Iatrogenicity: Causes and Consequences of Iatrogenesis in Cardiovascular Medicine 9780813586434

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Iatrogenicity ­ auses and Consequences of Iatrogenesis C in Cardiovascular Medicine

Iatrogenicity ­ auses and Consequences of Iatrogenesis C in Cardiovascular Medicine

Edited by Ihor B. Gussak and John B. Kostis Co-­Edited by Ibrahim Akin, Martin Borggrefe, Giovanni Campanile, Arshad Jahangir, William J. Kostis, and Gan-­Xin Yan

RUTGERS UNIVERSITY PRESS MEDICINE New Brunswick, Camden, and Newark, New Jersey, and London

A Cataloging-in-Publication record for this book is available from the Library of Congress. A British Cataloging-­in-­Publication rec­ord for this book is available from the British Library. Executive Editor: Kel McGowan Compositor: Westchester Publishing Services 978-0-8135-9040-0 978-0-8135-8641-0 978-0-8135-8642-7 978-0-8135-8643-4 978-0-8135-9059-2 This collection copyright © 2018 by Rutgers, The State University Individual chapters copyright © 2018 in the names of their authors All rights reserved No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, or by any information storage and retrieval system, without written permission from the publisher. Please contact Rutgers University Press, 106 Somerset Street, New Brunswick, NJ 08901. The only exception to this prohibition is “fair use” as defined by U.S. copyright law. The paper used in this publication meets the requirements of the American National Standard for Information Sciences—­Permanence of Paper for Printed Library Materials, ANSI Z39​.­48​-­1992. www​.­rutgersuniversitypress​.­org Manufactured in the United States of Amer­i­ca

Contents

Contributors ix The Concept of Iatrogenicity  1 John B. Kostis and Ihor B. Gussak

PART I

Medical Harm Ihor B. Gussak and William J. Kostis CHAPTER 1

Iatrogenicity: Definition, History, and Modern Context 5 Maria L. Gussak, Ihor B. Gussak, and John B. Kostis CHAPTER 2

Epidemiology and Public Health Aspects and Implications of Iatrogenicity: Regulatory, ­Legal and Ethical Dimensions  16 Miriam A. Gonzalez-­Siegel and Stephen K. Jones CHAPTER 3

Risk Management: The Medical Center Administration Perspective  22 Stephen K. Jones and Miriam A. Gonzalez-­Siegel CHAPTER 4

Iatrogenicity from the Patient’s Perspective  28 Jeanne M. Dobrzynski CHAPTER 5

A Naturopathic Perspective on Iatrogenesis  34 Christie Fleetwood

PART II

Iatrogenicity of Cardiovascular Drugs and Cardiovascular Toxicity of Noncardiac Drugs Arshad Jahangir and Gan-Xin Yan

CHAPTER 6

Clinical Manifestations of Acute and Chronic Drug-­Induced Iatrogenic Cardiovascular Diseases and Syndromes  47 Ihor B. Gussak, Gan-­Xin Yan, Arshad Jahangir, Georg Gussak, and John B. Kostis CHAPTER 7

Drug-­Induced Cardiac Arrhythmias and Sudden Cardiac Death  62 Aalap Narichania, Yasuhiro Yokoyama, and Win K. Shen CHAPTER 8

Chemotherapy-­Induced Cardiomyopathy  Edo Y. Birati and Mariell Jessup

77

CHAPTER 9

Iatrogenicity of Blood Pressure Mea­sure­ment in the Diagnosis of Hypertension  88 Thomas D. Giles, Gary E. Sander, and Camilo Fernandez CHAPTER 10

Antihypertensive Drug–­Induced Iatrogenic Cardiovascular Syndromes  101 Rigas G. Kalaitzidis and George L. Bakris CHAPTER 11

Iatrogenicity of Cardiovascular Drugs Associated With Cardiac and Noncardiac Toxicities: Antihypertensive Agents and Biologics 116 Evelyn R. Hermes-­DeSantis and Joseph A. Barone CHAPTER 12

Iatrogenic Aspects of Hypertension in Pregnancy: Focus on Preeclampsia  143 Costas Thomopoulos and Thomas Makris CHAPTER 13

­ omen and Iatrogenic Cardiovascular W Disease: Menopausal Estrogen as the Prime Suspect 156 Gloria Bachmann, Nancy Phillips, and Margaret Rees

vi / Contents CHAPTER 14

CHAPTER 20

Iatrogenic Aspects of Lipid-­Lowering, Antiplatelet, and Anticoagulant Agents  163 Konstantinos Tsioufis, Dimitris Konstantinidis, Nikolaos Vogiatzakis, Kyriakos Dimitriadis, and Dimitris Tousoulis

Iatrogenicity Associated With Interventional Treatment Modalities in Cardiology  233 Naga Venkata Pothineni, Aatish Garg, Hakan Paydak, and Jawahar L. Mehta

CHAPTER 15

Iatrogenic Effects of Urologic Drugs on the Cardiovascular System  175 Konstantinos Stavropoulos, Chrysoula Boutari, Konstantinos Imprialos, Vasilios Papademetriou, and Michael Doumas CHAPTER 16

Iatrogenicity and Antianginal Drugs  188 Abel E. Moreyra and William J. Kostis CHAPTER 17

Antidiabetic Drugs and Cardiovascular Risk: Where Do We Stand?  194 Rajesh Kumar CHAPTER 18

Cardiovascular Iatrogenicity in Older Adults 205 Ariba Khan, Fatima Ali, Vibha Iyengar, Yuya Hagiwara, VJ Periyakoil, Neela Patel, and Michael Malone

PART III

Iatrogenicity of Diagnostic and Therapeutic, Invasive and Noninvasive Cardiovascular Interventions, Devices, and Surgeries Ibrahim Akin, Martin Borggrefe, and William J. Kostis CHAPTER 19

Iatrogenic Aspects of Noninvasive and Invasive Diagnostic Methods in Interventional Cardiology 221 Christina Dösch, Dirk Loßnitzer, and Theano Papavassiliu

CHAPTER 21

Iatrogenicity of Diagnostic and Therapeutic, Invasive and Noninvasive Cardiovascular Interventions, Devices, and Surgeries  243 Michael Behnes, Tobias Becher, Stefan Baumann, Uzair Ansari, and Ibrahim Akin CHAPTER 22

Iatrogenic Aspects of Cardiac Electrophysiology 255 Boris Rudic, Erol Tülümen, Volker Liebe, and Martin Borggrefe CHAPTER 23

Iatrogenic Aspects in Cardiac Device Therapy 271 Susanne Röger and Jürgen Kuschyk CHAPTER 24

Cardiovascular Iatrogenicity of Respiratory Therapeutic Modalities  287 Michael S. Nolledo, Pauline O. Lerma, and Teodoro V. Santiago

PART IV

Iatrogenic Aspects of Sport Cardiology and Lifestyle Modifications Giovanni Campanile, John B. Kostis, and Ihor B. Gussak CHAPTER 25

Trained Athletes  309 Gino Seravalle, Guido Grassi, and Giuseppe Mancia CHAPTER 26

Sports Cardiology  318 Giovanni Campanile CHAPTER 27

Dangers of Lifestyle Modification Advice  327 Giovanni Campanile

Contents / vii

PART V

Iatrogenicity of Dietary Supplements, Herbal Products, and Other Nontraditional Therapies in Cardiovascular Medicine Arshad Jahangir, Ihor B. Gussak, and John B. Kostis CHAPTER 28

Safety of Dietary and Herbal Supplements: Side Effects and Contraindications  337 Sulaiman Sultan, Ahad Jahangir, Ihor B. Gussak, A. Jamil Tajik, and Arshad Jahangir CHAPTER 29

Interactions Between Supplements and Medi­cations  370 Sulaiman Sultan, Ahad Jahangir, Ihor B. Gussak, John B. Kostis, A. Jamil Tajik, and Arshad Jahangir

Index 415

Contributors

Ibrahim Akin, MD Se­nior Cardiologist, Alternate Director First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Fatima Ali, MBBS Researcher Aurora Health Care Milwaukee WI Uzair Ansari, MD First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany

Joseph A. Barone, PharmD Professor Acting Dean Ernest Mario School of Pharmacy Rutgers, the State University of New Jersey New Brunswick, New Jersey Stefan Baumann, MD First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Tobias Becher, MD Research Fellow First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany

Gloria Bachmann, MD, MMS Professor of Obstetrics and Gynecol­ogy and Medicine Associate Dean for ­Women’s Health Director ­Women’s Health Institute Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey

Michael Behnes, MD Se­nior Cardiologist Adjunct Lecturer First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany

George L. Bakris, MD Director ASH Comprehensive Hypertension Center The University of Chicago Medicine, Department of Medicine Chicago, Illinois

Edo Y. Birati, MD Assistant Professor of Clinical Medicine Department of Medicine, Division of Cardiovascular Medicine Perelman School of Medicine University of Pennsylvania Philadelphia, Pennsylvania

x / Contributors Martin Borggrefe, MD Director First Department of Internal Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Chrysoula Boutari, MD Second Propaedeutic Aristotle University of Thessaloniki Thessaloniki, Greece Giovanni Campanile, MD, FACC, ABIHM Assistant Professor of Medicine Rutgers New Jersey Medical School Newark, New Jersey Director, Integrative Nutrition Director, Dean Ornish Heart Disease Reversal Program Director, Cardiac Rehabilitation Morristown Medical Center / Atlantic Health System Morristown, New Jersey Kyriakos Dimitriadis, MD, PhD Con­sul­tant Cardiologist First Cardiology Clinic, University of Athens, Hippocratio Hospital Athens, Greece Jeanne M. Dobrzynski, BA Cardiovascular Institute Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Christina Dösch, MD First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany

Michael Doumas, MD, PhD Professor George Washington University Washington, District of Columbia Camilo Fernandez, MD, MSc, MBA, MCTA Se­nior Scientist | Cardiovascular Research HeartGEN Institute Boston, Mas­sa­chu­setts Christie Fleetwood, ND, RPh Supervisor Community Care Center Bastyr Center for Natu­ral Health Seattle, Washington Aatish Garg, MD Resident Department of Medicine University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System ­Little Rock, Arkansas Thomas D. Giles, MD Professor of Medicine Section of Cardiology Tulane University School of Medicine New Orleans, Louisiana Miriam A. Gonzalez-­Siegel, CCEP, CHRC, MA Vice President Risk Management and Compliance Robert Wood Johnson University Hospital New Brunswick, New Jersey Guido Grassi, MD Professor Institute of Clinical Medicine Department of Clinical Medicine, Prevention and Applied Biotechnologies University of Milan-­Bicocca Milan, Italy Georg Gussak Post-­Baccalaureate Research Fellow Experimental Cardiac Electrophysiology Feinberg Cardiovascular Research Institute Northwestern University Feinberg School of Medicine Chicago, Illinois

Contributors / xi Ihor B. Gussak, MD, PhD Clinical Professor of Medicine Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Executive Editor, Journal of Electrocardiology Maria L. Gussak Naturopathic Medicine Doctorate Program Bastyr University Kenmore, Washington Yuya Hagiwara MD Assistant Professor Division of Geriatrics and Palliative Care Department of ­Family and Community Medicine University of Texas Health Science Center in San Antonio Evelyn R. Hermes-­DeSantis, PharmD Clinical Professor Ernest Mario School of Pharmacy Rutgers, the State University of New Jersey New Brunswick, New Jersey Konstantinos Imprialos, MD Clinical Fellow Aristotle University of Thessaloniki Thessaloniki, Greece Vibha Iyengar, MD Geriatrician Palo Alto Medical Foundation Mountain View, California

Mariell Jessup, MD Professor of Medicine Department of Medicine, Division of Cardiovascular Medicine Perelman Center for Advanced Medicine, University of Pennsylvania Philadelphia, Pennsylvania Stephen K. Jones, FACHE Chief Academic Officer RWJ Barnabas Health West Orange, New Jersey Se­nior Policy Fellow Edward J. Bloustein School of Planning and Public Policy Rutgers, the State University of New Jersey New Brunswick, New Jersey Rigas G. Kalaitzidis, MD Outpatient Renal and Hypertension Clinic University Hospital of Ioannina Ioannina, Greece Ariba Khan, MD, MPH Department of Geriatrics Aurora Sinai Medical Center Milwaukee, Wisconsin Dimitris Konstantinidis, MD, PhD Cardiologist First Cardiology Clinic, University of Athens, Hippocratio Hospital Athens, Greece

John B. Kostis, MD John G. Detwiler Professor of Cardiology Ahad Jahangir, BS Professor of Medicine and Pharmacology Department of Materials Science and Engineering Associate Dean for Cardiovascular University of Wisconsin-­Madison Research Madison, Wisconsin Director Cardiovascular Institute Arshad Jahangir, MD, FAHA, FACC, FHRS Rutgers Robert Wood Johnson Medical School Director New Brunswick, New Jersey Center for Integrative Research on Cardiovascular Aging (CIRCA) William J. Kostis, PhD, MD Chair Cardiovascular Research Assistant Professor of Medicine Clinical Professor of Medicine Director of Research Con­sul­tant Cardiologist (Electrophysiology) Division of Cardiovascular Disease and Aurora St. Luke’s Medical Center, Aurora Hypertension Health Care Rutgers Robert Wood Johnson Medical School Milwaukee, Wisconsin New Brunswick, New Jersey

xii / Contributors Rajesh Kumar, MD, PhD Clinical Endocrinologist/Lecturer University College Cork Cork, Ireland Jürgen Kuschyk, MD Medical Faculty Medical Department University of Heidelberg German Centre for Cardiovascular Research (DZHK) Mannheim, Germany Pauline O. Lerma, MD Medical Director Heptner Cancer Center Campbell County Health Gillette, Wyoming Volker Liebe, MD Electrophysiologist First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Dirk Loßnitzer, MD First Department of Medicine University Medical Centre Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Thomas Makris, PhD Assistant Professor Department of Biochemistry and Molecular Biology University of South Carolina Columbia, South Carolina Michael Malone, MD Adjunct Clinical Professor of Medicine University of Wisconsin School of Medicine and Public Health Aurora Health Care Milwaukee, Wisconsin

Giuseppe Mancia, MD Department of Clinical Medicine, Prevention and Applied Biotechnologies University of Milan-­Bicocca Milan, Italy Jawahar L. Mehta, MD, PhD Professor of Medicine and Physiology and Biophysics Stebbins Chair in Cardiology Department of Medicine University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System ­Little Rock, Arkansas Abel E. Moreyra, MD Professor of Medicine Division of Cardiovascular Disease and Hypertension Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Aalap Narichania, MD Department of Internal Medicine Mayo Clinic Scottsdale, Arizona Michael S. Nolledo, MD, FAASM Medical Director Institute for Sleep Medicine and Pulmonary Rehabilitation Deborah Heart and Lung Center Browns Mills, New Jersey Vasilios Papademetriou, MD Professor Department of Cardiology Georgetown University Washington, District of Columbia Theano Papavassiliu, MD First Department of Medicine University Medical Centre Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany

Contributors / xiii Neela Patel, MD Associate Professor Chief of the Division of Geriatrics and Palliative Care Department of ­Family and Community Medicine University of Texas Health Science Center San Antonio, Texas Hakan Paydak, MD Professor of Medicine Director of Cardiac Electrophysiology Program and Laboratory Central Arkansas Veterans Healthcare System Department of Medicine University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System ­ ittle Rock, Arkansas L VJ Periyakoil, MD Clinical Associate Professor of Medicine Stanford University School of Medicine Director Stanford Palliative Care: Education and Training Program Stanford Hospice and Palliative Medicine Fellowship Program Palo Alto, California Nancy Phillips, MD Associate Professor of Obstetrics and Gynecol­ogy Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Naga Venkata Pothineni, MD Fellow in Cardiovascular Medicine Department of Medicine University of Arkansas for Medical Sciences Central Arkansas Veterans Healthcare System ­ ittle Rock, Arkansas L Margaret Rees, MA, DPhil Editor-­in-­Chief Maturitas Executive Director Eu­ro­pean Menopause and Andropause Society Chair Association for Research Ethics Reader Emeritus in Reproductive Medicine University of Oxford

Visiting Professor Faculty of Medicine, University of Glasgow Adjunct Associate Professor Rutgers Robert Wood Johnson Medical School Oxford, United Kingdom Susanne Röger, MD Heart Failure Specialist First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Boris Rudic, MD Electrophysiologist First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Gary E. Sander, MD, PhD Professor of Medicine Section of Cardiology Tulane University School of Medicine New Orleans, Louisiana Teodoro V. Santiago, MD Professor Emeritus of Medicine Division of Pulmonary and Critical Care Medicine Rutgers Robert Wood Johnson Medical School New Brunswick, New Jersey Gino Seravalle, MD Professor Department of Clinical Medicine, Prevention, and Applied Biotechnologies University of Milan-­Bicocca Milan, Italy Win K. Shen, MD Department of Cardiology Department of Internal Medicine Mayo Clinic Scottsdale, Arizona

xiv / Contributors Konstantinos Stavropoulos MD, Second Propedeutic Department of Internal Medicine Aristotle University of Thessaloniki Thessaloniki, Greece Sulaiman Sultan, MD Center for Integrative Research on Cardiovascular Aging Aurora Health Care Milwaukee, Wisconsin A. Jamil Tajik, MD President Aurora Cardiovascular Ser­vices Aurora St. Luke’s Medical Center Director Aurora Systemwide Cardiovascular Ser­vices Milwaukee, Wisconsin Costas Thomopoulos, MD Con­sul­tant in Cardiology Clinical Hypertension Specialist Department of Cardiology Helena Venizelou Hospital Athens, Greece Dimitris Tousoulis, MD, PhD Professor First Cardiology Clinic, University of Athens, Hippocratio Hospital Athens, Greece Konstantinos Tsioufis, MD, PhD Associate Professor First Cardiology Clinic, University of Athens, Hippocratio Hospital Athens, Greece

Erol Tülümen, MD Electrophysiologist First Department of Medicine University Medical Center Mannheim (UMM) Faculty of Medicine Mannheim University of Heidelberg German Center for Cardiovascular Research (DZHK) Mannheim, Germany Nikolaos Vogiatzakis, MD Cardiologist First Cardiology Clinic, University of Athens, Hippocratio Hospital Athens, Greece Gan-­Xin Yan, MD, PhD Professor Lankenau Institute for Medical Research Attending Cardiogist Lankenau Medical Center Wynnewood, Pennsylvania Professor of Medicine Thomas Jefferson University Philadelphia, Pennsylvania Professor Beijing Anzhen Hospital Beijing, China Yasuhiro Yokoyama, MD Department of Cardiology St. Luke’s International Hospital Tokyo, Japan

Iatrogenicity ­ auses and Consequences of Iatrogenesis C in Cardiovascular Medicine

The Concept of Iatrogenicity John B. Kostis and Ihor B. Gussak

In a narrow sense, iatrogenicity is harm caused by a physician’s diagnosis and treatment, although it does not imply an improper act by the physician. Merriam-­Webster Medical Dictionary defines iatrogenesis, the word from which iatrogenicity is derived, as “inadvertent and preventable induction of disease or complications by the medical treatment or procedures of a physician or surgeon” (1), and The ­Free Dictionary as “any injury or illness that occurs ­because of medical care” (2). This book proposes a wider definition of iatrogenicity to encompass intentional or unintended, immediate or delayed, yet preventable or avoidable harm to a person by ­either an action or inaction on the part of a health care provider or health delivery system. The harm may occur in any interaction of patients with health professionals, ranging from preventive interventions, lifestyle advice, and diagnostic procedures to major surgery. An adverse iatrogenic outcome may occur despite all appropriate interventions. Contrary to commonly held opinion, inaction may result in iatrogenic harm, for example, by not prescribing needed medi­cation or not performing needed high-­risk surgery for fear of the practice of publishing physician-­specific outcome data on the Internet. In some instances, indicated interventions are not administered ­because higher importance is placed on errors of commission rather than errors of omission. Ethical systems that consider harm from action more impor­tant than harm from inaction, introduce an asymmetry between t­hese two types of errors. Such systems hold health care providers responsible for (all) harm caused by actions but not for (some) harm that is not prevented. The physician has an obligation to optimize patient care by avoiding both types of errors. For example, statin therapy may prevent many fatal and nonfatal myo­ car­dial infarctions and strokes at the expense of a handful of serious adverse events among hundreds of patients. S­ imple utilitarianism implies that moral obligations depend on expected consequences (of action and inaction) without distinction between acts and omissions to produce the greatest happiness for the greatest number. “First, do no harm” may be acceptable when the interventions are not efficacious (placebo-­like). Iatrogenesis has been appreciated since ancient times. The word is rooted in the ancient Greek iatros (physician) and genesis (birth or origin). In Epidemics, Book I, Section XI, Hippocrates acknowledged the possibility of harmful effects of medical interventions by stating that the duty of the physician is to help, or at least to do no harm (ωϕελεειν η μη βλαπτειν) (3). In the first En­glish translation of Epidemics, Francis Adams wrote that the physician must “have two special objects in view with regard to disease, namely, to do good or to do no harm” (4). Placing primary emphasis on avoidance of harm could have been acceptable at the time of Hippocrates,

2  /  The Concept of Iatrogenicity when most interventions had an efficacy similar to placebo. It is not acceptable in the current era of pharmacological, device, interventional, and surgical interventions that have been proved by a wealth of evidence including randomized clinical ­trials, meta-­analyses, and high-­quality observational data. The aim of this book is to generate interest in iatrogenicity as a new clinical discipline and to focus on cardiovascular preventive diagnostic and therapeutic procedures and noncardiovascular interventions that result in adverse consequences on the circulatory system. The book covers the varied aspects of iatrogenicity including adverse effects of medi­cations, dietary supplements, and herbal products as well as medical errors, unnecessary procedures, negligence, malpractice, financial losses, discomfort, pain, suffering, disability, and loss of privacy. The target audience includes medical students, gradu­ate students, residents, fel-

lows, physicians, administrators, and allied health professionals. The intent of the authors is fourfold: • to outline available information in an easy-­to-­use compact volume • to highlight the ­human and financial cost of iatrogenicity • to explore the reasons and ­causes of iatrogenicity • to identify potential interventions to ameliorate the current situation.

References 1. Merriam-­Webster Medical Dictionary. https://­www​ .merriam​-­webster​.­com​/­medical​/­iatrogenesis. 2. The ­Free Dictionary. http://­medical​-­dictionary​.­the​ freedictionary​.­com​/­iatrogenesis. 3. Απαντα τον Ιπποκράτους. Omnia Opera Hippo­ cratis. Venice, Italy: Aldus Manutius; 1526. 4. Francis Adams. The Genuine Works of Hippocrates. London, UK: Sydenham Society; 1849.

CHAPTER 1

Iatrogenicity Definition, History, and Modern Context Maria L. Gussak, Ihor B. Gussak, and John B. Kostis

 . . . ​ωϕελεειν η μη βλαπτειν . . . ​( . . . ​to help, or at least to do no harm . . . ​) Hippocrates, Epidemics, Bk. I, Sect. XI, c. 400 b.c.

INTRODUCTION This book requires a caveat, one that all of its authors kept in mind while writing: the discussion of iatrogenicity is not motivated by emotional appeals, although we recognize with deep sadness that countless patients, ­family, friends, and medical personnel have been touched by iatrogenic complications or medical harm. This book is intended to lay a foundation for establishing iatrogenicity as a new clinical discipline. It is meant to serve as a reference for caregivers in better understanding the preventable nature of iatrogenic harm and learning from their own and ­others’ ­mistakes and misconceptions without accusing or blaming anyone. Rather, maintaining a scientific approach to and perspective on medical harm, ­whether intended or unintended, is crucial to furthering medicine. Moreover, we are cautious about calling iatrogenicity a “prob­lem.” The impor­tant message is that facts and statistics m ­ atter; this book was not written to point fin­gers or expose ill practices. We aim to prove that iatrogenicity has always been a part of medicine since its beginning and ­will continue to be for as long as medicine exists as an art and a science. We hope that this chapter finds you well, ­causes you to raise questions, and increases your awareness for ­doing what is right not only for your patient but also for yourself, the clinician, student, nurse, or caregiver for whom we wrote this book.

Defining Iatrogenicity It is impor­tant to review the definitions of health, medicine, medical harm, and adverse event. The word health comes from the word for ­whole. To heal means to restore to a state of ­wholeness, soundness, or integrity. “. . . Health is completeness and perfection of organ­ization, fitness of life, freedom of action, harmony of functions, vigor and freedom from all pain and corruption—in a phrase, it is ‘a sound mind in a sound body’ ” (1).

6 / Iatrogenicity “Not only is health a normal condition, but postponed, yet preventable or avoidable harm to it is a duty not only to attain it but to main- the h ­ uman body or mind by e­ ither action or inactain it” (2). tion (failure to prevent) of the medical caregiver (e.g., nurse, physician) resulting in discomfort, Taber’s Cyclopedic Medical Dictionary defines injury, disability, or death. Just as white light has medicine as (a) a drug or remedy and (b) the act of seven component colors when passed through a maintenance of health, and prevention and treat- prism, the concept of iatrogenicity has seven inherment of disease and illness. Note the emphasis on ent components. a health-­and prevention-­based system. Medical harm is defined as an outcome that negatively affects a patient’s health and/or quality of life, 1. Any intentional whereas adverse event is an event that results in or unintentional . . . ​ unintended harm to the patient. Both are iatroDetermining intentionality is not a requirement in genic, that is, related to the care and ser­vices prodeciding ­whether harm is of iatrogenic origin vided to the patient rather than to the patient’s ­because ­whether it was intended does not ­matter. It under­lying medical conditions. Iatrogenic disease is impor­tant not to get lost in subjective conclusions may result from medical error, malpractice, out-­of-­ or motives about w ­ hether a physician had malice scope practices, adverse events, harm that exceeded in choosing and executing a treatment. Thus, accibenefit of a drug or procedure, unnecessary treatdents are included just as errors, misjudgments, ments, unnecessary screening, improper training, side effects, and unexpected adverse events are. and miscommunications. Taber’s defines iatrogenesis (the term from which iatrogenicity is derived) as follows: 2. . . . ​immediate or postponed . . . ​ Timing can be subjective and open to interpretation. For one person, medical harm might be clearly attributable to delay of care, while another might deem it prudent to wait and try other ave­ nues of treatment. Fortunately, physicians are trained to justify their decision-­making pro­cess, and it is understood that not all may agree. The point is to acknowledge that timing itself can be a source of iatrogenicity. This includes delay of Of note is that this definition is followed imme- care, delay of diagnosis, postponed decision makdiately by ­these words: “A guiding princi­ple of ing or appointments, or even treatment and diaghealth care is to do ­little to patients while effect- nosis rendered too quickly. ing cures—­but this ideal is not always achieved. In the U.S., deaths that result from healthcare 3. . . . ​yet preventable errors and complications of treatment are among or avoidable . . . ​ the most common ­causes of mortality” (3). Iatrogenicity has existed as long as medicine Preventability or avoidance is key to iatrogenicitself. In Epidemics Bk. I, Sect. XI, the followers of ity. Can side effects or adverse events be preHippocrates acknowledged the possibility of harm- vented or avoided? Preventability is a challengful effects of medical interventions in the statement, ing notion b ­ ecause physicians treat according to “With re­spect to the diseases, [the physician] the practiced standards of care—­standards that should strive for two ­things: to benefit or not to often have difficulty keeping up with the latest harm.” In the modern day, iatrogenesis may occur evidence-­ based practices, and can sometimes at multiple points during interactions between become outdated or even dismissed as poor pracpatient and health professionals, ranging from tice. Current practices may be considered bardiagnosis and prevention to surgery and follow-­up. baric in the ­future, just as past practices that ­were For this book, the authors define iatrogenicity used inappropriately (such as bloodletting) are as any intentional or unintentional, immediate or rejected ­today. Iatrogenesis [from Greek: iatros, physician + ​ gennan, to produce] is any injury or illness that occurs as a result of medical care, for example, (a) chemotherapy used to treat cancer may cause nausea, vomiting, hair loss, or depressed white blood cell counts, or (b) the use of a Foley catheter for incontinence can create a urinary tract infection and urinary sepsis.

Introduction / 7 In a broad theoretical sense, the concept of iatrogenicity can be applied to any medical action or inaction that might debilitate the body, its organs or their functions, or the mind. As a rule, caregivers base their decisions and clinical judgment considering a risk-­benefit analy­sis, in which the benefits of their action, or inaction, ­will intentionally overcome the associated risk, harm, debilitation, discomfort, and other iatrogenic complications of the presenting complaint. ­There are exceptions to the rule. For instance, term often cardiologists risk the potential long-­ benefits of treatment with short-­term necessities (e.g., use of diuretics in acutely decompensated heart failure, recognizing that diuretics are associated with increased mortality in chronic stages of heart failure). Another example of calculated iatrogenicity: how many oncological patients are “sacrificed” during, say, a five-­year period of treatment with a life-­threatening torsadogenic QT-­ interval prolonging antineoplastic agent to prolong the lives of 50% of them by one year? Do poor outcomes necessarily equate to poor medical practice? Can iatrogenic consequences be completely avoided? No. While iatrogenic consequences should be avoided when pos­ si­ble, this is indeed why medicine is an art and not a pure science. The difficulty is that for e­ very discomfort, t­oday’s physician is armed with a suppressive treatment. Although the treatment may disguise and reduce the patient’s suffering, it is paramount to understand that medical treatment can have minor or major implications that push the patient in the opposite direction of cure, or health. Therefore, the heart of iatrogenicity is that medicine is a fine art, a practice of deciding, not according to an algorithm or completely objective formula, but according to the individual patient’s wishes, metabolism, and response. A purely rational provider could prescribe something for the nausea, and then something ­else for the headache that results from the first medicine, and then something ­else for the vertigo that resulted from the second medicine, ad infinitum. Treating symptoms only, then, is clearly not an ideal solution. Thus, a good provider cannot be entirely rational, but also practice medicine as an art in order to decrease unnecessary iatrogenic consequences; that is, she would treat disease according to her best knowledge of the laws that govern health of the h ­ uman body.

In medical decision making, t­ here is an art to weighing reduction in suffering against benefit to the patient. However, in the real world, the two may be in conflict. Often, this leads to discussions and teaching moments (recall that the term doctor comes from the Latin word docere, to teach) between medical provider and patient/family, as the medical provider explains what can reasonably be prevented or not. The clinical discipline of iatrogenicity would assist in discerning what is preventable or avoidable.

4. . . . ​harm to the ­human body or mind . . . ​ Medical harm to the ­human body is often obvious and may include discomfort, disfigurement, loss of function, and so forth. Such harm may be mea­ sured both objectively (with laboratory and imaging tests, for example) or subjectively (via patient reporting, ­family observations, e­ tc.), and are both equally valid when discussing iatrogenicity. ­Mental wellness, as compared with physical wellness, can prove to be more difficult to mea­sure. Suffering through an adverse event is not only a physical pro­cess, but also a ­mental one, subject to the perception of the patient and/or caregivers. In addition to the emotional component of suffering, t­here is the more outright type of m ­ ental harm that can occur directly due to treatment, such as psychological crises and distress.

5. . . . ​by ­either action or inaction (failure to prevent) . . . ​ Although inaction is less understood than action, it is no less an impor­tant feature of iatrogenicity. Patients expect that providers ­will care for them completely within their scope. Neglecting to perform or request proper diagnostic exams is an example of providers absolving themselves of the responsibility in the unspoken contract (implied consent to treat) between patient and provider. When the provider is making the decision not to act, that is an act in itself.

6. . . . ​of the medical caregiver (e.g., nurse, physician) . . . ​ The medical caregiver is anyone who provides a medical intervention for the purpose, and hope,

8 / Iatrogenicity of restoring health. Healing covers a wide spectrum from complete cure and palliation to restoring basic life signs, even if w ­ holeness cannot be restored. Medical care may be direct, for example, placing an intravenous catheter, administering drugs, or attending to patient care and comfort. Actions as basic as removing t­hings from the body and putting ­things into the body are included in this definition. Medical care may also be indirect, for example, consulting by telephone, diagnosing, or writing a prescription. Indirect care means that, although the hand of the caregiver did not come into direct contact with the patient, a decision was made or an order was carried out by someone ­else. Iatrogenicity as a clinical discipline ­ought to be limited to the professionally credentialed, including any health care provider (e.g., nurse, nurse practitioner, physician) and allied health professional (e.g. pharmacist, nursing assistant, patient care technician, imaging technician). Consequences from the actions of nonthose without medical medical caregivers (­ training and credentialing) are not included in this definition.

7. . . . ​resulting in discomfort, injury, disability, or death. Discomfort, injury, disability, and death are obvious results of iatrogenicity and many iatrogenic events are marked by one of t­ hese. The definition of iatrogenicity brings up this question: What are the intended consequences of medicine? The authors of this book offer the following enumeration: • To help patients live longer, healthier lives • To prevent disease, the best application of medicine • To identify and treat the cause of a disease • To treat the patient, not the disease or symptoms • To choose the least aggressive of several effective remedies • To not “cure to death” • To teach, inform, and educate patients and the community • To have “two special objects in view with regard to disease, namely, to do good or to do no harm.” (4) This is commonly referred to as primum non nocere.

Fi­nally, for the purposes of seeding iatrogenicity as a clinical discipline in as concise a manner as pos­si­ble, this book begins by addressing primarily physicians and honing in on cardiovascular considerations. A good reason for this is that cardiovascular drugs are among the worst offenders in adverse drug reactions (see Figure 1-1) (5).

IATROGENICITY IN HISTORY Prehistoric Context of Iatrogenicity Iatrogenesis has been recognized since h ­umans began manipulating health in ancient times. The practice of medicine (including surgery) goes back as far as the Neolithic period, about 8,000 years ago (6). A skull recovered from that period had holes neatly bored into it, and presumably someone performed the risky procedure now known as Today, such surgery would be trephination (7). ­ used to relieve pressure on the brain, but perhaps the skull was bored to release evil spirits thought to cause disease and illness. Medi­cations used by some of the first physicians about 4,600 years ago in ancient Egypt included honey as an antibiotic ointment, opium to pacify ­children, castor oil as a laxative, and marijuana to stimulate the appetite (7). One of the oldest systems of medicine is Ayurveda, which originated in India 3,500  years ago and is still used t­ oday (8). Ayurveda recognizes iatrogenicity as nidāna (“that which can manifest into pathogenesis”) (9), and the Sanskrit for iatrogenesis is “aushadhajā vyādi” (root words aushadi, meaning medicine or drug, and vyadi, meaning disease or complaint).

Hippocrates, Galen, Maimonides, and Hahnemann The first step in the evolution of ancient medicine was the dismissal of spiritual and super­natural ­causes of illness by Hippocrates (460–377 b.c.), the ­father of conventional modern medicine who “took health and illness out of the hands of gods” (7). Hippocrates may have been arrested and jailed for this view, which was considered blasphemy ­because, at that time, the sick went to local priests for healing. Hippocrates treated cautiously and conservatively, preferring to stimulate the body’s natu­ ral healing pro­ cess using

Iatrogenicity in History  /  9

Cardiovascular drugs 27% Chemotherapy 23%

Antibiotics 27%

Analgesics and anti-inflammatories 23%

FIGURE 1-1 ​Meta-­analysis of 39 prospective U.S. studies on ADR in hospitalized patients The incidence of serious adverse drug reactions (ADRs) (hospitalization, permanent disablement, or death) based on the class of drugs from meta-­analysis of 39 prospective U.S. studies on ADR in hospitalized patients. (Figure compiled from data in Lazarou et al. JAMA. 1998;279(15):1200.)

si­ ble. He the  least traumatic interventions pos­ believed that “natu­ral forces within us are the true healers of disease” (7). To him, the ideal physician’s first line of treatment was to adjust the patient’s regimen with carefully prescribed exercise and diet. Only if that failed would the physician “inflict riskier interventions, such as drugs and surgery” (7). Even in ancient Greece, the importance of minding the safety and comfort of the patient was the foremost princi­ple of medicine. To decrease adverse effects, Hippocrates advocated, “. . . of several effective remedies . . . ​ choose the least sensational . . .” (7). It is a widely held misconception that the familiar dictum primum non nocere (“first, do no  harm”) is part of the Hippocratic oath. In fact, the Hippocratic oath never contained t­ hose words. Nor was the author Galen, as is often suspected. It is thought that followers of Hippocrates originated the phrase in his Epidemics, Bk. I, Sect. XI. The translation “first, do no harm” is not entirely accurate. One of the authors of this chapter, Dr. Kostis, a native Greek speaker, translates the original Greek to mean that a physician must have “two special objects in view with regard to disease, namely, to do good or to do

no harm.” With re­spect to iatrogenic disease, the prime objective is to do good and prevent harm. The next milestone in iatrogenicity occurred during the Hellenistic period of ancient Greece. Galen (129–­c. 200) was a crucial contributor to the medical system of healing based on humoral theory, which asserted that disease resulted from an imbalance of the four humors, or body fluids (yellow bile, black bile, phlegm, and blood). Unlike Hippocrates, Galen used more radical interventions such as bloodletting, surgery, and extreme polypharmacy. In all likelihood, iatrogenic complications became more pronounced with this less conservative approach to medical care. About a thousand years l­ater, Maimonides (1135–1204) wrote an impor­tant text called Medical Aphorisms. He studied medicine in Egypt (where his ­ family fled from their native Spain because of persecution of Jews) and soon fol­ lowed in Galen’s footsteps as a prominent physician and phi­los­o­pher. Concerns about iatrogenesis are pres­ent in his writings. For example, in his third treatise, section  111–112, he wrote: “The following ­matter is of g­ reat importance, and you

10 / Iatrogenicity namely, that a remedy must keep it in mind—­ composed with a certain goal and aim is often mixed with other ingredients which do not fit that goal, not the intended use. But, this remedy is mixed so that it ­will not cause any kind of pain or harm” (10). The aim to reduce suffering from medical treatment, very pres­ent in modern medicine, is actually more than 800 years old. Astonishingly, at this early point in the understanding of iatrogenicity, physicians not only acknowledged that drugs might inflict harm, but they built within the remedy a suppressive to make the patient more comfortable and reduce avoidable suffering. For example, Maimonides suggested adding an astringent (an agent that stimulates the contraction of an organ) to a purgative remedy (an agent that has laxative effects) to reduce the patient’s urge to vomit. The astringent strengthened the stomach’s ability to keep the medicine in the body so that the purgative could work. Moving through time, physicians began noting a greater possibility of harm as medicine advanced. For example, Samuel Hahnemann (1755–1843), German physician and founder of homeopathy, was convinced that traditional polypharmacy did more harm than good. He and others questioned prior standards of practice, ­ and the result was a seemingly barbaric age of medicine in which bloodletting was a panacea and “hysterical” ­women ­were institutionalized or received hysterectomies. The danger of early stages of medicine is that what is known ­today may not be valid tomorrow.

MODERN CONTEXT OF IATROGENICITY The golden ­century of medicine occurred during the second half of the 19th ­century and first half of the 20th c­entury; vaccinations and g­reat advancements in treatment and medical research marked this era. However, by the 1960s, the public’s faith and trust in medicine began waning as iatrogenic diseases took the main stage. Two leading examples involved DES and thalidomide. Synthetic estrogen diethylstilbestrol (DES), first developed in 1938, was given to ­women to prevent miscarriage. In 1971, the Food and Drug Administration (FDA) advised against prescrib-

ing DES ­because of a study published that year showing the medi­cation caused a rare vaginal cancer in young w ­ omen who w ­ ere exposed in the womb, yet it continued to be prescribed (11). While DES is still on the market, in 2002, the Centers for Disease Control and Prevention (CDC) put out an update to providers as some still did not (or do not) know of the side effects. Thalidomide was originally introduced as a safe sleeping tablet (12). It was withdrawn in 1961 ­because of devastating fetal defects in more than 10,000 babies. The shocking aspect is that the manufacturer in Germany “turned a blind eye to warnings about its appalling side effects” (12). It would be more correct to call ­these adverse events than side effects. The historical implications of the thalidomide story are quite in­ter­est­ing, as laid out by Bothwell et  al. (13). The  U.S. Congress responded to the thalidomide incident with the Kefauver-­ ­ Harris Amendment to the Food, Drug, and Cosmetic Act of 1962, mandating that drugs be proved in “adequate and well-­ controlled investigations.” By 1970, randomized controlled ­trials (RCTs) ­were required for new phar­ma­ceu­ti­cals. RCTs ­were viewed as the way to make medicine rational and scientific, that is, by removing subjective influences and biases. However, the familiar pattern of unintentional consequences resulted despite the benevolent motive of trying to improve medicine. High trial costs w ­ ere more likely to be funded by private industry, which favored publication of positive outcomes. By the 1990s, more positive results than negative ones w ­ ere being published, at the expense of medical knowledge (13). RCTs did not succeed in making medicine more scientific. With an increase in studies came an increase in tabulating iatrogenicity. In 1968, an estimated 1.3 million Americans ­were made sick by drugs intended to make them well (1). Some 30  years ­later, the Institute of Medicine’s 1999 report To Err is ­Human: Building a Safer Health System (14) stated that in the United States medical errors accounted for tens of thousands of deaths, prob­ ably an underestimate. More recently, in 2016, the British Medical Journal confirmed the underestimation; medical errors are the third leading cause of death in the United States ­after cardiovascular and oncological diseases (15). More than 250,000 deaths per year in this country are due to medical error. That equates to four jumbo jets crashing

Number of hits per year

Modern Context of Iatrogenicity  /  11 2,000 1,500 1,000 500 0

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

FIGURE 1-2 ​PubMed search hits for term Iatrogenic Results of the lit­er­a­ture search for the term iatrogenic from PubMed as of May 10, 2016. (Raw data retrieved on May 10, 2016, from PubMed and formulated into a ­figure.)

e­ very day. Iatrogenicity includes injury and death from c­ auses other than medical error, so it is safe to assume that the overall iatrogenic death count is far higher. The report received widespread publicity and brought the issue to the attention of regulators and the general public. Today, the concept of iatrogenesis has ­ gained substantial research popularity as evidenced by the increase in searches for the term iatrogenic in PubMed (see Figure  1-2). What caused the surge of interest? Historically impor­ tant is the 1981 study, conducted at the Boston University Medical Center, in which doctors looked for iatrogenic complaints. The study followed 815 admitted patients, 290 (36%) of whom developed one or more iatrogenic disorders, many of them drug-­induced, with a total of 47 occurrences. Of t­hose patients, 57% had one complication and 43% more than one. A total of 76 (9.3%) patients had major complications and 15 (1.8%) died due to the iatrogenic illness arising from medical care (16). From its beginning, medicine has been one of the natu­ral c­ auses of disease, but ­today’s society is not happy with the situation, reasonably so. Journal of Patient Safety reports “the true number of premature deaths associated with preventable harm to patients was estimated at more than 400,000 per year. Serious harm seems to be 10-­to 20-­fold more common than lethal harm” (17). And so, although iatrogenicity has been a part of medicine since its inception, the modern context now involves new iatrogenic diseases and major complications arising from treatment of the original condition rather than s­imple reduction of suffering.

Medicalization and Iatrogenic Poverty Many f­actors have contributed to the burgeoning interest of medical and patient communities to medical harm occurring worldwide and in the United States, in par­tic­ul­ar. The fact that medicines are manufactured by for-­profit companies significantly complicates how to approach iatrogenesis. Although a physician may uphold the philosophical princi­ ples of practicing medicine, manufacturers are not prescribing physicians and are not held to the same ethical standard. Poor and biased decision making is inevitable when the phar­ma­ceu­ti­cal manufacturer’s primary motive is money compared with the physician’s primary objective of benefiting and not harming the patient. Among other reasons for increased iatrogenesis are medicalization and the imbalanced financial support of the health care system known as iatrogenic poverty. Medicalization is the often erroneous social tendency or pro­cess of considering h ­ uman conditions, be­hav­ior, and prob­lems as abnormal conditions and disorders requiring medical attention (medical investigation, diagnosis, treatment or intervention, prevention, and follow-up). It results from changing social attitudes, economic considerations, and development and promotion of new medi­cations or treatments. The pro­cess of medicalization is based on ­either of the following, or both: • Expansion of bound­aries of abnormalities or illnesses (pathologization) • Narrowing the definitions of normal ranges or health

12 / Iatrogenicity An editorial by Moynihan et al. (18) warned, “Inappropriate medicalization carries the dangers of the unnecessary labelling, poor treatment decisions, iatrogenic illness, and economic waste, as well as the opportunity costs that result when resources are diverted away from treating or preventing more serious disease. At a deeper level it may help to feed unhealthy obsessions with health, obscure or mystify so­cio­log­i­cal or po­liti­cal explanations for health prob­lems, and focus undue attention on pharmacological, individualized, or privatized solutions.” A concerning phenomenon of medicalization is that t­here are no healthy individuals, but rather undiagnosed patients. The clear trend, particularly in the United States, is to provide more pills to more p ­ eople sooner in life and for a longer period. As a result of medicalization, our lives, values, goals, priorities, and successes become heavi­ly influenced or even intruded upon by medical reasoning and postulates, and as a result the drug industry profits. ­These are examples of areas in which profit-­motivated decisions can potentially increase unintended and avoidable consequences: • Menstruation and pregnancy have come to be seen as medical prob­lems requiring intervention. ­ nder an • Shyness has been categorized u umbrella of disorders, including “avoidant personality disorder,” and hyperkinesis is used to describe an attention-­deficit/ hyperactivity disorder. • Natu­ral age-­related decline in sexual drive has been categorized in men as impotence, a dysfunction that requires specific treatment. grandparents Our grandparents or great-­ ­ ere born and died at home, whereas a majority w of us are born, live, and die u ­ nder medical supervision. Although true that our generation lives longer than previous ones, this is due mainly to improved medical care with sophisticated diagnostic and therapeutic modalities, improved public education, and greater awareness of healthy lifestyles and diet. Yet, while the American health care system is the most expensive in the world (19), Americans are living shorter lives and are in poorer health than p ­ eople in other industrialized nations (20). The 2007 data shows that the United States ranked 16th of 17 peer-­income countries in life expectancy (20).

The other aspect of iatrogenicity that must be considered is financial: iatrogenic poverty. The cycle described by Meessen et al. is all too familiar: “Distress caused by disease, the quest for treatment—­often through a succession of in­effec­ tive therapies, consumption of savings, indebtedness, sale of productive assets and eventually poverty” (21). Poverty induced by medicine is usually associated with low-­income countries but is also occurring in the United States. The skyrocketing cost of health care means that many ­people do not have access to appropriate medical care. The following realities illustrate iatrogenic poverty in the United States: • Rich patients are often over-­diagnosed and overtreated while patients with lower incomes are underdiagnosed and undertreated, despite the share of the economy devoted to health care increasing from 7.2% in 1970 to 17.9% in 2010 (22). • Lack of health insurance was associated with nearly 44,789 deaths in 2009 (23). • Nearly two-­thirds of all bankruptcy filings ­ ere due to illness or medical bills. in 2007 w Most of the filings ­were by well-­educated ­people who owned homes and ­were employed in middle-­class occupations; three-­quarters had health insurance (24). • It is reported that more than 50% of the population are considered chronically ill, that is, having at least one chronic health or ­mental condition, as of 2016 (25). The widening in­ equality gap further degrades the health care system, creating vulnerable populations such as the el­derly, youth, and undocumented immigrants. This gap is evidenced in the fact that the United States is the richest country in the world with the largest health care bud­get, yet ranks 35th in life expectancy, on par with low-­and middle-­income nations (26).

Methods of Reporting and Assessing Iatrogenicity Medical harm is difficult to detect, mea­sure, and compare. The national program Partnership for Patients (P4P), was launched in April 2011 (27) and funded by the Department of Health and ­Human Ser­vices (HHS), attempted to reduce preacquired conditions by 40% ventable hospital-­

Instead of Conclusions  /  13 and reduce 30-­day hospital admissions by 20% by 2013. The formal goal included only preventable harm and ­later covered all forms of harm. Difficulties in defining strategies to mea­sure harm proved both difficult and urgent (28). To improve detection, prevention, and mitigation of medical harm, particularly in hospitals, Parry et al. recommended grouping mea­sures of harm:

ern medicine and patient well-­being; they include National Patient Safety Foundation (L. Leape Institute), Public Citizen (“Worst Pills, Best Pills”), World Health Organ­ization (Department of Essential Medicines and Phar­ma­ceu­ti­cal Policies), Agency for Healthcare Research and Quality (HHS), the Institute for Healthcare Improvement, and the National Acad­emy of Medicine. As a new clinical field, the study of iatrogenic • Specific harm (the Harvard Medical disease is in harmony with the patient-­centered Practice Study, the Medicare Patient Safety movement financially incentivized by the Centers Monitoring System, and the Agency for for Medicare and Medicaid Ser­vices (CMS), as Healthcare Research and Quality [AHRQ], mea­ sured and reported by HCAHPS (Hospital Patient Safety Indicators) Consumer Assessment of Healthcare Providers • All-­cause harm (the Global Trigger Tool and Systems), which began patient satisfaction and derivative methods) (28) surveys in February  2006. Patients not only The findings, presented in the 2014 report, demand but also always deserve to receive g­ reat found that of the 11 areas the Partnership for care and effective communication of information. Patients campaign focused on, 5 showed decreased rates of harm. Although the 6 remaining categories showed mixed results, the cost savings ­were INSTEAD OF CONCLUSIONS substantial. Estimates, compared to a 2010 baseMedicine has had to deal with iatrogenic conseline, indicate that the decrease in harm has saved quences beginning with the first medical treat$4 billion and avoided 15,500 $3.1 billion–­ ments in antiquity. In the modern world, potential deaths (27). side effects are all too familiar; for example, To attain the most recent figures of deaths ma­ ceu­ ti­ cal ads contain lengthy lists of phar­ per year in the United States due to medical error unwanted consequences. Even the best medicine (over 250,000 deaths per year as calculated from can have unintentional effects. Not having to 2013 hospital admission data), the CDC coltreat the cure ­will save time and money in addilected information on death certificates (15). tion to reducing suffering, decreasing harm, and However, medical billing systems are not designed increasing benefit (primum non nocere). Despite to provide information on health statistics. Interthe explosion of scientific data, major issues with estingly, especially in the historical context of medi­cations remain: iatrogenicity, when the International Classification of Disease (ICD) billing codes ­were designed • Most drugs act by an increase-­or-­decrease in 1949, iatrogenic ­causes of death ­were undermechanism instead of attempting to recognized and as a result, “medical errors w ­ ere normalize. unintentionally excluded from national health • ­There is minimal or no consideration of the statistics” (15). It is of par­tic­ul­ ar interest that this body’s innate compensatory mechanisms. oversight was unintentional, one of the compo• ­There is incomplete understanding of the nents of this book’s definition for iatrogenicity. effects of polypharmacy, especially opiates, Although blame is not appropriate, once an overpain killers, sleeping pills, and antidepressight or ­mistake is caught, continuing without a sants. change of practice is negligent. Therefore, any • Overall, patients have a low adherence to effort that seeks to mea­sure iatrogenicity is commedi­cations and lifestyle a­ dvice. mendable and should be encouraged. • Over-­the-­counter dietary supplements, Hopefully, modern medicine w ­ ill see a ­future herbal products, and alternative nontradiwhen advanced knowledge of iatrogenicity ­will tional therapies may interfere with prescriphelp regain patient trust, adherence, and benefit. tion ­medicines. izations are not hesitant to Numerous organ­ • Drug-­drug and drug-­food interactions may express genuine concerns over the safety of modoccur.

14 / Iatrogenicity • Ubiquitous direct-­to-­consumer advertising, especially on tele­vi­sion, encourages patients to ask for par­tic­ul­ar drugs by name, thereby creating a conversation between the consumer and the drug com­pany and threatening to cut the doctor out of the loop. Because medicine ­ ­ isn’t entirely a science, t­here ­will be no perfect scientific resolution to medical harm. Science provides the factual scaffolding that supports the art of medicine, that is, the expression of critical thinking, imagination, and skill. The clinical discipline of iatrogenicity may attempt to unify the science and the art of medical practice. Hopefully, this first edition of a textbook for the new clinical discipline w ­ ill fill society’s need to address iatrogenicity as a growing concern. Although the nature of this book may elicit objections by some, the intention is to promote much needed healing in light of the negative publicity about and wavering faith of both patients and physicians in the current medical model. Let this book begin an effort to remediate ­ ill also serve as a reminder that the situation. It w iatrogenicity cannot be avoided but can and must be mitigated and managed.

References 1. Sheldon H. Natu­ral Hygiene: Man’s Pristine Way of Life. San Antonio, TX: Dr.  Shelton’s Health School; 1968. 2. Pilates J, Robbins J, Van Heuit-­Robbins L. Pilates’ Return to Life Through Contrology: Revised Edition for the 21st ­Century. Ashland, OH: Pre­ sen­ta­tion Dynamic; 2012. 3. Venes D, ed. Taber’s Cyclopedic Medical Dictionary. 20th ed. Philadelphia, PA: F.A. Davis Com­pany; 2005. 4. Smith CM. Origin and uses of primum non nocere—­above all, do no harm! J Clin Pharmacol. 2005;45(4):​371–377. 5. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a analysis of prospective studies. JAMA. meta-­ 1998;279(15):​1200–1205. 6. Lyons AS, Petrucelli RJ. Medicine: An Illustrated History. New York, NY: Harry N. Abrams; 1978. 7. Adler, RE Medical Firsts: From Hippocrates to the ­ uman Genome. Hoboken, NJ: John Wiley and H Sons; 2004. 8. Gerson S. Introduction. In: Frawley D. Ayurvedic Healing: A Comprehensive Guide. Twin Lakes, WI: Lotus Press; 2000:1–4.

9. Lad V. Textbook of Ayurveda: A Complete Guide to Clinical Assessment. Volume 2. Albuquerque, NM: Ayurvedic Press; 2007. 10. Maimonides: Medical Aphorism Treatises 1–5. Translated and annotated by Gerrit Bos. Brigham Young University Press. Provo, UT. 2004. 11. Centers for Disease Control and Prevention. About DES. Atlanta, GA: Centers for Disease Control and Prevention, US Dept of Health and ­Human Ser­ vices. http://­www​.­cdc​.­gov​/­DES​/­consumers​/­about​ /­his​tory​.­html​.­ Accessed September 1, 2016. 12. Emanuel M, Rawlins M, Duff G, et al. Thalidomide and its sequelae. Lancet. 2012;380(9844):​ 781–783. 13. Bothwell LE, Greene JA, Podolsky SH, et al. Assessing the gold standard—­lessons from the history of RCTs. N Engl J Med. 2016; 374(22):​2175–81. 14. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is ­Human: Building a Safer Health System. Institute of Medicine. Washington, DC: National Academies Press; 2000. 15. Makary MA, Daniel M. Medical error—­the third leading cause of death in the US. BMJ. 2016; 353:i2139. 16. Steel, K, Gertman, PM, Crescenzi, C, et al. Iatrogenic illness on a general medical ser­ vice at a ­university hospital. Qual Saf Health Care. 2004;​ 13:76–80. 17. James JT. A new, evidence-­ based estimate of patient harms associated with hospital care. J Patient Saf. 2013;9(3):​122–128. 18. Moynihan R, Heath I, Henry D. Selling sickness: the phar­ma­ceu­ti­cal industry and disease mongering. BMJ. 2002; 324(7342):​886–891. 19. Davis K, Stremikis K, Schoen C, et al. Mirror, Mirror on the Wall, 2014 Update: How the U.S. Health Care System Compares Internationally. New York, NY: The Commonwealth Fund; 2014. http://­www​.­commonwealthfund​.­org​/­publications​ /­fund​-­reports​/­2014​/­jun​/­mirror​-­mirror. Accessed May 1, 2017. 20. Woolf, SH, Aron, L, eds. US Health in International Perspective: Shorter Lives, Poorer Health. Washington, DC: National Academies Press; 2013. http://­www​.­nap​.­edu​/­read​/­13497​/­chapter​/­1. 21. Meessen B, Zhenzhong Z, Van Damme W, et al. Iatrogenic poverty. Trop Med Int Health. 2003;​ 8(7):​581–584. 22. Kaiser F ­ amily Foundation. Health care costs: a primer. May 1, 2012. http://­kff​.­org​/­report​-­section​ /­health​-­care​-­costs​-­a​-­primer​-­2012​-­report​/­. 23. Wilper AP, Woolhandler S, Lasser KE, et al. Health insurance and mortality in US adults. Am J Public Health. 2009;99(12):​2289–2295. 24. Himmelstein DU, Thorne D, Warren E, et  al. Medical bankruptcy in the United States, 2007: results of a national study. Am J Med. 2009;​ 122(8):​741–746.

References / 15 25. “More than 50% of Americans now have at least one chronic health condition, m ­ ental disorder or substance-­use issue.” Science Daily, October 25, 2016. www​.­sciencedaily​.­com​/­releases​/­2016​/­10​ /­1610​25092655​.­htm. Accessed May 1, 2017. 26. Bezruchka S. Epidemiological approaches to population health. In: Bryant T, Raphael, D, et al., eds. Staying Alive: Critical Perspectives on Health, Illness, and Health Care. Toronto, ON: Canadian Scholars’ Press; 2010; 19–20.

27. Proj­ect Evaluation Activity in Support of Partnership for Patients: Task 2 Evaluation Pro­ gress Report. February 2014. Submitted July 10, 2014 by Mathematica Policy Research and Health Systems Advisory Group. https://­innovation​.­cms​ .­gov​/­Files​/­reports​/­PFPEvalProgRpt​.­pdf. Accessed May 1, 2017. 28. Parry G, Cline A, Goldmann  D. Deciphering harm mea­sure­ment. JAMA. 2012;307(20):​2155– 2156.

CHAPTER 2

Epidemiology and Public Health Aspects and Implications of Iatrogenicity Regulatory, ­Legal, and Ethical Dimensions Miriam A. Gonzalez-­Siegel and Stephen K. Jones

INTRODUCTION The pro­cess by which a condition or be­hav­ior is defined as a medical prob­lem requiring a medical solution is known as medicalization. For medicalization to occur, one or more or­ga­nized social groups must have both a vested interest in the condition and sufficient power to convince ­others to accept the newly proposed need for a medical solution. Not surprisingly, the 1999 report released by the Institute of Medicine To Err Is ­Human: Building a Safety Health System (1), exposed treatment-­ related adverse conditions as the medicalization of harm (2–7). The report was a call to action, prompting regulators, physicians, payers, and providers including health care facilities and systems to focus on harm as a medical prob­lem requiring a medical solution. This focus led to the patient safety movement resulting in regulations and legislative initiatives to protect patients from medical harm. The medicalization of harm is influenced as much by ethics as regulatory and ­legal reform. For medicalization to occur it is impor­tant for one or more or­ga­nized social groups to have a vested interest and sufficient power to convince ­others. The release of the Institute of Medicine’s report was a compelling and shocking revelation about the h ­ uman, social and eco­nom­ical cost of medical errors. Although patients ­were likely to hear about this report in the popu­lar media, the report was widely examined in the permeations of professional meetings, conferences, and regulatory framework of providers, payers, and regulators. A collective social awareness of the prob­lem and sympathy ­toward sufferers and deceased victims gave rise to a proliferation of models to improve patient safety. At the heart of the models, the discussions, and the framework for improved responsibility was ethics. ­There arose a heightened sense that physicians and their extended providers must own the errors both morally and professionally, and provide disclosure to the patient and f­ amily as a first step ­towards that end. See Chapter  3 for information on the importance of disclosure and apology in healing the doctor-­patient relationship and mitigating the harm a­ fter an iatrogenic event.

Key Organ­izations in the Patient Safety Movement  /  17 Saving lives became paramount. The need to improve care and save lives, translated into the need for reliable care delivery and better outcomes coupled with cost containment and shared learning (shared learning? I’d rather say shared responsibility for the prevention of medical errors.. The rising concern about the quality of care available as well as rising health care costs begged the question, what is the cost of harm? In the United States in 2003, the average cost per capita for medical care, drugs, supplies, and health were care insurance was $5,241. Expenditures ­ expected to double by 2003. ­These costs continue to rise more quickly than in other industrialized nations. The sharp increase is often attributed to the propensity of Americans to file malpractice lawsuits, but this is just one myth about the price of health care (8–11). Another myth is that the defensive practice of medicine (doctors performing tests and procedures primarily to protect themselves against lawsuits) caused malpractice insurance costs to rise, which spiked costs throughout the system. Despite research revealing that the cost of malpractice insurance accounted for less than 1% ­percent of total U.S. health care costs (12–14), providers began to leave their specialties due to high malpractice insurance premiums, and access to high-­end specialists became a contributing f­ actor to the growing crisis. Without doubt, the cost of health care in the United States is at a crisis point, certainly more so than when the Institute’s report was released, but the relation between cost and iatrogenic events is unclear. However, the patient safety movement and its focus on uncovering the c­auses of and reducing medical error cannot help but make the U.S. health care system more efficient, which, in the long run, w ­ ill reduce costs. Currently, many organ­izations are involved in understanding iat­ rogenicity and working ­toward preventing it.

Institute for Healthcare Improvement (IHI) began its work in the late 1980s as part of the National Demonstration Proj­ect on Quality Improvement in Health Care. IHI initially focused on identifying and promulgating best practices and reductions in defects and errors in microsystems such as the emergency department or the intensive care unit. As the organ­ization entered its third de­cade, it recognized the need for a new health care model and created the IHI ­Triple Aim Initiative, a framework for optimizing health system per­for­mance mul­ ta­ neously focusing on the health of a by si­ population, the experience of care by individuals in the population, and the per capita cost of providing that care. IHI’s Innovation Series white paper published in 2011 (15) reported that ­every day clinical adverse events occur in the health care system, causing physical and psychological harm to patients and their families, staff, physicians and allied health professionals, the community, and the health care organ­ization. In the crisis that often emerges, what differentiates organ­izations, positively or negatively, is their culture of safety; the role of the board of trustees and executive leadership; advanced planning for adverse events; the balanced prioritization of the needs of patients and their families, staff, and organ­ization; and the way in which actions immediately and over time bring empathy, support, resolution, learning, and improvement. The risks of not responding to adverse events in a timely and effective manner are significant and include erosion in the delivery of competent and compassionate care, mixed messages about what is impor­tant to the organ­ization, increased likelihood of regulatory action and lawsuits, and challenges from the media.

Patient Safety Organ­izations

The federal government’s contributions to the patient safety movement are evident in the enactKEY ORGAN­IZATIONS ment of the Patient Safety and Quality ImproveIN THE PATIENT SAFETY ment Act of 2005 (Act), which came in response MOVEMENT to the Institute of Medicine report. The final Patient Safety Rule became effective in JanuInstitute for Healthcare ary  2009. The Agency for Healthcare Research Improvement and Quality (AHRQ), a division of the DepartOfficially founded in 1991 in response to the ment of Health and ­Human Ser­vices, oversees many crises confronting health care delivery, the the Patient Safety Rule. The intent of the Act is to

18  /  Epidemiology and Public Health Aspects and Implications of Iatrogenicity foster honest and frank discussion about iatrogenicity and to find solutions to system failures. The need to ensure momentum required assurance to the medical community in the form of confidentiality protections for providers who work with federally participating Patient Safety Organ­izations (PSOs). Currently, t­here are 81 PSOs in 28 states and the District of Columbia. The goal of PSOs is to learn how and why adverse events happen, and to inform providers and o ­ thers about how to prevent ­future occurizations is rences. Participation in the organ­ intended to promote shared learning and enhance quality and safety nationally. PSOs are required to meet certain criteria and must conduct activities to improve patient safety and health care quality. They must have expertise in the analy­sis of patient safety events and are expected to propose prevention and reduction or elimination of risk of harm and injury while addressing quality of care (Patient Safety Rule Section 3.102). Key activities of PSOs include collection and analy­sis of patient safety work product (PSWP); development and dissemination of information about patient safety, such as recommendations, protocols, and information regarding best practices; utilization of patient safety privileged for the purposes of encouraging a culture of safety; and feedback and assistance to effectively minimize patient risk. The activities of a PSO and its work product are confidential. The privilege and confidentiality conferred by the Act and the Patient Safety Rule is one of the many benefits of a PSO, mainly, protection of products and documents from use in ­legal proceedings. Additional benefits include the ability to hire outside experts to collect, analyze, and aggregate data locally, regionally, and nationally to lying ­ causes of develop insights into the under­ patient safety events. The protections are expected to remove significant barriers that can deter the participation of health care providers in patient safety and quality improvement initiatives, such as fear of l­egal liability and professional sanctions.

Department of Veterans Affairs An increased effort to improve safety led to the establishment, in 1998, of the Veterans Health Administration’s National Center for Patient Safety, which set up a nationwide centralized sys-

tem for reporting, capturing, and analyzing adverse events and near misses. In 1991, prior to the patient safety movement, the Department of Veterans Affairs established the National Center for Ethics in Health Care, which is charged with promoting ethical health care practices.

The Joint Commission In 2015, the in­de­pen­dent, nonprofit Joint Commission, which accredits and certifies nearly 21,000 health care organ­izations and programs in the United States, added a new chapter, entitled “Patient Safety Systems,” to its Comprehensive Accreditation Manual for Hospitals (CAMH). This addition exemplifies the Joint Commission’s commitment to enhance patient safety through its accreditation ser­vices and its mission to inform and educate hospital leaders on the importance and structure of an integrated patient safety system (16,17). The new chapter is intended to move the focus from a retrospective to a proactive approach, with a goal of reducing harm to zero. This resource is setting a new tone for the health care industry as a ­whole in addressing medical errors, medical malpractice, and adverse effects of medical care and harm.

FINDING AND ANALYZING ERROR The Institute of Medicine report, which became the cornerstone of the patient safety movement, emphasized the need for postiatrogenic event analy­sis. Retrospective analy­sis as well as mandatory reporting of errors took center stage. Focus was placed on illuminating the origin of defects and failures through root cause analy­sis, a well-­ supported methodology. Root cause analy­sis r­ ose from the broader field of total quality management, which applies an or­ga­nized methodology lem analy­ sis, prob­ lem solving, and to prob­ improvement tools and techniques. Root cause analy­sis is part of a more general prob­lem review pro­cess and as such is one of the building blocks in an organ­ization’s per­for­mance improvement efforts. The pro­cess of root cause analy­sis itself does not produce outcomes; it is a component of a larger problem-­solving effort, part of a conscious attitude or culture that embraces a relentless pursuit of safety and improvement at e­ very

Finding and Analyzing Error  /  19 level. This cultural shift became a focus for the medical community, regulators, and accrediting agencies. The need to bring teams comprised of physicians, providers, students, nurses and allied health professionals who play a critical role in the complex system configuration became standard practice. Since 1997, the Joint Commission has mandated the use of root cause analy­sis to examine sentinel events (patient safety events that result in death, permanent harm, or temporary severe harm, such as wrong-­site surgery) (18–21). As of 2009, a total of 25 states and the District of Columbia had mandated the reporting of serious adverse events, increasingly using the National Quality Forum’s list of “never events” (22–24). Additionally, many states require that root cause analy­sis be performed and reported ­after any serious event. The use of root cause analy­sis has likely increased with the growth of mandatory reporting systems. The methodology is intended to identify the root cause of the under­lying prob­ lems contributing to iatrogenicity, but it focuses on system errors rather than m ­ istakes by individuals. It identifies both active errors (occurring at the point of interface between ­humans and a complex system) and latent errors (hidden prob­ lems that are the by-­product of system design and contribute to adverse events). A root cause analy­ sis should generally follow a prescribed protocol  from data collection and reconstruction of the event through rec­ord review and participant interviews. A multidisciplinary team is convened to analyze the sequence of events leading to the error, with the goal of identifying how the event occurred. The ultimate aim, of course, is to prevent ­future harm by eliminating the ­factors contributing to adverse events and to implement a series of systematic changes to reduce the likelihood of a similar errors in the f­ uture. Root cause analy­sis is a widely used term, but many find it misleading. As illustrated by the Swiss cheese model (see Figure  2-1),  which views that most errors reflect predictable ­human failings in the context of poorly designed systems the systems factors approach seeks to identify situations or ­ likely to give rise to ­human error, and change the under­lying systems of care in order to reduce the occurrence of errors or minimize their impact on sis was piopatients. The field of systems analy­ neered by the British psychologist James Reason,

FIGURE 2-1 ​The Swiss cheese model of medical errors

whose analy­sis of industrial accidents led to fundamental insights about the nature of preventable adverse events. Reason’s analy­sis of errors in fields as diverse as aviation and nuclear power revealed that catastrophic safety failures are almost never caused by isolated errors committed by individuals. Instead, most accidents result from multiple, smaller errors in environments with serious under­ lying system flaws. He introduced the Swiss cheese model to describe this phenomenon. In this model, errors made by individuals result in disastrous consequences ­because of the flawed system—­the holes in the cheese. Each piece of cheese contains holes, but for an adverse event to occur, holes in several pieces of cheese must align. This model not only has tremendous explanatory power, but it also points the way t­ oward solutions: encouraging personnel to identify the holes and then shrinking their size and creating enough overlap so that they never line up in the f­ uture. Reason’s model uses the terms active errors and latent errors to distinguish individual errors from system errors. Active errors almost always involve frontline personnel and occur at the point of contact between a h ­ uman and some aspect of a larger system, for example, ­human–­machine interface. By contrast, latent errors are literally accidents waiting to happen, such as failures of organ­ization or design that allow active errors to happen. Reason provides even further specificity in the analy­sis of error with the terms sharp end and blunt end, which correspond to active error and latent error. In health care, personnel at the sharp end literally may be holding a sharp instrument when the error is committed (e.g., the surgeon who performs an incorrect procedure) or they may be administering some other kind of treatment in which the sharp end is figurative.

20  /  Epidemiology and Public Health Aspects and Implications of Iatrogenicity The blunt end refers to the many layers of the health care system that are not in direct contact with patients but influence the personnel and equipment at the sharp end, which comes into contact with patients. Thus, the blunt end consists of such ­people as policymakers, man­ag­ers of health care institutions, and medical device designers, who are removed from direct patient care but still affect the delivery of patient care. The work of James Reason and fellow British psychologist Charles Vincent, another pioneer in the field of error analy­sis, established a commonly used classification scheme for latent errors that includes ­causes ranging from institutional ­factors (e.g., regulatory pressures) to work environmental ­factors (e.g., staffing issues) and team ­factors (e.g., safety culture). The retrospective analy­sis methods (e.g., root cause analy­sis) and prospective methods (e.g., failure modes effect analy­sis) attempt to identify error-­prone situations within specific pro­cesses of care. Failure modes effect analy­sis begins by identifying all the steps that must occur for a given pro­cess to happen. Once this pro­cess mapping is sis identifies the ways in complete, the analy­ which each step can go wrong, the probability of each error being detected, and the consequences or impact of the error not being detected. The estimates of the likelihood of a par­tic­ul­ ar pro­cess failure, the chance of detecting such failure, and its impact are combined numerically to produce a criticality index. This index provides a rough quantitative estimate of the magnitude of hazard posed by each step in a high-­risk pro­cess. Assigning a criticality risk to each step allows prioritization of targets for improvement. Failure modes effect analy­sis makes sense as a general approach and is a commonly used patient safety model in health care. However, despite industry adoption and accrediting agencies such as the Joint Commission and many state regulations requiring such review pro­cesses, the reliability of the technique and its utility in health care are not yet clear. Dif­fer­ent teams charged with analyzing the same pro­cess may identify dif­ fer­ent steps in the pro­cess, assign dif­fer­ent risks to the steps, and consequently prioritize dif­fer­ent targets for improvement. An appropriate systems approach to improving safety requires paying attention to many ­factors that are routinely addressed in other high-­

risk industries but are only now being analyzed in modern medicine. Along with creating a culture of safety in which reporting of incidents and errors is encouraged, more rigorous standards for finding and fixing system flaws in health care systems must be applied.

SUMMARY The crisis of harm as a medical prob­lem gave rise to the Institute of Medicine’s 1999 landmark report on medical error, which, in turn, launched the patient safety movement and associated regulations and legislative initiatives. Vari­ous organ­ izations including the Institute for Healthcare izations, the Improvement, Patient Safety Organ­ Department of Veterans Affairs, and the Joint Commission have propelled the movement forward, as they work ­toward preventing or reducing iatrogenic events. In ser­vice of this goal, organ­ izations have focused attention on postiatrogenic event analy­sis. At least half of the states mandate the reporting of serious adverse events, and many require that root cause analy­sis be performed ­after any serious adverse event.

References 1. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is ­Human: Building a Safer Health System. Institute of Medicine. Washington, DC: National Acad­emies Press; 2000. 2. Efforts To Improve Patient Safety Results in 1.3 Million Fewer Patient Harms. Publication #15-0011–­ ­ EF, December  2014. Rockville, MD: Agency for Healthcare Research and Quality. http://­www​.­ahrq​.­gov​/­professionals​/­quality​-­pat​ ient​-­safety​/­pfp​/­interimhacrate2013​.­html 3. Illich  I. Medical Nemesis. New York, NY: Random House; 1976. 4. Ranulf S. The Jealousy of the Gods and Criminal Law in Athens, trans. Annie  J. Fausboll, 2 vols. Copenhagen, Denmark: Levin & Munksgaard; 1933. 5. Grene  D. Greek Po­liti­cal Theory: The Image of Man in Thucydides and Plato. Chicago, IL: University of Chicago Press; 1965. 6. Dodds ER. The Greeks and the Irrational. Berkeley, CA: University of California Press; 1951. 7. Jonas H. Technology and responsibility: reflections on the new task of ethics, Social Research. 1972;​ 40:31–54. 8. Boothman R, Imhoff SJ, Campbell DA. Nurturing a culture of patient safety and achieving lower

References / 21 malpractice risk through disclosure: lessons learned and ­future directions. Front Health Serv Manage. 2012;28(3):​13–27. 9. Brennan TA, Sox CM, Burstin HR. Relation between negligent adverse events and the outcomes of medical-­malpractice litigation. N Engl J Med. 1996;335(26):​1963–1967. 10. Studdert DM, Mello MM, Gawande AA, et  al. Claims, errors, and compensation payments in medical malpractice litigation. N Engl J Med. 2006;354(19):​2024–2033. 11. Clinton HR, Obama B. Making patient safety the centerpiece of medical liability reform. N Engl J Med. 2006;354(21):​2205–2208. 12. Heffernan M. The Health Care Quality Improvement Act of 1986 and the National Practitioner Data Bank: the controversy over practitioner privacy versus public access. Bull Med Libr Assoc. 1996;84(2):​263–269. 13. Kachalia A, Kaufman SR, Boothman R, et al. Liability claims and costs before and a­ fter implementation of a medical error disclosure program. Ann Intern Med. 2010;153(4):​213–221. 14. Mello MM, Gallagher TH. Malpractice reform—­ opportunities for leadership by health care institutions and liability insurers. N Engl J Med. 2010;362(15):​1353–1356. 15. Conway J, Federico F, Stewart K, et al. Respectful Management of Serious Clinical Adverse Events (2nd  ed.). IHI Innovation Series white paper. Cambridge, MA: Institute for Healthcare Improvement; 2011. 16. McKee A. Patient Safety Chapter in a pre­sen­ta­tion to The Joint Commission Con­sul­tant’s Forum.

17. New hospital accreditation chapter puts heightened focus on safety [news release]. Oakbrook Terrace, IL: The Joint Commission; October 20, 2014. http://­www​.­jointcommission​ .­org​ /­new​ _­hospital​ _­accreditation​_­chapter​_­puts​_­heightened​_­focus​_­on​ _­safety​/­default​.­aspx 18. Wilson PF, Dell LD, Anderson GF. Root Cause Analy­sis: A Tool for Total Quality Management. Milwaukee, WI: ASQ Quality Press; 1993;8–17. 19. Ohno  T. ­ Toyota Production System: Beyond Large-­Scale Production. Portland, OR: Productivity Press; 1988:17. 20. The Joint Commission. Patient safety systems: new accreditation manual chapter for hospitals. Joint Commission: The Source, 2014;12(9):​1,7–8,10. 21. The Joint Commission. 2015 comprehensive accreditation manual for hospitals: the patient safety systems chapter. CAMH Update 2, January 2015. 22. Wu AW, Lipshutz AK, Pronovost PJ. Effectiveness and efficiency of root cause analy­sis in medicine. 685–687.23. Agency for JAMA. 2008;299(6):​ Healthcare Research and Quality. Proactive reporting, investigation, disclosure, and remedying of medical errors leads to similar or lower than average malpractice claims costs. AHRQ Innovations Exchange. https://­innovations​.­ahrq​ .­g ov​/­p rofiles​/­p roactive​-­r eporting​-­i nvestigation​ -­disclosure​-­and​-­remedying​-­medical​-­errors​-­leads​ -­similar​-­or. Accessed November 28, 2012. 24. Clark PA. Medical practices’ sensitivity to patients’ needs: opportunities and practices for improvement. J Ambul Care Manage. 2003;26(2),​ 110–123.

CHAPTER 3

Risk Management The Medical Center Administration Perspective Stephen K. Jones and Miriam A. Gonzalez-­Siegel

WHAT IS RISK MANAGEMENT? Risk management is the business of reducing the likelihood of errors through a pro­ cess of identification, assessment, and prioritization of risks, followed by coordinated and eco­nom­ical application of resources to minimize, monitor, and control the probability and/or impact of unfortunate events or to maximize the realization of ous sources, such as unpredictability in opportunities. Risk can come from vari­ financial markets; threats from failures (at any phase in design, development, production, or sustainment life cycles); ­legal liabilities; accidents; or events of uncertain root causes. See definition from The Institute of Risk Management (1). Strategies to manage threats (uncertainties with negative consequences) typically include avoiding the threat, reducing the negative effect or probability of the threat, transferring all or part of the threat to another party, and even retaining some or all of the potential or a­ ctual consequences of a par­tic­u­lar threat. The majority of risk management–­related activities in health care aim to reduce medical errors and adverse effects that are costly in terms of damage, discomfort, disability, or distress to an individual and also result in financial loss to an organ­ization. Risk management as a business strategy has existed for about 50  years (2–4). Health care risk management in its pres­ent form emerged from the malpractice crisis of the mid-1970s, when physicians, hospitals, and other health care entities experienced rapid rises in claims costs and subsequent escalations in insurance premiums. The crisis contributed to the rapid departure of several major medical professional liability insurers from the market (5–8), but also led to the first risk management programs. The American Society for Healthcare Risk Management (ASHRM, formerly the American Society for Hospital Risk Management) was established in 1980 in response to the developing interest in risk management among health care organ­izations. Medical risk management activities include pro­cesses to manage loss by detecting, reporting, and correcting ­actual or potential deficiencies in care and operations that could lead to costly ­mistakes. Programs involve all aspects of work, production, and interactions within clinical and other health care settings. One of the dimensions of a risk management program is to strive for care that is ­free of iatrogenicity including medical errors, medical malpractice, adverse effect, and harm. A health care organ­ization’s risk management team is responsible for organ­izing, coordinating, and

The Importance of Disclosure  /  23 carry­ing out programs to control the clinical risks from getting worse, but such be­hav­ior only comassociated with patient care ser­vices. pounds risk, erodes trust, and conflicts with the patient safety movement.

THE EVOLUTION OF MEDICAL RISK MANAGEMENT

THE IMPORTANCE OF DISCLOSURE

Historically, the detection of iatrogenic harm in all its forms relied on analy­sis techniques predicated on both voluntary and mandatory reporting of incidents. The release in 1999 of a report by the Institute of Medicine, To Err is H ­ uman: Building a Safety Health System, which addressed the devastating consequences on care, prompted the modern patient safety movement (9). It spurred risk management professionals, who had primary responsible for investigating, analyzing, and maintaining data on medical errors and harm, to join with quality and per­ for­ mance improvement colleagues. A variety of clinical disciplines came together to systematically identify the ­causes of errors and effectuate organizationwide patient safety programs. It is impor­tant to note that the scope of risk management programs was broadly defined to encompass risk related to patient care, medical staff, employees, property, and financial stability. Over the past several years, the U.S. health care industry and prac­ti­tion­ers have faced larger jury verdicts, higher settlement amounts, costlier insurance premiums, and dwindling insurance availability in the medical malpractice market. Given t­hese ­factors and the emphasis on reducing harm, a substantial proportion of current health care risk management efforts are now focused primarily on issues related to patient care. In fact, the profession has renewed its focus on patient safety and recalibrated the steps for detecting and mitigating harm, in an effort to reduce risk. So, what then is the risk management approach to iatrogenicity? It must balance ethical considerations, regulatory requirements, and legal implications to both protect the patient ­ from harm and to mitigate the damage to the provider when harm has occurred. Risk management as a science understands that iatrogenic events lead to malpractice claims and lawsuits. It knows that ­humans often tend to avoid disclosing, documenting, and releasing details in the mistaken notion that they are keeping ­matters

In its current state, risk management is both rule based and art, a balance of regulations that guide the delivery of care and operations, and regulations that ­ favor documentation, transparency, and completion of incident reports—­a system directed at improving patient safety. Risk management operates in an environment in which consumers of health care are aware of system malfunctions and h ­uman errors. This understanding is predicated on the need of patients to understand what occurred when care goes wrong and, more importantly, to feel that such events are not in vain. Patients seek assurance that their exposure to harm and suffering has value in improving the quality and safety of care. This assurance, supported by compassionate communication, helps heal the provider-­patient relationship, de-­ escalates the adversarial relationship, and eliminates both the perception that facts are being concealed and the defensiveness that commonly surrounds iatrogenicity. Disclosure is one of the most valuable risk management strategies and the topic of much research. The early Harvard Medical Malpractice Study (10–11) illustrated that the failure to disclose was a strong contributing f­ actor in patients filing lawsuits. Patients’ perceptions postevent ­were that they ­were not told about the event, their questions w ­ ere not addressed, and providers ­were withholding information. ­After iatrogenic events, risk management plays a pivotal role in facilitating and repairing relationships and reestablishing confidence by guiding and supporting clinicians and their communications with patients and families. Medicine has never been error-­free. Physicians understand their responsibility to reduce spect to the rate of medical errors, show re­ patients and their rights, and to maintain trust. Physicians and providers recognize their ethical duty when error is committed. Disclosure, the moment in the patient-­provider relationship that is both experiential and educational, must be

24 / Risk Management carefully executed and appropriately managed. The opportunities for candor between provider and patient are rooted in the princi­ples of re­spect for autonomy and beneficence, in which physicians and providers have an ethical and l­egal obligation to disclose their errors to patients. Disclosure is made in an effort to heal and correct the adverse consequences of errors. Risk management balances the ethical, ­legal, and practical aspects of how disclosure is done. Ethics, professional policy, and the law, as well as relevant empirical lit­er­a­ture, suggest that timely and candid disclosure should be standard practice as it lessens rather than increases medical legal liability and may help to alleviate the ­ patient’s concerns. Guidelines, regulations, and laws for disclosure to patients and their families have been widely enacted or proposed. Disclosure guidance and requirements are commonly predicated on the physician or provider’s role in the patient’s care and the necessity to explain to the patient and ­family in understandable language what happened, or if not yet clear, what ­will be done to understand what happened. This component of disclosure from a risk management perspective is the science of disclosure. It is tangible, evident, factual and a right due to the patient who has been harmed. The patient deserves to understand what went wrong. A scientific explanation, with subsequent therapeutic interventions to mitigate further harm, is what providers do best. The provision of care, explanation of the facts, and exchange of questions and answers about risk and benefits are all within the expertise of a provider. ­After all, it is a component of informed consent and patient self-­ determination. The patient must be included in the discussion and decision of care, even ­after an iatrogenic event.

THE POWER OF APOLOGY ­ here is also an ele­ment of disclosure that is not T so tangible, but equally impor­tant to patients: an apology. Patients want to hear a heartfelt apology from the physician or provider for the error. They also want to hear how the failure leading to this harm ­will be remediated and what can be done to ensure the harm does not persist. Patients want specific information on what went wrong and how it happened, and they want an acknowledge-

ment of the sorrow that the harm has caused and, more importantly, how the harm can be repaired. The offer of repair introduces a key component that intersects the patient safety movement and the princi­ples of risk management: to do the right ­thing a­ fter we have done the wrong ­thing. Partnering with patients to improve care, and the offer of monetary compensation or remedy and the appropriate support to ­those affected by the harm can mitigate the damage to the patient and the provider (12–17). The risk management approach in the area of disclosure aims to balance the victims of iatrogenesis as a priority in the containment of errors with the inherit risk of litigation. The patient safety movement at times is obstructed and slowed by malpractice laws and the fear of retribution for telling the truth. This fear has led to the implementation of apology laws in many U.S. states. Doug Wojcieszak, founder of Sorry Works!, a disclosure training and advocacy organ­ization, has said that many physicians reflexively avoid the situation and say nothing or as l­ittle pos­si­ble in the aftermath of patient harm (17–22). Part of this response comes from a long-­standing mindset that physicians should “deny and defend” against the possibility of being charged with any culpability in cases of pos­si­ble medical malpractice. This advice was promoted by most l­awyers and malpractice insurers. With the advent of the patient safety movement, risk man­ag­ers began to regard nondisclosure as not only an ethical risk, but also a regulatory and reputational risk that must be managed. The benefit of prompt, transparent communication with patients and families is changing the ­legal landscape. Disclosure and apology are impor­tant ele­ ments of a patient safety program. It is worthwhile for providers and health care leadership to invest time and effort in comforting a patient or a ­family member immediately a­ fter an event. A disaster warrants both an ethical and moral imperative to address both parties’ needs to search for a remedy and to heal the harm. The partnership between providers and patients to find improvements in health care is changing the malpractice landscape. In 2012, Mas­sa­chu­setts ­adopted a policy of disclosure, apology, and offer (DA&O) when patients suffer avoidable medical harm (23). ­Under the DA&O model, when unanticipated adverse

The Key Role of Communication  /  25 outcomes occur, patients and their families are provided full disclosure of what happened, what it means for the patient medically, and what ­will be done to prevent the error from recurring. Physicians, providers, and health care organ­izations are given the opportunity to apologize without fear that their words ­will be used against them in court. Another successful model is the University of Michigan Health System (UMHS), which has been in the national spotlight since 2004 for its innovative approach to medical errors, mis­haps, and near misses (15). The Michigan model supports the changing concept of risk management and alignment with the patient safety movement. It articulates the core challenge to medical risk management as harm to patients, not litigation. Its central goal is patient safety, and its program is based on the princi­ples of early disclosure and offer. The UMHS program has two core beliefs: (a) honesty is indispensable for safety improvement, and (b) a short-­term focus on financial risk impedes long-­term improvement. The practices of the DA&O system include compensating patients quickly and fairly when inappropriate medical care c­auses injury, communicating openly with patients about errors, supporting staff vigorously when appropriate care has been provided, and reducing f­ uture injuries and claims through application of knowledge garnered through the discovery pro­ cess. The system emphasizes UMHS’s commitment to patient safety as well as its accountability to patients and to clinicians who provide high-­quality care. The DA&O program is a compelling demonstration of the power of honesty, transparency, and accountability as pillars of medical liability management, serving the dual goals of improving patient safety and ameliorating the costs of avoidable medical m ­ istakes. By making e­ very effort to put patients and their safety first, the program fulfills its commitment to serving and protecting physicians, providers, and health systems.

THE KEY ROLE OF COMMUNICATION Health care is meant to make p ­ eople well, but it can harm as it heals; this is the pervasive prob­ lem of iatrogenic injury (24–27). Medical care and the health delivery systems are inherently

risky. The movement to manage iatrogenic risk (2,28–31) intersects with the patient safety movement. Based on our experience and participation in a myriad of patient safety–­related activities such as root cause analy­sis, investigations, litigation discovery, and response to patient complaints and grievances, the most common complaint raised in postiatrogenic event reviews is lack of communication. Research indicates effec­ tive communication among health that in­ care professionals is one of the leading ­causes of de­ pen­ dent, nonpatient harm (32–33). The in­ profit Joint Commission, which evaluates and accredits nearly 21,000 health care organ­izations in the United States, revealed that communication failures ­were implicated as the root cause in more than 70% of sentinel events (patient safety events that result in death, permanent harm, or temporary severe harm) (34). In a study of 2,000 health care professionals, the Institute for Safe Medi­cation Practices (ISMP) found intimidation as a root cause of medi­cation error. In­effec­tive or insufficient communication among team members is a significant contributing ­factor in adverse events. In the acute care setting, communication failures have led to increases in patient harm, length of stay, and resource use, as well as more intense patient dissatisfaction (18,19,22). Effective communication among health care professionals is challenging due to a number of interrelated dynamics. It is widely understood that health care is complex and unpredictable, with professionals from a variety of disciplines involved in providing care at vari­ous times throughout the day, creating gaps with limited opportunities for regular communication and interaction among the health care professionals (19). Historically, health care facilities have had a hierarchical, chain-­of-­command orga­nizational structure. This frequently leads to a culture of inhibition and restraint in communication, rather than a sense of open, safe communication. Differences in education and training among professions often result in varying communication styles and methods that further complicate the provision of care In fact, in postevent reviews, failure in ­human communication is seen as a contributing ­factor in most cases of iatrogenicity. But further review is needed to determine the root cause of the communication breakdown, such as cognitive overload; the effects of stress, fatigue, distractions,

26 / Risk Management and interruptions; poor interpersonal communications; imperfect information pro­ cessing; and flawed decision making. Failure to recognize and understand ­these issues can lead to a culture of unrealistic expectations and blame, diverting efforts away from effective communication with patients and their families and the interdependence of team dynamics. ­These ­factors must be taken into account when implementing error mitigation strategies. The role of deficient communication in impacting care negatively has been recognized by a number of researchers citing common ele­ments in industries such as aviation and health care (30). Communication is a complex and dynamic activity involving words, body language, voice, tone, and volume, compounded by judgments that individuals bring to the health care setting. One of the tools in effective communication and training is crew resource management (CRM), which focuses on the key concepts of leadership, briefings, monitoring, cross-­ checking, decision making, and review of and modification to plans. Enhanced communication and teamwork through CRM can increase safety and change culture, attitudes and be­hav­ior (33, 35). The Joint Commission ­adopted the Situation, Background, Assessment and Recommendation (SBAR) technique as industry best practice for standardized communication in health care (36). Its goal is to structure critical information primarily for spoken delivery and to help caregivers function as effective team members while establishing a culture of quality, patient safety, and high reliability. SBAR promotes quality and patient safety, primarily b ­ecause it helps individuals communicate with each other based on a shared set of expectations. Staff and physicians use SBAR to share patient information in a clear, complete, concise and structured format; cess improves communication efficiency the pro­ and accuracy. One impor­tant aspect of SBAR is its inherent recognition of the expertise of nurses and other care providers so that they are encouraged to assertively make recommendations to physicians, thus facilitating a nonhierarchical structure. Communication is about more than exchanging information; it’s about understanding the emotions and intentions b ­ ehind the information. Effective communication is a two-­way street. It’s not only how a person conveys information so that it is received and understood by o ­ thers in exactly the

way intended, but it’s also how a person listens to gain the full meaning of what is being said and to make ­others feel heard and understood. Communication combines a set of skills including nonverbal communication, engaged listening, stress management in the moment, the ability to communicate assertively, and the capacity to recognize and understand the emotions of all parties engaged in the communication. Effective communication is the glue that helps providers deepen their connections to patients and families, and to improve teamwork, decision making, and prob­ lem solving. It enables the communication of even negative or difficult messages without creating conflict or destroying trust. Communication can be successfully implemented in the pro­cess of health care and can result in more efficient and effective strategies to support the patient safety movement, preserve trust, and foster a healthy relationship between providers and patients in postiatrogenic care.

References 1. Institute of Risk Management, Online Resource Center, https://­www​.­theirm​.­org​/­knowledge​-­and-re​ sources​/­online​-­resource​-­centre​.­aspx. Accessed June 26, 2017. 2. Rasmussen J, Pejtersen AM, Goodstein LP. Cognitive Systems Engineering. New York, NY: John Wiley & Sons; 1994. 3. Dauer EA, Marcus LJ, Payne SM. Prometheus and the litigators: a mediation odyssey. J Leg Med. 2000;21(2):​159–186. 4. Reason J. Managing the Risks of Orga­nizational Accidents. Aldershot, UK: Ashgate; 1997. 5. Heffernan, M. The Health Care Quality Improvement Act of 1986 and the National Practitioner Data Bank: the controversy over practitioner privacy versus public access. Bull Med Libr Assoc. 1996;84(2):​263–269. 6. Brennan TA, Sox CM, Burstin HR. Relation between negligent adverse events and the outcomes of medical-­malpractice litigation. N Engl J Med. 1996;335(26):​1963–1967. 7. Studdert DM, Mello MM, Gawande AA, et  al. Claims, errors, and compensation payments in medical malpractice litigation. N Engl J Med. 2006;​354(19):​2024–2033. 8. Mello MM, Gallagher TH. Malpractice reform—­ opportunities for leadership by health care institutions and liability insurers. N Engl J Med. 2010;​ 362(15):​1353–1356. 9. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is ­Human: Building a Safer Health System.

References  / 27 Institute of Medicine. Washington, DC: National Acad­emies Press; 2000. ­ eople 10. Vincent C, Young M, Phillips A. Why do p sue doctors? A study of patients and relatives taking l­egal action. Lancet. 1994;343(8913):​ 1609–1613. 11. Brennan TA, Leape LL, Laird NM, et  al. Incidence of adverse events and negligence in hospitalized patients—­results of the Harvard Medical Practice Study  I. N. Engl J Med. 1991;324(6):​​ 370–376. 12. Boothman R, Imhoff SJ, Campbell DA. Nurturing a culture of patient safety and achieving lower malpractice risk through disclosure: lessons learned and f­uture directions. Front Health Serv Manage. 2012;28(3):​13–27. 13. Kachalia A, Kaufman SR, Boothman R, et al. Liability claims and costs before and a­ fter implementation of a medical error disclosure program. Ann Intern Med. 2010;153(4):​213–221. 14. Gotbaum  R. Interview with Richard Boothman on a medical-­error disclosure program in Michigan. N Engl J Med. 2006;354(21):​2205–2208. 15. University of Michigan Health System. The Michigan model: medical malpractice and patient safety at UMHS. www​.­uofmhealth​.­org​/­michigan​ -­model​-­medical​-­malpractice​-­and​-­patient​-­safety​ -­umhs#summary Accessed June 26, 2017. 16. Rosner F, Berger JT, Kark P, et al.; Committee on Bioethical Issues of the Medical Society of the State of New York. Disclosure and prevention of medical errors. Arch Intern Med. 2000;160(14):​​ 2089–2092. 17. Asnani MR.  Patient-­ physician communication. West Indian Med J. 2009;58(4):​357–361. 18. Clark, PA. Medical practices’ sensitivity to patients’ needs: opportunities and practices for improvement. J Ambul Care Manage. 2003;26(2):​​ 110–123. 19. Wanzer, MB, Booth-­ Butterfield M, Gruber  K. (2004). Perceptions of health care providers’ communication: relationships between patient-­ centered communication and satisfaction. Health Commun. 2004;16(3):​363–384. 20. Duffy FD, Gordon GH, Whelan G, et al. Assessing competence in communication and interpersonal skills: the Kalamazoo II report. Acad Med. 2004;​ 79(6):​495–507. 21. Heisler M, Bouknight RR, Hayward RA, et  al. The relative importance of physician communication, participatory decision-­making, and patient understanding in diabetes self-­management. J Gen Intern Med. 2002;17(4):​243–252. 22. Renzi C, Abeni D, Picardi A, et al. ­Factors associated with patient satisfaction with care among dermatological outpatients. Br J Dermatol. 2001;​ 145(4):​617–623.

23. A Roadmap for Removing Barriers to Disclosure, Apology and Offer in Mas­sa­chu­setts (Funded by AHRQ Planning Grant #R21 HS19537-01) Executive Summary April  2012. www​.­massmed​.­org​ /­a dvocacy​/­s tate​-­a dvocacy​/­a​-­r oadmap​-­f or​ -­removing​ -­barriers​-­to​-­disclosure,​ -­apology​-­and​ -­offer​-­in​-­massachusetts​-­executive​-­summary​-(pdf). Accessed June 26, 2017. 24. Lerner MJ. The desire for justice and reactions to victims. In: McCauley J, Berkowitz L, eds. Altruism and Helping Be­hav­ior. New York, NY: Academic Press; 1970. 25. Marx  D. Discipline: the role of rule violations. Ground Effects. 1997;2:1–4. 26. The Honorable James McRuer, Ontario Royal Commission Inquiry into Civil Rights (Toronto: Queen’s Printer, 1968, 1969, 1971). On self-­ governing professions and occupations, see chap. 79. The granting of self-­government is a del­e­ga­ tion of legislative and judicial functions that can be justified only as a safeguard to public interests. 27. Schutz  A. Some equivocations in the notion of responsibility. In: Brodersen A, ed. Collected Papers II: Studies in Social Theory. The Hague, Netherlands: Nijhoff; 1964:274–276. 28. The Management Oversight and Risk Tree (MORT). International Crisis Management Association. Retrieved October 1, 2014. 29. The Joint Commission. 2015 comprehensive accreditation manual for hospitals: the patient safety systems chapter. CAMH Update 2, January 2016. www​.­jointcommission​.­org​/­assets​/­1​/­6​/CAMH​ _­24​_­SE​_­all​_­CURRENT​.­pdf. Accessed June  26, 2017. 30. Marx D. Maintenance error causation. Washington, DC: Federal Aviation Authority Office of Aviation Medicine; 1999. 31. Weick KE. Orga­nizational culture as a source of high reliability. Calif Manage Rev. 1987;29(2):​​ 112–127. 32. Nasca T, Weiss KB, Bagian JP. Improving clinical learning for tomorrow’s physicians. N Engl J Med. 2014;370(11):​991–993. 33. Goldmann  D. System failure versus personal accountability—­the case for clean hands. N Engl J Med. 2006;355(2):121–123. 34. The Joint Commission. Sentinel events. CAMH Update 2, January  2016. https://­www​.­joint​commission​.­org​/­sentinel​_­event​.­aspx. 35. Weick KE, Sutcliffe KM, Obstfeld D. Organ­izing for high reliability: pro­cesses of collective mindfulness. Res Organ Behav. 1999;21:23–81. 36. Dunsford J. Structured communication: improving patient safety with SBAR. Nursing for W ­ omen’s Health 2009;13(5):384–­390. http://­onlinelibrary​ .­wiley​.­com​/­doi​/­10​.­1111​/­j​.­1751​-­486X​.­2009​.­01456​ .­x​/­abstract. Accessed June 26, 2017.

CHAPTER 4

Iatrogenicity from the Patient’s Perspective Jeanne M. Dobrzynski

“The golden rule of medicine is ­simple but usually not easy: Put yourself in your patient’s place.” Richard B. Gunderman, MD, PhD(1)

Physicians have an ethical duty to their patients, who trust them and rely on them for their well-­being. Prior experiences related to adverse outcomes color the physician-­ patient interaction. Patient characteristics such as age, gender, education, use of the Internet, and frailty are key ­factors influencing the occurrence and perception of ­actual or potential iatrogenic adverse consequences. In the past, patients (especially older ones) did not question their doctors’ recommendations or treatments, but younger patients want to be involved in their own care (2). The Internet has made it easy for them to research symptoms, treatments, and potential side effects of treatments. It can also be a source of fear, for example, when an individual makes a self-­ diagnosis that may result in avoidance of medical care. This chapter specifically addresses the issues of physician-­patient communication, confidentiality, and adverse drug reactions.

PHYSICIAN-­PATIENT COMMUNICATION An impor­tant prob­lem under­lying the current increase in malpractice cases and higher malpractice premiums is the lack of appropriate physician-­patient communication. Patients complain that physicians do not listen, do not talk openly, and do not warn them about short-­and long-­term risks, especially for infants. More to the point, some patients state that physicians attempt to mislead them and o ­ thers have the impression that doctors desert them or, more often, are unavailable. Compounding this prob­lem is the common perception that physicians do not understand the patient’s perspective. The above concerns underscore that good communication is a cornerstone of the physician-­patient relationship. Studies have shown that the four main reasons prompting patients to file malpractice lawsuits are (a) a desire to prevent similar adverse events from happening to other ­people; (b) a desire for financial compensation for costs incurred as well as for pain and suffering; (c) a desire for an explanation from the physician on how the complication happened; and (d) a wish to

Confidentiality / 29 make the physician accountable for his or her m ­ istake. Frank communication between physician and patient prior to treatment and admission of errors may go a long way in decreasing enmity and the number of malpractice suits. Physicians who show empathy and re­spect, answer all questions, and are sensitive to the individual patient’s circumstances are more successful. Aligning the expectations of patient and doctor regarding therapy is essential; it can be accomplished when the physician carefully outlines treatment options, explains why one approach is preferrable, and gives the patient an opportunity for shared decison making. Patients should read consent forms carefully, but good physicians ­ will explain all potential complications to the patient and ­family during the informed consent pro­cess and discuss frankly any complications that may occur. More impor­ tant, physicians should educate patients about symptoms and signs that may suggest a complication has occurred and how to recognize and report any adverse occurrence in a timely fashion. lying the The emotional subtext under­ physician-­ patient relationship colors the discussion and the quality of care as perceived by the patient. When an adverse outcome occurs, a clear conversation, including an explanation of what happened and the reasons for it along with the physician’s admission of error if one occurred, is desirable. This conversation can decrease the chance of the patient filing a malpractice suit, but, in addition, it preserves the patient’s trust in the physician for ­future interactions. Successful interventions are as vital to healthcare facilities and insurance companies as they are to individual physicians and other healthcare providers. However, the physician should clarify at the onset that an intervention devoid of prob­lems cannot be guaranteed. When an adverse outcome or a less-­than-­ optimal outcome occurs, the physician should recognize his or her own anxiety and, more impor­tant, the patient’s fear. A physician should express regret but avoid blaming ­others, and should inform the patient and the ­family of the next treatment to amiolorate the situation (2). In cases of adverse occurrences, patients and their families may suffer not only medical injury but also financial losses and psychological trauma. In some instances, patients experience

prolonged distress that may include the development of post-­traumatic stress disorder. In other instances, the financial losses are catastrophic. Many professional codes, from that of Hippocrates to t­hose of the American Medical Association and the Center for Medicare and Medicaid, emphasize the ethical responsibility of physicians and the obligation to have a defined greivance pro­cess (3,4). With the current emphasis on patient satisfaction and marketing of physician practices and healthcare facilities, addressing iatrogenic injuries in addition to other quality-­of-­ life issues such as parking and meals has become impor­tant. As stated earlier, open and early disclosure of all adverse events is crucial for resolving disagreements, decreasing the possibility of litigation, and maintaining the physician-­patient relationship. Ways in which the current situation may be improved include consideration of humanistic perspective and compassion in the se­lection of applicants to medical schools and residency programs; emphasis on compassion and dedication in healthcare education programs at all levels; and fostering of more person-­to-­person interaction with patients in the healthcare system (1).

CONFIDENTIALITY Patients understand that recording accurate medical information, including past history as well as information pertaining to their current visit, is essential for good patient care. This came to the forefront with the approval by the Governing Board of the National Research Council of the Institute of Medicine report in 1999 that was published in 2000. (5). In an anonymous survey of 1,126 internists and internal medicine subspecialists, 59% noted questionable reporting of patient information and documentation in the medical rec­ord (6). More than 80 countries have comprehensive laws for health data protection. All data collected should be for a stated purpose and an individual’s data should not be disclosed to other indi­ nless authorized. Rec­ viduals or organ­izations u ords should be accurate and deleted when they are not needed for the purpose they w ­ ere collected, and some data should not be collected. In the United States, the Health Insurance Portability and Accountability Act (HIPAA), enacted by

30  /  Iatrogenicity from the Patient’s Perspective the U.S. Congress in 1996, states that individual identifiable health information should be protected by the individual’s privacy rights and disclosure of such information should be ­ either authorized or required by law. It includes financial, and on occasion civil and criminal, penalties for unauthorized release of medical rec­ords. Individuals should have access to their own data. Other information such as credit reports is not protected in the United States, although partial regulations are available. As a result of HIPAA, patient confidentiality is taken very seriously by physicians as well as healthcare organ­izations. However, some patients are confused about the ethical, ­legal, and practitant, cal limits of confidentiality. More impor­ some patients may not fully understand the meaning of confidential, and almost all patients are confused about what medical information should be protected and the remedies for unauthorized disclosure. Patients may underestimate or overestimate the level and method of confidentiality protection, especially as it pertains to disclosing information to other healthcare professionals. In some instances, fear of confidentiality breaches may lead to avoidance of therapy altogether. This is not uncommon in the field of HIV as well as among adolescents, who fear disclosure to their teachers or parents. Also, a fear of disclosure to employers (current or ­future) is a  major concern on the part of patients. ­There are many regulations to protect confidentiality throughout the United States, but in practice patients care primarily about the local implications in their own circumstances and as they pertain to their own environment. Some patients have gone to the extreme in suggesting that health professionals not live in the same community as their patients. Many patients assume that physicians discuss their cases with each other and with nursing staff well beyond what is necessary for patient care and, more crucial, that the physicians may share information with their patients’ relatives or talk about them during social gatherings. They are afraid of the potential consequences if confidential information travels to their friends, relatives, teachers, and employers. Patients want any medical information collected or shared to be used only for their treatment rather than for administration, research, or other purposes. Patients usually do not want

information sent to health insurance companies ­unless absolutely necessary. For the patient, the only reason to collect medical information is to provide excellent medical care. The most malignant potential outcome of confidentiality breaches is that patients forgo all treatment, change their history, or withhold information, especially of past illnesses. This is more common among vulnerable subsets such as ­mental patients, ­those suffering from depression, battered ­women, adolescents, and patients with HIV. Patients try to protect themselves more than appropriate b ­ ecause they do not know the current state of confidentiality rules and legislation. Almost uniformly, patients do not agree to healthcare providers sharing information with doctors who are not involved in their healthcare or with ­family or employers. Adolescents, in par­ tic­u­lar, are afraid of disclosure of their illness to ­family, peers, and teachers. With re­spect to HIV, patients prefer anonymous testing with no link between the test and the individual’s personal information. They ­favor it over confidential testing, in which a healthcare provider knows the results of the test and the individual to whom it pertains (7). In summary, patient confidentiality is of utmost importance to patients, healthcare providers, and healthcare organ­ izations. Further clarification and education of all parties w ­ ill provide benefits to all.

ADVERSE DRUG REACTIONS Adverse reactions to marketed drugs result in hundreds of thousands of hospital admissions annually and may result in minor discomfort, serious physical and psychological symptoms, addiction, or death. Patients experience the adverse events from their own perspectives, and they attribute the adverse events to the medi­cation used, trials did not even in cases where randomized ­ show t­hose adverse effects. Healthcare providers, on the other hand, have a more objective view of the relationship between an adverse event and medi­cation, and they consider some of them unrelated to the medi­ cation. Patients may feel that their points of view are not appreciated, which underscores the need for focused, proactive education of physicians in preventing misunderstandings as well as real adverse events.

Adverse Drug Reactions  /  31 Patients may become aware of adverse cation events or adverse effects of given medi­ classes through tele­vi­sion commercials, the Internet, or discussions with f­ amily and friends. They may know that clinical t­ rials in which a low risk of adverse effects was reported ­were carried out among participants who do not represent the public at large, especially individual subsets of patients such as the el­derly or ­those with specific ge­ne­tic polymorphisms. Many patients are aware of the relationship between clinical trial leaders and the phar­ ma­ ceu­ ti­ cal industry, which may introduce unconscious bias in describing relevant adverse events. On the other hand, publicity surrounding individual cases of adverse events due to pharmacological agents can cause patients to be concerned about taking drugs, even when an adverse event is rare or ­there is no proof of a connection between drug and event. Adverse events are more likely to occur among ­those using excessive amounts of alcohol, during dehydration or malnutrition, or in the very old. Patients may request a careful and well-­ planned withdrawal of successive medi­cations in order to identify the culprit of an adverse event. The relationship of statins to musculoskeletal complaints is a current example of the dif­fer­ent perceptions of adverse events from the point of view of patient versus that of clinical trialist or physician. Randomized clinical t­rials have shown no marked excess of musculoskeletal complaints. On the other hand, such complaints occur in up to 30% of patients who take statins. The complaints have been acknowledged by the Food and Drug Administration (FDA), which recently approved antibodies to PCSK9 for patients who do not tolerate statins and require additional lowering of LDL cholesterol. The product insert does not specify that t­here is proof of intolerance in patients who cannot increase the statin therapy before they are candidates for antibody prescription. The prob­lem with adverse effects from medi­ cations is confounded by the prob­lem of polypharmacy, in which the number of interactions increases with the number of medi­cations used. It has been estimated that approximately 2.8% of hospital admissions are due to drug to drug interactions (DDI) (8). Drug to drug interactions are cations address more common when the medi­ more than one disease and their effect is influenced by both the type of medi­cation and the

characteristics of the patient. Patients are not interested in understanding specific pharmacokinetic and pharmacodynamic details, detoxification and elimination of the medi­ cations, and time course of serum concentrations, but they are interested in getting specific information on the interactions to expect from their own therapies. Tranquilizers, hypnotics, and sedatives as well as opiates are specific issues in which patients need education and counseling about the risks of addiction. Recently, emphasis has been placed on avoidance of opioid overdose. ­There has been a marked increase in such overdoses, which have become one of the leading ­ causes of injury-­ related deaths. States such as Ohio have issued guidelines for the management of acute pain, which include a plan for alleviating pain or discomfort with minimum risk. Nonpharmacologic therapies have been found useful in many instances and patients would like to know and understand the use of them (9). They include ice packs, heat packs, bracing, splinting, massage therapy, and, for longer duration pain, acu­punc­ture, biofeedback, and meditation. A recent article describes how tai chi provided similar benefits as physical therapy to patients with osteoarthritis of the knee (10). In a given year, about 100 million adults are affected by chronic pain, for a total cost exceeding $600 billion, a number higher than the cost of heart disease and cancer combined. The estimated total cost of back pain in the United States ($200 billion) is about the same as the gross domestic product of Portugal. The cost of taking care of back prob­lems more than doubled between 1987 and 2000, and most of the increase was due to increased prevalence of back pain (11). Pregnant w ­ omen are very careful to avoid medi­cations, alcohol, and over-­the-­counter drugs as well as excessive weight gain for fear of harming the fetus. It is impor­tant for healthcare providers to describe the known and unknown risks of any medi­cations necessary for the well-­being of the m ­ other (12). Patients know that physicians now practice in groups and may be employees of large organ­ izations. They also know that in some reimbursement plans, appropriate utilization of therapeutic procedures and medi­cations may be curtailed for financial reasons. At the other end of the spectrum, productivity incentives may result in

32  /  Iatrogenicity from the Patient’s Perspective overutilization (13). Also, patients may be afraid that their insurance w ­ ill be terminated without cause, a situation that discourages complaints about quality of care. Patients want the physician responsible for their care to be the person obtaining consent for surgical procedures, and the person responsible for prescribing medi­cations to be the one explaining the benefits and risks to them. Also, patients do not want their care to be dictated by insurance companies rather than their personal physician. This becomes pivotal when preapproval is required for expensive diagnostic testing or medi­cations. The importance of iatrogenicity from the patient’s perspective is emphasized by the existence of the Association of Patient Experience and its publication, Journal of Patient Experience (14). They focus on cost of care, quality, access, and expectation for transparency, con­ve­nience, and personalized medicine. Patients want access to their own health information and expect a shared decision-­making plan. Patients are aware that, in many instances, patient-­level data are ­housed in dependable and secure cloud applications. However, the confidentiality, integrity, availability, reliability, and safety of the information in ­these systems is not optimal and, more impor­tant, the data security applications have their own life cycle of creating, storing, using, sharing, archiving, and then destroying the data. Breaches of confidentiality can occur at any of ­these six points in the data security life cycle. Data security is vital during use of cloud applications, but also during storage. Among the techniques that have been proposed to ensure data security are public ­ auditing, use of eraser-­coded data, detection of use, and audit violations to identify the person who is accountable (15). Patients are also aware that technology companies collect health-­related data, for example, through wearable fitness devices and health-­ related Internet searches. Patients want to remain in control of their personal health data. When information is collected about individuals, health data must be where the line is drawn (16). In summary, patients expect a physician-­ patient relationship with open, frank communication, shared decision making, and early and honest disclosure of all adverse events of their ­

therapy. They want personal information limited to what is necessary for addressing their clinical issue, and they do not want data shared with healthcare professionals or ­others uninvolved in their care. They also expect doctors to explain diagnoses and treatment options in plain language. Moreover, they want to feel that their physician genuinely cares about them on a personal level.

References 1. Gunderman RB. Ethics and professionalism: the patient’s perspective. J Am Coll Radiol. 2008;5(5):​ 612–615. 2. Huntington B, Kuhn N. Communication gaffes: a root cause of malpractice claims. Proceedings BUMC. 2003;16(2):157–161. 3. Medicare and Medicaid programs: hospital outpatient prospective payment; ambulatory surgical center payment; hospital value-­based purchasing program; physician self-­referral; and patient notification requirements in provider agreements. Final rule with comment period. Fed Regist. 2011;​ 76:74122–584. 4. Wynia MK, Kishore SP, Belar CD. A unified code of ethics for health professionals: insights from an IOM workshop. JAMA. 2014;311(8):799–800. 5. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is H ­ uman: Building a Safer Health System. Institute of Medicine. Washington, DC: National Acad­emies Press; 2000. 6. Sharma R, Kostis WJ, Wilson AC, et al. Questionable hospital chart documentation practices by physicians. J Gen Intern Med. 2008;23(11):1865– 1870. 7. Sankar P, Moran S, Merz JF, Jones NL. Patient perspectives on medical confidentiality: a review of the lit­er­a­ture. J Gen Intern Med. 2003;18(8):​ 659–669. 8. Wiggins BS, Saseen JJ, Page RL 2nd, et al. Recommendations for management of clinically significant drug-­drug interactions with statins and select agents used in patients with cardiovascular disease: A Scientific Statement from the American Heart Association. Circulation 2016;134(21):​e468–­e495. 9. Ohio Guideline for the Management of Acute Pain Outside of Emergency Departments. http://­ mha​.­ohio​.­gov​/­Portals​/­0​/­assets​/­Initiatives​/­GCOAT​ /­Guidelines​-­Acute​-­Pain​-­20160119​.­pdf. Accessed April 21, 2017. 10. Wang C, Schmid CH, Iversen MD, et al. Comparative effectiveness of tai chi versus physical therapy for knee osteoarthritis: a randomized trial. Ann Intern Med. 2016;165(2):77–86. 11. Holmes D. The pain drain. Nature. 2016;​535(7611);​ S2–­S3.

References / 33 12. Kieve  M. Adverse drug reactions (ADRs): a 14. Journal of Patient Experience. SAGE journals. http://​ journals​.­sagepub​.­com​/­home​/­jpx. patient perspective on assessment and prevention in primary care. Quality in Primary Care. 2007;​ 15. Weber I, Nepal S, Zhu L. Developing dependable and secure cloud applications. IEEE. 2016;30–32. 15:221–227. 13. Poses RM, Smith WR. How employed physicians’ 16. Wilbanks JT, Topol EJ. Stop the privatization of  health data. Nature. 2016;535(7612):345– contracts may threaten their patients and profes348. sionalism. Ann Intern Med. 2016;165:55–56.

CHAPTER 5

A Naturopathic Perspective on Iatrogenesis Christie Fleetwood

IATROGENESIS: DEFINITIONS AND INTRODUCTIONS Iatrogenic disease literally means “illness caused by medical exam or treatment” (1). In the United States, iatrogenicity is the third leading cause of death, with preventable harm killing between 210,000 and 440,000 patients each year (2). Some estimates are as high as 700,000 (3,4). This means that harm—up to and including death—­has occurred, even though the doctor ordered the right prescription or procedure for the right patient with the right directions for use and the patient took the medicine or had the procedure done correctly. Iatrogenicity is ­doing all the right ­things, according to conventional medicine, yet having a poor outcome. In other words, mainstream medicine ranks just b ­ ehind cancer and cardiovascular disease as a top killer in this country. The author of this chapter is not a conventional medical or osteopathic doctor (MD or DO); rather I’m a naturopathic doctor (ND). I chose to pursue my doctorate in naturopathic medicine ­after working for a de­cade as a retail pharmacist in central ­Virginia. As a pharmacist, I witnessed firsthand disenfranchised consumers of conventional medicine who, despite being compliant with drug therapy, ­weren’t getting better. In the short term, with the use of pain medi­cations for a broken arm or a course of antibiotics for an infection, p ­ eople did improve. But when symptom control for the acute situation was prescribed for the long term, ­people too often got worse. For example, Mr. Jones came into the pharmacy with his prescription for a commonly prescribed beta-­blocker for hypertension. A compliant patient, he faithfully refilled his prescription monthly. His blood pressure readings ­were better initially. The following year, however, he returned ­after his annual exam and blood work with two prescriptions: the first for a slightly increased dose of his beta-­blocker, and the second for a lipid-­lowering agent. The following year, he brought in four prescriptions: the beta-­blocker in an even higher dose, the lipid-­lowering agent, a sleep aid, and an antidiabetic drug. What happened? When prescribers consider only the symptoms—­which are a consequence of the disease pro­cess, not the cause—­and no education is provided to individuals on how they might change their lifestyle to correct the under­lying imbalance (most often the cause), well-­chosen phar­ma­ceu­ti­cal entities often push the patients into a secondary disease pro­cess. This is called iatrogenic disease. Drugs can cause disease ­either through nutrient depletions caused by the drug itself or through direct and/or indirect mechanisms of action exerted by the drug on

Iatrogenesis: Definitions and Introductions  /  35 the body. An example of a drug causing a nutrient depletion, which then can cause a second disease state, is a statin depleting coenzyme Q10. CoQ10 is a vital piece of the mitochondrial electron transport chain, which makes energy for the cell. Without coQ10, energy production within the cell declines, which can precipitate muscle aches and fatigue. Hyperhomocysteinemia is an in­de­pen­dent risk ­factor for cardiovascular disease as well as other disease states. Diseases such as coronary artery disease, stroke, atherosclerosis, ischemic heart disease, early onset vascular disease, pediatric atherosclerosis, myo­car­dial infarction, and aneurysm are all increased in ­people with homocysteine levels elevated above 15  umol/1. To operate healthily, the homocysteine cycle is utterly dependent on specific nutrients: vitamins B2, B6, B12, and folate. Some drugs, notably niacin, fenofibrate, and furosemide, cause elevations in homocysteine. Other drugs can increase homocysteine ­because of depletions of one or more of the necessary nutrients—­another route to iatrogenicity. A focus on folate is also warranted. ­There suddenly seems to be an abundance of patients with inherited defects in methylation pathways (MTHF­R, homo-­or heterozygotes), or are ­there? Perhaps it is r­ eally the insidious changes in foods: the stripping out of dozens of natu­ral nutrients to prolong product shelf life, with the addition (“enriching pro­cess”) of four or five of the least expensive synthetic substitutes. Foods that are naturally rich in folate inherently contain plenty of methyl groups, so methylation defects go undetected in ­ people who have the defects but continue to eat real food. Foods that are “enriched” with folic acid do not contain the necessary methyl groups and, as a consequence, ­those who have defects are being diagnosed with numerous diseases. Conventional medicine is beginning to catch on to the basics of nutrition. The following appeared in the Journal of the American Medical Association: . . . ​insufficient vitamin intake is apparently a cause of chronic diseases. Recent evidence has shown that suboptimal levels of vitathose causing defimins, even well above ­ ciency syndromes, are risk f­actors for chronic diseases such as cardiovascular dis-

ease, cancer, and osteoporosis. A large proportion of the general population is ­ apparently at increased risk for this reason (5). Returning to the subject of cardiovascular-­ specific diseases due to proper administration of conventional medicine, let’s look at direct and indirect effects. An example of a direct effect is a beta-­ blocker disrupting normal blood glucose regulation, causing type 2 diabetes. An example of an indirect effect is when the same beta-­ blocker precipitates anxiety or depression (due to the deviation away from normal blood glucose). A nutritional depletion that can occur with beta-­blockers involves the naturally secreted hormone, melatonin. This wasting effect may well explain the sleep disturbances, including nightmares, that some beta-­blocker users experience. Despite, or perhaps ­ because of, the multitudes of books published on the “best” way to eat, exercise, and sleep for any number of diseases, it is no doubt confusing for healthcare providers with l­ittle to no education about nutrition or lifestyle counseling to provide useful information to patients. Rather, it’s easier to prescribe drugs for the current constellation of symptoms. This route takes far less time, which accommodates insurance-­and administrator-­ driven demands for greater productivity in less time. Yet the United States continues to become sicker at a faster rate. For the first time in the country’s history, ­children are not expected to live as long or as well as their parents (6). The armed forces are turning young p ­ eople away b ­ ecause of obesity and its associated chronic health complaints, causing a potential security issue for the nation (7). Americans make up 5% of the world’s population but top the chart of obesity, consuming an excess of calories that could feed 80 million starving p ­ eople elsewhere daily (8). This is a large, lem. Although this book multifactorial prob­ focuses on drugs and medical procedures causing cardiovascular disease, it is impor­tant to keep the bigger picture in mind ­ because more must be done. Reducing iatrogenicity is a good start. Because this chapter offers an alternative ­ perspective on iatrogenesis and cardiovascular disease, it focuses on the frequently encountered cardiovascular triad in patients: high blood pressure, high cholesterol/triglycerides, and high blood glucose (which can lead to type 2 diabetes).

36  /  A Naturopathic Perspective on Iatrogenesis It also pres­ents a naturopathic approach to treating p ­ eople with t­ hese issues. ne­ tic expression cause this triad? Does ge­ What ­else do we get from our parents other than genes? Perhaps we could look at acquired habits and values and opinions around vari­ous foods and exercise—in short, lifestyle. Parents raise their ­children in the same environments in which they ­were raised u ­ nless they make conscious decisions to do other­wise. Socioeconomic status and lifestyle choices set the stage for chronic disease. The current design of the conventional medical system is the “pill for ­every ill” mindset. Often, the cause of one or more ele­ments of the cardiovascular triad is iatrogenic—­caused by the drug initially prescribed.

HYPERTENSION Drugs That Can Cause Hypertension Corticosteroids: betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, fluticasone, mometasone, clobetasol. Nutrients depleted: calcium, chromium, folic acid, magnesium, potassium, selenium, beta carotenes, zinc, vitamins B6, B12, C, D, and K. Antidepressants Tricyclic antidepressants: amitriptyline, nortriptyline. Nutrients depleted: coQ10, vitamin B2 (riboflavin), sodium. Select norepinephrine reuptake inhibitors (SNRIs): duloxetine, venlafaxine, desvenlafaxine. No known nutrient depletions. Aty­pi­cal antidepressants: bupropion. Nutrient depleted: melatonin. Nonsteroidal anti-­inflammatory drugs (NSAIDs): celecoxib, aspirin, diclofenac, naproxen, meloxicam, ibuprofen. Nutrients depleted: folic acid, iron (secondary to gastrointestinal irritation/bleeding), melatonin, zinc (increased excretion), vitamin C. Hormones: ethinyl estradiol, conjugated estrogens, vari­ous progestins. Nutrients depleted: folic acid, calcium, magnesium, selenium, zinc, tyrosine, vitamins B1, B2, B3 (variable), B6, B12, and C.

Decongestants: alpha-1 agonists phenylephrine, oxymetazoline, tetrahydralazine, xylometazoline, methoxamine, pseudoephedrine. No known nutrient depletions. Triptans, ergotamines (for migraine headaches); triptans include sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan. Ergotamines are rarely used any longer. No known nutrient depletions. Central ner­vous system stimulants ­ egal: caffeine, attention deficit with or L without hyperactivity disorder (ADD/ ADHD) drugs (methylphenidate, mixed amphetamines, dextroamphetamine, lisdexamphetamine, dexmethylphenidate), phentermine. Nutrient depleted: tyrosine. Illegal: methamphetamine, cocaine, phencyclidine (PCP), anabolic ste­roids. Immunosuppressants: cytokine inhibitors (infliximab, etanercept, adalimumab, abatacept, omalizumab, ranibizumab, ustekinumab); agents to decrease the chance of transplant rejection (cyclosporine, everolimus); agents used for multiple sclerosis (fingolimod, dimethyl fumarate, glatirimer acetate); disease-­modifying antirheumatic drugs (DMARDs); all classes of chemotherapeutic agents. Nutrients depleted depend on agent. Acetaminophen. Nutrients depleted: coQ10, glutathione. Bronchodilators: beta agonists albuterol, salmeterol, formoterol. Nutrients depleted: potassium; possibly calcium, magnesium, phosphorus.

Drugs to Treat Hypertension The following are the drugs often prescribed to treat hypertension and the secondary cardiovascular disease states they may cause. Thiazide diuretics (for example, hydrochlorothiazide, or HCTZ): high blood sugar (potentially leading to type 2 diabetes), high cholesterol, high triglycerides. Nutrients depleted: coQ10, magnesium, sodium, potassium, zinc, vitamin D, calcium, phosphorus. Note: Given the nutrients wasted by the very commonly prescribed thiazide diuretics, what next disease pro­cess might be diagnosed?

Hypertension / 37 Arrhythmias secondary to potassium loss? Depression secondary to vitamin D depletion? Asthma secondary to magnesium depletion? Fatigue and muscle pain secondary to coQ10 loss? Immune system deficiencies secondary to insufficient zinc? Osteoporosis secondary to lack of calcium and phosphorus? The potential ­here is enormous for iatrogenicity, misdiagnoses, and poor management of patients—­but also for education to patients and providers alike on the need for real food and ­water, exercise, healthy relationships, restful sleep, meaningful employment, and so on. True prevention of disease and better health outcomes require a change in how the patient lives, rather than a drug to mask the clues to the under­lying prob­lem.

Loop diuretics (such as furosemide): high blood sugar, high cholesterol, high triglycerides. Nutrients depleted: calcium, magnesium, potassium, sodium, zinc, folic acid, coQ10, mixed tocopherols, phosphorus, vitamins B1, B6, B12, and C.

Angiotensin-­converting enzyme inhibitors (ACE inhibitors: lisinopril, benazepril, captopril, enalopril, ramipril, quinopril): chest pain, heart attack, stroke, pulmonary embolism, arrhythmias. As with potassium-­sparing diuretics, ACE inhibitors and their angiotensin receptor blocker (ARB) cousins can cause an accumulation of potassium, resulting in cardiac arrhythmias. Nutrients depleted: sodium, zinc. Angiotensin receptor blockers (ARBs: valsartan, losartan, irbesartan, olmesartan, candesartan): potassium accumulation can occur, precipitating cardiac arrhythmias. No known nutrient depletions. Beta-­blockers (atenolol, propranolol, bisoprolol, metoprolol, acebutolol, carvedilol, nevibolol, nadolol): chest pain, dyslipidemia, dysglycemia. Nutrients depleted: coQ10, melatonin, chromium. Calcium channel blockers (amlodipine, nicardipine, nifedipine, verapamil, diltiazem): fluid retention in the legs, feet, arms, or hands; heart throbbing or pounding; dizziness; heart attack; angina; arrhythmias; bradycardia; tachycardia; high blood glucose. Nutrient depletions: potassium, vitamin D.

Potassium-­sparing diuretics: While dif­fer­ent nutrients may be depleted, depending on the agent (triamterene, spironolactone, or amiloride), potassium may be increased. Potassium has a very narrow therapeutic win­dow; too much or too l­ittle Treating Hypertension can precipitate cardiac arrhythmias. Triamterene Naturopathically depletes calcium, folic acid, zinc, magnesium, phosphorus. No known depletions with spironoHow might a patient presenting with hypertension lactone. Amiloride may waste calcium, but may be treated by this naturopathic doctor? Treatment cause an increase in magnesium and zinc. would follow the Therapeutic Order (Figure 5-1)

What is the therapeutic order?

High force interventions Synthetic symptom relief

Suppress pathology Synthetic symptom control

A set of guidelines to help physicians completely Use of drugs to palliate resolve the patient’s symptoms and address the underlying cause while Natural symptom control using the least force safely possible. Use of natural substances to palliate

Naturopathic symptom relief Restore structural integrity to the body

Address physical alignment

Restore proper structural integrity

Aid damaged organ systems

Support & restore weakened systems

Stimulate the healing power of nature

Stimulate the self-healing mechanisms

Determinants of health

Aid regeneration of damaged organs

Recognize the Vis Medicatrix Naturae

Establish the foundation for optimal health

Identify and remove the obstacles to cure; assess the determinants of health

FIGURE 5-1 ​Therapeutic Order, Association of Accredited Naturopathic Medical Colleges (AANMC) poster

38  /  A Naturopathic Perspective on Iatrogenesis

BOX 5-1 ​Naturopathic Basics • Read labels. Avoid hydrogenated oils, trans fats, chemical sugar substitutes (examples would include Splenda/sucralose, Nutrasweet/aspartame, Sweet’N Low/ saccharin, Sweet One/acesulfame potassium, Equal/aspartame + acesulfame potassium. Stevia is outside of this list, as it is a sweet-­tasting plant that can easily be grown year round on a windowsill), nitrites/nitrates, artificial ingredients, high fructose corn syrup, sodium benzoate, and anything you cannot pronounce. Topically, avoid sodium lauryl/laureth sulfates, parabens, petrolatum, mineral oil, aluminum. • Adopt a ­whole foods diet, organic when pos­si­ble, locally grown in season. • Aim for five dif­fer­ent vegetables and two dif­fer­ent fruits daily, mixed colors. Choose red, orange, yellow, green, blue, purple, and black (olives, berries, currants, grapes). • If you eat beef, consume grass-­pastured beef only. • Best places to shop: farmers’ markets, community-­supported agriculture (CSA), Whole Foods, PCC, Trader Joe’s, natu­ral foods sections in local grocery stores. • Recognize potential for food allergies or intolerances. The Roman poet Lucretius said, “One man’s meat is another man’s poison,” meaning what is healthy for one person may not be so healthy for someone ­else. Once you know the foods that make up your “preferred fuel” or “medicine,” rotate them. This w ­ ill prevent the overuse of par­tic­u­lar enzymes needed to break down par­tic­u­lar foods, allow for greater plant nutrient ingestion (dif­fer­ent colors provide dif­fer­ent vitamins, minerals, and other plant nutrients), and ward off boredom at the kitchen ­table. • Avoid micro­wave use. • Sleep. The body can repair only while in parasympathetic ner­vous system dominance. In other words, you need to relax to heal. • Drink filtered ­water. Consume one-­third to one-­half your body weight in fluid ounces daily. Green and herbal teas count. • Exercise daily. Move your body ­every day, rain or shine, indoors or outdoors. “Start low, go slow.” • Every­thing is connected to every­thing ­else. What impacts one area of your life w ­ ill, to some degree, impact other areas of your life. • List the top three priorities in life. Does your lifestyle reflect t­ hose, in that order? If not, consider what steps are needed to align your lifestyle with your priorities.

and use the least amount of intervention needed to stimulate a response. 1. Remove obstacles to cure. • Teach the patient the “naturopathic basics”: eat real food, drink clean ­water, move your body, sleep, and live congruently. See Box 5-1 for a complete list. • Point out destructive be­hav­iors and relationships. A hard heart, holding a grudge, unforgiveness, and the sheer stress of destructive thought patterns and relationships can cause blood pressure to rise.

• Decrease sodium and sugar consumption. Most p ­ eople know that consumption of foods with a high sodium content, most notably pro­cessed foods, is linked to high blood pressure, but they may not know that too much sugar can also lead to high blood pressure (9). • Rule out thyroid dysfunction, as hypo-­or hyperfunction can cause hypertension. 2. Stimulate the healing power of nature. • Exercise, nutrition, and lifestyle counseling are key components of good health.

Dyslipidemia / 39 • Resupply depleted nutrients (coQ10, B vitamins, vitamin C, potassium, sodium, calcium, magnesium, zinc) if the patient is currently taking phar­ma­ ceu­ti­cal agents that cause depletion. 3. Strengthen weakened systems. • Exercise helps strengthen the entire cardiovascular system, throwing off the hormones associated with acute and chronic stress, which decreases blood pressure. • Meditation decreases the stress response, lowering blood pressure along with it. • Gratitude practices help reset the body from sympathetic ner­vous system dominance to parasympathetic. ­ ecause a figuratively hard • Forgive, b heart often corresponds with increased blood pressure. In the absence of positive change on the physical plane (when ­doing all the “right” ­things), consider the m ­ ental, emotional, and spiritual aspects of the patient. • Contrast hydrotherapy—­alternating hot and cold ­water applications while taking a shower—­provides alternating vasodilation and vasoconstriction, supporting healthy, normal vascular tone. 4. Correct structural integrity. • Exercise. For many ­people with elevated blood pressure, exercise is medicine. • Make the mind-­body connection. What we think and believe plays a role in how our physical bodies function. 5. Prescribe specific natu­ral substances for pathology. • Botanicals: hawthorn, lycopus, cactus, rauwolfia, garlic, dandelion, parsley, gallium. • Homeopathy specific to the patient. • Nutrient therapy: fiber, essential fatty acids, potassium/magnesium, calcium citrate. 6. Prescribe phar­ma­ceu­ti­cal agents for pathology if warranted for the short term (three weeks to six months while the patient incorporates lifestyle changes). Note: I’ve only done this once. I wrote a prescription for a combination antihypertensive agent for a new patient with emergent hypertension and

referred him to a cardiologist for immediate evaluation. The patient d ­ idn’t know he’d walked into a naturopathic clinic, but he recognized that he desperately needed to make significant changes to his lifestyle. Change can be scary, and he ­wasn’t yet ready for a lifestyle overhaul, so he got a prescription and a referral—­medicine congruent with his understanding of disease. In cases of urgent hypertension (or less extreme), I have found that naturopathic therapies are quite sufficient. However, if the patient is unwilling to make lifestyle changes, a referral to an appropriate prescriber—­usually a medical or osteopathic doctor—is in order for chronic disease management. I have no interest in managing a chronic disease when I know that it can be halted or even reversed.

DYSLIPIDEMIA Drugs That Can Cause Dyslipidemia Thiazide diuretics (see p. 36) Beta-­blockers (see p. 37) Estrogen/progestins (see p. 36) Corticosteroids (see p. 36) Retinoic acid (isotretinoin). Nutrients depleted: calcium, vitamin E. Bile acid sequestrants (cholestyramine, colestipol, colesevelam), fibrates (gemfibrozil, fenofibrate): both categories of cholesterol reducers can raise triglycerides. Nutrients depleted by bile acid sequestrants: carotenoids, folate, calcium, iron, magnesium, zinc, vitamins A, D, E, K, B2, B3, and B12. Nutrients depleted by fibrates: vitamins E and B12, copper, zinc, coQ10. Alcohol. Nutrients depleted: calcium, magnesium, melatonin, vitamin B12. Cigarette smoking. Nutrients depleted: vitamic C and E. Synthetic vitamin A and/or synthetic beta-­carotene can exacerbate the oxidative stress of smoking, potentially promoting lung cancer and cardiovascular complications. Antiretrovirals (zidovudine, lamivudine, darunavir, abacavir, emtricitabine, tenofovir). Depletions due to ­either disease state or drug therapy: carnitine, DHEA, vitamin B12, zinc.

40  /  A Naturopathic Perspective on Iatrogenesis Vitamin E, copper, folic acid, coQ10 can protect from certain adverse reactions. Lithium. Nutrient depleted: inositol. Anticonvulsants (gabapentin, phenytoin, carbamazepine, valproate, lamotrigine). Nutrients depleted depend on agent. Hyperhomocysteinemia can be a concern with valproate. Select serotonin reuptake inhibitors (SSRIs) (some). Nutrients depleted: sodium, melatonin (less so with fluoxetine), folic acid. Antipsychotics, both classical (haloperidol, thioridazine) and aty­pi­cal (risperidone, aripiprazole, quetiapine, olanzapine, ziprasidone). Nutrients depleted: vitamins B6 and E.

Drugs to Treat Dyslipidemia The following are the drugs often prescribed for dyslipidemia and the secondary disease states they may cause. Statins (atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin): blood sugar irregularities—to the point of a large class action suit against the maker of atorvastatin for its causal relationship with type 2 diabetes, especially in ­women. Nutrient depleted: coQ10. Fibrates (fenofibrate, gemfibrozil): chest pain, hypertension, peripheral edema, diabetes. Nutrients depleted: vitamins E and B12, copper, zinc, coQ10. Ezetimibe: severe muscle damage that can lead to kidney failure. No known nutrient depletions. Niacin: abnormal heart rhythm, high blood glucose, hyperhomocysteinemia, ­water retention, heart throbbing or pounding, orthostatic hypotension. No known nutrient depletions.

Treating Dyslipidemia Naturopathically The following is how a person with dyslipidemia might be treated in my office. 1. Remove obstacles to cure. • Teach the patient the “naturopathic basics”: eat real food, drink clean ­water, move your body, sleep, and live congruently. See Box 5-1 (p. 38) for a complete list.

• Weight loss, if necessary. Encourage the patient to find an enjoyable activity that requires about 65% maximum heart rate. An algorithm for determining the target heart rate: (220 minus age in years) times 0.65 equals desired beats per minute. For most ­people, this is between a fast walk and a slow jog. For weight loss, the activity at the target heart rate should be sustained for 40 minutes per day, 6 days a week. 2. Stimulate the healing power of nature. • Increase dietary fiber. Americans tend to eat about 10g of fiber per day when a target of 35g daily would be healthier (10). In addition to making us feel satisfied and full, fiber helps prevent vari­ous kinds of cancer and improves bowel health. • Consume all the colors of the rainbow, to provide the body with a variety of antioxidants and plant nutrients. • Exercise raises “good”, protective HDL and lowers “bad” LDL. • Use food as fuel and as medicine. ­There is no one right way to eat. I teach my patients which foods w ­ ill optimally fuel their bodies and become their medicine. This is tailored to each individual. The goal is to put effort and dollars into healthful food, rather than into prescriptions. 3. Strengthen weakened systems. • ­Because the liver is where cholesterol is made, I recommend consuming foods that support the liver: burdock, dandelion, garlic, onions, basil, beets, artichokes. While t­ hese foods ­don’t affect cholesterol production, they do help protect the liver from damage by oxidized cholesterol obtained through diet. • CoQ10, essential fatty acids (especially docosohexanoic acid, or DHA, and eicosopentanoic acid, or EPA, but note they may cause a transient rise in total cholesterol before a steady decline is seen). 4. Correct structural integrity. • Resolve anger issues and feelings of constraint. Taking the patient’s history

Type 2 Diabetes  /  41 (literally, from “his story”) gives ­great insight into the under­lying cause of ­ ill listen. P ­ eople disease if the doctor w use descriptive language that points to where emotions are stored. The liver is the organ of constraint, frustration, and irritable anger. Once t­ hese issues can be brought to the patient’s own conscious awareness, resolution is often quickly obtained. 5. Prescribe specific natu­ral substances for pathology. • Cod liver oil, guggul, policosanols, garlic, and pantethine are among my favorites. 6. Prescribe phar­ma­ceu­ti­cals for pathology. Note: I’ve never prescribed a phar­ma­ceu­ti­ cal for dyslipidemia.

Adrenergic agonists: beta agonists (albuterol, salmeterol, formoterol), alpha-1 agonists (phenylephrine, oxymetazoline, tetrahydralazine, xylometazoline, methoxamine) (see bronchodilators and decongestants, p. 36) Nicotinic acid/niacin: watch for hyperhomocysteinemia. Antiepileptic drugs (see anticonvulsants, p. 40) Antineoplastic agents: particularly streptozocin, L-­asparaginase, mithramycin. Cyclosporine. Nutrients depleted: magnesium; (arginine, melatonin, omega-3 fatty acids, vitamin E, vitamin C help protect; watch for hyperkalemia). Theophylline. Nutrients depleted: magnesium, potassium, vitamin B6. Statins (see p. 40)

TYPE 2 DIABETES

Drugs to Treat Type 2 Diabetes

Drugs That Can Cause Type 2 Diabetes

The following are the drugs often prescribed to treat type 2 diabetes and the secondary disease states they may cause, along with a caution about The third leg of the cardiovascular triad is high oral hypoglycemic agents. blood glucose, which can lead to type 2 diabetes. SPECIAL WARNING ON INCREASED The following drugs can increase blood glucose RISK OF CARDIOVASCULAR levels. ­MORTALITY: Diuretics: thiazide diuretics (see p. 36) and loop The administration of oral hypoglycemic diuretics (see p. 37). drugs [sulfonylureas] has been reported to Antihypertensive agents: beta-­blockers (see be associated with increased cardiovascular p. 37), clonidine. No known nutrient depletions mortality as compared to treatment with with clonidine. diet alone or diet plus insulin (11). Diazoxide. Rarely used anymore. No known ­There have been no clinical studies estabnutrient depletions. lishing conclusive evidence of macrovascular Adrenocorticotropic hormone. Nutrients risk reduction with metformin hydrochlodepleted: vitamins C and K, selenium, zinc. ride tablets USP or any other anti-­diabetic Pentamidine. Nutrient depleted: magnesium; drug (12). especially problematic for cardiac function. Dipeptidyl peptidase-4 (DPP-4) inhibitors Antiprotozoal drugs: disrupt the gut flora. (sitagliptin, saxagliptin, other “gliptins”): Corticosteroids (see p. 36) tachycardia; not cardiovascular but worthy of note—­acute pancreatitis, including fatal and Hormones (see p. 36) nonfatal hemorrhagic and necrotizing pancreatitis Psychoactive agents: lithium, aty­pi­cal antipsychotics (aripiprazole, quetiapine, paliperidone, with sitagliptin. No known nutrient depletions. olanzapine, risperidone, lurasidone), classical antipsychotics (haloperidol, thioridazine). See lithium and antipsychotics, p. 40.

Biguanides (metformin): throbbing or pounding heart. Nutrient depletions: vitamin B12, folic acid (watch for subsequent hyperhomocysteinemia).

42  /  A Naturopathic Perspective on Iatrogenesis Thiazolidinediones (rosiglitazone, pioglitazone): edema, heart failure, worsening of heart failure; also worthy of note—­rosiglitazone has been pulled from the market in the United Kingdom, New Zealand, India, and South Africa, and its use has been suspended in Eu­rope due to an increase in the risk of heart failure and heart attack. The Food and Drug Administration (FDA) has deemed rosiglitazone “safe and effective” and removed the Risk Evaluation and Mitigation Strategy placed on it a few years ago when other countries began removing the product from their pharmacy shelves. Pioglitazone has a black box warning about an increased risk of bladder cancer. Sulfonylureas (glipizide, glyburide): increased risk of cardiovascular mortality. Nutrients depleted: chromium, coQ10.

Treating Type 2 Diabetes Naturopathically The following is how a person with diabetes might be treated in my office. 1. Remove obstacles to cure. • Teach the patient the “naturopathic basics”: eat real food, drink clean ­water, move your body, sleep, and live congruently. See Box 5-1 (p. 38) for a complete list. • Absolutely no chemical sugar substitutes or “lite” foods. Decrease sugar and ­simple carbohydrate consumption; decrease coffee consumption. Excessive consumption of coffee has been correlated with poorer outcomes in patients with diabetes. That may be due to dehydration (tannins in coffee act as diuretics) and/or the common addition of cream, cream substitutes, sugars, sugar substitutes and other pro­cessed “food stuffs” to the coffee rather than the coffee itself. Low to moderate consumption of black coffee may have some protective benefit against the development of diabetes. • A meta­phorical question to ask the patient with diabetes would be, “Where is the sweetness in your life?”

• Excess iron (ferritin) damages beta cells of pancreas, secreted insulin molecules, and insulin receptors. Check iron levels; encourage blood donation if warranted. 2. Stimulate the healing power of nature. • Exercise, nutrition, and lifestyle counseling are key components of good health. • Weight loss, but only if needed (see p. 40) 3. Strengthen weakened systems. • Use food as medicine. Increase fiber— 50g or even as much as 80g daily (guar gum, pectin, oat bran from fresh fruits and vegetables before supplementing). • Consume essential fatty acids and beans/legumes. • Provide gastrointestinal and endocrine system support. 4. Correct structural integrity. • Exercise (increases insulin receptor receptivity); make the mind-­body connection to correct structural integrity. • Zinc picolinate, as diabetics tend to hypersecrete zinc (involved in synthesis, secretion, utilization of insulin); magnesium; vitamin C; vitamin D if deficient (stimulates insulin production). 5. Prescribe specific natu­ral substances for pathology. • Botanicals: gymnema directly on tongue to blunt sugar taste/addiction, berberine (sulfate and maybe the hydrochloride salt of berberine), cinnamon, tea (green and black), blueberry/bilberry, garlic, fenugreek seeds. • Nutrient therapy: chromium and magnesium to improve insulin sensitivity; natu­ral vitamin E; bioflavonoids/ quercetin. 6. Prescribe phar­ma­ceu­ti­cals for pathology. Note: Dysglycemia can precipitate depression in many p ­ eople. Look at the astonishing increase in the number of ­people being diagnosed with ­mental health diseases such as depression, anxiety, and bipolar disease. Given that dysglycemia pushes ­people into depression, and aripiprazole—an aty­pi­cal anti-­psychotic drug used for

Summary / 43 refractive depression and bipolar II disease—is clinical sciences as well as population groups, the among the top-­selling drugs, t­ here is much work philosophy—­ and therefore the emphasis of to be done. study—is very dif­fer­ent. MDs and DOs study from a view of pathology—­what a disease looks like and which phar­ma­ceu­ti­cal agent or surgical procedure NATUROPATHIC PRINCI­PLES ­ will remove it. NDs study from a view of physiology—­what the h ­ uman body needs in order AND THE THERAPEUTIC T ­ hese very dif­fer­ent approaches to to perform well. ORDER medicine can be articulated with the meta­phor of The pattern in the naturopathic treatment options the body as a battlefield (conventional medicine) is prob­ably noticeable. Naturopathic medicine is or an organic garden (naturopathic medicine). guided by the Therapeutic Order, in which prac­ti­ In a ­battle, opposing forces fight each other, tion­ ers strive to use the least amount of force for example, antimicrobials versus microbes, anti(intervention) to encourage stimulation of the depressants versus depression, anti-­inflammatories patient’s own inherent healing capacity. Each of versus inflammation, and chemotherapeutic agents the treatment plans—­for hypertension, dyslipidversus cancer. Necessarily with this approach, the emia, and type II diabetes—­follows this order. A body is the battlefield. While the war rages, casualset of princi­ ples of naturopathic medicine also ties ensue, and t­ here’s a mess to clean up in adverse assists naturopathic physicians in their decision-­ effects, including iatrogenic disease. In a ­ battle, making pro­cess. I have listed the princi­ples in the generals (doctors) plan the strategy and leave solcontext of iatrogenicity, which naturopaths call diers (drugs/surgery) to fight. Citizens (patients) the Law of Suppression. have l­ittle responsibility or role to play. This is the Many phar­ma­ceu­ti­cal agents actually push reductionistic paradigm. ­people into disease states that they may not have In a garden, the goal is harmony among experienced other­wise. (Naturopathic physician’s plants, soil, and environment. This harmonious role: Primum non nocere; First, do no harm.) approach includes pest-­repelling plants that ward off bugs that would other­wise damage crops. The Diseases ­don’t happen secondary to a lack of phar­ma­ceu­ti­cals in the ­human system. (Naturo- vari­ous plants contribute dif­fer­ent ingredients to the soil in which t­hey’re planted and absorb dif­ pathic physician’s role: Vis medicatrix naturae; fer­ ent nutrients from the plants around them. stimulate the inherent healing ability within Although weeds w ­ ill grow and maintaining the each patient.) garden may be time consuming, this approach Use symptoms as clues to the under­lying cause leaves the garden (the ­ uman body) radiant and h (often lifestyle), and correct the cause. (Naturobeautiful, a testimony to vitality and brilliant pathic physician’s role: Tolle causam; treat the design. In a garden, the gardener (doctor) plants cause of the disease.) the seeds, but the garden (patient) takes on a life Recognize that in the absence of physical findings, of its own. Ultimately, the patient is solely responthe cause may have a m ­ ental, emotional, or sible for his or her health; it is the doctor’s role to spiritual etiology. (Naturopathic physician’s role: educate, inspire, and empower the patient to start Tolle totum; treat the w ­ hole person.) the healing journey. This is the vitalistic paradigm. Sometimes, the therapeutic alliance between doctor and patient ­will be “the medicine”—­the healing modality. (Naturopathic physician’s SUMMARY role: Docere; doctor as teacher, model, guide.) Physicians from any medical training go into the healing arts with a desire to help their patients. ­There are many diets, lifestyles, and philosophies BELIEFS DICTATE that guide prac­ti­tion­ers and patients alike in their EDUCATIONAL LENS views on health, medicine, wellness, and healing. Although medical, osteopathic, and naturopathic Some modalities inherently contain more risk than doctors have in common the study of basic and ­others.

44  /  A Naturopathic Perspective on Iatrogenesis All who call themselves medical or osteopathic doctors in this country have attended accredited schools, successfully passed their licensing exams, and can be recognized in all states in the United States. This is not currently the case for naturopathic doctors. Although t­here are now eight accredited schools of naturopathic medicine in North Amer­i­ca, ­there are also on-­line certificate programs in naturopathy that do not provide any medical training. In working with anyone using the title naturopath, naturopathic doctor, naturopathic physician, or naturopathic medicine doctor, the conventional practitioner and the layperson should know ­whether the naturopath is licensed (or licensable) by a state regulatory board. Not all states license naturopathic doctors, but all naturopaths who have graduated from an accredited school and passed their licensing exams are licensable.

References For nutrient depletions, see Stargrove M, et  al., Herb, Nutrient, and Drug Interactions. St. Louis, MO: Mosby/ Elsevier, 2008; for adverse events associated with prescription drugs, see www​.­Drugs​.­com​/­professional​.­ 1. Oxford Dictionary. https://­en​.­oxforddictionaries​ .­com​/­definition​/­iatrogenic. 2. James JT. A new, evidence-­based estimate of patient harms associated with hospital care. Journal of Patient Safety. 2013; 9(3):122–128. doi: 10.1097/ PTS.0b013e3182948a69.

3. Starfield B. Is US health r­ eally the best in the world? JAMA. 2000; 284(4):483–485. doi:10.1001​/jama​.​ 284.4.483. 4. Null G, et.al. Death by Medicine. Mt. Jackson, VA: Praktikos Books/Axios Press; 2010. 5. Fairfield K, Fletcher R. Vitamins for chronic disease prevention in adults. JAMA. 2002;287(23):3116– 3126. doi:10.1001/jama.287.23.3116. 6. Olshansky J, Passaro D, Hershow R, et  al. A potential decline in life expectancy in the United States in the 21st ­century. N Engl J Med. 2005; 352:1138–1145. doi: 10.1056/NEJMsr043743. 7. Council for a Strong Amer­i­ca. Too fat to fight: retired military leaders want junk food out of Amer­i­ca’s schools, 2010. http://­www​.­mission​readi​ ness​ .­o rg​/­w p​-­c ontent​/­u ploads​/­M R​_­Too​_­F at​_­t o​ _­Fight​-­11​.­pdf​.­ 8. Washington State University. Consumption by the United States, 2008. http://­public​.­wsu​.­edu​/­~mreed​ /­380American%20Consumption​.­htm. 9. Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med. 2014;174(4):516–524. 10. Mayo Clinic Staff. Dietary fiber: essential for a healthy diet. http://­www​.­mayoclinic​.­org​/­healthy​ -­lifestyle​/­nutrition​-­and​-­healthy​-­eating​/­in​-­depth​ /­fiber​/­art​-­20043983​?­pg​=­1 11. Mortality results, The University Group Diabetes Program. Diabetes. 1970; 19(2 SUPP):747– 830. 12. Drugs​ .­ com. Professional information concerning metformin. https://­www​.­drugs​.­com​/­pro​/­met​form​in​ .­html.

CHAPTER 6

Clinical Manifestations of Acute and Chronic Drug-­Induced Iatrogenic Cardiovascular Diseases and Syndromes Ihor B. Gussak, Gan-­Xin Yan, Arshad Jahangir, Georg Gussak, and John B. Kostis

­Great deeds are usually wrought at ­great risks. Herodotus (Ἡρόδοτος), c. 484–­c. 425 b.c. (Book 7, Chapter 50, The Histories, trans. Robin Waterfield, 1998)

INTRODUCTION Medicine is a part of life, and iatrogenicity is a part of medicine. Iatrogenicity in cardiovascular (CV) medicine, a part of general (medical) iatrogenicity, is well known among clinicians, drug developers, regulators, and patients, and caretakers long ago realized that even intended effects of drugs ­were not always or entirely beneficial. Iatrogenic complications of drugs and interventions culminating in sudden and unexpected cardiac death is of major concern in modern CV medicine. Many ­factors can be contributed to CV iatrogenicity, among them: • • • • • • • • •

Poor overall medical assessment Erroneous diagnosis or treatment Delay of correct diagnosis or treatment Negligence and malpractice Insufficient knowledge of pharmacological peculiarities of the drug Misuse of guidelines Unnecessary procedures or interventions Inadequate efforts in identification and mitigation of risk f­ actors Improper or inadequate follow-­up.

The significance and role of each of ­these ­factors (and their combination) in CV iatrogenicity vary significantly among patients and even within the same patient,

48  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes depending on stage and progression of disease, age, gender, comorbidity, and medi­cations. While clinical manifestations of cardiac toxicity of a variety of cardiac and non-­cardiac medi­ cations have been recognized in modern clinical cades, arguably the first cardiology for many de­ clinical study that attracted broad and renewed attention to CV iatrogenicity was the report by the Cardiac Arrhythmia Suppression Trial (CAST) study published in 1989 (1). This study revealed increased mortality in patients with recent myo­ car­dial infarction and premature ventricular complexes (PVCs) who ­were on active treatment with a sodium (Na+) channel blockers compared with ­those on placebo, thus highlighting the potential hazard of antiarrhythmic drugs that w ­ ere other­ wise highly effective in suppressing premature ventricular complexes (2). Since then, many examples threatening cardiac proarrhythmia have of life-­ been demonstrated for antiarrhythmic drugs as well as for other cardiac and non-­cardiac drugs. In another example of drug-­induced cardiac toxicity that includes proarrhythmia, worsening arrhythmia, and increased cardiac mortality, a link was established between drugs with potassium (K+) channel blocking properties and QT-­prolongation culminating in development of torsade de pointes (TdP). It appears that agents with a potential to shorten the length of ventricular repolarization (QT-­shortening) are also far from benign. In addition to the aforementioned examples of acquired induced arrhythmogenic channelopathies, drug-­ other commonly recognized clinical manifestations of drug-­induced CV toxicity include:

DRUG-­INDUCED CARDIOVASCULAR TOXICITY AND ITS CLINICAL CONSIDERATIONS Drug Toxicity: Terminology and Definitions

Drug toxicity is defined as the degree to which any chemical or biological substance, other than food, used for medicinal (diagnostic, preventive, or therapeutic) purposes can do the following: (a) produce an appreciably harmful or unpleasant body response impacting the patient’s management or prognosis; (b) predict a hazard from ­future administration; and/or (c) warrant prevention or treatment modifications or alteration of the dosage regimen, “black label” warnings or precautions, or withdrawal from the market. Commonly, the term drug toxicity does not include accidental or intentional poisoning and also differs from overdose or combined drug intoxication (known as “multiple drug intake” or polydrug / polypharmacy). Polypharmacy is commonly defined as simultaneous multiple (five or more) prescribed medi­cations per patient. It is often associated with unintended drug-­drug interactions that can result in deterioration of health or sudden iatrogenic death, particularly in the el­ derly. The risk of iatrogenic complications is likely to be higher in patients who take over-­the-­counter medi­cations in addition to prescribed drugs. A considerable number of cardiac and non-­ cardiac drugs on the market or in development • Cardiomyopathies and heart failure are known for their toxic effects on the CV sys• Arterial hypertension and hypotension tem, and many have been withdrawn or severely • Myo­car­dial ischemia and infarction restricted to specific indications ­because of an • Thrombosis and thromboembolic unexpected adverse effects (AEs). Typically, AEs ­disorders are detected by laboratory tests (e.g., biochemi• Valvular and pericardial diseases cal, hematological, immunological, radiological) Iatrogenicity of cardiac medical devices and or by clinical investigation (e.g., endoscopy, cardiagnostic and therapeutic procedures is dis- diac catheterization, X-­ray), whereas an adverse drug reaction (ADRs) are recognized by their cussed separately in Part III of this book. clinical manifestations (symptoms and/or signs). This distinction suggests several dif­fer­ent causal relationships between AE and ADR, for example: (a) ADR can result directly from AE or can occur without preceding AE, whereas AE may not necessarily result in appreciable ADR; (b) AE and ADR may not have a causal relationship; or

Drug-­Induced Cardiovascular Toxicity and its Clinical Considerations  /  49 (c) both AE and ADR may constitute clinical syndromes. Therefore, if ADR can be defined as an appreciably harmful or unpleasant yet unintended body or organ response to a drug that occurs at a dose normally used in ­humans for its therapeutic, preventive, or diagnostic intervention, then AE can be referred to as a potentially harmful effect of a medicinal product. AE constitutes a hazard and may or may not be associated with a clinically appreciable ADR and/or an abnormal laboratory test or clinical investigation. ADRs and/or AEs may occur following (a) a single dose, (b) multiple doses, (c) a combination of two or more drugs, or (d) prolonged administration of a drug. ADRs and/or AEs are often caused by “off-­label” dosing regimen, inappropriate target population, label” or target indications (e.g., nesiritide “off-­ use in outpatients with heart failure [3,4]). All instances of ADRs are undesirable and unintended, many of them are unpredictable, some of them are serious and potentially life-­threatening, yet a majority of them are avoidable or preventable. The terms “avoidable” or “preventable” are key terms in defining the iatrogenic effect of a drug. Based on etiology, ADRs can be classified into several c­ ategories: 1. Dose-­related (augmented): This is the most common and pharmacologically predictable category (e.g., warfarin, insulin). For many drugs a substantial proportion of patients show suboptimal response at standard doses while ­others experience ADRs. 2. Non-­dose-­related (idiosyncratic or bizarre): This category consists of two types of r­ esponses. • Immune-­mediated (e.g., angioedema by ACE i­ nhibitors). • Non-­immune-­mediated (e.g., porphyria, malignant hyperthermia). Very difficult to predict, an idiosyncratic ADR is most commonly caused by unexpected pharmacokinetic and/or pharmacodynamic peculiarities in metabolic pathways and/or drug targets (e.g., drug absorption, distribution, metabolism, excretion, drug-­drug or drug-­food interactions), particularly in genet­ically predisposed individuals. Of note, even in an individual with a

normal genotype, a serious ADR can result from drug interactions or co-­administration of an agent that is a potent inhibitor of the enzyme system normally degrading the drug. Furthermore, ­because of the narrow therapeutic index of some drugs (e.g., digoxin), ­these pharmacokinetic interactions are of extreme importance and a major cardiac safety concern in clinical practice, clinical pharmacology, and ­ evelopment. drug d 3. Dose-­related and time-­related (chronic): (e.g., hypothalamic-­pituitary-­adrenal suppression from glucocorticoid ­therapy). 4. Time-­related (delayed reaction): (e.g., tardive dyskinesia). 5. Withdrawal (end of dose reaction): an example could serve as withdrawal from narcotics, statins, or beta-­blockers. 6. Unexpected failure of therapy: This type of ADR may be caused by drug interactions (e.g., failure of oral contraceptives due to induction of enzymes by another drug). ADRs can also be classified based on: 1. Presence or absence of symptoms: Symptomatic versus asymptomatic. 2. Reversibility of signs and symptoms: Transient versus irreversible. 3. Nature of damage: Functional changes versus structural remodeling. 4. Severity: Mild, moderate, or severe. A severe ADR is associated with the ­following: • Death • Life-­threatening • Hospitalization (initial or prolonged) • Intervention to prevent permanent impairment or damage • Disability (significant, per­sis­tent, or permanent change, impairment, damage or disruption in the patient’s body function or structure, physical activities, or quality of life) • Congenital anomaly The extent of serious and fatal ADRs is largely underestimated. In 2000, the Institute of Medicine reported that 44,000 to 98,000 deaths occurred annually due to medical error (5). Of this total, an estimated 7,000 deaths ­were attributed

50  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes to ADRs. Meta-­analysis of 39 prospective U.S. studies on ADR in hospitalized patients revealed that among the nearly 2.2 million documented in-­hospital patients per year with ADRs, 6.7% of ­ ere serious and 0.32% ­were fatal (6). the ADRs w The worst drug “offenders” w ­ ere: • Cardio­vascular drugs 17% • Antibiotics 17% • Analgesics and anti-­inflammatory agents 15% • Chemotherapy drugs 15% In clinical practice, it is impor­tant to differentiate iatrogenic ADR from side effects of the drug, a possibly potential hazardous health effect. Side effects occur within the drug’s therapeutic ranges and can be of potential benefit ­under certain circumstances (e.g., the side-­ effect drowsiness induced by a low dose of antidepressants or antihistamines may subjectively improve insomnia).

Common ­Causes and Risk ­Factors

Some signs and symptoms may be new, and some may be due to worsening of existing ones. Some symptoms are life-­threatening and require immediate medical attention, including urgent hospitalization (e.g., angioedema, tachyarrhythmia). ­Others require adjustment of treatment, and yet ­others drug withdrawal. and all require mandatory follow-­up. Signs and symptoms of CV toxicity can be grouped into two major categories: cardiac and extra-­cardiac. CV toxicity can manifest in the following ways: • • • • • • •

Palpitations or irregular heart rate Dizziness or light-­headedness Syncope or near-­syncope Chest pain or discomfort Shortness of breath or dyspnea Pedal edema ­ ental status (e.g., depression, Changes in m confusion, violent be­hav­ior) • Excessive sleepiness, drowsiness, somnolence, lethargy, or coma • Changes in taste or smell • Changes in vision • Coughing • Loss of appetite • Dry mouth • Nausea, vomiting, or diarrhea • Itching or skin excoriation • Failure to thrive

Harmful drug-­induced CV toxicity may develop in vari­ous functional and structural ele­ments of the heart and vessels, compromising electrical (e.g., excitability, automaticity, depolarization, conduction, repolarization) and mechanical (e.g., contractility, relaxation) functions of the heart, resulting in the compromised perfusion and metabolism of vari­ous organs including the heart. Factors predisposing an individual to drug-­ ­ induced CV toxicity can vary significantly depend- Laboratory and ing on the nature and stage of cardiac diseases, Instrumental Tests age, gender, concomitant diseases (e.g., renal and/ In a patient with suspected CV toxicity by ­either cations, cardiac or non-­ or liver impairments), concurrent medi­ cardiac drugs or toxic herbal and metabolic and electrolyte disorders. Most medicines, laboratory blood testing is of ­great commonly, iatrogenic drug-­induced CV toxicity is value to diagnose, assess severity of toxicity, pre­ ith: associated w dict prognosis, stratify risk, and follow-up. Components of the initial laboratory examination include complete blood count with differential, comprehensive metabolic panel, inflammatory markers, auto-­ antibodies, and flow cytometry. More comprehensive blood testing includes assessment and monitoring of vari­ous markers of CV; hepatic, renal, neurologic, and carcinogenic Clinical Manifestation, Signs, markers; electrolytes and heavy metal levels; and and Symptoms specialized testing of hemostatic and thrombotic Drug-­induced CV toxicity may manifest in dif­fer­ abnormality markers. Instrumental diagnostic ent ways and sometimes in more than one way. tests may include resting ECG, serial ECG com• “Off-­label” use of medi­cation • Drug-­drug and drug-­food interactions • Polypharmacy, including over-­the-­counter supplements with unknown, undervalued, or compromised safety

Acute and Chronic Syndromes and Diseases of Cardiovascular Toxicity  /  51 parison, and ambulatory Holter monitoring to assess timing of interval durations (e.g., QT/QTc, PR, QRS), morphological pattern of ST-­T segment, presence of pathologic U-­waves, ec­topic activity, and conduction defects. Magnet multi-­ gated acquisition scan and echocardiography are routinely used to identify and monitor the decline in cardiac contractility function associated with chemotherapeutic agents (e.g., anthracyclines, tyrosine kinase inhibitors).

ACUTE AND CHRONIC SYNDROMES AND DISEASES OF CARDIOVASCULAR TOXICITY

of myo­car­dial ischemia, heart failure, syncope, “near-­syncope,” and sudden cardiac death (SCD). • Abnormal automaticity and increased ec­topic activities (e.g., sinus tachycardia, bradycardia, premature atrial and/or ventricular beats, atrial fibrillation). • Depolarization abnormalities and conduction defects (e.g., widening of the QRS complex, sinoatrial, atrioventricular, intraventricular blocks). • Repolarization abnormalities, such as prolongation or shortening of the length of repolarization (e.g. acquired long or short QT syndromes) and its pattern (e.g. “bifid” or inverted T-­waves, abnormal U-­waves, Brugada syndrome-­like ST-­segment appearance).

The variety of clinical manifestations of iatrogenic, or drug-­induced, CV toxicity is summaIn the past, prolongation of cardiac refractorirized and presented in the following list of iatroness, manifested on the surface ECG as QT/QTc genic CV diseases and syndromes (7): prolongation by a drug (acquired long QT syn1. Cardiac arrhythmia, syncope, and sudden drome [LQTS]), was considered a desired effect of cardiac death vari­ ous antiarrhythmic agents. However, over 2. Cardiomyopathies and heart failure time, medical community learned that in many 3. Arterial hypertension cases QT prolongation can be proarrhythmic for 4. Arterial hypotension cardiac and non-­cardiac drugs. Numerous cases of 5. Myo­car­dial ischemia and infarction SCD and life-­ threatening ventricular tachyar6. Thrombosis and thromboembolic disorders rhythmias, such as TdP in association with pro7. Valvular diseases longed QT/QTc intervals, ­ were reported to the 8. Pericardial diseases worldwide post-­marketing database. As a result, a It is impor­tant to emphasize that the list of substantial number of torsadogenic drugs with acute and chronic syndromes and diseases of CV “QT liability” have been withdrawn from the toxicity in the first edition of this book is abbre- market, severely restricted, or contraindicated. It is viated and does not include drug-­induced auto- noteworthy that not all QT-­prolonging drugs are immune CV disorders and abnormal conditions, proarrhythmic, yet a vast majority of proarrhythincluding metabolic, electrolyte, and acid-­base mic drugs removed from the market did demonstrate QT prolongation. disorders. The majority of QT-­prolonging torsadogenic drugs act through an inhibition of the rapidly 1. Cardiac Arrhythmia, Syncope, activating delayed rectifier potassium channels (IKr) and, to some extent, the slowly activating and Sudden Cardiac Death delayed rectifier potassium channels (IKs). The Drug-­induced electrical instability of the heart lists of cardiac medi­cations (e.g., amiodarone, fle(iatrogenic arrhythmogenic cardiotoxicity) is cainide, azimilide, ibutilide, bepridil, procainusually viewed in the context of acquired cardiac amide, bretylium, propafenone, disopyramide, channelopathies associated with: quinidine, dofetilide, tedisamil, D-­sotalol) as well as non-­cardiac medi­cations including antibiotics • Development or worsening of supraven(e.g. azithromycin, clarithromycin, erythromycin, tricular and ventricular arrhythmia and/or fluoroquinolones, ciprofloxacin, gatifloxacin, conduction disturbances, resulting in hemodynamic compromise with symptoms levofloxacin, moxifloxacin), antidepressants (e.g.,

52  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes

Case Study A 76-­year-­old female was hospitalized with right upper quadrant abdominal pain. She was found to have obstructive jaundice and underwent an endoscopic retrograde cholangiopancreatography with a stent placement, due to stenosis of the common bile duct. The initial treatment included an orally administered fluoroquinolone antibiotic Levaquin. As a result, the patient developed prolonged QT interval with inverted T -­waves (see Figure 6-1) culminating in recurrent tor-

sade de pointes (TdP) ventricular tachycardia (see Figure 6-2). For this, she was treated at the local hospital with intravenous amiodarone, which failed to suppress TdP.  She was then transferred to another hospital to be further evaluated by a cardiac electrophysiologist. ­After discontinuation of levofloxacin and amiodarone, her QT interval become shorter and TdP dis­appeared (see Figure 6-3).

FIGURE 6-1 ​12-­lead ECG (on Levaquin) Note: Sinus rhythm with premature atrial complexes; QTc ~ 580 ms; notched or inverted T -­waves. Paper speed—25 mm/sec, calibration—10 mm/mV.

FIGURE 6-2 ​Continues ECG monitoring strip Note: Significant QT interval prolongation, premature ventricular complexes and development of torsade de pointes. Paper speed—25 mm/sec, calibration—​10 mm/mV.

FIGURE 6-3 ​12-­lead ECG recorded on day 10 a­ fter discontinuation of Levaquin and amiodarone Note: Sinus rhythm with premature atrial complexes; QTc ~ 485 ms; nonspecific T wave abnormalities. Speed—25 mm/sec, calibration—10 mm/mV.

Acute and Chronic Syndromes and Diseases of Cardiovascular Toxicity  /  53 amitriptyline, desipramine, doxepin, fluoxetine, In the early 1960s, both congenital and imipramine, paroxetine, sertraline), and antipsy- drug-­induced LQTS w ­ ere thought of as rare; by chotics (e.g., droperidol, haloperidol, mesorida- the late 1990s, drug-­induced QT/QTc prolongazine, pimozide, quetiapine, risperidone, sertin- tion became common enough that e­very new dole, thioridazine, chlorpromazine, enlafaxine) drug is now required to be characterized for QT known for their association with both QT pro- -­liability. It took de­cades to sensitize medical and threatening scientific communities, drug developers, and reglongation and propensity to life-­ tachyarrhythmias are extensive. ulatory authorities to the serious ADRs. A turnAmong the many cardiac conditions known ing point came ­after the highly publicized withto increase predisposition to iatrogenic CV tox- drawal of the gastrointestinal drug cisapride and icity are the following: (a) history of clinically rel- the non-­sedating antihistamine terfenadine in the evant arrhythmias, (b) ischemic heart disease, (c) late 1990s. heart failure and cardiomyopathies, and (d) arteA prokinetic agent, cisapride was approved rial hypertension and left ventricular hypertro- for nighttime heartburn in July  1993 and was phy. ECG abnormalities associated with a high withdrawn from the h ­ uman market in March risk of TdP development include: (a) prolonged 2000. This QT-­ prolonging drug is primarily baseline QT/QTc intervals, (b) alternans of beat-­ metabolized by CYP3A4 and, when co-­ to-­beat QT interval duration, (c) abnormal or administered with any other drug or substances markedly accentuated U-­waves ­after prolonged known to inhibit this enzyme (e.g., grapefruit pause (e.g., ­after PVC), (d) deeply inverted or juice, macrolides, ketoconazole, alcohol overnotched T-­waves and their alternans, (e) brady- dose), it can become torsadogenic as its blood cardia, especially in ­children, or tachycardia, and concentration ­will be greatly elevated. Five times (f) abrupt changes in heart rate. between its approval and January  2000, cisNumerous extracardiac f­actors can partici- apride’s labeling required progressively stronger pate in development of TdP. They include: (a) warnings about life-­threatening ADRs u ­ ntil its acute neurological events (e.g., intracranial and removal from the market. The drug was associsubarachnoid hemorrhage, stroke, head trauma, ated with at least 341 reports of cardiac arrhyth(b) electrolyte disturbances (e.g., hypokalemia, mias, including 80 reported cases of SCD through hypomagnesemia, hypothermia, abrupt shift in December 31, 1999 (8). An analy­sis of 341 cases electrolyte balance during hemodialysis), (c) met- of patients on cisapride diagnosed with QT proabolic disorders (e.g., acidosis, diabetes mellitus, longation and ventricular tachyarrhythmias hypoglycemia, hypothyroidism, obesity, pituitary revealed the following confounding variables (7): insufficiency, altered nutrition including anorexia • CYP3A4 inhibitors 126 (37%) nervosa, starvation diet, alcoholism), (d) impaired • Electrolyte imbalance 17 (5%) drug elimination (renal or hepatic dysfunction), • Proarrhythmic drugs 17 (5%) (e) poisoning (e.g., arsenic, organophosphates, • Heart failure 29 (8.5%) nerve gas), (f) female gender, and elderliness (over • Other cardiac disease 66 (19.4%) age 65). • Cisapride overdose 9 (2.6%) As with other cases of arrhythmogenic SCD, • No risk ­factors 38 (11%) symptomatic patients with acquired LQTS often experience ­ either palpitations, fainting, pre-­ Terfenadine is another classic example of an syncope, or syncope. Unfortunately, it is not arrhythmogenic QT-­prolonging drug with tremenuncommon for the first arrhythmic event to be dously increased torsadogenic potential when the last one. In the case of drug-­induced prolon- administered si­mul­ta­neously with a corresponding gation of QT/QTc intervals, the most pathogno- enzyme inhibitor. It was the most popu­lar non-­ monic sign of arrhythmogenic drug-­induced car- sedative antihistamine agent in its time (by 1992, it diotoxicity is TdP, a life-­threatening ventricular was the tenth most prescribed medi­cation in the tachyarrhythmia commonly associated with United States) and was being considered for a inversion of T waves or abnormal U waves and a change in status to “over-­the-­counter,” but instead, high likelihood to degenerate into irreversible terfenadine was removed from the market due to ventricular fibrillation and death. numerous cases of TdP and SCD reported to the

54  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes worldwide post-­marketing database. A retrospec• It has a high incidence of ventricular tive detailed ECG analy­sis revealed a linear dose-­ tachycardia/fibrillation, atrial fibrillation, response relationship with an increase in QTc syncope, and SCD. interval of 0.28 msec for e­ very 1 mg of terfenadine • In contrast to acquired LQTS, an arrhythdosed (9). Of note, the QTc-­prolonging effect was mic event typically occurs without “prodroevident only with the parent compound, but not mal” arrhythmias (e.g., PVCs, TdP). terfenadine’s acid metabolite. It was speculated that if some drugs can proAt pres­ent, it is widely acknowledged that the long QT/QTc intervals and mimic congenital unintended prolongation of ventricular repolarizaLQTS with all the associated consequences, then tion, as determined by prolongation of the QT/ it should be no surprise if other drugs that shorten QTc interval, is the most common cause for delays QT/QTc intervals mimic congenital SQTS with in the drug development pro­cess and for removal all associated consequences (11). Drawing a parof drugs from the market. In addition to cisapride allel from experiences with LQTS, the immediate and terfenadine, other drugs withdrawn due to QT question is w ­ hether drugs are capable of proarprolongation are the antibiotic grepafloxacin, the rhythmic shortening of the QT interval. Among antispasmodic terodiline, the calcium channel the already marketed, phenytoin and digoxin are pi­ cal antipsychotic blocker lidoflazine, the aty­ believed to shorten the QT interval, and both are sertindole, and the opioid levomethadyl (8). Despite known to be proarrhythmic, although the causthe fact that most drugs that prolong the duration ative relationship between QT-­ shortening and of the QT/QTc intervals can cause fatal ventricular proarrhythmic potential needs to be established. tachyarrhythmias, t­here are still more than 100 It is impor­tant to emphasize that the majority of such drugs on the market. The vast majority are cases of drug-­induced shortening of the QT internon-­cardiovascular drugs recognized by regulatory val ­were observed in patients with pre-­existing agencies for their ability to prolong ventricular prolongation of QTc intervals. Possibly the first repolarization and the QT/QTc intervals, and with label approved by the Food and Drug Administrathe potential to aggravate or precipitate malignant tion (FDA) containing a “warning” on acquired ventricular tachyarrhythmias. Based on a retroSQTS was for rufinamide, a triazole-­derived antispective analy­sis of overlapping prescriptions in a convulsant introduced in 2011 and designated an cohort of about 5 million outpatients, researchers orphan drug (12). from Duke University concluded that nearly 1.1 In clinical practice, drug-­induced electrical million subjects (22.8%) filled 4.4 million prescripinstability could arguably be classified as suprations for QT-­prolonging drugs. Of ­these, 103,119 ventricular or ventricular, with regular or irregusubjects (9.4%) filled overlapping prescriptions for lar heart rate, too slow or too fast, resulting from two or more of the drugs or for a QT-­prolonging conduction block or increased ec­topic activities, drug and another drug that inhibited its clearance, or a combination of the above, causing further and 7,249 subjects (0.7%) filled overlapping predeterioration of hemodynamics. Some arrhythscriptions for three or more of ­these drugs (10). mias are life-­threatening and require immediate Although drug-­induced torsadogenicity valmedical attention; some are less malignant, ues of ECG markers (QT/QTc prolongation, requiring cardiac monitoring or routine followinverted T-­ waves, abnormal U-­ waves, increased up. The following are examples of arrhythmias ec­topic activities) is well established, drug-­induced and causative medi­cations. QT/QTc shortening associated with life-­ threatening arrhythmia (acquired short QT syndrome [SQTS]) is less investigated, as its congeni- Supraventricular tal and acquired forms w ­ ere discovered much • Supraventricular bradyarrhythmias and ­later. The “bad news” about e­ ither congenital or conduction defects: Sinus bradycardia or acquired SQTS can be summarized as follows: arrhythmia, escape complexes and rhythms, and asystole, sinoatrial, inter• High false-­negative diagnoses occur in atrial, and atrioventricular (supra-­His) patients with tachycardia, especially in the blocks. The most common mechanisms pediatric population include:

Acute and Chronic Syndromes and Diseases of Cardiovascular Toxicity  /  55 1. Direct inhibition of sinus node automaticity (e.g. ivabradine). 2. Direct inhibition of sympathetic ner­vous system discharge (e.g., beta-­blockers). 3. Direct stimulation of parasympathetic ner­vous system discharge (e.g., neostigmine). 4. Indirect stimulation of alpha-­receptors by suppressing release of norepinephrine (e.g., clonidine) or via stimulation of peripheral sensory receptors (e.g., nitroglycerin). • Among the drugs with the highest incidence of clinically relevant bradycardia and bradyarrhythmias are thalidomide (up to 53%), propofol (up to 50%), remifentanil (up to 39%), halothane (up to 24%), clonidine (up to 17%), sotalol, (up to 17%), diltiazem (up to 16%), flecainide (up to 13%), milrinone (up to 13%), verapamil (up to 11%), propafenone (up to 10%), adenosine (up to 8%), digoxin (up to 7%), ketamine (up to 5.5%), and dronedarone (up to 2.3%). • Among the drug classes known to induce atrioventricular block are most antiarrhythmics (e.g., amiodarone, sotalol), beta-­ blockers (atenolol), and calcium channel blockers (e.g., verapamil). • Fast supraventricular arrhythmias and ec­topic activities: Sinus tachycardia, accelerated junctional rhythm, premature atrial complexes, atrial fibrillation/flutter, paroxysmal atrial or atrioventrucular nodal tachycardia. The most common drug overdose include alcohol, caffeine, adenosine, digoxin (2.0 ng / ml), and many antiarrhythmics (­either excessive prolongation or shortening of atrial refractoriness). Among the most common abnormal conditions (relevant to the differential diagnosis) that increase ec­topic activities are hypokalemia, hyperthyroidism, and left atrial enlargement/hypertrophy (e.g., mitral stenosis). • Combination of slow and fast supraventricular arrhythmias: Sick sinus syndrome (brady-­tachy form). Brady-­tachy form of sick sinus syndrome can be iatrogenic in origin (significant suppression of activity of sinus

node by antiarrhythmics, beta-­blockers or calcium channel blockers) or associated with vari­ous abnormal conditions, including significantly low resting heart rate in athletes.

Ventricular • Slow ventricular arrhythmias: Escape ventricular complexes and rhythms, atrio-­venticular block. • Fast ventricular arrhythmias: Ec­topic premature complexes and rhythms, tachycardia, flutter, fibrillation. The incidence of drug-­induced ventricular tachyarrhythmias is unknown. However, many cardiovascular drugs (e.g. amiodarone, disopyramide, flecainide, propafenone, procainamide) affecting ventricular refractoriness and conduction velocity (e.g., sodium channel blockers) are associated with monomorphic ventricular tachycardia, particularly in patients with pre-­existing cardiac conditions (e.g., ischemic heart disease, impaired left ventricular function). In addition to re-­entry mechanism of paroxysmal tachycardia, TdP is often associated with QT-­prolonging potassium channels inhibitors. Adenosine can induce ventricular tachycardia, especially in patients with compromised coronary artery circulation, as a result of increased sympathetic activity and so-­called “coronary steal” phenomenon. Digoxin-­induced tachyarrhythmia is not an uncommon life-­threatening arrhythmia. The very low safety margin of digoxin and many predisposing ­factors (e.g., hypokalemia, age, compromised hemodynamic, atrial fibrillation) are among the major risk f­ actors for developing ventricular tachycardia. Similar to TdP, digoxin-­induced ventricular tachyarrhythmia is highly resistant to therapeutic and direct electrical current (defibrillation) therapies.

2. Cardiomyopathies and Heart Failure Heart failure (HF) is a clinical syndrome caused by vari­ous cardiac diseases and abnormal conditions that manifest as a variety of signs and symptoms dependent on etiology, pathophysiology, stage of progression, concomitant diseases, and medi­cation.

56  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes Symptoms of HF include t­hose due to excess fluid accumulation (dyspnea, orthopnea, edema, pain from hepatic congestion, abdominal distention from ascites) and ­those due to a reduction in cardiac output (fatigue, weakness) that is most pronounced with exertion. HF remains the leading discharge diagnosis among patients older than 64  years of age. The estimated cost for treatment of HF in Medicare patients is already $31 billion and is expected to increase. Hospitalization for HF is the largest segment of that cost. In a 2016 scientific statement, the American Heart Association (13) emphasized that “it is likely that the prevention of drug-­drug interactions and direct myo­car­dial toxicity would reduce hospital admissions, thus both reducing costs and improving quality of life.” Evaluation of the iatrogenicity of drugs used to treat HF is often obscured by the multiplicity of symptoms and f­actors contributing to this syndrome, and causality of symptoms in many cases is intuitive rather than definitive. For instance, one of the clinical manifestations of digoxin intoxication in patients treated for HF is deterioration of the contractility function of the heart and associated worsening of signs and symptoms. Among the most common “drug offenders” are antiarrhythchannel blockers, anthracymic agents, calcium-­ clines, nonsteroidal antiinflammatory agents, glitazones, and beta-­ ­ receptor adrenoagonists. Drug-­induced HF is usually viewed in the context of acute or chronic CV toxicity associated with: • Direct cytotoxic injury to myocytes resulting in loss of contractile function and development of cardiomyopathy and congestive HF (e.g., adriamycin, cyclophosphamide). • Acute or chronic myo­car­dial ischemia (e.g., 5-­fluorouracil [5-­FU]) and non-­ischemic cardiomyopathies (e.g., Takotsubo cardiomyopathy). • Circulatory overload with or without an increase in afterload (e.g., carbenoxolone, fludrocortisone, nonsteroidal anti-­ inflammatory drugs). The list of antineoplastic drugs used in oncology and implicated in e­ ither development or worsening of HF is long and exhaustive. Even though it has been more than 30 years since anthracyclines were introduced, severe cardiotoxicity remains ­

one of the chief safety concerns in oncology. In most cases, the main harm from antineoplastic drugs is direct cytotoxic injury to myocytes, resulting in loss of myocytes (“myofibrillar dropout”) due to swelling of the sarcoplasmic reticulum. In more advanced stages of damage, t­here is complete loss of myofibrils, impaired contractility and relaxation functions of the heart, progressive HF, chronic and acute cardiomyopathies, electrical instabilities, conduction defects, and cardiac death. Decline in left ventricular (LV) function is nonspecific and, if detected, may indicate significant and irreversible cardiac damage that is often advanced even when cardiotoxic therapy is stopped. As both cancer and heart disease are common (and the incidence of both increase with age), the two often coexist, particularly in older patients. In addition, many cancer patients receive more than one class of cardiotoxins (e.g., anthra­ cylines plus Herceptin). ­Because of the high risk of cardiac side effects, careful and detailed cardiac monitoring is essential. At pres­ent, cardiotoxicity is monitored by serial evaluation of LV function, ­either by multigated acquisition scan (MUGA), a nuclear cardiology imaging study, or basic echocardiography. For anthracyclines, many targeted therapeutics, and tyrosine kinase inhibitors, the recommended frequency of monitoring is four times per year while on therapy, and at least one time per year thereafter. Monitoring of heart function ­ought to be intensified (as frequently as ­every three weeks) if cardiac symptoms are pres­ent or if ­there is evidence of pos­si­ble decline in heart function. In spite of the cost, serial evaluation of LV function is poorly predictive of cardiovascular outcomes. Cardiotoxicity from cancer therapy is a frequent source of malpractice and product liability lawsuits. (See Chapter 8 for more details on chemotherapy-­induced cardiomyopathies.) • Doxorubicin (Adriamycin): Doxorubicin-­ induced cardiomyopathy pres­ents as a severe and potentially fatal biventricular chronic HF with symptoms occurring ­either during therapy or months to years a­ fter termination of therapy. The incidence of cardiotoxicity has been reported to be less manifested when doxorubicin is given as a prolonged infusion (e.g., 96 hours) instead of at higher doses e­ very three weeks.

Acute and Chronic Syndromes and Diseases of Cardiovascular Toxicity  /  57 Drug-­induced arrhythmias are reported to occur during or within 24 hours of administration. Rarely, sudden death and life-­ threatening ventricular arrhythmias have been reported. Arrhythmias appear to be more common in patients with abnormalities detected on baseline ECG. The probability of developing impaired myo­car­dial function based on a combined index of signs, symptoms, and decline in LV ejection fraction (LVEF) is estimated to be 1% to 2% at a total cumulative dose of 300 mg / m² of doxorubicin, 3% to 5% at a dose of 400 mg / m², 5% to 8% at 450 mg / m², and 6% to 20% at 500 mg / m². The risk of developing chronic HF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 450 mg / m². Cardiotoxicity may occur at lower doses in patients with prior mediastinal irradiation, concurrent cyclophosphamide therapy, and advanced age. Data also suggests that preexisting heart disease is a cofactor for increased risk of doxorubicin cardiotoxicity. In such cases, toxicity may occur at doses lower than the recommended cumulative dose of doxorubicin. Cardiomyopathy and/or congestive HF may be encountered several months or years ­after discontinuation of doxorubicin therapy. The risk of congestive HF and other acute manifestations of doxorubicin cardiotoxicity in ­children may be equal to or lower than in adults. C ­ hildren appear to be at par­tic­u­lar risk for developing delayed cardiac toxicity b ­ ecause doxorubicin-­ induced cardiomyopathy impairs myo­car­dial growth as c­ hildren mature, subsequently leading to pos­si­ble development of congestive HF during early adulthood. As many as 40% of c­ hildren who w ­ ere taking the drug may have subclinical cardiac dysfunction and 5% to 10% of c­ hildren may develop congestive HF on long term follow-­up. • Daunomycin: Known to induce effects similar to doxorubicin cardiomyopathy, daunomycin has an incidence of nearly 1.5% at a total dose of 600 mg / m² and 12% at 1000 mg / m². • Herceptin (trastuzumab): Herceptin, a monoclonal antibody that interferes with

HER2/neureceptor can cause LV cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death. Herceptin can also cause asymptomatic decline in LV ejection fraction (LVEF). ­There is a four-­to six-­fold increase in the incidence of symptomatic myo­car­dial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with t­ hose not receiving Herceptin. The highest absolute incidence occurs when Herceptin is administered with an anthracycline. • Imatinib (Gleevec): Severe congestive HF and LV dysfunction have occasionally been reported in patients taking imatinib, a tyrosine-­kinase inhibitor. Most of the patients with reported cardiac reactions have had other comorbidities and risk ­factors, including advanced age and previous medical history of cardiac disease. Patients with cardiac disease or risk ­factors for HF should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. • Sutent (sunitinib): Physicians are advised to weigh the risk against the potential benefits of this drug, a multi-­targeted receptor tyrosine kinase (RTK) inhibitor. Patients should be carefully monitored for clinical signs and symptoms of chronic HF while receiving Sutent, and baseline and periodic evaluations of LVEF should also be considered. In patients without cardiac risk ­factors, a baseline evaluation of LVEF should be considered. In the presence of clinical manifestations of congestive HF, discontinuation of Sutent is recommended. The dose of Sutent should be reduced in patients without clinical evidence of congestive HF but with an LVEF less than 50% and greater than 20% below baseline. • Cyclophosphamide (Cytoxan): Acute cardiac toxicity has been reported with doses as low as 2.4 g / m² to as high as 26 g / m², usually as a portion of an intensive antineoplastic multi-­drug regimen or in conjunction with transplantation procedures. In a few instances of high doses of cyclophosphamide, severe and sometimes

58  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes fatal congestive HF has occurred a­ fter the first dose. Histopathologic examination has primarily shown hemorrhagic myocarditis. Takotsubo cardiomyopathy, also known as transient apical ballooning syndrome or stress-­ induced nonischemic cardiomyopathy is a well-­ recognized cause of acute heart failure, lethal ventricular arrhythmias, and ventricular rupture. The typical pre­sen­ta­tion is sudden onset of congestive HF (possibly ischemic symptoms without HF) associated with ECG changes mimicking a myo­car­dial infarction of the anterior wall. Takotsubo cardiomyopathy is commonly triggered by severe emotional or psychological stress and occurs primarily in postmenopausal ­women. Several classes of drugs are also known to produce temporary acute cardiomyopathy symptoms consistent with Takotsubo cardiomyopathy, most commonly, catecholamine administration (e.g., epinephrine, adrenaline). HF may also occur in situations in which the heart cannot compensate for an acute or chronic augmentation of the circulation blood. This type of “high output” HF occurs in an excessive intravascular volume expansion/overload situation (e.g., blood or serum infusions, overhydration) with or without an increase in afterload (e.g., carbenoxolone, fludrocortisone, nonsteroidal inflammatory drugs). The circulatory overload can result in an increased LV diastolic pressure even with increased cardiac output and culminate in pulmonary congestion or even pulmonary edema. Glitazones (e.g., rosiglitazone, pioglitazone) are known antidiabetic agents that can cause excessive fluid retention and increase the incidence of HF.

3. Arterial Hypertension Iatrogenic, or drug-­induced, arterial hypertension is unintended higher-­ than-­ normal systolic, diastolic, or mean arterial blood pressure (BP) caused by e­ither use or withdrawal (“rebound hypertension”) of the therapeutic agent. The main mechanisms b ­ ehind drug-­induced arterial hypertension are: • Activation of the adrenergic ner­vous system (e.g., amphetamines, beta-­agonists, abrupt withdrawal of noncardiac selective beta-­ blockers or alpha-­receptor agonists, monoamine oxidase inhibitors).

• Activation of the renin-­angiotensin-­ aldosterone system and decrease of renal perfusion (e.g., nonsteroidal anti-­ inflammatory drugs such as cyclooxygenase inhibitors, some immunodepressants, estrogens). • Hormonal (e.g., adrenal cortical hormone, vasopressin, thyroid, insulin) regulation (e.g., oral contraceptives, corticosteroids). • Increased production of prostaglandin (calcineurin inhibitors), erythropoietin, darbepoetin, and testosterone. One could speculate that like primary hypertension, per­sis­tent drug-­induced increases in BP may result in aggravating morbidity/mortality due to increase in risk of cardiovascular diseases (e.g., CAD, CHF, cerebrovascular diseases, chronic kidney disease, peripheral arterial disease,) and target organ damage (e.g., stroke, transient ischemic attacks, LV hypertrophy, retinopathy). More details on iatrogenic arterial hypertension are provided in Chapters 10 and 12.

4. Arterial Hypotension Drug-­ induced arterial hypotension is commonly suspected in patients with symptomatic episodes headedness, dizziness, near-­ of dizziness, light-­ fainting, loss of consciousness, falls and associated injury, and syncope normally associated with compensatory increase in heart rate. ­These symptoms are usually exacerbated in the upright position (orthostatic hypotension). Worsening symptoms when upright may result from modulation of autonomic ner­vous system associated with drug effects on central and peripheral autonomic pathways. Chronic debilitation of the sympathetic ner­ vous system by vari­ous drugs is suspected of playing a major role in the failure of vascular tonus adjustment to the postural changes of the body participating in symptomatic orthostatic hypotension, especially in patients with reduced physical mobility, such as the geriatric population and patients with diabetes mellitus or Parkinson’s disease. Additional f­ actors that commonly participate in development of drug-­induced arterial hypotension, including orthostatic hypotension, are dehywater intake or excessive dration due to lower ­ diuresis, heat, and malnutrition. Two main groups of drugs are associated with arterial hypotension:

Acute and Chronic Syndromes and Diseases of Cardiovascular Toxicity  /  59 1. Antihypertensive agents (ACE-­I, ARBs, aldosterone antagonists, peripheral or centrally mediated alpha-­receptors modulators, peripheral vasodilators, renin inhibitors, beta-­blockers, calcium channel blockers, dopamine agonists). 2. Agents that cause unintended adverse drug effects (tricyclic antidepressants, diuretics, phenothiazines, anesthetics, antianginal, antimimetics, antiepileptics, antihistamines, chemotherapy agents, phosphodiesterase inhibitors, opiates, prostaglandins, natriuretic peptides, endothelium-­receptors antagonists). The most common mechanisms by which drugs can induce unintended arterial hypotension include inhibition or blockade of: • Angiotensin II with increases in bradykinin (e.g., captopril, enalapril, lisinopril, ramipril) • Angiotensin at the receptor level (e.g., candesartan, irbesartan, valsartan) • Renin (e.g., aliskiren) • Beta-­adrenoreceptors (e.g., atenolol, esmolol, propranolol, metaprolol) • Combined beta and alpha1-­adrenoreceptors (e.g., carvedilol) • Central and/or peripheral alpha-­ adrenoreceptors (e.g. chlorpromazine) • Renal sodium reabsorption and associated intravascular volume depletion (e.g., chlorotiazide, ­furosemide) • L-­type calcium channel blocker (e.g. amlodipine, diltiazem)

5. Myo­car­dial Ischemia and Infarction

ease. Administration of short-­ term drugs (e.g., amphetamine, marijuana, cocaine, ergonovine) or drug withdrawal (e.g. beta-­blockers, nitrates, aspirin, clonidine, clopidogrel, heparin) are more often associated with acute forms of coronary artery insufficiency, including coronary artery spasm with or without a superimposed thrombosis. Therapeutic agents that can aggravate chronic myo­car­ dial ischemia or induce acute de novo symptoms of myo­car­dial ischemia can be classified into several groups, including but not limited ­to: • Beta-­adrenergic agonists • Sympathomimetic ­agents • Diuretics • Hormone-­modulating agents (e.g., corticosteroids, prostaglandins, thyroid hormones, female sex hormones) • Illicit agents (e.g., ketamine, narcotics, stimulants, depressants, hallucinogens, LSD, marijuana, heroin, cannabis) • Nonsteroidal anti-­inflammatory drugs (NSAID), including selective COX-2 inhibitors • Phosphodiesterase inhibitors (e.g., Viagra) • Methylenedioxymethamphetamine (MDMA, or ecstasy) • Antidiabetics (e.g., rosiglitazone) • Anticancer drugs (e.g., 5-­FU) For instance, 5-­ FU has been implicated in cardiotoxicity, often manifested as ischemic pain, within hours of a dose. Myo­car­dial infarction has been reported. The toxicity is not clearly dose related, although it has been suggested that the incidence is considerably higher when the drug is given as a continuous infusion rather than a bolus. Cyclophosphamide is an example of a drug that can cause ischemic cardiac necrosis resulting in acute or subacute development of congestive HF, particularly at high doses (120 mg / kg to 140 mg / kg) in preparation for bone marrow transplant. Cisplatin is another example of a drug that can cause vascular damage and trigger acute coronary syndrome.

Myo­car­dial ischemia, coronary artery vasospasm, acute coronary syndrome, infarction, coronarogenic arrhythmia, or SCD can be induced by a variety of cardiac and non-­ cardiac medi­ cations. Most commonly, drug-­induced chronic symptomatic and asymptomatic (“­silent”) forms of coronary artery insufficiency (­either at rest or exertion) are associated with long-­term therapies that facili6. Thrombosis and tate coronary artery atherosclerosis (e.g., selective COX-2 inhibitors, nonselective NSAIDs, rosigli- Thromboembolic Disorders tazone), increase inotropic and/or chronotropic Although the incidence of drug-­induced thrombofunctions resulting in oxygen demand, particularly sis and thrombolytic complication is unknown, the in patients with pre-­existing coronary artery dis- list of medi­cations that may link to inappropriate

60  /  Acute and Chronic Drug-Induced Iatrogenic Cardiovascular Diseases and Syndromes clot formation with or without subsequent emboli- this anorexiant drug as relating to moderate or zation, including pulmonary embolism, is exhaus- greater severe mitral regurgitation, mild or greater tively long. Likely, the best recognized class of aortic regurgitation, or both. Structurally, excision drugs associated with venous thromboembolic of affected native valves revealed glistening white complication are estrogen-­containing drugs (e.g., leaflets and chordae covered with a thick coating oral contraceptives, hormone replacement). Other consistent with a proliferation of myofibroblasts common “offenders” include hemostatic drugs and deposition of abundant extracellular matrix. (e.g., recombinant f­actor VIIa), anticoagulants This type of valvular fibrosis is similar to so-­called (e.g., heparin), androgenic drugs (e.g., megestrol), “carcinoid heart,” and has been attributed by antineoplastic drugs (e.g., asparaginase, lenalido- some to the high concentration of circulating seromide, thalidomide), immune modulators (e.g., tonin, which is structurally similar to ergot derivaimmunoglobulins), antipsychotics (e.g., clozapine, tives. Discontinuation of the drugs led to only a lithium), and contrast agents (e.g., lohexol). The partial improvement of valve lesions, at best. most common mechanisms under­ lying drug-­ induced hypercoagulability and thromboembolic 8. Pericardial Diseases complications include: Drug-­ induced pericardial diseases include acute • Inhibition of fibrinolysis and chronic pericarditis with or without car• Endothelial injury diac tamponade, including systemic lupus • Platelet activation, aggregation, hyperactiv- erythematosus-­like syndrome, acute effusive periity, and adhesion carditis, constrictive pericarditis, and hemoperi• Increase in fibrinogen and clotting ­factors cardium. The most common drugs that are known • Increase in prothrombin for their association with pericardial diseases Of note, anticoagulation drugs to prevent include hydralazine, isoniazid, methyldopa, cycloand treat deep venous thrombosis can promote phosphamide, clozapine, dantrolene, cromolin, hypercoagulability and thrombosis (e.g., warfa- methotrexate, minoxidil, mesalamine, procainrin, heparin). Warfarin can cause thrombosis in amide, ergotamine, methysergine, busulfan, and the microvasculature (so-­called “skin necrosis”) fibrinolitics (e.g., alteplase, reteplase, streptokiin patients with protein C or protein S deficiency, nase). The most recognized class of drugs are long-­ whereas heparin is responsible for “heparin-­ term ergot alkaloid derivatives for migraine and acutely administered fibrinolytics for acute myo­ induced thrombocytopenia and thrombosis.” car­ dial infarction. Most cases of drug-­ induced pericarditis are self-­ limiting and usually resolve within a month a­ fter the drug’s withdrawal. 7. Valvular Diseases Historically, the first references to drug-­ induced cardiac disease w ­ ere documented in the early 1960s and w ­ ere traced to ergotamine, an ergot derivative, and methylsergine, a serotonin antagonist; both ­were indicated for relief and prevention of migraines and linked to the development of aortic and mitral valvular fibrosis. Several other ergot derivatives (e.g., bromocriptine, cabergoline, pergolide) possessed similar “regurgitant valvular disease” liability. Black label warning for pergolide was issued by the FDA in 2006, and the drug was withdrawn from the U.S. market in 2007. Arguably, the drug most widely known to cause damage to the mitral valve was anorectic agent fenfluramine, especially in combination with phenteramine (“fen-­phen”); both w ­ ere withdrawn from the U.S. market in 1997. The FDA defined

LIMITATIONS AND ­FUTURE DIRECTIONS The list of iatrogenic cardiovascular diseases and syndromes is far from complete. In the next edition of the book, we intend to expand this list by including drug-­induced autoimmune CV disorders and variety of additional drug-­induced metabolic and electrolyte disorders with a special emphasis on their diagnosis, differential diagnosis, pathophysiologic mechanisms, prevention, treatment, and follow-up recommendations. More detailed information w ­ ill be provided on an agents for hypertensive emergencies, agents for pulmonary hypertension, aldosterone receptor antagonists, angiotensin converting enzyme

References  / 61 inhibitors, angiotensin receptor inhibitors and neprilysin inhibitors, antiadrenergic agents, centrally acting, antiadrenergic agents, peripherally acting, antianginal agents antiarrhythmic agents (groups I-­V), anticholinergic chronotropic agents, antihypertensive combinations, ACE inhibitors with calcium channel blocking agents, ACE inhibitors with thiazides, angiotensin II inhibitors with calcium channel blockers, angiotensin II inhibitors with thiazides, antiadrenergic agents (central) with thiazides, antiadrenergic agents (peripheral) with thiazide, beta blockers with thiazides, potassium sparing diuretics with thiazides, cardioselective and non-­ cardioselective beta-­ adrenergic blocking agents, calcium channel blocking agents, catecholamines, diuretics, carbonic anhydrase inhibitors, loop diuretics, potassium-­sparing diuretics, thiazide diuretics, inotropic agents, peripheral vasodilators, renin inhibitors, sclerosing agents, vasodilators, vasopressin antagonists, vasopressors. Of note, due to the size limitation of this book, the list of references is significantly abbreviated.

References 1. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression a­ fter myo­car­dial infarction. Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1989;321(6):406–412. 2. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324(12):781–788. 3. Sackner Bern­ stein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111:1487–1491. 4. Sackner-­Bernstein JD, Kowalski M, Fox M, et  al. term risk of death a­fter treatment with Short-­ nesiritide for decompensated heart failure: a pooled sis of randomized controlled t­rials. JAMA. analy­ 2005;293:1900–1905.

5. Institute of Medicine (US) Committee on Quality of Health Care in Amer­ic­ a; Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is ­Human: Building a Safer Health System. Washington, DC: National Academies Press; 2000. 6. Lazarou J, Pomeranz B, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-­ analysis of prospective studies. JAMA. 1998;279:1200–1205. 7. Litwin JS, Kleiman BB, Gussak I. Acquired (drug-­ induced) long-­QT syndrome. In: Gussak I, Antzelevitch C, eds. Electrical Diseases of the Heart: Ge­ne­tics, Mechanisms, Treatment, Prevention. Springer-­Verlag: 2008:705–728. 8. Wysowski DK, Corken A, Gallo-­Torres H, et al. Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. Am J Gastroenterol. 2001;​96(6):​ 1698–1703. 9. Morganroth J, Brown AM, Critz S, et al. Variability of the QTc interval: impact on defining drug effect and low-­frequency cardiac event. Am J Cardiol. 1993;72:26B–32B. 10. Curtis LH1, Østbye T, Sendersky V, et al. Prescription of QT-­prolonging drugs in a cohort of about 5 million outpatients. Am J Med. 2003;114(2):​ 135–141. 11. Shah RR, Gussak I. Acquired (drug-­induced) long and short QT syndromes. In: Gussak I, Antzelevitch C, eds. Electrical Diseases of the Heart: Ge­ne­ tics, Mechanisms, Treatment, Prevention. 2nd ed., volume 1. London, Springer-­Verlag: 2013:​ 123–140 122. 12. See “Banzel, QT shortening,” paragraph 5.3 at https://­www​.­drugs​.­com​/­pro​/­banzel​.­html​.­ 13. Page RL II, O’Bryant CL, Cheng D, et al.; American Heart Association Clinical Pharmacology and Heart Failure and Transplantation Committees of the Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular and Stroke Nursing; and Council on Quality of Care and Outcomes Research. Drugs that may cause or exacerbate heart failure: a scientific statement from the American Heart Association. Circulation. 2016;134:00–00. doi: 10.1161/​ CIR.0000000000000426.

CHAPTER 7

Drug-­Induced Cardiac Arrhythmias and Sudden Cardiac Death Aalap Narichania, Yasuhiro Yokoyama, and Win K. Shen

Case Study A 72-­year-­old female with depression, sleep apnea, and ischemic cardiomyopathy presented with worsening dyspnea and nausea. She was admitted for heart failure exacerbation. Her previous ejection fraction was 35%. Her medi­cation list included fluoxetine. She was hemodynamically stable but required 4 liters of oxygen. Central venous pressure was elevated. Admission ECG revealed normal sinus rhythm at 62 beats per minute, no ST-­T changes, and a prolonged QTc of 490 milliseconds (ms). Compared with previous ECGs, ­there was no change. Chest radiograph revealed bilateral pulmonary edema. The patient was mildly hypokalemic and hypomagnesemic. She was treated for heart failure with furosemide and given ondansetron for per­sis­ tent nausea. ­Because she had missed her morning dose of carvedilol, it too was administered. Four hours ­after admission, the patient had a syncopal episode while in bed. She was placed on telemetry and an ECG was ordered. Heart rate was 56 ppm, and QTc interval was 560 ms; ­there was a single premature ventricular contraction (PVC). Fluoxetine and ondansetron ­were discontinued. However, the patient subsequently became transiently light-­headed and confused. Telemetry showed a polymorphic ventricular tachycardia (VT) with a twisting axis across the isoelectric line that subsequently self-­terminated. Intravenous (IV) magnesium was given and an isoproterenol infusion was started. Eventually the patient’s QTc interval shortened to her baseline, and the isoproterenol drip was discontinued.

This case typifies the pre­sen­ta­tion and management of torsade de pointes (TdP). How does the clinician approach this case? What is the under­lying mechanism? Why was this patient at risk and what amplified her risk? Could TdP have been predicted? What other arrhythmias may be the result of drugs? What does the f­uture hold? The goal of this chapter is to address t­ hese questions and review current understanding of drug-­induced cardiac arrhythmias and sudden cardiac death (SCD).

DEFINITIONS AND SCOPE Drug-­induced cardiac arrhythmia usually refers to ventricular tachyarrhythmia caused by pharmacologic agents, w ­ hether cardiovascular, noncardiovascular, or nonprescrip-

Review of the Action Potential  /  63 tion drugs. The term proarrhythmia refers to the situation in which a drug given at what is considered to be a therapeutic and nontoxic serum concentration c­ auses an arrhythmia. Although many agents, especially cardiovascular agents such as digoxin, may contribute to dangerous cardiac arrhythmias at supratherapeutic or toxic levels, ­these predictable dose-­dependent side effects are considered separately. The most dangerous drug-­induced cardiac arrhythmias are related to QTc interval prolongation and the effect that vari­ous drugs have on potassium-­mediated repolarizing currents, creating a substrate for TdP and subsequent devolution to ventricular fibrillation (VF). One unique challenge of QTc prolongation–­ related drug-­ induced arrhythmias is that many noncardiac agents are responsible and thus all clinicians, not just cardiologists and subspecialists, require aptitude and understanding of this clinical entity. Acquired long QT syndrome (aLQTS) is a focus of this chapter. However, drugs that induce other surface ECG changes such as QRS prolongation and the Brugada pattern are also considered. ­These phenomena, although rarer than aLQTS, may be underappreciated ­causes of SCD. Proarrhythmia related to drug-­induced QRS prolongation is particularly more likely in the diseased heart; as the burden of heart failure continues to increase with an aging population, it may become an increasingly relevant topic.

HISTORY OF DRUG-­INDUCED ARRHYTHMIA An association between quinidine and syncope was recognized in the 1920s. The cause was unknown. In addition, the terms quinidine shock and quinidine attack w ­ ere used to describe sudden death related to quinidine therapy. Central ner­vous system toxicity was thought to be the mechanism. However, with the advent in the 1960s of continuous electrocardiographic monitoring, quinidine syncope was observed to be due to a pause-­dependent polymorphic VT (1). Dessertenne coined the term torsade de points, which translates from French as twisting of the points, to describe the characteristic beat-­to-­beat sinusoidal change in axis seen on the surface electrocardiogram of an el­derly w ­ oman with complete

atrioventricular (AV) block and syncopal attacks associated with TdP (2). Contemporaneously, several cardiologists described congenital long QT syndrome (LQTS) and observed episodes of syncope or sudden death characterized by TdP in patients with baseline QT interval prolongation on the surface ral history and basic ECG. However, the natu­ mechanisms of congenital LQTS remained ill defined ­until two impor­tant developments: (1) the establishment of a large international registry and (2) the development of molecular and ge­ne­ tic methods to isolate specific ion channels (3). The American LQTS registry was established in 1979 and allowed for prospective follow-up of patients with well-­specified clinical phenotypes (4). Several Eu­ro­pean registries w ­ ere also created. As molecular methods advanced, strong genotype-­ phenotype relationships w ­ ere established. Despite the final common pathway of QT prolongation seen in the congenital syndrome and the drug-­ associated acquired form, t­hese studies established the ge­ ne­ tic heterogeneity of congenital LQTS whereas aLQTS was almost universally seen to be caused by blockade of the delayed rectifier potassium currents, as discussed in the next section. With the realization that certain drugs w ­ ere strongly associated with QT prolongation and ventricular arrhythmias, both the scientific community and the phar­ma­ceu­ti­cal industry directed a large number of resources and effort ­toward identifying ­ these drugs and characterizing the risk. The first noncardiac drug found to be associated with TdP was the antipsychotic thioridazine; it was ultimately withdrawn from the market specifically ­because of cardiac risk (5). Since then, a large number of noncardiac drugs with diverse chemical structures and intended therapeutic effects have been identified as causing QT prolongation.

REVIEW OF THE ACTION POTENTIAL To understand the basic differences among the drug-­induced arrhythmias discussed in this chapter, it is necessary to review the currents that mediate the cardiac action potential (AP) in myocytes. The AP consists of a series of ste­reo­typed changes

64  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death Phase 0 = Depolarization (INa) +20

1: Cl– (in), K+ (out)

1 = Repolarization (I1, 2) 2 = Plateau (ICa-L, KS)

Transmembrane potential (mV)

3 = Rapid repolarization (IKS, KR, K1) 4 = Resting potential (IK1)

0 2: Ca++ (in), K+ (out) 0: Na+ (in)

3: K+ (out)

4: K+ (out)

4: K+ (out) –90

0

200 Milliseconds (ms)

FIGURE 7-1 ​Ventricular action potential Repre­sen­ta­tion of the action potential (AP) in ventricular myocytes. Once the membrane potential has reached the threshold potential (not depicted), an AP is initiated. Phase 0 is mediated by an inward sodium current that ­causes rapid depolarization. Phase 1 is mediated by a transient outward current mediated by chloride and potassium flux. Phase 2 is mediated by relatively balanced calcium and potassium flux leading to a plateau in the membrane potential. Phase 3 rapid repolarization is mediated by several potassium currents. Phase 4 is the resting potential mediated primarily by a potassium current and balanced by the Na-­K-­ATPase pump.

in the membrane potential. The predominant current and ionic flux responsible for generating each phase of the AP are outlined in Figure 7-1. Once the membrane potential reaches the threshold potential, an AP is initiated. Phase 0 is mediated by an inward sodium current that ­causes rapid depolarization. Phase 1 is mediated by a transient outward current mediated by chloride and potassium flux. Phase 2 is mediated by relatively balanced calcium and potassium flux leading to a plateau in the membrane potential. Phase 3 rapid repolarization is mediated by several potassium currents. Phase 4 is the resting potential mediated primarily by a potassium current and balanced by the Na-­ K-­ATPase pump. Each of the currents depicted is mediated by a specific type of voltage-­ sensitive ion channel (6). The interaction between vari­ous drugs and ­these ion channels is the general mechanism of the drug-­induced arrhythmias examined in this chapter.

Mechanisms of Acquired QT Prolongation and Torsade de Pointes The under­lying mechanism of acquired QT prolongation can be understood as both cellular and organ-­level phenomena. The clinician observes QT interval prolongation on the surface electrocardiogram; this reflects a prolonged AP in at least some subset of ventricular cells due to delayed repolarization (see Figure 7-2). In drug-­ induced LQTS, drug interactions with cardiac ion channels mediate the changes in repolarization that cause AP prolongation. In contrast to congenital LQTS, in which repolarization changes are mediated by several dif­fer­ent currents depending on the specific form of congenital LQTS and the corresponding mutated channel, the majority of drugs act on the rapid component of the delayed rectifier potassium current (IKr), which is con-

Review of the Action Potential  /  65

EAD

Torsade de Pointes

QRS T

P

QT

QT QT

FIGURE 7-2 ​Early afterdepolarization and torsade de pointes Prolonged action potential (AP) duration is depicted in the top left, with corresponding QT prolongation on surface ECG depicted in the bottom left. In the top right, an early afterdepolarization (EAD) is depicted during phase 3 of the AP. In the bottom right, the EAD is seen to induce a polymorphic ventricular tachycardia, or torsade de pointes.

ducted by the ­human ether-­a-­go-­go-­related gene (hERG) potassium channel. Thus, aLQTS is analogous to the congenital Long QT Syndrome Type 2 in terms of proximate cause of AP prolongation. Over the past several de­cades, advances in molecular and genomic techniques such as cloning, site-­directed mutagenesis, X-­ray crystallography, and patch-­clamp recording have allowed for greater understanding of the normal physiology of the hERG channel, as well as how vari­ous drugs act on hERG to inhibit IKr and thus prolong AP duration. The ­human gene KCNH2 encoding hERG is located on chromosome 7. The pore-­forming subunit contains six transmembrane segments (S1–­S6) with S1 through S4 forming the voltage-­ sensing domain and S5 through S6 forming the pore domain. Beyond cardiac myocytes, the channel is expressed in a variety of cells and organ systems in which voltage-­gated potassium efflux plays a physiological role, including within neurons, gastrointestinal and genitourinary smooth muscle cells, and endocrine cells populations such as pancreatic beta-­cells and pituitary cells (7).

hERG has been labeled a “promiscuous” protein, ­because it has multiple antigen-­binding sites where a wide array of drugs and exogenous chemicals can potentially bind, affecting its function and thus the amplitude and kinetics of IKr (8). The relatively larger-­diameter inner cavity of hERG is thought to contribute to the promiscuity of the channel. Indeed, many structurally dif­fer­ent drugs and chemicals of vari­ous sizes have been seen to bind to distinct sites within the inner cavity (9,10). Direct drug binding to hERG may not be the only induced changes in mechanism mediating drug-­ repolarization. In vitro and animal studies suggest that chronic exposure to QT-­prolonging drugs may decrease expression of hERG or disrupt channel trafficking to the myocyte membrane (11). ­Whether the channel is directly or indirectly affected, the final common pathway for prolongation of the AP is IKr blockade. However, it is impor­tant to realize that delayed repolarization on a cellular level and prolonged QT interval on the surface ECG do not, in isolation, significantly increase the risk for TdP (12). TdP is induced by early afterdepolarizations (EADs), which occur during phase 2 or 3 of the AP. EADs are mediated by ICa during phase 2 or

66  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death INa or ICa during phase 3 (8). The risk of TdP is related to variances in repolarization across the myocardium in both time and space. This organ-­ level variation in repolarization is mechanistically impor­ tant in conferring additional risk to the patient with aLQTS. Spatial dispersion of repolarization can cause local voltage differences that increase the risk of ventricular arrhythmias. This spatial variability is more marked at slower heart rates. Similarly, temporal dispersion of repolarization, manifest as beat-­to-­beat variability in the QT interval, confers increased risk and arrhythmogenic potential (13). Fi­nally, AP configuration is also predictive of TdP. A triangular AP configuration or shape is associated with an increased risk for TdP. The triangular shape is likely produced by marked prolongation of phase 3 of the AP. This prolongation may increase the probability that calcium channels reactivate and cause EADs (13).

Drug Classes and Torsade de Pointes ­ able 7-1 reviews drug classes and examples of T medi­cations that can cause a prolonged QT interval and confer risk for TdP. However, it is by no means an exhaustive list. An up-­to-­date list is maintained on an online database at www​ .­crediblemeds​.­org (14). Antiarrhythmic drugs of class IA and III (see Table  7-2) predictably increase the risk of TdP. ­ They confer the highest risk but are usually prescribed by specialists (15). Class IA drugs block not only sodium channels but also IKr and prolong the AP (see ­Table  7-1). As discussed previously, quinidine was the first drug observed to increase the risk of TdP. On the other hand, class III drugs archetypally prolong the AP via IKr blockade. It should be noted

TABLE 7-1 ​Drugs associated with acquired long QT syndrome and torsade de pointes Medi­cation Class Antiarrhythmics

Examples IA

disopyramide, procainamide, quinidine

III

amiodarone, azimilide, dofetilide, ibutilide, N-­acetyl procainamide, sotalol,

IV

bepridil, terodiline amsacrine, doxorubicine, zorubicine

Anticancer Drugs Antidepressants

Antihistamines

Antimicrobials

Tricyclics

amitriptiline, clomipramine, desipramine, imipramine, nortriptiline,

Other

citalopram, doxepine, maprotiline, zimelidine

Sedating

diphenhydramine, hydroxyzine

Nonsedating

astemizole, fexofenadine, loratadine, terfenadine

Virostatic

amantadine

Macrolides

clarithromycin, erythromycin, spiramycin, troleandomycin

Quinolones

ciprofloxacin, levofloxacin

Other antibiotics

clindamycin, trimethoprim/sulfamethoxazole

Antifungals

fluconazole, itraconazole, ketoconazole, miconazole

Antiparasitics

chloroquine, halofantrine, pentamidine, quinine

Psychotropics and Phenothiazines Related Agents

Miscellaneous

chlorpromazine, fluphenazine, mesoridazine, prochlorperazine, thioridazine, trifluoperazine

Butyrophenones

haloperidol, droperidol

Other

lithium, pimozide, risperidone, sertindole, sultopride cisapride, domperidone, potassium-­wasting diuretics (indirectly through hypokalemia)

Note: For an up-­to-­date and complete list, see crediblemeds​.­org (14).

Conceptualizing Risk / 67 ­TABLE 7-2 ​Selected antiarrhythmics and their effect on the action potential Predominant Current Blocked

Use Dependence

ajmaline, disopyramide, procainamide, quinidine

INa

++

IB

lidocaine, mexiletine, phenytoin

INa

+

IC

encainide, flecainide, moricizine, propafenone

INa

+++

III

amiodarone, dofetilide, dronedarone, ibutilide, sotalol

IKr

reverse

Class

Examples

IA

AP Shape Change

Note: AP, action potential.

FIGURE 7-3 ​Rhythm strip of 46-­year-­old female a­ fter three doses of sotalol Polymorphic ventricular tachycardia follows a premature ventricular complex, in the setting of sotalol-­induced prolonged QT interval.

that amiodarone in par­tic­u­lar confers low risk of TdP, whereas sotalol confers high risk (see Figure 7-3) (16). This discordance between two class III agents may be related to less spatial dispersion of repolarization, multiple channel blockade, and a less triangular AP shape with amiodarone (15). Antimicrobials are another drug class that confers risk of TdP. Among macrolides, erythromycin and clarithromycin in par­tic­u­lar have been implicated, whereas azithromycin has less risk (17,18). Other antimicrobials are reviewed in Table  7-2. Additional classes of drugs include ­ antipsychotics, antidepressants, and antihistamines. It should be noted that many of the drugs in ­these classes pose a risk with only isolated case reports of TdP.

CONCEPTUALIZING RISK The advances in molecular understanding have certainly led to far deeper insight into aLQTS. Yet this molecular understanding can be deceptive; the ability to accurately predict aLQTS and the risk of deadly ventricular arrhythmias remain elusive. Indeed, in vitro assays largely mea­sure drug binding to hERG and blockade of IKr. However, the drug affinity for hERG is not predictive of prolonged QT c and prolonged QT c does not specifically predict TdP or SCD. Many clinical confound­ers add to the complexity of prolonged repolarization and clinical arrhythmia interactions. The concept of repolarization reserve has been used to describe the resiliency that the

68  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death ­TABLE 7-3 ​Risk ­factors for drug-­induced torsade de pointes Structural heart disease   Congestive heart failure Myo­car­dial infarction  

Advanced age Female Hypokalemia Hypomagnesemia Hypocalcemia Occult (subclinical) congenital LQTS Baseline QT prolongation Ge­ne­tic ion-­channel polymorphisms Treatment with diuretics Impaired hepatic drug metabolism (hepatic dysfunction or drug-­drug interaction) Bradycardia, frequent pauses Rapid infusion rate with QT-­prolonging drug

electrophysiologic system of a par­tic­u­lar patient possesses in response to a f­actor, such as a drug, that acts to decrease the current IKr and increase the AP duration (19). This concept, while somewhat nebulous, is impor­tant to appreciate; seeking to understand and estimate a par­ tic­ ul­ar patient’s repolarization reserve is a critical step in managing the risk of drug-­induced QT prolongation. Patients with preserved repolarization reserve can likely tolerate initiation of a drug that blocks IKr and prolongs QT without a significant risk of TdP. Inversely, ­there may be patients with multiple subclinical ge­ne­tic or environmental risk ­factors that affect repolarization but are compensated for in the normal state. However, once a culprit drug is initiated in such a patient, IKr decreases, the AP prolongs, and the patient—­ unable to compensate—is exposed to significant risk of TdP and SCD. ­Table 7-3 reviews risk f­ actors for TdP, including ­those contributing to decreased repolarization reserve. Some patients with ge­ne­tic vulnerabilities due to hERG polymorphisms may not have classic congenital LQTS. ­These patients may typically have a low baseline risk, but the presence of addifactors such as QT-­ prolonging drugs or tional ­

electrolyte imbalance may put them at higher risk than the wild-­type population. Polymorphisms in genes KCNQ1, KCNH2, KCNE, KCNE2, and ANKB have been identified in some patients with drug-­induced TdP (20,21). Gender is a significant risk modifier for TdP; females are at increased risk (22,23). Given this clinical observation, a hormonal mechanism has been postulated. ­There is some evidence that both testosterone and progesterone contribute to differences in repolarization among men and ­women (24). Testosterone may modulate the calcium current in phase 2 of the AP and thereby decrease the risk of TdP (25). Structural heart disease is a significant contributor to decreased repolarization reserve. Heart failure likely decreases repolarization reserve through multiple mechanisms. In vitro studies have demonstrated that angiotensin II (ATII)–­mediated activation of angiotensin receptors increases proteosomal degradation of hERG via the protein kinase C pathway, thus effectively downregulating hERG (26). The decrease in amplitude of IKr mediated by ATII is abrogated by the angiotensin receptor blocker losartan (27). Drug-­drug interactions and pharmacokinetic effects play a significant role in drug-­ induced arrhythmia. Many of the antiarrhythmics and other QT-­prolonging agents are metabolized by the liver, and specifically by the CYP3A4 enzyme. Thus, medi­cations that inhibit CYP3A4, when concomitantly administered with QT-­prolonging medi­cations, may create enhanced risk of TdP (8). Commonly used inhibitors of CYP3A4 include diltiazem, verapamil, hydralazine, fluoxetine, macrolide antibiotics, contraceptives, and grapefruit juice. Other risk f­actors are reviewed in ­Table 7-3. ­There has been some in­ter­est­ing work in elucidating potential additional risk ­factors and sources of decreased repolarization reserve. For instance, disrupted sleep-­wake cycles and obstructive sleep apnea may be sources of risk. Apneic episodes during sleep are associated with QT prolongation thought to be secondary to increased vagal activity. In addition, QT prolongation persists during the day, likely contributing to the increased risk of ventricular arrhythmias in t­hese patients (28). In addition, the risk of SCD varies in a diurnal pattern. Electrocardiographically, QTc interval ­ length has a diurnal pattern; it is longer during

Clinical Considerations / 69 sleep and reaches a peak shortly ­after awakening (29). Molecular correlates have been described in increasing detail (30). The circadian rhythm governs cardiac repolarization by modulating the expression of KCNH2 (31). Another recently described potential source of risk is systemic inflammation. Studies have demonstrated that patients with rheumatoid arthritis (RA), for instance, have an increased risk of death from ventricular arrhythmias (32). In ­human studies, serum levels of IL1-­beta, IL6, and TNF-­alpha have been shown to correlate with extent of QTc prolongation (33). RA patients treated with tocilizumab, an anti–­IL6 receptor antibody, experience shortening of QTc interval (34). Experimental models support ­these observations. In vitro, TNF-­alpha has been seen to reduce IKr and expression of hERG in a concentration-­dependent manner. This effect was blocked by TNF-­alpha antibodies (35). Decrease in IKr by TNF-­alpha seems to be mediated by reactive oxygen species (35,36).

CLINICAL CONSIDERATIONS Management of the patient with incidental drug-­ induced long QT is not straightforward and t­ here is no evidence-­based interval length of the QT at which a stepwise increase in risk occurs. Common practice is to investigate and monitor the patient with a QT interval greater than 500 ms who is other­wise asymptomatic. Monitoring may be done with intermittent surface ECGs ­until the QT interval normalizes. The clinician must look for the specific drug or drugs that contributed to the QT prolongation and then weigh the dosage and medical necessity. Furthermore, if the source of new QT prolongation is not obvious, a workup to determine if ­there has been a change in the repolarization reserve of the patient may be useful. For instance, a patient who has had a change in liver function (pharmacokinetics) or kidney function (electrolyte imbalances) may also pres­ent with a change in QT interval. Management of TdP is more straightforward. If the patient is hemodynamically unstable, then an immediate electrical nonsynchronized defibrillation should be delivered to the patient, per Advanced Cardiac Life Support guidelines (37). If the patient is hemodynamically stable, then magnesium should immediately be

­TABLE 7-4 ​Acute management of torsade de pointes First-­line therapy   Magnesium sulfate (2 grams, intravenous bolus)  Isoproterenol (2 mcg /min, titrated to achieve heart rate of 100 beats per minute)  Temporary transvenous overdrive pacing to a heart rate of 100 beats per minute (alternative to isoproterenol) Ancillary therapy  Lidocaine  Phenytoin  Sodium bicarbonate (for quinidine-­related arrhythmia)

given intravenously as a temporizing mea­sure. The next step in management is to increase the heart rate to above 100 beats per minute, e­ ither with an isoproterenol infusion or placement of a transvenous pacer. ­These and additional mea­ sures are outlined in ­Table 7-4.

Sodium Channel Blockers and Proarrhythmia The prevailing understanding of drug-­induced proarrhythmia was challenged by the outcomes of the landmark Cardiac Arrhythmia Suppression Trial (CAST). To understand the current paradigm of antiarrhythmic usage and the careful approach required in patients with preexisting left ventricular dysfunction, it is helpful to understand this impor­tant trial. Multiple clinical observations and studies had demonstrated that ventricular arrhythmias caused by reentry cir­ cuits formed from scarred myocardium ­ after myo­ ­ ere a significant car­ dial infarction (MI) w cause of post-­MI morbidity and mortality. Given this observation, clinicians routinely sought to suppress asymptomatic ventricular premature depolarizations (VPDs) with antiarrhythmic drugs ­after an MI. Although suppression of VPDs was often achieved in this setting, it was unclear if this practice improved outcomes. Thus, the CAST study was initiated, a double-­blind prospective randomized trial comparing placebo with vari­ous antiarrhythmics. In 1989, the first results published clearly demonstrated excess mortality in patients randomized

70  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death to the class IC drugs flecainide and encainide (38). This portion of the trial was terminated early ­because, over an average of 10 months of follow-up, flecainide and encainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (relative risk of 3.6 and 95% confidence interval of 1.7 to 8.5). The second CAST trial similarly demonstrated excess mortality in a group receiving moricizine versus placebo, and the Data and Safety Monitoring Board for the study stopped the trial early (39). The results of CAST definitively showed that sodium channel blockade in the structurally abnormal heart can lead to cardiac arrest and SCD. Based on CAST, class I antiarrhythmics are contraindicated ­after MI and, in practice, are not used in the presence of any structural heart disease. CAST not only contributed to the more conservative approach to antiarrhythmic therapy ­today, but also had broader implications in cardiology and medicine by validating the controlled clinical trial and contributing to the impetus for evidence-­and guideline-­based medicine. The mechanism of sodium channel blocking drug (NCBD) toxicity and proarrhythmia is distinct from TdP. Unlike TdP, which is dependent on abnormalities in repolarization (prolonged QT) and induced by EADs, NCBD proarrhythmia is thought to be related to the slowing of conduction, a delay in depolarization, and the promotion of reentrant ventricular arrhythmias. On the surface ECG, this may manifest as a prolonged QRS interval. An abnormal substrate seen in an ischemic or scarred myocardium a­ fter an MI amplifies the risk, as CAST observed. NCBDs prolong conduction to a greater degree in a diseased (scarred or ischemic) myocardium than in a healthy myocardium. This property ­causes nonuniform conduction and therefore increases the risk of reentrant ventricular arrhythmias (40). tant consideration is that Another impor­ NCBDs and in par­tic­ul­ar class IC agents exhibit use dependence; they are more effective in blocking sodium current at faster heart rates. This is ­because NCBDs bind to the open state of sodium channels and then release when the channels adopt a closed conformation. The kinetics of dissociation are slow; therefore, at faster heart rates, when the probability of the channel being open is greater and less time is available for dissociation, t­ here is more effective channel blockade and

slowing of conduction. Subgroup analy­ sis in CAST revealed that patients not on beta-­blockers had significantly higher mortality (8,39). ­These NCBDs often prolong the QRS interval on the surface ECG even at normal heart rates. Examples include flecainide, propafenone, and other IC agents. However, any of the class I drugs may be implicated. Other noncardiovascular drugs are also impor­tant to consider. Tricyclic antidepressants (TCAs) possess class I activity and cause QRS prolongation and increased risk for ventricular arrhythmias. The anticholinergic ­ ecause effect of TCAs exacerbates cardiotoxicity b of the parasympatholytic effect and associated tachycardia (41). Other NCBDs that have been implicated include anticonvulsants such as phenytoin, drugs used to treat neuropathic pain and diabetes, and immunomodulators (8). Treatment is directed principally at identifying the iatrogenic agent that is causing the proarrhythmia and discontinuing its administration. Of course, in the hemodynamically unstable patient, standard advanced cardiovascular life support should be initiated. However, certain additional interventions can be helpful in the hemodynamically stable patient. Contributing metabolic aberrations such as acidosis and hyperkalemia should be identified and reversed. Hypertonic saline or sodium bicarbonate infusion can be helpful in overcoming sodium blockade. In addition, the heart rate can be slowed with negative chronotropic agents, usually beta-­blockers, in order to lessen the effect of use dependence.

Drug-­Induced Brugada Syndrome Brugada syndrome is a familial condition with autosomal dominant transmission and incomplete penetrance that predisposes affected individuals to ventricular arrhythmias, syncope, and SCD. The surface ECG is characterized by coved ST elevation and J point elevation of at least 2  mm in at least two of three right precordial leads (V1 to V3). Diagnosis requires the aforementioned ECG findings (so-­ called type 1 pattern), exclusion of structural heart disease, and symptoms in the patient that can be ascribed to ventricular arrhythmias: documented VF, polymorphic VT, aborted SCD, syncope, nocturnal agonal respiration, palpitations, or chest discomfort (42,43). Fever and increased vagal tone have

Clinical Considerations / 71

V1

V1

V2

V2

V3 V3 Baseline

Procainamide 10mg/kg

FIGURE 7-4 ​Patient with a ­family history of sudden cardiac death The patient’s baseline ECG does not show a type 1 Brugada pattern. However, ­after procainamide challenge, a type 1 pattern is unmasked.

been observed to induce the Brugada ECG pattern and trigger SCD (41). In patients with one or more of t­hese clinical features but with a normal baseline ECG, the Brugada surface ECG phenotype may be unmasked with intravenous or oral administration of sodium channel blockers (ajmaline, flecainide, pilsicainide, or procainamide). In some patients, the type 1 ECG Brugada pattern may be pres­ent, ­whether before or ­after sodium channel blocker administration, but the patient may be asymptomatic without documented clinical manifestations of ventricular arrhythmias. In 2013, guidelines ­were published to address this subset of patients (43). A list of electrocardiographic findings are considered supportive of the diagnosis of Brugada syndrome in the asymptomatic patient. They include attenuasegment elevation during exercise tion of ST-­ stress test, first-­degree AV block with left-­axis deviation, atrial fibrillation (AF), fragmented QRS, and several other findings. However, ­there remains a subset of patients that are asymptomatic, lack the suggestive electrocardiographic findings published in the 2013 guidelines, and yet demonstrate a type 1 Brugada pattern on their surface ECG, ­after the adminis-

tration of certain drugs (see Figure 7-4). It is currently unknown if this subset of patients possess true Brugada syndrome with a ge­ne­tic basis and an increased risk of SCD that has been unmasked by medi­cation, or if the Brugada pattern is a benign finding without an altered prognosis (45). Brugada syndrome itself is mediated by a variety of autosomal dominant ge­ne­tic mutations. The implicated gene most commonly identified is SCN5A (with more than 300 mutations identified) (46). SCN5A encodes the alpha subunit of the cardiac sodium channel that mediates phase 0 of the cardiac AP. However, at least 12 other genes have been implicated: ­These include genes that encode for subunits of cardiac sodium, potassium, and calcium channels (44,46). At this time, a ge­ne­tic substrate is found in only about one-­third of Brugada syndrome patients who are genotyped (43). The electrophysiological mechanisms that underlie the Brugada syndrome phenotype are not precisely defined. The repolarization theory suggests that a relatively decreased inward sodium or calcium current or enhanced outward potassium current in the right ventricular epicardium, but not in the endocardium, ­causes a transmural voltage gradient observed on the surface ECG as the

72  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death Brugada pattern. This repolarization pattern may induce phase 2 reentry due to transmural dispersion of refractoriness, mediating VT, or fibrillation. Any drugs that act similarly to decrease the inward current or enhance the outward current at the end of phase 1 of the AP may similarly cause a transmural voltage gradient to form in the right ventricle. However, it remains unclear if this drug-­ induced Brugada pattern on the surface ECG and its correlation to Brugada syndrome is mediated by a ge­ne­tic substrate and is unmasked by the culprit drug or if it is a normal variant in a wild-­type patient exposed to a cardiac current-­modulating drug without prognostic implications. Several drug classes have been linked to the drug-­induced Brugada pattern. For the practicing clinician, an up-­ to-­ date database of drugs that should be avoided in patients with Brugada syndrome is located at www​.­brugadadrugs​.­org (47). This database correlates with drugs that have been implicated in drug-­induced Brugada ECG pattern. Among antiarrhythmics, class IA and IC sodium channel blockers are the most likely to induce the Brugada pattern, and intravenous administration of many of ­these agents is used as a diagnostic procedure to confirm Brugada syndrome in cases of transient Type 1 ECG changes. Both classes strongly block INa. Class IA drugs disassociate from the channel binding site quickly, possessing less use dependence, and therefore are thought to induce less dramatic ST elevation than class IC agents. Notably, quinidine, although a class IA drug, has been observed to normalize ­ST-­segment elevation and has been used as a treatment. This effect is likely ­because quinidine blocks both Ito (see Figure 7-1) and IKr. Several nonantiarrhythmic agents have been implicated in inducing the Brugada pattern. As discussed previously, TCAs are associated with drug-­ induced cardiac arrhythmias and SCD through a variety of mechanisms, resulting in QT prolongation (blockade of IKr) and QRS prolongation (blockade of INa). TCAs have also been associated with drug-­induced Brugada pattern, although the incidence appears rare (45). Similarly, selective serotonin reuptake inhibitors, such  as  fluoxetine, have been reported to unmask a Brugada pattern. Lithium and antihistamines have been reported as additional unmasking agents (48,49). If the Brugada pattern is seen in response to drug administration, the clinician should attempt to identify the offending agent and ensure that the

ST elevation resolves a­ fter the drug is discontinued. A careful history should be taken to ensure that the patient has not experienced symptoms consistent with previous episodes of ventricular arrhythmia. In addition, a careful f­amily history should be obtained and any familial SCD should be elicited. If the patient is deemed to be asymptomatic, referral and further risk stratification may be appropriate with an electrophysiology study to assess for inducibility. The prognostic value of inducible sustained ventricular arrhythmia in asymptomatic patients appears to be modest which warrants further investigation (50).

Antiarrhythmic Drug–­Induced Malignant Early Repolarization Syndrome A potential emerging entity remains less defined than the other drug-­induced arrhythmias. Initially, ST-­segment elevation in the absence of chest pain was referred to as early repolarization (ER). More recently, ER has referred to a sharp positive deflection or notch a­ fter a positive QRS complex, at the onset of the ST segment. Currently, t­ here is no widely ­adopted precise definition of ER (51). The ECG findings are common and have been historically thought of as benign. However, several studies have found a correlation between ER and SCD (52,53). A ge­ne­tic basis has begun to emerge with a combination of observational reports and genomewide association studies (43). A case of malignant early repolarization syndrome is discussed on page 73.

CONCLUSION Much pro­gress has been made in understanding drug-­induced arrhythmias and SCD. However, the clinician is still faced with uncertainty and a lack of data when faced with aLQTS in par­tic­u­lar and other drug-­ induced ECG abnormalities. The 72-­year-­old female patient described at the beginning of this chapter certainly had decreased repolarization reserve and was at risk for TdP. Tools for better risk stratification are needed. More research into the mechanisms and more robust correlations between genotype, phenotype, and epidemiology may allow for better risk stratification and management of both sodium and potassium channel–­related drug-­induced arrhythmias.

Conclusion / 73

Case Study An in­ter­est­ing case of antiarrhythmic drug–­induced malignant ERS was reported in 2014 (54). This was a 49-­year-­old Japa­nese man with symptomatic paroxysmal AF who experienced repeated syncope 30 minutes ­ after oral pilsicainide 150  mg and verapamil 80  mg administration in the early morning. He was instructed by his ­family doctor to take ­these drugs together as a “pill in the pocket” when having palpitations. Verapamil was added to prevent class IC drug–­induced atrial flutter-­medicated rapid ventricular rate. The emergency crew confirmed a self-­ terminating repetitive polymorphic VT on the ECG monitor. Lidocaine 50 mg was administrated intravenously in the emergency room to inhibit frequent PVCs. Unexpectedly, this caused J wave elevation in leads I, II, aVL, and V2–6, and accelerated PVCs. The J waves showed pause-­ dependent augmentation, and polymorphic VT was initiated a­ fter a short-­long sequence (see Figure 7-5). A malignant ERS was sus-

pected at this point. Intravenous isoproterenol immediately attenuated the J waves and inhibited the PVCs. A systematic examination ruled out an electrolyte abnormality, inflammatory diseases, coronary artery disease, and structural heart diseases. The patient was diagnosed with a drug-­induced malignant ERS. He stopped oral antiarrhythmic drugs and underwent successful PVI. Since then, the patient has had no significant J wave elevation or ventricular arrhythmias. J wave elevation, PVCs, and polymorphic VT ­were reproducible only by both intravenous administrations of pilsicainide and verapamil u­nder parasympathetic ­ activation (prepared with intravenous edrophonium 10 mg and propranolol 2 mg). Pilsicainide alone or pilsicainide and verapamil without parasympathetic activation ­were unable to reproduce t­hese changes. Ge­ne­tic studies for malignant ERS have identified rare gene mutations associated with the ATP-­ sensitive

FIGURE 7-5 ​A case of pilsicainide-­induced malignant early repolarization syndrome The patient experienced polymorphic ventricular tachycardia ­after taking oral pilsicainide 150 mg and verapamil 80 mg as “pill in the pocket” therapy early in the morning for atrial fibrillation.

74  /  Drug-Induced Cardiac Arrhythmias and Sudden Cardiac Death potassium channel, L-­type calcium channel, and cardiac sodium channel (43). The patient may have a latent gene abnormality associated with cardiac ion channels, but, unfortunately, he ­ didn’t agree to

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CHAPTER 8

Chemotherapy-­Induced Cardiomyopathy Edo Y. Birati and Mariell Jessup

INTRODUCTION Cancer remains one of the leading c­auses of morbidity and mortality worldwide. According to the World Health Organ­ization, t­here ­were 14 million new diagnoses of cancer in 2012, and the incidence of new cancer cases is expected to increase by 70% over the next two de­cades (1). The most common sites of cancer in men are lung, prostate, colorectal, stomach, and liver, whereas breast, colorectal, lung, cervix, and stomach are the most common sites in ­women (1). Although t­here has been a significant improvement in survival of most cancers over the past three de­cades, one in e­ very four deaths in the United States is related to cancer (2). The improvement in survival is secondary to early diagnosis, improvement in treatment protocols, and new targeted therapies (2). For example, acute lymphocytic leukemia saw an increase in the five-­year survival rate from 41% in 1970 to 70% in 2010 (2). In chronic myeloid leukemia, treatment with BCR-­ABL tyrosine kinase inhibitors doubled the survival rate from 31% in 1990 to 60% in 2010 (2,3). As more patients survive cancer, t­ here is increased evidence of early and late consequences of chemotherapy. This chapter focuses on the cardiotoxicity of vari­ous chemotherapy agents.

Definition and Prevalence of Chemotherapy-­Induced Cardiomyopathy Chemotherapy-­induced cardiotoxicity is defined by the National Cancer Institute (NCI) as a toxicity of chemotherapy agents that affects the heart (4). As for other chemotherapy-­related adverse events, NCI classifies cardiovascular (CV) adverse events into Grades 1 through 5: Grade 1 is for asymptomatic patients with evidence of cardiac abnormality on imaging or elevated cardiac biomarkers; Grade 2 indicates mild symptoms; Grade 3, moderate symptoms; Grade 4, severe life-­threatening symptoms; and Grade 5, death (5). A commonly used clinical definition formulated by “the cardiac review and evaluation committee supervising trastuzumab clinical ­trials” defines drug-­associated cardiotoxicity as one or more of the following: (a) cardiomyopathy characterized by a decrease in cardiac left ventricular ejection fraction (LVEF); (b) symptoms of heart failure (HF); (c) associated signs of HF; or (d) a decline in LVEF of at least 5% to less than 55% with

78 / Chemotherapy-Induced Cardiomyopathy ­TABLE 8-1 ​Definitions of chemotherapy-­related cardiac dysfunction Authority

Definitions

Reference

National Cancer Institute

Toxicity of chemotherapy agents that affects the heart.

5

Grade 1 – Asymptomatic patients with evidence of cardiac abnormality on imaging or elevated cardiac biomarkers Grade 2 – Mild symptoms Grade 3 –­Moderate symptoms Grade 4 –­Severe life-­threatening symptoms Grade 5 –­Death The cardiac review and evaluation committee supervising trastuzumab clinical ­trials

One or more of the following:

6

1) Decrease in LVEF 2) Symptoms of HF 3) Signs of HF 4) Decline in LVEF of at least 5% to less than 55% with accompanying signs or symptoms of HF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms.

Joint committee of the American Society of Echocardiography and Eu­ro­pean Association of Cardiovascular Imaging

Decrease in the LVEF of more than 10%, to a value less than 53%. Repeat study with similar results in 2–3 weeks.

7

Note: LVEF, Left ventricular ejection fraction; HF, heart failure.

accompanying signs or symptoms of HF, or a decline in LVEF of at least 10% to below 55% without accompanying signs or symptoms. The presence of any one of ­these four criteria is sufficient to confirm a diagnosis (6). A joint committee of the American Society of Echocardiography (ASE) and the Eu­ro­pean Association of Cardiovascular Imaging (EACI) defined cancer therapeutics–­related cardiac dysfunction (CTRCD) as a decrease in LVEF of more than 10%, to a value of less than 53%. This finding should be confirmed on repeat imaging done two to three weeks ­after the initial study (7). Thus, the incidence of cardiotoxicity varies between studies and definition criteria, and depends on dif­ fer­ ent ­ factors including type of drug, cumulative dose, route of administration, combination with other cardiotoxic drugs, association with radiotherapy, patient’s age, and other CV risk ­factors (8,9). For example, among patients treated with anthracyclines, 1% to 5% of the patients suffered from clinical HF and as many as 20% of the patients had an asymptomatic decrease in LVEF (10,11).

Myo­car­dial dysfunction can occur immediately a­ fter exposure to chemotherapy, as usually occurs with anthracyclines. However, the change in myo­car­dial function may become apparent cades a­fter therapy is only years or even de­ given (7,12). ­Table 8-1 summarizes the vari­ous definitions.

Classification of Cancer Therapeutics–­Related Cardiac Dysfunction CTRCD is classified according to the extent of injury and reversibility. Type I is dose related and irreversible. It is thought to be related to production of oxygen f­ ree radicals, resulting in oxidative stress and subsequent influx of intracellular calcium; the exact mechanism is not well understood. Anthracyclines as well as mitoxantrone may cause type I CTRCD (7,13,14). Type II is not related to cumulative dose and is thought to be reversible in 79% of patients ­after discontinuation of therapy (2 to 4 months) (13,15). Trastuzumab is the common agent associated with type

Main Agents that Cause Cardiomyopathy  /  79 ­TABLE 8-2 ​Classification of chemotherapy-­related cardiac dysfunction

Characteristic agent

Type I

Type II

Doxorubicin

Trastuzumab

Clinical course, response May stabilize, but under­lying damage appears to be High likelihood of recovery (to to CTRCD therapy permanent and irreversible; recurrence in months or near baseline cardiac status) or years may be related to sequential cardiac stress in 2 to 4 months (reversible) Dose effects

Cumulative, dose related

Not dose related

Mechanism

­Free radical formation, oxidative stress/damage

Blocked ErbB2 signaling

Ultrastructure

Vacuoles; myofibrillar disarray and dropout; necrosis No apparent ultrastructural abnormalities

Effect of rechallenge

High probability of recurrent dysfunction

Increasing evidence for the relative safety of rechallenge

Adapted from Ewer MS, Lippman SM. Type II chemotherapy-­related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900–2902. Note: CTRCD, cancer therapeutics–­related cardiac dysfunction.

II CTRCD (13). The mechanism of trastuzumab cardiotoxicity prob­ably involves the ErbB2 pathway, which is required for the growth, repair, and survival of cardiomyocytes, and is essential in maintaining cardiac contractility, function, and structure (16,17). ­ Table  8-2 summarizes the CTRCD classification.

MAIN AGENTS THAT CAUSE CARDIOMYOPATHY This chapter focuses on the main groups of chemotherapy agents and their effect on the heart. It is beyond the scope of this text to overview all chemotherapy agents.

Anthracyclines Anthracyclines (doxorubicin, daunorubicin, epirubicin, idarubicin) remain an impor­tant component of many cytotoxic regimens for treating vari­ous types of malignancies, including hematologic (leukemia, lymphoma) and solid tumors (e.g., lung, breast, ovarian, stomach) (18,19). Some 40 years ago, a study showed that 2.2% of patients treated with doxorubicin suffered from drug-­induced HF; the incidence was related to the drug dose, reaching 18% at a cumulative dose of 700 mg / m² (20). However, t­hese percentages likely underestimated the true incidence of doxorubicin cardiotoxicity; a more recent study reported that the incidence might be as high as 48% among patients treated

with a cumulative dose of 700  mg / m2 (21). For this reason, the recommended cumulative dose is limited to 450 mg / m2 to 500 mg / m2. Other risk factors for anthracycline-­ ­ induced cardiotoxicity are detailed in ­ Table  8-3. Acute cardiotoxicity occurring immediately ­after infusion of the drug may affect fewer than 1% of patients. Late onset or chronic cardiotoxicity is more frequent and may occur 10 to 20 years ­after therapy (19). ­TABLE 8-3 ​Risk ­factors for anthracycline-­induced cardiotoxicity ­Factors Female Young age Concomitant mediastinal radiation Cumulative dose

Daunorubicin > 550–800 mg /m2 Doxorubicin > 400–550 mg /m2 Epirubicin > 900–1000 mg /m2 Idarubicin > 150–225 mg /m2 Amsacrine > 580 mg /m2 Mitoxantrone > 100–140 mg /m2

Previous Hypertension, coronary cardiovascular disease disease Electrolyte disturbances

Hypocalcemia, hypomagnesemia

80 / Chemotherapy-Induced Cardiomyopathy DOX

TOP2β poisoning

ROS 2+

Fe

Oxidative stress

Mitochondrial dysfunction

Transcriptome changes

DNA damage response p53

mitochondrial biogenesis antioxidant enzymes

Apoptosis Senescence Energetic failure Unbalanced autophagy Altered signaling

FIGURE 8-1 ​Mechanism of anthracycline-­induced cardiomyopathy Anthracycline stimulates production of reactive oxygen species (ROS) and also ­causes inhibition of topoisomerase 2-­beta, resulting in double-­stranded breaks in DNA, mitochondrial dysfunction, and further generation of ROS, leading to cardiomyocyte death. (Mercurio V, Pirozzi F, Lazzarini E,et al. Models of heart failure based on the cardio­ toxicity of anticancer drugs. J Card Fail. 2016 Jun;22(6):449–458.)

Note: DOX, doxorubicin; ROS, reactive oxygen species; TOP2β, topoisomerase 2-­beta.

The extensive study of anthracycline-­induced ous potential cardiomyopathy has revealed vari­ mechanisms. ­Until recently, the accepted hypothesis was that anthracycline-­induced cardiomyopathy is associated with the generation of reactive oxygen radicals (19,22–25). ­These reactive oxygen species (ROS) are generated by electron exchange from cellular oxygen molecules and the anthracycline moiety as well as from the interaction of anthracycline with iron (26,27). ROS cause membrane lipid peroxidation and mitochondrial dysfunction, leading to apoptosis and cell death (19,22–25). The reduction in the number of myocytes secondary to cell death, with limited regenerative ability of the heart, leads to ventricular remodeling and reduced ejection fraction (19,22). However, t­rials of treatment with antioxidants and iron chelation did not prevent cardiomyopathy, and thus alternative hypotheses of the mechanism for anthracycline-­induced cardiomyopathy are needed (27,28). An impor­tant breakthrough involves topoisomerase 2-­ beta. Inhibition of topoisomerase beta by anthracyclines was found to cause 2-­ double-­stranded breaks in DNA, mitochondrial dysfunction, and further generation of ROS, leading to cardiomyocyte death (29). See Figure 8-1.

Trastuzumab and HER2-­Targeted Agents Trastuzumab (Herceptin) is a humanized monoclonal antibody that binds to the extracellular domain of the ­human epidermal growth ­factor receptor 2 (HER2), resulting in disruption of HER2 regulatory functions in cell growth and differentiation (30,31). The HER2 gene (also known as c-­erbB-2) is amplified in 20% to 25% of ­human breast cancer, and ­these HER2-­positive tumors have a more aggressive phenotype. Treatment with trastuzumab has been associated with improved survival as well as reduced risk of disease recurrence; it has become the standard of care for w ­ omen with early stages of HER2-­positive breast tumor (30,32). Cardiotoxicity is common among patients treated with HER2-­targeted agents. Studies have shown that 27% of patients treated with combined therapy of trastuzumab and anthracycline had CTRCD, and 13% of patients when trastuzumab was combined with paclitaxel (30,31). However, a recently published meta-­analysis evaluated the cardiotoxicity of trastuzumab in 58 studies of more than 29,000 patients treated with the drug (33). Severe cardiotoxicity (defined as the occurrence of HF, myo­car­dial infarction, arrhyth-

Diagnosis of Chemotherapy-­Induced Cardiomyopathy  /  81 ­TABLE 8-4 ​Risk prediction for trastuzumab-­ associated cardiotoxicity ­Factors

Points Assigned

Adjuvant therapy  Anthracycline

2

 Nonanthracycline

2

Age (years)  67–74  75–79

1

 80–94

2

Cardiovascular conditions and risk f­ actors

Taxanes

  Coronary disease

2

  Atrial fibrillation or flutter

2

  Diabetes mellitus

1

 Hypertension

1

  Renal failure

2

Risk score

electronegative molecules presented on cells. Alkylating agents inhibit DNA transcription, preventing cell replication. They are currently used in the treatment of breast, bladder, ovarian, lung, and hematologic cancers (25,35,36). Cyclophosphamide has been associated with myo­car­dial dysfunction in 7% to 28% of patients. Generally, it is not associated with classic cardiotoxicity and more commonly induces severe acute pericarditis and hemorrhagic myocarditis. The mechanism is unclear but is thought to be secondary to oxidative stress, resulting in endothelial damage (35,36).

Heart failure or cardiomyopathy in 3 years (%)

0,1,2,3

14.5

4 or 5

26.2

6,7,8, or 9

42.9

Ezaz G, Long JB, Gross CP, et al. Risk prediction model for heart failure and cardiomyopathy a­ fter adjuvant trastuzumab therapy for breast cancer. J Am Heart Assoc. 2014;3(1):e000472.

mias, reduction in LVEF, or other cardiac toxicity of Grade 3 or 4, according to the NCI Common Toxicity Criteria for Adverse Events (5) occurred in 3% of the patients (95% CI 2.41–3.64) (33). A risk model for prediction of cardiotoxicity in ­women treated with trastuzumab found that the factors associated with increased risk for main ­ cardiotoxicity are el­derly age, cotreatment with anthracycline, history of coronary artery disease, hypertension, diabetes mellitus, atrial fibrillation, and renal failure (see ­Table 8-4) (34).

Taxanes (paclitaxel, docetaxel) bind and inhibit the disassembly of microtubules, resulting in dysfunctional microtubules and disruption in cell division. Another potential mechanism of action of this group is through histamine release (19,37). The main cardiac effects of taxanes involve the conduction system and usually resolve following discontinuation of therapy. Almost one-­ third of patients treated with paclitaxel have asymptomatic sinus bradycardia, which does not require intervention in the majority of cases. Approximately 5% of patients may pres­ent with more significant conduction blocks, ventricular tachycardia, and myo­car­dial ischemia (37,38,39). Importantly, taxanes may significantly increase the risk for anthracycline-­induced cardiotoxicity when combined with an anthracycline agent (39).

DIAGNOSIS OF CHEMOTHERAPY-­INDUCED CARDIOMYOPATHY Noninvasive Imaging Echocardiography

Echocardiography is the most commonly used cardiac imaging modality (40) as well as the most commonly used test for detecting and following chemotherapy-­induced cardiotoxicity (19). Transthoracic echocardiogram is a noninvasive test with minimal incon­ve­nience to the patient and no assoAlkylating Agents ciated risks. The test provides accurate data on ­These drugs (cyclophosphamide, ifosfamide, cis- cardiac structures, including chambers and valves. platin) have the ability to add alkyl groups to Moreover, this test assesses systolic and diastolic

82 / Chemotherapy-Induced Cardiomyopathy function, evaluates valvular function, and estimates intracardiac hemodynamics (40). A joint consensus report of ASE and EACI recommends obtaining noninvasive imaging at baseline in all cancer patients with a history or clinical findings of myo­car­dial dysfunction and in ­those with risk ­factors for cardiac events (age, hypertension, family history of coronary hyperlipidemia, ­ artery disease) (7). We would argue that this imaging should be an echocardiogram in almost every situation. One of the main advantages of echocardiography is the ease in which comparisons with previous tests can be done, allowing for evaluation of serial changes in left ventricular (LV) function. dimensional echocardiography However, two-­ may not detect small (less than 10%) changes in LVEF. This may result in failure to detect early stages of cardiotoxicity. In addition, significant changes in volume conditions, potentially frequent during chemotherapy, may affect the LVEF value. Thus, it is recommended that calculation of LVEF be done with the best method available in the echocardiography laboratory, such as three-­ dimensional echocardiogram, which is the modality of choice for monitoring cardiac changes secondary to chemotherapy (7). The LVEF calculation should be combined with the estimation of wall motion score index. Moreover, according to current recommendations, contrast should be considered when two contiguous LV segments are not well visualized (7). Another impor­tant method is speckle-­tracking echocardiography to assess myo­ car­dial strain. Myo­car­dial strain is calculated as the fractional change in the length of myo­car­dial segment. The peak systolic global longitudinal strain was found to be very sensitive for early detection of myo­car­dial dysfunction secondary to chemotherapy (41,42). Unlike LVEF, diastolic par­ameters of the LV have not been found to have a prognostic role in cardiotoxicity. However, the joint consensus of ASE and EACI recommends conducting a conventional assessment of LV diastolic function as part of the echocardiographic evaluation (7). An echocardiogram should be conducted in all patients with symptoms concerning for cardiac dysfunction. Most authors recommend performing an echocardiogram before initiation of cardiotoxic agents, especially in patients with any

CV risk f­actor (e.g., diabetes mellitus, hypertension, age over 60 years, prior radiation). Repeating the echocardiogram should be considered ­after treatment with half of the planned dose or after administration of high cumulative dose ­ (e.g., doxorubicin greater than 300 mg / m2, doxorubicin greater than 240 mg / m2 for patients over 60  years of age) and in patients with CV risk ­factors. Most authors repeat the LVEF evaluation by echocardiogram 3 to 12 months a­fter the completion of therapy (19). Patients with intermediate or high pretest probability of coronary artery disease who are candidates for regimens that may cause myo­car­dial ischemia (e.g., fluorouracil, bevacizumab, sorafenib) should undergo a stress echocardiogram (7).

Multigated Acquisition Scan A MUGA scan mea­sures LV function with ­either first-­pass or equilibrium radionuclide angiography. It was first used in the 1970s in an effort to detect patients treated with anthracyclines who suffered from asymptomatic decline in LVEF (43). Although MUGA has been shown to be highly reproducible and was validated in many studies, especially in patients treated with anthracyclines (44,45), exposure to radiation and inability to obtain data on the function of the right ventricle as well as atrial size and valvular function, make this modality only complementary to echocardiography (7).

Cardiac Magnetic Resonance Imaging Although not well studied in oncology patients, cardiac MRI is the gold standard in assessing the function and volumes of the left and right ventricles, making it ideal for assessment of cardiotoxicity (46,47). Moreover, cardiac MRI is the only noninvasive imaging technique that can assess the tissue characteristics of the myocardium (myo­car­ dial inflammation, edema, fibrosis), allowing early detection of cardiac injury. It may also detect masses or metastases in the ventricles and pericardial space. Unlike echocardiography, which has no side effects, a rare but severe complication of gadolinium, the contrast agent used in cardiac MRI, is nephrogenic systemic fibrosis. The occurrence

Management of Chemotherapy-­Induced Cardiomyopathy  /  83 of this complication increases in patients with renal insufficiency, and the use of contrast MRI should be limited to patients without significant kidney dysfunction (7). Most authors recommend the use of cardiac MRI in both asymptomatic and symptomatic patients when an echocardiogram is not available, with preference given to cardiac MRI over MUGA.

Biomarkers Although well studied, the role of cardiac biomarkers in early detection and prediction of patients who ­will develop cardiotoxicity remains unclear. The two potential benefits of biomarkers are in identifying patients at risk for developing cardiac toxicity and in early detection of cardiac toxicity (48). Although imaging modalities are used to detect early cardiac toxicity, the use of biomarkers as a screening tool is less expensive and has the potential to detect toxicity earlier than imaging (49). The most frequently used biomarkers include troponin (Tn) and natriuretic peptides. Tn assays are commonly used in the evaluation of acute coronary syndrome. However, this enzyme is released into the blood a­ fter any insult to the myocardium that ­causes an injury or cell death, such as ischemia, oxidative stress, or apoptosis. Cardiac Tn-­I was found in 30% of patients treated with high-­ dose anthracycline and was associated with the degree of LV dysfunction (50). Interestingly, elevation of Tn soon ­after chemotherapy (within 12 to 24 hours) identifies patients with f­ uture development of LV dysfunction (51,52). Based on ­these studies (48–52), Tn levels in the first 24 hours ­after chemotherapy are an effective tool for prediction of early and chronic cardiac toxicity (48). B-­type natriuretic peptide (BNP) is another impor­tant biomarker. This peptide is secreted by the ventricles upon myocyte stretch and elevation in LV filling pressures. BNP is commonly used as a prognostic f­ actor in HF patients. B ­ ecause of its high negative predictive value (approaching 100%), the peptide is used in order to rule out HF in patients with concerning symptoms. Interestingly, BNP was found to identify patients at risk for cardiotoxicity. Patients with elevated NT-­pro-­BNP (amino-­terminal cleavage

equivalent) before chemotherapy, had a higher risk of cardiac toxicity, HF, and death ­after chemotherapy. Moreover, high NT-­pro-­BNP at 72 hours ­after chemotherapy was associated with a high risk of LV dysfunction a­ fter the first year (48,53,54).

MANAGEMENT OF CHEMOTHERAPY-­INDUCED CARDIOMYOPATHY Initial Evaluation Patients with signs or symptoms of HF (e.g., shortness of breath, fatigue, orthopnea, paroxysmal nocturnal dyspnea, S3 heart sound, elevated jugular venous pressure, leg edema) should be referred to a cardio-­oncologist or HF specialist, and should undergo thorough evaluation. According to the current guidelines (55,56), initial evaluation for an HF patient includes 12-­ lead ECG, lab tests (complete blood count, urinalysis, serum electrolytes, renal and liver function tests, thyroid stimulating hormone, fasting lipid profile, and glucose), and a transthoracic echocardiogram. In selected patients, screenings for hemochromatosis and HIV are recommended (55,56). The use of biomarkers such as BNP and NT-­ proBNP is helpful, especially in the setting of clinical uncertainty and as a prognostic tool. In addition, a chest X-­ray should be taken in all patients with new-­onset HF in order to assess pulmonary congestion and to detect alternative entities that may cause the symptoms. Noninvasive imaging to detect ischemia and viability is recommended in all patients who are eligible for revascularization. Moreover, coronary angiography should be considered in patients with high risk for coronary artery disease and when ischemia may be contributing to HF (55,56).

Medical Management The current data are limited regarding management of chemotherapy-­induced cardiomyopathy (57). Most authors recommend treating patients with symptomatic HF or asymptomatic LV dysfunction in accordance with HF guidelines (55,56). It is beyond the scope of this chapter to discuss the vari­ous therapies for HF. However,

84 / Chemotherapy-Induced Cardiomyopathy

Palliative care NYHA Class IV

Transplant Ventricular assist device End of life discussions

NYHA Class III–IV

Assess biomarkers, evaluate risk Consider implantable monitoring device Consider ivabradine Consider sacubitril/valsartan (LCZ696)

NYHA Class II–III

Consider cardiac resynchronization therapy and/or ICD Hydralazine-nitrates in African Americans Evaluate for iron deficiency Refer for cardiac rehabilitation

NYHA Class I

Mineralocorticoid receptor antagonist ACEI, ARB’s, beta blocker. Diuretics if volume overload Treat hypertension, diabetes mellitus, coronary artery disease, dyslipidemia. Use ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB) Risk factor reduction, patient and family education

FIGURE 8-2 ​Approach to the patