addition, gabapentinoids have an increased risk of substance misuse and diversion. Data show gabapentinoids may potentiate and increase the duration of euphoric effects when used solo or in combination with other substances that alter the sensorium. The benefits of gabapentinoids should outweigh the risks. Abrupt discontinuation may lead to gabapentinoid withdrawal therefore should be de-escalated slowly over time. Withdrawal symptoms closely resemble alcohol withdrawal including confusion and agitation. Symptoms typically subside within 24–48 h after reintroduction of gabapentinoids [35, 36].

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Muscle Relaxants

Opioid Analgesics

Diazepam is the most used benzodiazepine that is indicated for management of muscle spasms and spasticity. However, older adults have increased sensitivity to benzodiazepines and decreased metabolism, which can lead to accumulation of metabolites, particularly with medications with an extended half-life, such as diazepam [23]. Steadystate plasma concentrations of diazepam were 30% higher in older patients compared to younger patients, and the half-life of diazepam also significantly increased in advanced age due to age-related pharmacokinetic changes in metabolism [37]. A reduction in hepatic blood flow and liver mass can occur with increasing age, leading to a decreased rate of drug delivery and hepatic enzymes, which can increase the half-life of medications [33]. Concomitant use of benzodiazepines with opioids increases the risk of respiratory depression and over sedation. If prescribed together, the lowest dose and shortest duration should be used. Benzodiazepine use in older adults should be avoided unless benefits outweigh risks. Other medications indicated for spasticity include baclofen and tizanidine, while medications used for muscle spasms include cyclobenzaprine and methocarbamol. The American College of Physicians recommends skeletal muscle relaxants (antispastics and antispasmodics) as pharmacologic treatment of acute/subacute low back pain, but not for chronic use [38]. Cyclobenzaprine has a chemical structure closely related to TCAs therefore have a similar side effect profile including anticholinergic symptoms including dizziness, drowsiness, delirium. Cyclobenzaprine, methocarbamol, and carisoprodol increase the risk of injury, including falls and fractures, in older adults [39]. As such, the use of these medications should typically be avoided in older adults. In addition to safety concerns, there is mixed data to support the efficacy of muscle relaxants in the geriatric population [23].

Full Agonists Although nonopioid therapies should be considered as first-line or as opioid-sparing adjuvants, they are not benign and should be used with caution. Opioids remain an effective analgesic for certain acute and chronic pain syndromes. Opioids have an important role for acute pain related to severe traumatic injuries, invasive surgeries, and other severe acute pain conditions when NSAIDs and other therapies are contraindicated or likely to be ineffective [40]. Opioids should not be considered first-line or routine therapy for subacute or chronic pain. However, in certain clinical scenarios, opioids might be appropriate regardless of previous therapies. Examples of clinical scenarios include serious illness in a patient with poor prognosis for return to previous levels of function, contraindications to other therapies, and goals of care focused on patient comfort. Most importantly, if opioids are prescribed, clinicians should ensure that patients are aware of benefits and risks associated with opioids and involve patients in decisions regarding initiation of opioid therapy as well as potential exit strategies [40].

Partial Agonists Buprenorphine is a Schedule III, partial μ-opioid receptor agonist that has emerged as a safer alternative for treatment of chronic pain compared to Schedule II, full μ-opioid receptor agonists as discussed in the earlier section. Although buprenorphine is a partial agonist at the μ-opioid receptor, it retains high-receptor affinity and thus able to maintain potent analgesia that mirrors full μ-opioid receptor agonists. More recent research indicates that buprenorphine is a full opioid receptor-like 1 (ORL1) agonist, which may contribute to its potent analgesic properties [41]. Buprenorphine’s partial agonism at the

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μ-opioid receptor leads to a ceiling effect, where the risk of respiratory depression plateaus with increased doses [42, 43]. It also exhibits fewer rewarding effects compared to full μ-opioid receptor agonists and blocks psychological dependence [44]. Additionally, buprenorphine acts as an antagonist at the δ- and κ-opioid receptors, possibly resulting in decreased adverse events [45]. Buprenorphine has shown to have a lower incidence of constipation and less impact on cognitive and psychomotor function compared to full μ-opioid receptor agonists [44]. Buprenorphine is available in several dosage forms, including transdermal, sublingual, and buccal formulations. In clinical scenarios where opioids are unable to be administered orally, buprenorphine can be considered if a long-acting opioid is warranted for chronic pain. Transdermal buprenorphine has shown benefit for use particularly in older patients. The transdermal patch is changed every 7 days. In addition to ease of administration, the patch has increased compliance and adherence, less risk of accidental missed doses or double dosing, and a slow increase of plasma concentration without a sudden peak, which reduces the risk of adverse drug reactions [46, 47]. Due to these benefits, it could be appropriate to consider buprenorphine as a first-line therapy for chronic pain in older adults [48].

Adverse Events Related to Opioids Opioids are associated with various adverse events, which especially impact patients of advanced age. These side effects include, but are not limited to, respiratory depression, sedation, constipation, cognitive impairment, delirium, falls, and fractures. Chronic constipation is common in older adults. In fact, symptoms occur in up to 50% of nursing home residents [49]. Constipation is experienced by up to 80% of patients on chronic opioid therapy [50]. Unlike most opioid-induced side effects, tolerance to constipation does not develop over time. Therefore, particularly in the older adult population, it is important to reduce opioid-induced constipation (OIC) through the

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routine use of prophylactic bowel care with laxatives prescribed for the duration of opioid therapy [68]. Up to 60% of patients may experience sedation upon initiation of opioid therapy or dose escalation [51]. Tolerance can develop within days to weeks, but sedation can persist. Delirium is another concerning CNS adverse event, particularly in older adults. Additionally, opioid use in older adults increases the risk of falls and fractures. The European Palliative Care Research collaborative (EPCRC) provides guidelines on the management of opioid-induced adverse events that utilize four strategies. The first is a dose reduction of the opioid, which can help reduce dosedependent side effects such as sedation and delirium [53]. Opioid rotation is the second strategy, which involves switching one opioid to another to optimize analgesia and reduce adverse effects [52, 53]. Changing the route of administration is another option that may mitigate complications. For example, transdermal administration may be more appropriate for patients with dysphagia. The last strategy involves symptomatic management of adverse effects by using a medication to target a specific symptom. For example, laxatives can be used to manage OIC. For the specific adverse effects of sedation and delirium, patient’s concomitant medications should be evaluated for ones that may exacerbate sedation and/or cognitive function and removed if appropriate [52]. The addition of psychostimulants such as methylphenidate can be considered for patients experiencing sedation in the palliative care setting [54]. These events are often exacerbated in older adults due to changes in pharmacokinetics. A decline in renal function and first-pass metabolism can lead to accumulation of drug and active metabolites, which may increase the incidence of adverse events. Methadone, buprenorphine, fentanyl, and hydromorphone are the safer options in patients with renal dysfunction. Oxycodone and hydrocodone may be used if renally dose adjusted; however, accumulation of metabolites and side effects may be seen. Morphine is typically avoided in patients with renal insufficiency.

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Nonpharmacological Strategies to Treat Pain Physical Therapy Physical therapy has been recommended as a prudent low-risk, high-yield, treatment strategy for various pain conditions. Moreover, physical therapy when employed strategically acts as a preventative and protective mechanism, building the patient’s physical endurance and resilience. A more recent study suggested that high physical activity is associated with a reduced likelihood of developing musculoskeletal pain complaints compared to sedentariness, over and above age, weight, gender, and socioeconomic status. Various physical therapy paradigms are in existence to pace and accommodate to the patient’s needs. The primary objective of well-defined physical therapy is to improve impairment (loss of physiologic or anatomical structure or function), which is accomplished through modalities that address the underlying pathophysiologic etiology (e.g., core strengthening and stabilization exercises of surrounding muscle). Strength training-focused physical therapy programs are particularly effective in improving overall mobility, balance, and physical function in older adults population [63]. Older adults can engage in physical therapy with either land-based or aqua therapy regimens. These defined protocols limit impact, improve range of motion, and strengthen the body in the most accommodating of methods [55].

Behavioral Therapy Pain management is a multidisciplinary specialty. The use of specialized psychological techniques such as cognitive behavioral therapy (CBT), reframing, guided imagery, acceptance and commitment therapy, mindfulness-based interventions, novel group therapy paradigms, among other strategies can be exceedingly helpful for some patients. These interventions often complement if not anchor the existing portfolio of pain medicine treatments [56]. In a recent study, researchers evaluated 291 older adults, greater

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than 60 years of age suffering with depression and insomnia. These individuals were treated with cognitive behavioral therapy. The treatment paradigm resulted in a decreased likelihood of incident and recurrent depression for 36 months (about 3 years) of follow-up compared with an active comparator control, sleep education therapy. Sustained insomnia remission in adults undergoing CBT resulted in a decreased likelihood of depression versus no insomnia remission in adults receiving sleep education therapy [56]. More novel approaches in the last few years have been specifically tailored to older adults. The approach begins with reviewing patients’ pain, psychosocial, and medical histories to elicit evidence of a subtype of chronic pain called centralized (primary, nociplastic, or psychophysiologic) pain, which is highly influenced and may even be caused by life stress, emotions, and alterations in brain function [57]. Patients then undertake a novel psychotherapy approach called emotional awareness and expression therapy (EAET) that aims to reduce or eliminate centralized pain by resolving trauma and emotional conflicts and learning healthy communication of adaptive emotions [57].

Acupuncture Acupuncture is a low-risk, high-yield intervention. The age-old treatment strategy has existed for thousands of years with its beginnings in mainland China. The practice entails utilizing small needles to guide internal energy, called Chi, with either manual or electrical stimulation of the needles. Most recently, in 2020, acupuncture has been an established benefit for Medicare beneficiaries, specifically for chronic low back pain. Acupuncture offers a low-risk option that can be easily employed in most settings. As with other therapies, effective acupuncture may require more than one session. Acupuncture has been utilized as an alternative to various medications, from NSAIDs to opioid therapy. A 2003 study by Meng demonstrated that acupuncture is a safe and effective adjunct treatment for chronic low back for older adults [58]. Currently, there is an

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ongoing clinical trial, the BackInAction pragmatic clinical trial, that aims to further understand the effectiveness, dose-dependence, and safety of acupuncture in a Medicare population [58]. Additionally, future study results may encourage broader adoption of more effective, safer, and more satisfactory options rather than continuing the over-reliance on opioid- and invasive medical treatments for chronic low back pain in older adults [59].

Interventional Pain Medicine A detailed and thorough physical exam is imperative to ascertain the appropriate pain generator. Once the pain generator has been evaluated and diagnosed through provocative physical exam maneuvers, the physical exam is corroborated with evaluation of additional diagnostic tests such as imaging and/or electromyography and nerve conduction studies. Pain medicine procedures serve as diagnostic interventions further solidifying the diagnosis should the patient receive analgesia from the proposed intervention. Next, specified injections may also serve as a therapeutic modality and a means to manage pain periodically. Lumbosacral pain can be placed into two broad categories: pain that radiates down the lower extremities or pain that radiates along the axis of the lumbar spine. These two constructs are termed radicular and axial lumbosacral spine pain, respectively. The more common procedure for lumbar radicular pain or nerve root-related inflammation, radiculitis, is an epidural steroid injection. The more common diagnose(s) that compose axial lumbosacral spine pain are sacroiliitis, lumbar facet-mediated pain, and myofascial pain. Interventions such as intra-articular sacroiliac joint, lumbar facet joint injections, and trigger points for myofascial pain may be offered should each these conditions be diagnosed. Further, should more sustained therapy be required, there are ablative techniques where radio frequency ablation can be performed to ablate sensory innervation to a specified joint. Medial branch nerve radio frequency ablation can treat axial cervical, thoracic, and lumbar

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facet-mediated pain. Moreover, radiofrequency ablation of specified sensory nerves can provide 6 months to a year or longer of sustained pain relief. Lateral branch nerve radiofrequency ablation can be applied to treat sacroiliitis by addressing innervation to the sacroiliac joint and overlying sacrotuberous ligamentous structures. [Brooks, Mathis]. Large joint injections are an interventional strategy that can also be employed to treat pain in older adults. Intra-articular shoulder, knee, and hip injections can be provided not only with local anesthetic but also steroid. Additionally, the use of visco supplementation with hyaluronan, a nonsteroid approach, can be applied to the knee joint. Further, for many joints, including the knee and the shoulder, the use of platelet-rich plasma (PRP), a highly concentrated mixture of the patients own platelets can be injected into the joint. Theoretically, PRP can reduce pain, and promote healing of injured tendons, ligaments, muscles, and joints [60, 61]. Radiofrequency ablation therapy can also be provided to address knee pain with targeted ablation of the genicular nerves. Sophisticated radiofrequency ablation of the sensory branches of the femoral and obturator nerves can be offered to address intra-articular hip pain in cases where hip replacement surgery may carry more risk for the older adult with substantial comorbid burden [60, 61]. Percutaneous techniques to address lumbar spinal stenosis can include the placement of interbody spacers to augment space via a nonsurgical approach in the appropriate candidate. Interbody spacers are devices that can be placed percutaneously under fluoroscopic guidance and utilized to expand and maintain a modest increase in central canal circumference to alleviate neurogenic claudication from lumbar stenosis. Older adult patients who have constant axial and radicular cervical and lumbar spine pain after spine surgery may be candidates for the placement of dorsal column spinal cord stimulators. Spinal cord stimulators are placed via a minimally invasive surgical procedure performed by pain medicine specialists. The use of spinal cord stimulators or neuromodulatory devices offers a nonmedication modality to modulate the central

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nervous system. Sophisticated software and specialized programs delivering energy at a unique frequency and amplitude can allow for therapeutic benefits. Spinal cord stimulators have been utilized to treat several conditions from postherpetic neuralgia to painful diabetic neuropathy, in addition to, persistent back and leg pain postspine surgery. Prudent use of interventions, pending the procedure type, and disease burden, can even be accomplished in the setting of anticoagulation and comorbid disease. Often pain medicine interventions are an alternative to medications that have their own potential side effects and risks in older adults. Therefore, procedural pain medicine offers a unique modality to afford older adults in pain-sustained relief.

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disease. She reports the pain is distracting and makes her feel depressed. The pain worsens with movement and improves with morphine. She reports drowsiness, dizziness, and falling since morphine initiation. The patient reports severe radiating heartburn that decreases her appetite.

Analgesics Ibuprofen 600 mg po q 4 h. Morphine solution 2.5 mg po q 6 h around the clock. Vitals: Within normal limits. Labs: Creatine clearance is 21 mL/minute, and all other labs are within normal limits. Allergies: Gabapentin and pregabalin (shortness of breath); patient reports trying venlafaxine and duloxetine in the past without analgesic benefit.

Conclusion Pain is a complex phenomenon that has physical, emotional, and psychological factors to be considered. Pain assessment in the older adult can be challenging and relies on many strategies to ascertain and evaluate pain and functional limitations. A mindful approach that incorporates a sophisticated understanding of ongoing medical comorbidities and their implications to certain medications and interventional pain modalities is key to developing a customized plan for the patient. Once the pain medicine diagnoses have been made, there are many methods on how best to treat the pain. A detailed risk/benefit analysis is fundamental, incorporating the person’s goals and preferences, and then weighing the risk versus benefit of each treatment strategy with a subsequent shared decision-making process to communicate what therapy will be provided and how the care will be delivered in safest way possible.

What Analgesic Options May Be Appropriate? Discontinue ibuprofen (patient presents with heart failure, chronic kidney disease, and GI symptoms) Discontinue morphine (metabolites can accumulate in renal dysfunction leading to toxicities such as dizziness, drowsiness, and falls) Begin acetaminophen up to 1000 mg po q 6 h Begin Butrans 5 mcg/hour patch: apply 1 patch TD every 7 days Referral for a physical medicine and rehabilitation evaluation and treatment program Referral for psychological interventions for pain management, including cognitive behavioral therapy and other interventions Referral to pain management for a targeted exam to prioritize pain generators and discern the suitability of specified interventions for pain

References Patient Case 73-year-old patient who presents with uncontrolled chronic pain that limits her ability to sleep, grocery shop, and play with her grandchildren. Patient has a history of heart failure, obesity, sleep apnea, and chronic kidney

1. Stompór M, Grodzicki T, Stompór T, Wordliczek J, Dubiel M, Kurowska I. Prevalence of chronic pain, particularly with neuropathic component, and its effect on overall functioning of elderly patients. Med Sci Monit. 2019;25:2695–701. https://doi.org/10.12659/ MSM.911260. PMID: 31018630; PMCID: PMC6475124.

1182 2. Booker SQ, Herr KA. Assessment and measurement of pain in adults in later life. Clin Geriatr Med. 2016;32 (4):677–92. https://doi.org/10.1016/j.cger.2016.06. 012. Epub 2016 Aug 11. PMID: 27741963; PMCID: PMC5444331. 3. Tinnirello A, Mazzoleni S, Santi C. Chronic pain in older adults: mechanisms and distinctive features. Biomol Ther. 2021;11(8):1256. 4. Gagliese L, Gauthier LR, Narain N, Freedman T. Pain, aging and dementia: Towards a biopsychosocial model. Prog Neuropsychopharmacol Biol Psychiatr. 2018;87(Pt B):207–15. https://doi.org/10.1016/j. pnpbp.2017.09.022. Epub 2017 Sep 22. 5. Schofield P. The assessment of pain in older people: UK national guidelines. Age and Ageing. 2018;47 (suppl_1):i1–i22. 6. Kaye AD, Baluch A, Scott JT. Pain management in the elderly population: a review. Ochsner J. 2010;10 (3, Fall):179–87. PMID: 21603375; PMCID: PMC3096211. 7. Hadjistavropoulos T, Herr K, Prkachin KM, Craig KD, Gibson SJ, Lukas A, et al. Pain assessment in elderly adults with dementia. The Lancet Neurol. 2014;13(12): 1216–27. 8. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc. 2009;57(8):1331–46. 9. Fillingim RB, Loeser JD, Baron R, Edwards RR. Assessment of chronic pain: domains, methods, and mechanisms. J Pain. 2016;17(9 Suppl):T10–20. https:// doi.org/10.1016/j.jpain.2015.08.010. PMID: 27586827; PMCID: PMC5010652. 10. Raja S, Liu SS, Fishman S, Cohen SP. Chapter 5 pain assessment. In: Essentials of pain medicine. Philadelphia: Elseiver; 2018. p. 39–45. 11. Morley JE, Vellas BJ, Sinclair A, Cesari M, Munshi MN. Chapter 59 chronic pain. In: Pathy’s principles and practice of geriatric medicine. Chichester: Wiley Blackwell; 2022. p. 743–55. 12. Wolters FJ, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium. Neurology. 2020;95(5):e519–31. https://doi.org/10.1212/WNL. 0000000000010022. Epub 2020 Jul 1. PMID: 32611641; PMCID: PMC7455342. 13. Fain KM, Alexander GC, Dore DD, Segal JB, Zullo AR, Castillo-Salgado C. Frequency and predictors of analgesic prescribing in U.S. Nursing Home Residents with persistent pain. J Am Geriatr Soc. 2017;65(2): 286–93. https://doi.org/10.1111/jgs.14512. Epub 2016 Nov 7. PMID: 28198563; PMCID: PMC9588418. 14. Rollin Wright MD, et al. Deconstructing chronic low back pain in the older adult–step by step evidence and expert-based recommendations for evaluation and treatment: part XI: dementia. Pain Med. 2016;17(11): 1993–2002. https://doi.org/10.1093/pm/pnw247. 15. Herr K. Pain assessment strategies in older patients. J Pain. 2011;12(3 Suppl 1):S3–S13. https://doi.org/10. 1016/j.jpain.2010.11.011.

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30. Mintzer J, Burns A. Anticholinergic side-effects of drugs in elderly people. J R Soc Med. 2000;93(9): 457–62. 31. Moraczewski J, Aedma KK. Tricyclic antidepressants. 2022 Nov 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. 32. Muanda FT, Weir MA, Ahmadi F, Sontrop JM, Cowan A, Fleet JL, et al. Higher-dose gabapentinoids and the risk of adverse events in older adults with CKD: a population-based Cohort study. Am J Kidney Dis. 2022;80(1):98–107.e1. 33. Andres TM, McGrane T, McEvoy MD, Allen BFS. Geriatric pharmacology: an update. Anesthesiol Clin. 2019;37(3):475–92. 34. Sreekantaswamy SA, Mollanazar N, Butler DC. Gabapentinoids for pruritus in older adults: a narrative review. Dermatol Ther. 2021;11(3):669–79. 35. Tran KT, Hranicky D, Lark T, Jacob N. Gabapentin withdrawal syndrome in the presence of a taper. Bipolar Disord. 2005;7(3):302–4. https://doi.org/10.1111/j. 1399-5618.2005.00200.x. 36. Singh H, Handa R, Kak V, Wasilewski A. Complex encephalopathy arising from the combination of opioids and gabapentin. Case Rep. 2019;12(4):e228354. https://doi.org/10.1136/bcr-2018-228354. 37. Greenblatt DJ, Harmatz JS, Zhang Q, Chen Y, Shader RI. Slow accumulation and elimination of diazepam and its active metabolite with extended treatment in older adults. J Clin Pharmacol. 2021;61(2):193–203. 38. Qaseem A, Wilt TJ, McLean RM, Forciea MA. Noninvasive treatments for acute, subacute, and chronic low Back pain: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2017;166(7):514–30. 39. Spence MM, Shin PJ, Lee EA, Gibbs NE. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother. 2013;47(7–8):993–8. 40. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC clinical practice guideline for prescribing opioids for pain — United States, 2022. MMWR Recomm Rep. 2022;71(RR-3):1–95. https://doi.org/10.15585/ mmwr.rr7103a1. 41. Webster L, Gudin J, Raffa RB, Kuchera J, Rauck R, Fudin J, et al. Understanding buprenorphine for use in chronic pain: expert opinion. Pain Med. 2020;21(4): 714. 42. Gudin J, Fudin J. A narrative pharmacological review of buprenorphine: a unique opioid for the treatment of chronic pain. Pain Ther. 2020;9(1):41. 43. Dalal S, Chitneni A, Berger AA, Orhurhu V, Dar B, Kramer B, Nguyen A, Pruit J, Halsted C, Kaye AD, Hasoon J. Buprenorphine for chronic pain: a safer alternative to traditional opioids. Health Psychol Res. 2021;9(1):27241. 44. Khanna IK, Pillarisetti S. Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859–70. 45. Webster L, Gudin J, Raffa RB, Kuchera J, Rauck R, Fudin J, Adler J, Mallick-Searle T. Understanding

1183 buprenorphine for use in chronic pain: expert opinion. Pain Med. 2020;21(4):714–23. https://doi.org/10. 1093/pm/pnz356. PMID: 31917418; PMCID: PMC7139205. 46. Widenka M, Leppert W. Assessment of analgesic effects of different initial doses of transdermal buprenorphine in the treatment of chronic pain in older adults diagnosed with osteoarthritis. J Physiol Pharmacol. 2020;71(5):745–47. 47. Gianni W, Madaio AR, Ceci M, Benincasa E, Conati G, Franchi F, et al. Transdermal buprenorphine for the treatment of chronic noncancer pain in the oldest old. J Pain Symptom Manag. 2011;41(4):707– 14. 48. Case AA, Kullgren J, Anwar S, Pedraza S, Davis MP. Treating chronic pain with buprenorphine-the practical guide. Curr Treat Options Oncol [Internet]. 2021;22(12):116. 49. Mounsey A, Raleigh M, Wilson A. Management of constipation in older adults. Am Fam Physician. 2015;92(6):500–4. 50. Nee J, Zakari M, Sugarman MA, Whelan J, Hirsch W, Sultan S, Ballou S, Iturrino J, Lembo A. Efficacy of treatments for opioid-induced constipation: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(10):1569–1584.e2. https://doi.org/10.1016/j. cgh.2018.01.021. Epub 2018 Jan 31. 51. Swegle JM, Logemann C. Management of common opioid-induced adverse effects. Am Fam Physician. 2006;74(8):1347–54. 52. Rogers E, Mehta S, Shengelia R, Reid MC. Four strategies for managing opioid-induced side effects in older adults. Clin Geriatr [Internet]. 2013 Apr [cited 2022 Oct 26];21(4). 53. Dale O, Moksnes K, Kaasa S. European palliative care research collaborative pain guidelines: opioid switching to improve analgesia or reduce side effects. A systematic review. Palliat Med. 2011;25(5):494– 503. 54. Stone P, Minton O. European palliative care research collaborative pain guidelines. Central side-effects management: what is the evidence to support best practice in the management of sedation, cognitive impairment and myoclonus? Palliat Med. 2011;25(5):431–41. 55. Niederstrasser NG, Attridge N. Associations between pain and physical activity among older adults. PLoS One. 2022;17(1):e0263356. https://doi.org/10.1371/ journal.pone.0263356. PMID: 35089966; PMCID: PMC8797193. 56. Irwin MR, Carrillo C, Sadeghi N, Bjurstrom MF, Breen EC, Olmstead R. Prevention of incident and recurrent major depression in older adults with insomnia: a randomized clinical trial. JAMA Psychiatr. 2022;79(1): 33–41. https://doi.org/10.1001/jamapsychiatry.2021. 3422. PMID: 34817561; PMCID: PMC8733847. 57. Yarns BC, Zhu TA, Najafian JA. Chronic pain in older adults: a neuroscience-based psychological assessment and treatment approach. Am J Geriatr Psychiatry.

1184 2022;30(12):1342–50. https://doi.org/10.1016/j.jagp. 2022.07.009. Epub 2022 Jul 30. 58. Meng CF, Wang D, Ngeow J, Lao L, Peterson M, Paget S. Acupuncture for chronic low back pain in older patients: a randomized, controlled trial. Rheumatology (Oxford). 2003;42(12):1508–17. https://doi.org/10. 1093/rheumatology/keg405. Epub 2003 Jul 30. 59. DeBar LL, Justice M, Avins AL, Cook A, Eng CM, Herman PM, Hsu C, Nielsen A, Pressman A, Stone KL, Teets RY, Wellman R. Acupuncture for chronic low back pain in older adults: design and protocol for the BackInAction pragmatic clinical trial. Contemp Clin Trials. 2023;128:107166. https://doi.org/10. 1016/j.cct.2023.107166. Epub 2023 Mar 27. 60. Brooks AK, Udoji MA. Interventional techniques for management of pain in older adults. Clin Geriatr Med. 2016;32(4):773–85. 61. Mathis MR, Naughton NN, Shanks AM, et al. Patient selection for day case-eligible surgery: identifying those at high risk for major complications. Anesthesiology. 2013;119(6):1310–21. 62. Kolasinski SL, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72(2):149–62. https://doi.org/10.1002/acr.24131. Epub 2020 Jan 6. Erratum in: Arthritis Care Res (Hoboken). 2021 May;73(5):764. 63. de Vries NM, van Ravensberg CD, Hobbelen JSM, Olde Rikkert MGM, Staal JB, Nijhuis-van der Sanden MWG. Effects of physical exercise therapy on

D. Sapell et al. mobility, physical functioning, physical activity and quality of life in community-dwelling older adults with impaired mobility, physical disability and/or multi-morbidity: a meta-analysis. Ageing Res Rev. 2012;11(1):136–49. 64. Sostres C, Gargallo CJ, Lanas A. Nonsteroidal antiinflammatory drugs and upper and lower gastrointestinal mucosal damage. Arthritis Res Ther. 2013;15 (Suppl 3):S3. 65. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation. 2008;118(18):1894–909. 66. Masclee GMC, Sturkenboom MCJM, Kuipers EJ. A benefit–risk assessment of the use of proton pump inhibitors in older adults. Drugs Aging. 2014;31(4): 263–82. 67. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151(6):737. 68. Crockett SD, Greer KB, Heidelbaugh JJ, Falck-Ytter Y, Hanson BJ, Sultan S. American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology. 2019;156(1):218–26. 69. Fleet JL, Dixon SN, Kuwornu PJ, Dev VK, MonteroOdasso M, Burneo J, et al. Gabapentin dose and the 30-day risk of altered mental status in older adults: a retrospective population-based study. PLoS One. 2018;13(3):e0193134.

Pressure Injury and Chronic Wounds

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Jeffrey M. Levine

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186 Aging Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1187 Wound Healing Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1188 Psychosocial Aspects of Chronic Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1189 Nutritional Aspects of Wound Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Infectious Aspects of Chronic Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Necrotizing Soft Tissue Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cutaneous Candidiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1190 1191 1192 1192 1192

Pressure Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193 Lower Extremity Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Venous Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arterial Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diabetic Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Leg Ulcers from Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pyoderma Gangrenosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Martorell’s Hypertensive Ischemic Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Calciphylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wounds Related to Vasculitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1196 1196 1197 1198 1199 1200 1200 1201 1201

Lymphedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1201 Nonhealing Surgical Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202 Traumatic Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lacerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Skin Tears . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Burns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Factitious (Self-inflicted) Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1203 1203 1203 1204 1205

J. M. Levine (*) Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_91

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J. M. Levine Wounds Related to Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205 Moisture Associated Skin Damage (MASD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206 Principles of Chronic Wound Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1206 Palliative Care for Chronic Wounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208 Conclusions/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1209

Abstract

Chronic wounds in older persons include a spectrum of pathologies and generally occur with a backdrop of multiple comorbidities rendering them a model geriatric syndrome. Care of chronic wounds is interdisciplinary and involves nursing, nutrition, rehabilitation, and surgical subspecialties. Complications include pain, decreased quality of life, longer hospital stay, increased chance of readmission within 30 days after hospital discharge, increased chance of admission to a long-term care facility, and increased risk of death. Infectious complications include cellulitis, abscess, sepsis, pyarthrosis, osteomyelitis, and necrotizing soft tissue infection. Chronic wounds require surgical procedures including debridements, endovascular interventions, myocutaneous flaps, amputations, and ostomies for fecal diversion. A vexing variety of treatments is available with few studies to prove efficacy of one over the other. The standard of care for chronic wounds is evolving, and geriatricians need to be aware of prevention strategies, documentation standards, treatment choices, and how to co-manage wounds with other disciplines. Treatment strategies include a palliative care approach, which can avoid unnecessary and futile procedures, improve quality of life, preserve dignity, and curtail health care costs. Keywords

Wound care · Chronic wounds · Wound healing · Pressure injuries · Vascular wounds · Leg ulcers · Wound healing · Skin failure · Dermatoporosis

Introduction Clinical decision making for chronic wounds requires an interdisciplinary person-centered approach and a breadth of knowledge that spans several medical and surgical subspecialties [1]. Chronic wounds affect 5.7 million Americans and incur annual costs of over $20 billion. Adverse outcomes include pain, infection, altered functional status, prolonged treatments and rehabilitation, social isolation, depression, repeated hospitalizations and procedures, and death. Despite the prevalence and consequences of chronic wounds, wound care is undertaught in medical training, and research and education on wound care has lagged behind other geriatric syndromes such as falls, dementia, and frailty. The differential diagnosis of chronic wounds covers a wide spectrum of pathology, often posing a diagnostic challenge. The geriatrician needs to be familiar with concepts of prevention, diagnosis, treatment, and how to best collaborate with colleagues in allied specialties for co-management of chronic wounds to promote dignity, autonomy, quality of life, and favorable outcomes. Wound care is not a specialty recognized by the Accreditation Council for Graduate Medical Education (ACGME), and the knowledge and techniques of wound assessment and treatment are spread among a variety of disciplines. These include medicine, geriatrics, dermatology, general surgery, vascular surgery, plastic surgery, podiatry, nursing, and physical therapy. Each of these specialties maintains their own knowledge base and treatment priorities, often rendering the field of wound care a Tower of Babel where healthcare providers of different backgrounds speak different languages. Older adults commonly transition

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through all levels of the healthcare continuum, and management may differ depending upon resources available at each site. Considering the complex nature of chronic wounds and the overlap with psychosocial issues, multiple comorbidities, and functional status, geriatricians are in a unique position to take the lead in research, education, teaching, and coordination of care to fulfill the goal of a person-centered approach to clinical decision making.

Aging Skin Skin is an organ that changes profoundly over a lifetime, becoming progressively compromised in structure and functional reserve [2]. Under normal conditions, the physiologic compensation for age-related deficits is sufficient, but during stress the lack of physiologic reserve becomes evident. This is further impacted by comorbidities both acute and chronic. The result of age-related changes and superimposed comorbidities is increased vulnerability to hypoperfusion and mechanical stress with predisposition to impaired wound healing and chronic wounds. In addition, the increased mutational burden due to accumulation of DNA damage renders aging skin more susceptible to cancer [3]. Cutaneous functions that decline with age are presented in Table 1. Factors that cause skin to age are conceptualized as intrinsic and extrinsic. Intrinsic aging refers to genetically dependent changes, while extrinsic refers to environmental influences. Table 1 Cutaneous functions that decline with age Barrier function Immune response Cellular replacement Injury response Drug absorption Vascular response Sebum production Sweat production Thermoregulation Sensory perception Vitamin D production Modified from Levine [2]

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Intrinsic aging is dependent upon cellular aging, telomere shortening, mitochondrial DNA mutations, oxidative stress, changes in hormone levels, and stem cell exhaustion. Extrinsic aging arises primarily from ultraviolet light and biologic reactions to sun exposure, cigarette smoke, and air pollution. Type A ultraviolet light (UVA) penetrates deeply into skin, generating reactive oxygen species (ROS) that damage lipids, proteins, and DNA. Dark skin with increased melanocytes is protective against UV radiation. Cigarette smoke induces harmful matrix metalloproteases (MMPs) similar to UV exposure, and persons who smoke have premature aging skin with deeper wrinkles. Toxins in air pollution cause generation of free radicals, induction of the inflammatory cascade, disruption of the skin barrier, activation of hydrocarbon receptors, and alteration of the microbiome, all of which results in premature aging of skin. A variety of macromolecular, anatomic, and physiologic changes occur with aging skin. Collagen decreases in volume, becomes fragmented, and leads to impaired fibroblast function. Other components of the extracellular matrix have altered function including elastic fibers, glycosaminoglycans (GAGs), and proteoglycans (PGs). In the epidermis, there is reduced keratinocyte proliferation and turnover, atrophy of the stratum spinosum, and surface pH is less acidic. Desquamation is less effective, and lipid biosynthesis in the stratum corneum is impaired. There are decreased melanocytes that protect from UV radiation and decreased Langerhans cells which are critical components of the skin’s immune system. This is accompanied by altered T and B cell function and a pro-inflammatory environment that some authors have termed “inflammaging.” A schematic diagram of histologic changes with age is presented in Fig. 1. The dermal-epidermal junction is flattened with effacement of rete ridges, which leads to decreased contact between dermis and epidermis and predisposition to separation with shear forces. The dermis becomes atrophic with reduced fibroblasts and mast cells, and decreased mechanoreceptors including Meissner and Pacini corpuscles result in diminished sensation to touch, pressure, and vibration. The number

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Fig. 1 Histologic changes of aging skin. Major features include flattened dermal-epidermal junction, disorganized collagen, thinning, attenuation of elastic fibers, decline in glandular activity, and graying of hair

and function of skin appendages such as pilosebaceous units and sweat glands decreases with age. Impaired thermoregulation results from loss of subcutaneous fat along with decreased autonomic nerves from the sympathetic nervous system and decreased dermal vascularity. There is decreased ability to manage water balance in response to antidiuretic hormone (ADH). The number, growth rate, and diameter of hair follicles decline with aging. Aging has a direct effect on microcirculation, including arterioles, capillaries, and venules, with reduction in microvascular reactivity and vascular dysregulation. Larger arteries become stiff with atherosclerotic changes, and there is decreased blood vessel density with vascular disorganization. Skin failure is a proposed term for the state in which tissue tolerance is so compromised that cells can no longer survive in zones of physiological impairment that includes hypoxia, local mechanical stresses, impaired delivery of nutrients, and buildup of toxic metabolic byproducts [4]. Dermatoporosis is another term to capture the scope of cutaneous fragility that results from combined factors of aging, environmental, pathophysiologic, and pharmacologic factors that result in breakdown of protective mechanisms of skin [5]. Consequences of dermatoporosis include

senile purpura, subcutaneous hematomas, lacerations and skin tears, delayed wound healing, and stellate pseudoscars, which are whitish lesions composed of hypocellular bands of collagen under atrophic epidermis that contains decreased elastic fibers and mucin.

Wound Healing Overview Normal wound healing is a complex sequence of cellular and molecular events that includes hemostasis, inflammation, proliferation, and remodeling. Hemostasis is marked by vasoconstriction and platelet aggregation, with release of clotting factors, cytokines, and growth factors. Neutrophils, mast cells, monocytes, and macrophages are involved in the inflammatory phase, releasing proinflammatory cytokines and cleansing the wound of bacteria and debris. The proliferation or repair phase is marked by fibroblast migration and creation of granulation tissue that consists of new blood vessels (angiogenesis), endothelial cells, myofibroblasts, and extracellular matrix. Fibroblasts produce collagen that increases the strength of the wound, plus other critical substances such as elastin, fibronectin, glycosaminoglycans, and proteases. Myofibroblasts, descended from fibroblasts, assist in contraction.

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The remodeling or maturation phase consists of collagen deposition and formation of extracellular matrix with fibronectin, hyaluronic acid, and proteoglycans. The tensile strength of a healed wound is only 50–80% of that of undamaged skin, which renders these areas vulnerable to recurrence. Chronic wounds are stalled in the inflammatory and proliferative phases. There is little agreement among experts regarding the time interval that qualifies a wound as chronic, but proposed frameworks range from 1 to 3 months. The surface of a chronic wound contains proinflammatory cytokines, cells that do not respond to reparative stimuli, and polymicrobial biofilms. A biofilm is a community of microorganisms that secretes a mucilaginous extracellular coating that protects them from antibiotics, delays epithelialization and granulation tissue formation, and impairs healing. Conditions leading to chronic wounds include repetitive trauma, decreased vascular perfusion and oxygenation, malnutrition, edema that interferes with nutrient delivery, and chronic moisture and bacterial contamination. Geriatric patients have often been exposed to agents that impair skin integrity or compromise the immune system, and this can impact wound healing. This includes radiation therapy and chemotherapeutic drugs administered for malignancies and immunomodulators for diseases such as psoriasis and rheumatoid arthritis [6]. Systemic and topical corticosteroids cause thinning and atrophy of the skin because of the suppressive action on cell proliferation and inhibition of collagen synthesis which impairs wound healing [7]. These factors have greater impact on wound healing in older adults because they are synergistic with age-related anatomic and physiologic changes. Physiologic and pathologic changes that decrease delivery of oxygen and nutrients to the skin will adversely impact wound healing. These include anemia, chronic lung disease, low cardiac output states, and vascular disease. Edema leads to impaired delivery of oxygen and nutrients and causes include fluid overload, congestive heart failure, venous insufficiency, and hypoalbuminemia leading to anasarca. Diabetes mellitus leads to neuropathy, microvascular disease, dysfunctional leukocytes, and altered

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inflammatory pathways that cause dysfunctional wound healing. Nutritional depletion and sarcopenia can contribute to skin fragility and impair wound healing as well. Urinary and fecal incontinence cause maceration, inflammation, and bacterial contamination leading to folliculitis, cellulitis, fungal dermatitis, and loss of integrity that can result in pressure ulceration. The geriatrician who practices person-centered care can recognize these factors and provide interventions in the form of patient and family education, discussions with nursing staff and other primary care providers, pressure-relieving interventions, and referrals to dietitians or rehabilitation specialists.

Psychosocial Aspects of Chronic Wounds Person-centered care of chronic wounds always requires addressing psychosocial issues that include healthcare inequities. Chronic wounds generally develop in the setting of multiple longstanding comorbidities, some of which may not have been properly addressed. Lifestyle and mental health issues, medication compliance, and substance abuse including illicit drugs, alcohol, and cigarette smoking often play into wound genesis and delayed wound healing and are factors to consider when constructing a treatment plan. Socioeconomic background may provide clues to access to care, and social support networks and cultural and religious considerations can impact the treatment plan [8]. Management of the older adult with chronic wounds includes complex clinical decisions, and providers must consider the psychological consequences of wounds as well as the impact upon quality of life [9]. This will assist not only in determining feasibility of specific procedures and treatments but will aid in prognostication and communication with the patient and family [10]. Chronic wounds often result in social isolation, financial hardship, anxiety, depression, and mobility limitations that require environmental adaptations. Any factor leading to nutritional deficit, including poverty, living alone, lack of access to food and safe drinking water, neuropsychologic

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problems, and issues such as malabsorption, malignancy, and others will render skin vulnerable to chronic wounds and contribute to prolonged healing. These considerations are within the scope of the geriatric assessment, placing geriatricians in an ideal position to promote person-centered care for patients with chronic wounds.

Nutritional Aspects of Wound Care Evaluation of nutritional status has an established place in geriatric assessment and is an integral component of person-centered evaluation of patients at risk for pressure injuries and chronic wounds. Carbohydrates and fats supply energy to cells, protein is used in anabolic repair, and vitamins and trace elements are essential for healing. Identification of malnutrition and correction of nutritional deficits will promote healing and enhance quality of life. Essential elements of assessment include weight history, current weight and physical examination, psychosocial evaluation, functional and cognitive status, nutritionrelated comorbidities, and relevant laboratory values. Formulating a nutritional plan is a multidisciplinary endeavor, and the geriatrician needs to rely upon assessments and interventions employed by team members such as nutritionist and speech-language pathologist (SLP) to promote optimal healing. Nutritional recommendations should be individualized in response to clinical conditions and goals of care [11]. Person-centered nutritional assessment begins with psychosocial evaluation including economic status and support system. Poverty promotes fragmented care and inadequate access to treatments, and wound care always requires social infrastructure to provide nutritious food and encourage supplements. Ethnic, spiritual, and cultural background must be considered. Relevant aspects of functional status include the ability to feed oneself and maintain sufficient intake which includes swallowing. Cognitive status and depression will impact the ability to eat and maintain adequate intake. Medical history includes presence of anorexia, quantification of weight loss with

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determination whether weight loss was intended or unintended, medication history including herbal supplements, and nutrition-related comorbidities that include diabetes mellitus, malabsorption, and abdominal surgery. There is no specific laboratory test that reflects nutritional status; however, relevant evaluations include CBC, serum albumin and prealbumin, glucose, hemoglobin A1C, and tests that reflect state of hydration including sodium, urea nitrogen, and creatine. Serum albumin, with a half-life of 20–22 days, was once felt to reflect protein stores, but is now recognized as a negative acute phase reactant affected by inflammation and other factors such as liver disease and state of hydration. Prealbumin is a transport protein for thyroxine, has a short half-life of 2–4 days, and is affected by many of the same factors as albumin. That said, prealbumin has value in determining positive or negative nitrogen balance. Anthropometrics should include accurate current weight and determination of BMI, which is weight-to-height ratio derived from body weight in Kg divided by the square of height in meters. Although controversial, BMI is helpful in determining the presence of cachexia or sarcopenia. Aspects of physical examination include oral cavity and dentition, muscle mass and strength, and loss of subcutaneous fat evidenced by temporal wasting and loose skin in the extremities. Estimating a patient’s daily caloric requirement is a key component of nutritional intervention, and recommendations should include carbohydrates, fat, protein, and micronutrients that meet basic needs plus additional energy and building blocks to promote healing. For individuals with chronic wounds including pressure injuries, the recommendation is 30–40 kcal/kg/day and protein supplement of 1.25–1.5 g/kg/day for increased demands of protein synthesis. Strategies to enhance oral intake include oral supplements, fortified foods, improved eating environment, and pharmacologic appetite stimulants. When a patient has a pressure injury or other chronic wound and oral intake is inadequate to promote healing, parenteral nutrition should be considered if consistent with advance directives and goals of

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care. Once implemented, the tube feeding formula should include additional protein and calories to promote wound healing. Patients and families should be counseled regarding risks and adverse outcomes imposed by tube feedings, and that the benefit of wound healing may not be achieved.

Infectious Aspects of Chronic Wounds There is a broad spectrum of manifestations of infection in chronic wounds. Infections lead to delayed wound healing and if unchecked can progress to sepsis, osteomyelitis, necrotizing soft tissue infection, and mortality. Classical signs and symptoms including pain, erythema, warmth, and purulent exudate are often absent in chronic wound infections. Laboratory findings such as elevated white blood cell count may not be present, and surface culture swabs are not helpful due to colonizing microorganisms. Chronic wound infection may manifest in delayed healing, enlargement of the wound, increased drainage or pain, discoloration of the wound bed, increased devitalized tissue, and malodor; however, these signs may be nonspecific or reflective of intrinsic factors related to underlying medical conditions [12]. There is currently no consensus on diagnostic criteria for infection in chronic wounds. Chronic wounds have colonizing organisms that are continually changing, rendering surface swabs unreliable for clinical guidance. Quantitative microbiologic assay using deep tissue culture is the gold standard in establishing infection from specific bacteria; however, this requires sterile tissue biopsy and special handling of the specimen – techniques unavailable in many settings and beyond the scope of most primary care practitioners. Tests for biomarkers of chronic infection such as leukocyte esterase activity are in development, but none are reliable enough to be established as standard of care. Many factors affect both occurrence and progression of chronic wound infection including advanced age, steroids, diabetes mellitus, malnutrition and sarcopenia, foreign bodies, necrosis, and any factor that impedes circulation and delivery of oxygen and

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nutrients to tissue. These conditions include macrovascular and microvascular disease, anemia, hypoxia, endothelial dysfunction, and edema. Any factor that dysregulates the immune system can promote wound infection including longstanding diabetes mellitus and pharmacologic agents such as immunosuppressants, immunomodulators, chemotherapeutic agents, and glucocorticoid administration [13]. Debilitated patients often undergo multiple courses of antibiotics which promote proliferation of drug -resistant bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin resistant Enterococcus (VRE), and extended spectrum beta lactamase (ESBL) producing Gram-negative bacteria. Biofilm is present in at least 70% of chronic wounds and is a recognized cause of delayed healing [14]. Chronic wounds offer an ideal environment for biofilm due to exposed proteins, cellular debris, and underlying illnesses that inhibit oxygen and nutrient delivery to tissue. Biofilms are composed of a complex extracellular matrix of glycocalyx that acts as a barrier to antimicrobial agents. Pathogenic bacteria within the biofilm are metabolically dormant; however, fluctuations in population density and alterations in cellular communication can trigger invasiveness into adjacent tissue. Biofilm differs from slough in that it cannot be visualized during physical examination, and removal of biofilm with serial debridement or nontoxic antiseptics can stimulate healing. Wound infection is component of a microbiologic continuum that begins with contamination followed by colonization with bacteria that do not initiate a host reaction. Critical colonization occurs with increased bacterial burden, and the wound enters a nonhealing chronic inflammatory state that may be accompanied by pain. Critical colonization transforms into infection when bacterial proliferation overcomes host defenses and invades deeper tissue causing soft tissue infection or cellulitis. This series of events is influenced by host factors such as diabetes, malnutrition, local hygiene, immunosuppression, poor perfusion, and medications such as steroids, immunomodulators, and chemotherapeutic agents.

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Osteomyelitis

Necrotizing Soft Tissue Infections

Osteomyelitis is a progressive infectious process that results in bone destruction and sequestrum formation that begins with inoculation of pathogens into bone from bacteremia, trauma, wound contaminants, or surgical procedures such as insertion of hardware [15]. Most common organism is Staphylococcus aureus, but other microbes may be identified. It is classified as acute or chronic depending on imaging and histopathology, and manifestations include pain, impaired wound healing, drainage, and low-grade fever. Complications include abscess, sinus tracts, and extension to adjacent structures. Diagnosis is best made by MRI, which has the advantage of assessing bone marrow and surrounding soft tissue and can be used to assess the response to therapy. Plain radiography and radionuclide imaging have less sensitivity and specificity and may not be helpful. Definitive diagnosis of osteomyelitis is made by bone biopsy with microbiologic identification of specific organisms. Elevated C-reactive protein (CRP) can be an adjunct for diagnosis and monitoring clinical course, and elevated white blood cell count may not be present. Treatment should be tailored to each patient with consideration of extent of boney involvement, presence of hardware, medical comorbidities, advance directives, and quality of life [16]. Four to six weeks of antibiotics is the preferred treatment to allow revascularization of bone and opportunity for antimicrobial agents to infiltrate the inflamed area, but controversy exists regarding route of antibiotic administration. Risks of long-term intravenous therapy include adverse events such as line infection, thrombosis, antibiotic resistance, and recurrence after therapy is completed. Surgical treatment includes removal of hardware, debridement of diseased bone and surrounding soft tissue, insertion of local antibiotics in the form of polymethylmethylacrylate (PMMA) beads antibioticimpregnated cement spacers [17]. Osteomyelitis in diabetic foot ulcers often results in amputation of digits, partial foot, and/or lower limb amputation.

Necrotizing soft tissue infections, also called necrotizing fasciitis, sometimes occur from chronic wounds, which provide a portal of entry for pathogens, particularly in debilitated patients with diabetes mellitus and poor nutritional state [18]. These infections are manifested by rapidly progressive necrosis of fascia and subcutaneous tissue and result in septic shock, hypotension, capillary leak syndrome with profound hypoalbuminemia, and mortality of 25–30%. Necrotizing soft tissue infections can be polymicrobial involving aerobic and anaerobic organisms including Clostridium, and polymicrobial with organisms that include group A Streptococcus and Methicillin-resistant Staphylococcus aureus (MRSA) [19]. Clinical findings include severe pain, bullae, necrosis, erythema, soft tissue edema, elevated white blood cell count and C-reactive protein, crepitus, and imaging evidence of gas in the soft tissues. Necrotizing soft tissue infection represents a medical emergency and requires immediate surgical consultation, as early debridement is a critical first step in management followed by broad spectrum antibiotics guided by deep aerobic and anaerobic cultures.

Cutaneous Candidiasis Yeast infections are an under-appreciated cause of worsening pressure injuries and poor healing of chronic wounds. Cutaneous candidiasis is commonly caused by Candida albicans, a yeast that is part of normal skin flora and usually responds quickly to topical antifungals [20]. Candida albicans is a dimorphic organism that undergoes phenotypic change to hyphal growth that invades tissue and precipitates an inflammatory reaction when host defense mechanisms are impaired [21]. Clinical infection is manifested by local inflammation, redness, and patient discomfort. Cutaneous candidiasis is commonly seen in elderly, bedbound patients who are incontinent, and clinical appearance overlaps with incontinence associated dermatitis (IAD), moisture associated skin damage (MASD), and stage 1 pressure

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injury. Diabetes mellitus, antibiotic use, and immunocompromise are additional risk factors. Clinicians need to maintain a high level of suspicion, looking closely for typical demarcated satellite lesions and scaling that are manifestations of cutaneous candidiasis. Candida dermatitis also occurs in areas adjacent to chronic wounds, particularly when there is drainage and maceration, causing further inflammation and impaired wound healing. Candida auris is an emerging novel pathogen first reported in Japan in 2009 that is resistant to many commonly used antifungals, and has been identified in nosocomial outbreaks in the ICU across the globe [22].

Pressure Injuries A pressure injury is a debilitating, chronic wound that occurs across all healthcare settings and is associated with major quality of life consequences and high levels of comorbidity and mortality [23]. Pressure injury is defined by the National Pressure Injury Advisory Panel (NPIAP) as localized damage to the skin and/or underlying tissue, usually over a bony prominence that results from pressure, or pressure in combination with shear. Of the array of chronic wounds, pressure injuries receive a high level of attention because of their association with poor quality of care. Pressure injuries have been spotlighted in value-based purchasing and pay-for-performance initiatives, which reinforces their association with quality deficit. For example, in 2008, the Centers for Medicare and Medicaid Services (CMS) introduced a policy to decline payment to hospitals for certain hospital-acquired conditions that include Stage 3 or 4 pressure injuries. Although pressure injuries are designated a quality indicator, many are unavoidable due to underlying comorbidities. The term “skin failure” has been proposed as the state in which tissue tolerance is so compromised that cells can no longer survive in zones of physiological impairment that includes hypoxia, local mechanical stresses, impaired delivery of nutrients, and buildup of toxic metabolic byproducts. The Kennedy Terminal Ulcer (KTU) describes a wound occurring to the sacrum

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or buttocks in the dying process. There is limited research confirming its existence, and broader concepts such as skin failure may account for the same phenomenon [24]. The person-centered approach to a patient with pressure injury includes not only history, physical, and laboratory values, but also nutritional, functional, psychosocial, and pain assessment. The team approach in collaboration with nutritionist, social work, nursing, and rehabilitation specialists is essential for this process. Pressure injuries should be staged in accordance with NPIAP criteria [25]. Staging of pressure injuries is determined by visible depth (see Fig. 2). Stage 1 is nonblanchable erythema with intact skin, while Stage 2 is a partial thickness wound or intact or serum-filled blister. Stage 3 is full-thickness skin loss, and Stage 4 is determined by exposed fascia, tendon, muscle, or bone. Reverse staging is not a recognized standard because it does not accurately characterize the anatomic and physiologic processes that occur during healing. If the base of the wound cannot be seen, the wound is determined as unstageable (see Fig. 3). A wound is designated a deep tissue injury (DTI) when the skin is intact, and a purple bruise-like area is present in an area subjected to pressure (see Fig. 4). A DTI can dissipate leaving intact skin, or it can evolve into a wound of varying severity. Stage 1 and DTI can be difficult to assess in persons with dark skin, and examinations should include adequate lighting and palpation for detection of induration or warmth. Timely and consistent documentation is required for coding and reimbursement, public reporting, risk management, and transmittal of information as patients traverse the health care continuum. Proper wound documentation includes stage, location, length, width, depth, presence of odor and/or drainage, presence of undermining and tunneling, as well as characteristics of the wound bed, margin, and surrounding skin. Supplemental information can include warmth, capillary refill, presence of pulses, edema, anasarca, and lymphedema. The extent of tunneling and undermining can be determined with a cotton-tipped swab. Many providers employ structured documentation sheets with diagrams to designate location

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Fig. 2 Schematic diagram of pressure injury stages. See text for features of each staging classification

Fig. 3 Infected, unstageable pressure injury. This pressure injury is infected, and coated with purulence and slough rendering it unstageable because the base of the wound is not visible

Fig. 4 Deep tissue injury (DTI). The area appears as a deep bruise with mostly intact skin at the surface

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as well as current treatment and wound progress. Wounds should be formally assessed at least weekly, with descriptors that include measurements, nature of the wound bed and periwound area, pressure redistribution modalities, treatments in progress, and response to healing. Some authorities recommend a validated healing scale such as the Pressure Sore Status Tool or the Pressure Ulcer Scale for Healing (PUSH Tool). Patients with pressure injuries are often transitioned between locations within the health care continuum, and wounds should be documented on both admission and discharge. Photographs can be valuable adjuncts to pressure injury documentation; however, their implementation in a medical record must be consistent and within a formal policy and procedure guideline. Photographs should be of reasonable quality and accompanied by a label within the visual field that contains a patient identifier (name, initials, or medical record number), location of the wound, and date. Pressure injury prevention is an ongoing process for debilitated patients. The standard of care for prevention includes risk assessment followed by appropriate pressure redistribution interventions if the patient is deemed at risk. The most widely used tool for assessment of risk factors is the Braden Scale which combines measurements of sensory perception, moisture, activity, mobility, friction, and shear. The Braden Scale does not contain information related to physiologic factors such as hypoxia and hypotension, which may also increase pressure injury risk. Clinical judgment should be relied upon to determine “at risk” status in addition to a formalized risk assessment scale. Medical device-related pressure injury (MDRPRI) is caused by tubing, orthopedic splints, casts, limb immobilizers, abdominal binders, and CPAP masks (see Fig. 5). Pressure injuries can develop over internally placed medical devices such as implantable neurostimulators and pain-control pumps that create new pressure points under the skin. Areas exposed to chronic moisture, over bony prominences, or under medical devices require special attention to detect early signs of impairment.

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Fig. 5 Medical device-related pressure injury (MDRPRI). This pressure injury mirrors the tubing from a Foley Catheter

The cornerstone of pressure injury prevention includes offloading measures such as turning and proper support surfaces, along with routine nursing care that includes incontinence management, regular skin assessment, and efforts to minimize both dryness and excessive moisture. Other interventions include maximizing nutritional status and minimizing friction and shear. Shear is a mechanical force that occurs when skin is pulled parallel to the body and is commonly caused by sitting up in bed. Backrest elevation of 30–45 is associated with reduced risk of ventilatorassociated pneumonia and aspiration; however, this can increase pressure and shear to the lower back and buttocks. The industry standard for turning and positioning is every 2 hours, but there is limited research to support this schedule and patients are often resistant to this intervention particularly if they are in pain. Patients who sit for long periods of time in chairs should be assessed for proper posture and alignment and provided with pressure relief schedules and cushioning. Strategies for preventing heel wounds include local skin care, cushioning, and lifting the heels off the mattress by placing a pillow under the legs when supine, also called “floating the heels.” A pressure redistribution surface is a device designed for management of tissue loads, microclimate, and/or other therapeutic needs. There is a large variety of support surface technologies and features. Surfaces designed to prevent pressure

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injuries are defined by “immersion” and “envelopment.” Immersion refers to the depth that a mechanical load sinks, and envelopment is the characteristic that takes the shape of the applied load, and their combination gives the protective pressure redistribution effect to prevent pressure injuries. Low air-loss (LAL) technology provides zones of vented air cells that redistributes pressure and manages skin microclimate including heat and humidity. An alternating pressure air mattress (APAM) uses “force redistribution” by taking a load from one location to another and allowing reperfusion of previously loaded area, thereby preventing pressure injuries. Air-fluidized beds are a technology that minimizes pressure over boney prominences with pressurized air that circulates fine ceramic beads. A recent Cochrane review of beds, mattresses, and overlays found the evidence to be insufficient or of very low certainty for both prevention and treatment of pressure injuries [26].

Lower Extremity Wounds Lower extremity ulcerations affect more than 6.5 million Americans each year and have significant implications in terms of cost and quality of life [27]. Most common are venous leg ulcers and diabetic foot ulcers, followed by arterial ulcers [28]. Mixed arterial and venous disease affects up to 26% of patients with lower extremity ulcerations, and 10% are considered atypical. Atypical wounds include wounds related to sickle cell disease, pyoderma gangrenosum, calciphylaxis, Martorell’s hypertensive ulcer, and wounds related to vasculitis.

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term treatments. Pathophysiology includes elevated venous pressure and reflux due to loss of valve function and poor contraction of the calf muscle which serves to pump blood against gravity. Microcirculatory consequences include inflammation, fibrosis, proteolytic activity, edema, decreased PO2, and increased carbon dioxide. Symptoms of chronic venous insufficiency include aching and discomfort exacerbated by gravitational dependency and relieved by leg elevation. History includes surgery or trauma to the lower extremity, obesity, low physical activity, hypertension, smoking, family history, number of pregnancies, and history of deep vein thrombosis (postphlebitic syndrome). Physical examination includes venous dermatitis, hemosiderosis from breakdown of erythrocytes, atrophie blanche which appears as stellate atrophic plaques, and lipodermatosclerosis which is manifested by induration and fibrosis. Venous ulceration in older patients can begin with minimal trauma, and many wounds have no obvious precipitating cause. Venous ulcers are most often located over the medial aspect of the lower leg between the calf and the medial malleolus and are usually shallow and moist, and the surface varies from rich granulation tissue to yellow fibrous film (see Fig. 6). Ulcer edges may be irregular and healing wounds display epithelium spreading across the granulating base. Graduated compression therapy is the mainstay of treatment for venous leg ulcers. Prior to initiating compression therapy, noninvasive

Venous Ulcers Venous ulcers, also known as venous stasis ulcers, are caused by chronic venous insufficiency [29]. Prevalence increases with age, and geriatricians can play an active role in prevention, diagnosis, and treatment. Venous ulcers account for nearly 80% of all leg ulcers and severely impact quality of life with pain, discomfort, and the need for long-

Fig. 6 Venous insufficiency ulcer. This is a typical venous stasis wound with shallow granulating base, lipodermatosclerosis, and leg swelling

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arterial studies such as pulse-volume recordings are recommended to assess the presence and extent of arterial insufficiency, as compression can cause or exacerbate limb ischemia [30]. Leg elevation above the right atrium for 30 min three to four times daily and at night will enhance microcirculatory flow and aid in healing. Compression is often accompanied by serial debridement to remove slough and biofilm and dressings that promote an appropriate level of moisture that protects from maceration and further injury [31]. Pentoxifylline is recommended as a pharmacologic agent to heal venous ulcers in conjunction with compression therapy. Once healed, patients should wear graded compression stockings or other compression device to prevent recurrence. Several other medications have been tried with mixed results including stanozolol and oxandrolone. Nonprescription compounds containing horse chestnut seed extract may be effective for safe, short-term treatment of chronic venous insufficiency. Surgical options for venous ulcers in addition to selective excisional debridement include autologous splitthickness skin grafts, grafts using bioengineered skin equivalents, and venous sclerotherapy. Clinical evidence supporting hyperbaric oxygen for healing venous leg ulcers is limited. Biopsy should be considered for any wound that does not respond to treatment. Patient education is paramount for ensuring ongoing compliance, along with lifestyle modification such as weight loss, regular physical activity, and discontinuation of smoking.

Arterial Ulcers Arterial leg ulcers result from peripheral arterial disease (PAD), leading to hypoperfusion resulting from atherosclerosis, and over 80% have multiple causes including trauma, diabetes, venous, and lymphatic disease [32]. Risk factors include age, hypertension, diabetes, hyperlipidemia, elevated homocysteine level, hypercoagulable state, cigarette smoking, and family history of cardiovascular disease. Patients with lower extremity PAD will usually have obstructive arterial disease

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elsewhere such as coronary artery and cerebrovascular disease. Comorbidities have a role in causing or exacerbating arterial ulcers including malnutrition, anemia, and any condition leading to decreased cardiac output or hypoperfusion. Ischemia caused by diminished arterial flow will always contribute to poor wound healing, and therapeutic strategies are therefore directed at restoring tissue perfusion. Advances in revascularization procedures such as angioplasty, bypass surgery, and endarterectomy have revolutionized the treatment of ischemic limbs; however, these procedures are not suitable for every patient and do not guarantee healing. Geriatricians can serve as an integral part of the interdisciplinary team, assisting in psychosocial, cognitive, and functional assessment to guide balanced, personcentered decision making when considering risks and benefits of revascularization. Major amputation may be preferable when debilitated patients are subjected to potentially futile limb salvage procedures and related complications [33]. Symptoms of PAD begin with claudication, commonly described as cramping, aching, or weakness in the lower extremity. Symptoms can be unexpressed or expressed atypically with behavior changes in persons with dementia or aphasia, or absent in persons with sensory neuropathy. Physical signs of advanced PAD include trophic changes, pale skin, poor capillary refill (>2 seconds), muscle atrophy, numbness and paresthesias, thickening of the toenails, diminished pulses, and cool skin. Arterial ulcers can appear as painful “punched out” lesions with sharply demarcated borders or gangrenous eschars (see Fig. 7). Acute limb ischemia is caused by emboli, thrombosis, major trauma, vasoactive drugs, and hypoperfusion due to shock. Tissue death and gangrene of the toes and foot is a consequence of advanced PAD and is often multifactorial. Dry gangrene is visible necrotic tissue which becomes dessicated and black, and wet gangrene is caused by secondary infection and accompanied by edema, erythema, purulent drainage, and malodor. Gas gangrene is a specific type of necrotizing infection with gas in soft tissue demonstrated by crepitus on physical examination or subcutaneous

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lucencies on x-ray and is considered a surgical emergency. Diagnosis of PAD includes history and physical examination, followed by noninvasive or invasive vascular studies. Commonly available noninvasive vascular studies include Doppler waveforms and pulse-volume recordings (PVR). Ankle-brachial index (ABI) that reflects the ratio of systolic arm to systolic ankle blood pressure is unreliable in older patients due to arterial noncompressibility that causes false negatives. PVR relies on pressure cuffs to generate waveforms that reflect arterial flow and is a more accurate diagnostic test. Other vascular tests include toe pressures, peripheral arterial tone, and transcutaneous oximetry (tcpO2). Invasive vascular studies include angiogram, computerized tomography (CT) angiography, and magnetic resonance angiography (MRA). Preventive and conservative treatment strategies include blood pressure control, lipid-lowering therapy, management of diabetes, and lifestyle considerations such as weight loss, smoking cessation, and exercise which promotes collateral circulation. Symptom management with control of pain, odor and drainage is important; however, there are few evidence-based nonsurgical treatments available. Several modalities have been tried including prostaglandins, growth factors, ultrasound therapy, spinal cord stimulation, intermittent pneumatic compression, and hyperbaric oxygen, but none are currently recommended for treatment of arterial leg ulcers [34].

Fig. 7 Arterial wounds. Dry gangrene in an 87-year-old female with advanced peripheral arterial disease

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Diabetic Ulcers Because of the demographics of aging along with increasing rates of obesity, diabetes and its pathologic sequelae are dramatically on the rise. Age-adjusted prevalence of diabetic complications is greater among African Americans and Hispanics than Caucasian Americans. Diabetes, particularly when poorly controlled over extended periods of time, results in a spectrum of disease that renders skin susceptible to enhanced fragility and poor healing [35]. Chronic hyperglycemia results in inflammation, overproduction of reactive oxygen species (ROS) with oxidative stress, and irreversible cellular damage that leads to autonomic, sensory, and motor neuropathy, reduced vasodilatation, and micro- and macrovascular dysfunction resulting in local hypoxia and poor tissue perfusion [36]. Altered immune response resulting from glycosylation of immunoglobulins and leukocyte dysfunction leads to lower resistance to infection. Healing is delayed by decreased fibroblast proliferation and growth factor expression, impaired angiogenesis, and slower migration of keratinocytes. The diabetic foot syndrome (DFS) includes sensory neuropathy, peripheral arterial disease, structural foot deformities such as Charcot ankle neuroarthropathy, joint mobility limitation, and microvascular disease (see Fig. 8). Underlying pathology is irreversible and may worsen over time. Neuropathy is one of the most common

Fig. 8 Diabetic foot ulcer. This wound occurred in a patient with Charcot neuroarthropathy in an area of constant repetitive pressure

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risk factors for lower extremity ulcers, and screening methods include the Semmes-Weinstein monofilament test and vibration perception threshold (VPT). Consequences of DFS include ulceration, poor healing, amputations, and infection. Mortality after diabetes-related amputation exceeds 70% at 5 years for all patients with diabetes. In addition to wounds related to DFS, diabetes alters the natural history and prognosis for other chronic wounds including pressure injuries and arterial and venous ulcers. Classical signs and symptoms of infection in diabetic wounds are often absent, leading to delayed diagnosis. Polymicrobial infections are common, with complications that include osteomyelitis and necrotizing soft tissue infection. Clinicians therefore need to have high index of suspicion and if infection is suspected initiate broad-spectrum antibiotics for greater coverage of potential pathogens. Diagnostics for diabetic ulcers include routine laboratory tests such as CBC and chemistries and should always include HbA1C. Physical examination should include palpation of pulses, capillary refill time, monofilament screen for sensation, and description and measurement of the wound including determination as to whether the wound probes to bone. Noninvasive vascular assessments include pulse volume recordings (PVR), transcutaneous oxygen tension (TcPO2), and others depending upon the capability of your local vascular laboratory. Ankle-brachial index (ABI) measurement is unreliable in geriatric populations due to the high incidence of noncompressible arteries. Radiographic evidence of osteomyelitis is best obtained through MRI, but bone biopsy offers more information by providing bone pathology and culture results to direct antibiotic therapy. Prevention and treatment of diabetic wounds is an ongoing, multidisciplinary process that involves education of the patient and support system. This includes glycemic control and management of concomitant risk factors such as diet, smoking, hypertension, and hyperlipidemia. Psychosocial reasons for noncompliance must be evaluated such as inability to understand self-management due to inadequate knowledge, language barriers, cognitive

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problems, financial barriers, and limited access to care. Treatment incorporates therapeutic footwear such as sandals, half shoes, removable cast walkers, and total contact casting. Surgical options include serial sharp debridement to remove devitalized tissue and reduce biofilm and bacterial load. Other approaches include endovascular procedures to increase blood flow to the extremity and a variety of ostectomies, amputations, and reconstructive procedures. Adjunctive treatments are available such as transcutaneous electrical nerve stimulation (TENS), hyperbaric oxygen therapy (HBO), and negative pressure wound therapy (NPWT). Geriatricians are in a unique position to co-manage patients undergoing procedures to treat diabetic foot ulcers. The philosophy of limb salvage through multiple endovascular and reconstruction procedures, serial debridements, and sequential partial amputations must be balanced by optimization of quality of life with patientoriented, palliative outcome measures. Persons with dementia and preexisting mobility limitations will have limited benefit from aggressive and medically futile limb salvage procedures. The skills involved with assessment, team approach, and realistic patient and family education fall squarely in the realm of geriatric practice.

Leg Ulcers from Sickle Cell Disease Leg ulcers resulting from sickle cell disease are a devastating contributor to morbidity and are considered a marker for disease severity. Primarily associated with homozygous Hb SS, these wounds occur in areas with less subcutaneous fat with thin skin and decreased blood flow including medial and lateral malleoli, anterior tibial area, dorsum of foot, and Achilles tendon area [37]. Like other types of leg ulcers, these lesions are physically disabling and have negative consequences in terms of anxiety, depression, high medical cost, and decreased quality of life. Precipitating factors include minor trauma, and chronicity and resistance to therapy are major clinical features. Many treatment strategies have been tried including the standard arsenal of dressings plus pharmaceutical

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interventions such as antioxidant agents, topical pharmaceuticals, stem cell therapies, and hyperbaric oxygen; however, evidence for therapeutic benefit is inconclusive [38].

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immunosuppressive agent. Debridement should be avoided as this can exacerbate PG ulcers. Local treatment includes gentle daily wound cleansing and absorbent, antibacterial dressings.

Pyoderma Gangrenosum Pyoderma gangrenosum (PG) is a rapidly progressing and debilitating disease that features severe pain, unsightly wounds, and negative impact on quality of life. Although PG is an uncommon cause of leg ulceration in older adults, it must be considered in the differential diagnosis because treatment is much different. The history will often reveal pathergy – a rapid, exaggerated skin injury that occurs after minor trauma that may include a bump, bruise, laceration, or skin biopsy [39]. Clinical features include severe pain, pockmarked indentation in the wound bed, and violaceous borders with undermining (see Fig. 9). PG is a neutrophilic dermatosis that results from autoinflammation and is associated with systemic illnesses such as inflammatory bowel disease, autoimmune arthritis, and malignancy. Diagnostic delays and misdiagnosis are common, and there are no defining histopathologic or laboratory findings. Treatment includes fast acting immunosuppression with systemic corticosteroids, followed by a steroid-sparing

Fig. 9 Pyoderma gangrenosum. This 85-year-old female presented with painful wounds showing pockmarked indentations in the wound bed and violaceous borders

Martorell’s Hypertensive Ischemic Ulcer Martorell’s hypertensive ischemic leg ulcer is an often-misdiagnosed wound. Patients with a Martorell’s ulcer characteristically have hypertension and 60% of patients are diabetic [40]. It is histologically characterized by subcutaneous arteriolosclerosis and obliterating lesions of the small vessels. Clinically they present with painful black eschar on the lateral-dorsal aspect of the calf or in the Achilles tendon region with bilateral involvement in 50% of cases (see Fig. 10). This wound must be differentiated from other causes including venous ulcer, arterial ulcer, pyoderma gangrenosum, and calciphylaxis as the treatment is much different. The diagnosis is based on history and clinical presentation and confirmed by biopsy from the wound border. Unlike arterial leg ulcer, the pain is not exacerbated by exercise and leg elevation. The management of Martorell’s ulcer includes control of cardiovascular risk factors, cessation of vitamin K antagonists, analgesia, surgical debridement,

Fig. 10 Martorell’s hypertensive ulcer. This wound appeared in hypertensive 58-year-old female and was excruciatingly painful

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split thickness graft, and negative pressure wound therapy.

Calciphylaxis Calciphylaxis, also known as calcific uremic arteriolopathy, is an uncommon but devastating disease that occurs primarily in patients with chronic kidney disease, antiphospholipid syndrome, and cryoglobulinemia [41]. Arterioles become calcified with resulting tissue ischemia that causes painful, necrotic, nonhealing wounds involving epidermis and dermis. Diagnosis is made by clinical suspicion and biopsy, and treatment is sodium thiosulfate (OL), the mechanism for which is unknown.

Wounds Related to Vasculitis Vasculitis is an inflammatory disorder of blood vessels which can present with skin ulceration and delayed wound healing. Vasculitic ulcers, like other painful chronic wounds, incur significant financial burden and decreased quality of life. Autoimmune, rheumatic, and connective tissue disease such as rheumatoid arthritis, systemic lupus erythematosus, and scleroderma can be accompanied by vasculitis, with etiology that is idiopathic or triggered by medication, infection such as hepatitis B and C, and malignancy such as multiple myeloma [42]. The cocaine diluent levamisole is another cause of vasculitic ulcers. Inflammation is triggered by circulating immune complexes deposited in blood vessels causing tissue ischemia, and necrosis that impairs the skin’s barrier function. Clinical presentation is varied and may appear as macular rash, pain, nodules, livedo reticularis, or patches of necrotic tissue. Cutaneous vasculitis usually presents in the lower extremity and often confused with other causes of leg ulcers like venous insufficiency. Treatment is directed at causative comorbidities and local care based on principles of wound bed preparation [43]. Corticosteroids or immunosuppressants are employed depending upon etiology and severity of disease.

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Lymphedema Lymphedema is the interstitial accumulation of protein-rich fluid resulting from interrupted drainage of the lymphatic system [44]. The result is edema, inflammation, adipose tissue hypertrophy, fibrosis, and induration that leads to disfigurement and impaired functional status, which in turn leads to psychological morbidity including anxiety, depression social avoidance, and decreased quality of life [45]. Lymphedema can be primary or secondary. Primary lymphedema is due to congenital abnormality or dysfunction in the lymphatic system, while secondary lymphedema results from disruption or obstruction of the lymphatic system due to disease or iatrogenic causes. Risk factors for secondary lymphedema include malignancy, trauma, infection, and obesity. Lymphedema of the lower extremities often presents with acute or chronic cellulitis that may progress to ulceration. Diagnosis is based upon clinical presentation, although radionuclide lymphoscintigraphy is sometimes used to determine early stages of lymphedema. Nodular fibrosis is a subtype of lymphedema that results from tissue proliferation due to chronic inflammatory process of the skin (see Fig. 11). The standard of care for conservative treatment is complete decongestive therapy (CDT), which includes manual lymphatic drainage by massage combined with exercise and compression bandages. Maintenance

Fig. 11 Lymphedema, nodular fibrosis subtype. This subtype of lymphedema shows nodules from tissue proliferation due to chronic inflammation and growth factors in interstitial fluid

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therapy includes pneumatic compression pumps, exercise, and compression bandages and garments. Surgical options are limited and include reductive techniques, liposuction, lymph node transfer, and laser therapy. Diuretics have no role in treating lymphedema and can lead to increased fibrosis due to worsening protein accumulation.

Nonhealing Surgical Wounds Over half of all operative procedures are performed in patients over 65 years of age, and this percentage is on the rise. Advances in surgical and minimally invasive techniques have shifted the risk-benefit ratio to favor surgery in older, more medically complex patients with multiple comorbidities. However, even in the absence of underlying pathology, physiologic changes with age predispose to adverse postoperative events which include dehiscence, infection, hematoma, seroma, and infection [46]. Infection can manifest in purulent discharge, periwound warmth and redness, abscess adjacent to the incision line, fever, and elevated white blood cell count; however, patients with multiple comorbidities may not manifest classical signs and symptoms. A multidisciplinary approach that includes geriatric input can assist in minimizing adverse outcomes related to nonhealing postoperative wounds. Routine postoperative care includes measures that allow the wound to heal rapidly with the best functional and aesthetic results. Wounds should be kept as clean as possible and free of debris such as devitalized tissue or excessive exudate that will delay wound healing. Postoperative wounds should be irrigated and protected with dressings that protect against bacterial contamination and wick away drainage. Negative pressure wound therapy (NPWT) is increasingly used for prophylaxis of surgical site infections, but its effectiveness when compared to standard dressings remains uncertain. Postoperative infection involving orthopedic hardware and other implantable devices is a costly and devastating complication. Prosthetic joint infection should be suspected in any patient with

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acute onset of pain or persistent wound drainage. Radiographic findings and blood tests can be nonspecific, and treatment includes long-term intravenous antibiotics directed by organism sensitivities, operative revision with hardware removal, antibiotic impregnated material placed into the infection site, pain management, and rehabilitation. Many wounds under the care of surgical specialists receive reconstruction procedures that include skin grafts and tissue flaps, and the geriatrician can assist with both pre- and postoperative assessment and decision making. Successful grafts and flaps require adequate nutrition and a vascularized recipient bed capable of angiogenesis with the potential to develop granulation tissue, and complications include hematoma, seroma, infection, dehiscence, and necrosis. Types of grafts include split thickness, full thickness, and engineered skin substitutes. Autologous skin grafts require a donor site, which will result in a separate wound that requires attention. Postoperative care includes avoidance of pressure that interrupts blood flow and mechanical shearing that disrupts the suture margins and delicate microcirculation required for revascularization. Pharmacologic management includes avoidance of anticoagulants, corticosteroids, chemotherapeutic agents, and immunosuppressive drugs. Geriatricians should be on the alert for postoperative complications of aesthetic or “anti-aging” procedures. The demand for these procedures has engendered an industry of unlicensed personnel performing cosmetic procedures such as injectables and liposuction, sometimes in unsafe environments. In addition, cosmetic surgery tourism is increasing for abdominoplasty, gluteal enhancement, breast enlargement or reduction, and sex reassignment surgery. Complications include dehiscence, infection, and inflammation related to injections of foreign material [47]. Patients seeking cosmetic procedures by unlicensed practitioners in foreign countries may not have extensive preoperative assessment or postoperative follow-up. Geriatricians must be prepared to include questions regarding cosmetic surgery and be on the alert for complications that may include chronic wounds.

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Traumatic Wounds Traumatic injuries result in a growing number of hospital admissions and are the fifth leading cause of death in older adults [48]. Advancement in the management of chronic disease has resulted in a more active lifestyle in older adults, predisposing them to injury. Epidemiologic surveys of geriatric trauma reveal higher mortality despite less severe injuries. Frailty, decreased physiologic reserve, multimorbidity, impaired mobility, pharmacologic factors, and changes in skin morphology with age result in increased vulnerability of aging skin [49]. Lifestyle factors such as cigarette smoking and sun exposure also increase risk for skin fragility and impaired healing. Because of these underlying anatomic and physiologic changes, patients are at higher risk for impaired healing and infection. Most common causes of traumatic wounds include falls, blunt force injuries, burns, skin tears, and self-induced excoriations.

Lacerations Pretibial lacerations are common in geriatric patients, particularly those with multiple comorbidities and mobility limitations. Because of changes in aging skin and underlying illness, healing is often prolonged. Pretibial lacerations are often poorly treated at home, and initial presentation may include necrosis, slough, or infection (see Fig. 12). Most can be managed

Fig. 12 Pretibial laceration. Typical pretibial laceration in a 91-year-old female who fell while climbing stairs

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conservatively with nontoxic cleansers such as chlorhexidine gluconate to decontaminate and reduce opportunistic bacterial dressing [50]. The presence of necrosis may require sharp excisional debridement. There is insufficient evidence to recommend specific dressings in pretibial lacerations other than complying with basic principles of wound bed preparation. Sutured lacerations in geriatric patients are twice as likely to suffer from skin necrosis. Depending upon the size and depth of the wound, treatment may require grafting or negative pressure wound therapy (NPWT). For patients with edema or underlying venous insufficiency, compression therapy will accelerate healing by reducing interstitial fluid.

Skin Tears A skin tear is separation of the epidermis and dermis that results from mechanical force such as shear, friction, or blunt injury and may be classified as a subtype of laceration [51]. They occur at the extremes of age in infants and older adults and are most common in the upper extremities (see Fig. 13). A recent study estimates the prevalence of skin tears in nursing homes between 14% and 24%. Precipitating causes include minor trauma, medical adhesive related skin injury (MARSI), wheelchair injuries, and shear forces during handling and transfers. Many of these

Fig. 13 Skin tear. This is a Type 2 skin tear with partial flap loss in which the skin flap cannot be repositioned to cover the entire wound bed

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wounds display delayed healing and can be classified as chronic wounds. The currently recommended system for describing skin tears is called the ISTAP (International Skin Tear Advisory Panel) classification [52]: • Type 1 skin tears involve no skin loss with a linear or flap tear in which the skin flap can be utilized to cover the wound bed. • Type 2 skin tears involve partial flap loss in which the skin flap cannot be repositioned to cover the entire wound bed. • Type 3 skin tears involve total flap loss with exposure of the entire wound bed. Management includes protecting skin from further injury and infection, hemostasis, and basic principles of wound bed preparation to promote healing. Delayed treatment can result in desiccation of the skin flap or contamination and infection. There is insufficient evidence to advocate one specific dressing type over another, but all skin tears should be rinsed with normal saline then patted dry with sterile gauze. For Type 1 skin tears, the skin flap should be approximated as closely as possible and application of topical antibiotic and protective dressing. Some authorities recommend Steri-Strips, but these can add risk for adhesive related injury when removed. For Type 2 and 3 skin tears, a variety of dressings can be utilized provided they provide a moist environment, minimize local pain and discomfort, and protect from contamination and further injury. Some authorities recommend the new class of cyanoacrylate-based adhesives as a wound closure device, which can be applied to wound edges in Type 1 skin tears and directly on the wound bed for Types 2 and 3 skin tears.

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Most major burns occur in domestic settings from residential fires and are accompanied by systemic response that includes release of inflammatory and vasoactive mediators, fluid loss, increased vascular resistance, hypovolemia, and hypoperfusion, also known as “burn shock.” Cigarette smoking is associated with major burns and death in older adults. Minor burns affect less than 15% of body surface area with the primary symptom being pain. Contact burns occur from spills of hot liquid, hot water bottles, steam, heating pads, and radiators, and persons with impaired cognition, mobility, and sensation are at increased risk (see Fig. 14). Most can be treated conservatively, but larger burn areas may require hospitalization or grafting. The decision to treat in a burn center is determined by the extent of body surface involved, depth of the burns, and patient characteristics such as age and comorbidities. Burn symptoms and depth of injury vary with duration of exposure to heat source and temperature of the source. A 1st degree burn is superficial and affects only the epidermis and may cause redness and pain. A 2nd degree burn is partial thickness, affects both epidermis and dermis, and is accompanied by redness, swelling, blisters, and pain. A 3rd degree burn is full-thickness and reaches the fat layer beneath the skin, and the affected area may be black, brown, or white. Numbness can result from sensory nerve destruction. The first step for treating a minor burn is removing the heat source from skin contact and

Burns Burns are lesions that result from heat, overexposure to sun or other radiation, or chemical or electrical contact. Burns in older adults are associated with increased mortality and morbidity, prolonged hospital length of stay, and delayed healing [53].

Fig. 14 Contact burn. This 76-year-old man fell in home landing on the heating grate on his floor and could not get up, suffering first and second degree burns

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cooling with liquids like tap water or saline. Acute treatments include pain medications, topical analgesics, antibiotic ointments, occlusive dressings, and tetanus booster if needed [54]. Burns are dynamic injuries and should be reassessed regarding extent and depth after several days. Most minor burns have good prognosis, but some heal slowly and require prolonged topical treatments, hydrotherapy, or skin grafts. Third debree burns have high risk for infection and are usually treated with debridement and grafting. Maintaining optimal nutrition for wound healing is always a consideration, and side effects of opiate pain medication such as somnolence and constipation should be monitored. A treatment plan for burns includes addressing underlying comorbidities such as anemia and diabetes mellitus. Once a burn-related wound becomes chronic, principles of wound bed preparation apply. This includes removal of necrotic and devitalized tissue, minimization of biofilm, control of exudate and metabolic waste, maintaining a moist healing environment, and control of bacterial balance.

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Fig. 15 Factitious wound. This chronic wound resulted from constant picking at the patient’s own skin. He had undergone extensive workup including biopsy before the diagnosis was made

consultation and a supportive, empathetic approach in a stable therapeutic relationship [56]. Patients with severe cognitive impairment with psychocutaneous lesions may benefit from antianxiety and antidepressant medications and protective measures such as mesh sleeves.

Factitious (Self-inflicted) Wounds

Wounds Related to Malignancy

Chronic wounds are sometimes the result of selfinflicted trauma. Also known as dermatitis artefacta, factitious wounds have a variety of clinical variations and result in misdiagnosis, delayed detection, and prolonged treatment [55]. Factitious lesions can present with a bizarre appearance that does not fit into any known disease process (see Fig. 15). They can present as single erosive plaques or multiple chronic excoriations limited to accessible regions of the body, with lesions displaying various phases of healing including chronic scarring. Differential diagnosis includes xerosis, vasculitis, contact dermatitis, and insect bites such as scabies. Once pathologic etiologies are ruled out, the clinician must consider psychocutaneous syndromes that include malingering, Munchausen’s syndrome, and neurotic excoriation (also known as psychogenic excoriation, subconscious picking, and dermatillomania). The diagnosis of psychocutaneous syndrome is one made by exclusion, and treatment includes psychiatric

Wounds related to malignancy are frequently encountered by geriatricians who need to be prepared to recognize and treat them. Cancer is the second most common cause of death in the USA after cardiovascular disease, and epidemiologists predict a 67% increase in incidence for older adults compared with 11% increase for younger persons [57]. A significant proportion of cancer patients develop malignant wounds, which are generally nonhealable and managed with palliative methods (see Fig. 16). Specific lesions include primary skin tumors or metastatic lesions from breast, lung, head, and neck and genital malignancies. Malignant wounds can present as nodules, induration, fungating masses, malignant ulcers, zosteriform, and mixed appearance. Distressing symptoms include pain, malodor, mass effect, drainage, odor, pruritis, bleeding, crusting, and aesthetic distress, any of which can adversely impact dignity and quality of life [58]. Social isolation and depression are common

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Fig. 16 Wound related to malignancy. This is a wound from breast cancer with tissue distortion and drainage

consequences of malignant wounds. Palliative methods that incorporate multidisciplinary teamwork can manage specific symptoms once they appear. Interventions include topical and systemic analgesics, moisturizers, neutral soaps, antimicrobial and absorptive dressings, antipruritics, topical metronidazole (OL), targeted radiation therapy, and complementary therapies such as relaxation, aromatherapy, music therapy, meditation, and others [59]. Marjolin’s ulcer is an aggressive skin cancer that develops from malignant transformation in scar tissue or chronic inflammation [60]. They have been reported in burns, pressure injuries, nonhealing traumatic wounds, leg ulcers, and chronic fistulas. Most common histology is squamous cell carcinoma, although other tumor types has been reported. An indurated, exophytic, or otherwise atypical area developing in a scar or chronic wound should be biopsied. Prognosis and treatment depend upon histology and presence and extent of regional spread or metastases.

Moisture Associated Skin Damage (MASD) Moisture-associated skin damage (MASD) is defined as inflammation and erosion of the skin caused by prolonged exposure to moisture, including urine or stool, perspiration, wound exudate, stomal effluent, mucus, or saliva [61]. A related entity is incontinence-associated

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dermatitis (IAD), which occurs directly from urinary and/or feces, both of which contain noxious substances in addition to moisture that impairs the skin’s barrier function [62]. Diagnosis is based on visual inspection of vulnerable areas that are contiguous with sources of moisture that can reveal redness, inflammation, warmth, maceration, vesiculation, and sloughing of the epidermis. Inflamed and eroded skin from chronic moisture exposure is a risk factor for cutaneous candiasis and can transform into pressure injury when areas of moisture exist over boney prominences. Other organisms associated with MASD include ß-hemolytic Streptococcus, Staphylococcus aureus, Pseudomonas aeruginosa, Corynebacterium, and Proteus mirabilis. There is considerable clinical overlap between erythema and excoriation related to moisture, cutaneous candidiasis, and pressure injury Stages 1 and 2. Prevention and treatment relies on basic hygiene and keeping skin dry, incontinence care including fecal diversion devices where indicated, and topical skin protectants and barrier products.

Principles of Chronic Wound Management A patient-centered approach to treating chronic wounds involves evaluating psychosocial status, addressing underlying comorbidities, assessing and monitoring the wound, and employing principles of wound bed preparation. Assessment entails examination, description, measurement, and documentation. All wounds should be assessed for infection and consideration of biopsy if malignancy is suspected. There is a broad array of dressings for chronic wounds but little evidence-based research to guide choices [63]. Dressing choices are often based on product availability, insurance coverage, personal preference, cost considerations, expert opinion, and intrinsic rationale for product type. The clinician must plan treatment in accordance with goals of care, recognizing when a palliative approach is appropriate. A summary of common dressing types and rationale for each is presented in Table 2.

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Table 2 Common wound treatment modalities Type Gauze

Content Cotton, polyester, or other fabrics

Rationale Versatile, can be absorptive or protective, primary or secondary dressing

Hydrocolloid

Adhesive pad with moistureactivated, gel-forming material; gelatin and pectin Transparent polymer with acrylic adhesive

Moisture retention

Water in a delivery vehicle such as glycerin or cross-linked polymer sheets Polyurethane with or without adhesive borders

Promote moist wound healing and autolytic debridement Absorb exudate, cushioning, secondary dressing Absorptive dressing

Semipermeable films Hydrogel

Foam

Alginate

Collagen

Silver-containing dressings Enzymatic debriding agent Cadexomer iodine dressing Honey

Topical antiseptics

Petrolatumimpregnated gauze

Seaweed derivative; can be in different forms, including sheet or rope, and combined with other materials such as silver or charcoal Animal-derived collagen formulated into gel, powder, paste, or sheet Silver can be impregnated into multiple types of dressings Enzyme in a petrolatum vehicle Iodophor in a polysaccharide polymer Medicinal grade honey can be used as a gel or impregnated into other dressing types Includes hydrogen peroxide, Dakin’s solution (hypochlorite), povidoneiodine Woven mesh; medical petrolatum and 3% bismuth tribromophenate

Moisture retention

Deactivates matrix metalloproteases that inhibit wound healing Silver has broad-spectrum antimicrobial activity Selected degradation of denatured collagen Absorbent, antimicrobial Antimicrobial properties, anti-inflammatory Reduce bacterial burden of wounds

Bacteriostatic, nonadherent, retains moisture

Best use Secondary dressing, wet to moist, or wet to dry, or as a protective to the wound and surrounding skin. Note: wet to dry is not recommended Superficial, clean pressure ulcers with no necrosis or infection Superficial, clean pressure ulcers with no necrosis or infection Dry wounds; wounds with some necrosis Control of exudate, protect the wound Control of exudate

Partial- or full-thickness wounds with minimal necrosis Wounds requiring control of bacterial balance Wounds with necrosis and slough Wounds with slough, infected wounds Autolytic debriding agent on noninfected wounds Can be cytotoxic to healing wounds; for limited use in heavily contaminated or nonhealable wounds Use with larger wounds with minimal necrosis and slough

Reprinted with permission. Levine JM. Pressure injuries and wound care. In: Harper GM, Lyons WL, Potter JF, et al., eds. Geriatrics Review Syllabus: A Core Curriculum in Geriatric Medicine. 11th Edition. New York: American Geriatrics Society; 2022. http://geriatricscareonline.org

Wound bed preparation is a systematic framework to guide to chronic wound treatment [64]. This tool focuses on critical components including moisture, bacterial balance, and removal of devitalized tissue. A moist environment promotes autolytic debridement and encourages matrix formation, while excess moisture

inhibits healing through maceration. Bacterial balance is facilitated by cleansing, topical antibiotics, disinfectants, and debridement. Autolytic debridement uses moisture-retentive dressings to facilitate endogenous enzymes. Mechanical debridement includes irrigation, wet-to-dry dressings, and abrading the wound base and periwound

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area with gauze or a blunt instrument. Enzymatic debridement uses a proteolytic enzyme to digest cellular debris. Surgical debridement, also called excisional debridement, uses a sharp tool and requires written-informed consent. Depending on the extent of eschar and presence of infection, patients may require general anesthesia in an OR setting. Some clinicians advocate biologic debridement, also called larval therapy, which involves sterilized larvae of the Lucilia sericata fly. Other methods of debridement are available using ultrasonic or laser technology and hydrotherapy with pulsed lavage. The COVID-19 pandemic accelerated the need for remote technology applied to wound care, but its practical use is limited because excisional debridement requires a clinician at the bedside [65]. Many adjunctive therapies are available for wound care, including electrical stimulation, therapeutic ultrasound, light therapy, negative-pressure wound therapy (NPWT), hyperbaric oxygen, platelet-derived growth factors, engineered skin substitutes, and others. NPWT is the application of a suction device to the wound bed to facilitate healing. The wound is packed with foam and sealed with adhesive membrane, and negative pressure is applied which collects exudate into a collection chamber or absorptive pad. Postulated mechanisms by which NPWT promotes healing includes removal of excess fluid, improved circulation, reduced bacterial load, and the effect of negative pressure. Despite its widespread use, there is uncertainty as to whether NPWT compared with a standard dressing impacts outcomes such as mortality, dehiscence, or seroma, or if it increases costs of care [66]. Pain occurs with all types of wounds and adds to wound-related debility. Pain from wounds is conceptualized as chronic, cyclic, and noncyclic. Chronic wound pain results directly from the wound and occurs in the absence of any movement or manipulation. Cyclic wound pain occurs periodically during repetitive interventions such as turning or dressing changes. Noncyclic pain occurs from sporadic procedures such as sharp debridement. Infection causes pain through local inflammation and tissue expansion in the setting

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of abscess. The stepwise approach to pain management begins with nonsteroidal antiinflammatory medication and advances to opiates beginning with lower dosage. Side effects of opiates such as constipation and altered mental status must be closely monitored. Adjunctive medications can include antidepressants and antiepileptic drugs which target neuropathic pain. Topical medications include anti-inflammatory medication or morphine mixed with hydrogel (OL), and topical lidocaine.

Palliative Care for Chronic Wounds There are clinical situations when treatment options become limited due to their burdensome nature and where healing is not expected. Factors leading to decreased expectations for healing include irreversible malnutrition, underlying malignancy, autoimmune disease and/or immunomodulating medication, advanced age, irremediable macrovascular disease with arterial insufficiency, microvascular disease with diabetes mellitus, and end-of-life situations. Other factors include chronic wounds that do not respond to 3–6 months of conservative treatment and are not candidates for aggressive modalities such as skin grafts, vascular procedures, or major surgical debridements. When there is little expectation for healing, the patient will benefit from a palliative approach rather than futile, aggressive care that may involve costly treatments and surgical procedures [67]. The goal of palliative care is symptom control rather than healing, with maximization of quality of life and preservation of dignity [68]. Distressing symptoms associated with chronic wounds include social isolation, depression, pain, drainage, bleeding, malodor, restricted mobility, sleep disturbance, anger, dissatisfaction with caregivers, loss of sexuality, fear of infection, impaired sense of well-being, and altered body image [69]. Unrealistic expectations of wound healing must be addressed through counseling, using sensitive language outlining risks, benefits, and burdens of aggressive care. Surgical procedures must be carefully considered taking into

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account additional burden to the patient. Co-management consisting of open communication with surgical subspecialties is essential when deciding on palliative options. Autolytic debridement and maintenance of bacterial load can be accomplished by enzymatic debriding agents and topical antiseptics such as Dakin’s-soaked gauze. Other options include cadexomer iodine, povidine-iodine, and silver impregnated dressings. Large areas of necrosis, particularly when accompanied by odor, may necessitate selective excisional debridement. Dressings containing honey can inhibit bacteria and promote autolytic debridement. Odor can be controlled by topical metronidazole (OL), activated charcoal dressings, and frequent dressing changes if tolerated. Several options are available for draining wounds, including treatment of underlying infection and protection of the peri-wound area with topical barrier products. Depending upon goals of care and patient tolerance, antibiotics can be intravenous, intramuscular, oral, or topical. Frequent dressing changes are an option if tolerated, with materials that absorb moisture such as gauze and alginate. Infection must always be considered in the presence of exudate and drainage, particularly if purulence and/or pain is noted. Drainage and moisture in a peri-wound area can promote fungal infection. Bleeding and oozing of blood are common consequences of open wounds, particularly in patients who have coagulopathy or require anticoagulation. The risk of bleeding is decreased with nonstick dressings and oozing can be treated with topical epinephrine 1:1000 applied with gauze and pressure, gelling hemostatic agents, or sclerosing substances such as Moh’s paste. Pinpoint bleeding sites can be treated with silver nitrate application. Pain control is essential in all wounds including those considered palliative and is discussed in the Treatment section above. Local wound care and dressing changes cause pain and discomfort through aggravation of sensory fibers and irritation of surrounding skin. This can be addressed through fewer dressing changes and dressings that have less adhesive properties. Nonpharmacologic strategies

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include healing touch, music, meditation, or simply position changes.

Conclusions/Summary Chronic wounds represent a wide spectrum of clinical pathologies that severely impact older adults in terms of pain, suffering, cost, and quality of life. The variety of chronic wounds necessitates an understanding of pathophysiology and a multidisciplinary approach that includes co-management with medical and surgical specialties. The combination of physiologic changes with age, presence of multiple comorbidities, and overlap with psychosocial issues render chronic wounds an essential geriatric syndrome. Given the known lack clinical training for medical doctors regarding wound care, the geriatrician must fill the gap by taking the lead in personcentered care of patients afflicted with chronic wounds.

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Matteo Tosato, Emanuele Marzetti, Anna Picca, and Riccardo Calvani

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The European Working Group on Sarcopenia in Older People . . . . . . . . . . . . . . . . . . . . . . . The Foundation for the National Institutes of Health (FNIH) Sarcopenia Project . . . . The European Working Group on Sarcopenia in Older People 2 . . . . . . . . . . . . . . . . . . . . . Physical Frailty and Sarcopenia, According to SPRINTT Consortium . . . . . . . . . . . . . . .

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Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220 Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220 Muscle Mass Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Body Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anthropometric Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biochemical Markers for Muscle Mass Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Assessment of Muscle Strength and Muscle Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Handgrip Strength . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Chair Stand Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Knee Flexion/Extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Short Physical Performance Battery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Timed Get-Up-and-Go Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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M. Tosato · A. Picca · R. Calvani Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy e-mail: [email protected]; [email protected]; [email protected] E. Marzetti (*) Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy e-mail: [email protected] © Springer Nature Switzerland AG 2024 M. R. Wasserman et al. (eds.), Geriatric Medicine, https://doi.org/10.1007/978-3-030-74720-6_116

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M. Tosato et al. 400-m Walk Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 Non-pharmacological Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225 Pharmacological Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226 Conclusion/Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1226 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227

Abstract

During the last decade, sarcopenia has become one of the hottest topics in geriatrics. Sarcopenia is a major challenge in geriatrics due to its association with numerous negative health-related outcomes, such as falls, fractures, disability, loss of independence, need for long-term care placement, reduced quality of life, and death. The theoretical construct of sarcopenia as a generalized disorder of skeletal muscle tissue, which involves a reduction in muscle mass and muscle function, is widely accepted. Yet, its practical implementation is hampered by the existence of multiple and only partly overlapping operational definitions. As a result, sarcopenia remains very often underdiagnosed and, consequently, undertreated in daily practice. No drugs are currently recommended for the prevention or treatment of sarcopenia. On the other hand, evidence has accumulated on the efficacy of non-pharmacological treatments for the management of sarcopenia, above all physical exercise and nutritional interventions. Keywords

Sarcopenia · Aging · Biomarkers · Diagnosis · Treatment · Muscle mass · Muscle function · Muscle strength · Physical performance · Exercise

Introduction The term sarcopenia comes from the ancient Greek where “sarx” is flesh and “penia” is poverty. During aging, the body composition undergoes profound modifications, with

changes in fat and lean body mass following different trajectories. More specifically, lean mass increases through early adulthood and begins to decline thereafter. Such a downward trajectory becomes progressively steeper with advancing age. Conversely, fat mass continues to accrue over the years, with a slight reduction only in very old age (Fig. 1). Although lean body mass comprises several components, the skeletal muscle represents the most important element from a functional and clinical perspective. The pattern of changes in muscle mass over the life course closely follows that of lean mass. Past the age of 40, healthy adults lose about 8% of their muscle mass every 10 years (Fig. 2). This implies that, between 40 and 70 years of age, healthy adults lose on average one fourth of their muscle mass. Past the age of 70, the rate of muscle loss increasing, reaching about 15% every decade [1–4]. If on the one hand this phenomenon is physiologic and ineluctable, on the other hand, some individuals tend to lose muscle mass faster, which has important functional and clinical implications. Indeed, as discussed later in this chapter, sarcopenia is associated with several negative health outcomes. Hence, understanding the mechanisms responsible for accelerated muscle wasting and devising preventive or treatment strategies are a top priority in geriatrics. The relevance of the sarcopenia phenomenon is reflected by the scientific interest attracted by this condition. From its first description in the 1980s, the number of articles dealing with sarcopenia has increased exponentially, reaching more than 2000 in 2019 (Fig. 3). Furthermore, in 2016, sarcopenia has gained the “dignity” of clinical entity through the assignment of a specific ICD 10 code [5, 6].

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Fig. 1 Trajectory of body composition during aging

Fig. 2 Changes in muscle mass during aging

Diagnosis Several definitions of sarcopenia have been proposed over the years (Fig. 4). The first to introduce the term sarcopenia was Rosenberg [7] in 1989, when in his comments to a consensus panel held in Albuquerque on “Epidemiologic and methodologic problems in determining nutritional status of older persons,” he emphasized an aspect that had not been sufficiently considered, i.e., the

reduction of lean mass with aging. Rosenberg claimed that no decline during the aging process is as important or potentially more significant as the decline in lean body mass, which impacts deambulation, mobility, independence, and energy intake. He thought that this phenomenon had not received proper attention because at that time there was not a term to identify the condition. He suggested to use a name derived from the ancient Greek and proposed two different terms,

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Fig. 3 Number of publications containing the search term “sarcopenia” indexed in PubMed as of November 30, 2020

Fig. 4 Main definitions of sarcopenia proposed over the years

sarcomalacia and sarcopenia. The last one met the greatest consensus. Originally described simply as the age-related loss of muscle mass [8], sarcopenia is now recognized as a generalized disorder of skeletal muscle, which involves a reduction in muscle mass and function, regardless of the operational definition adopted. Moreover, all of the existing operational definitions of sarcopenia have shown to predict negative health-related events in older people. In the next sections, we briefly describe some of the definitions of sarcopenia, with an emphasis on those that have marked the “history” of the condition. The evolution of the operationalization of sarcopenia reflects a continuous effort to facilitate the implementation of its theoretical construct in clinical practice.

The European Working Group on Sarcopenia in Older People A first milestone has been the European Working Group on Sarcopenia in Older People (EWGSOP) [9] that developed in 2010 a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. The operational definition of sarcopenia was a major change at that time, as it added muscle function to former definitions only based on detection of low muscle mass. According to this consensus, sarcopenia was defined as “a syndrome characterised by progressive and generalised loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life and death” [9]. The diagnosis is based on three criteria:

58

Sarcopenia

1217

Older subject

Measure gait speed

>0.8 m/s

d0.8 m/s

Measure grip strength

Measure muscle mass

Normal

Low

No sarcopenia

Low

Normal

Sarcopenia

No sarcopenia

Fig. 5 EWGSOP algorithm for sarcopenia case finding. (Adapted from Cruz-Jentoft et al. [9])

1. Low muscle mass 2. Low muscle strength 3. Low physical performance The diagnosis requires documentation of criterion 1 plus documentation of either criterion 2 or criterion 3. EWGSOP proposed to assess muscle mass using technique-specific cut-points, to quantify muscle strength using handgrip strength test (cutoffs: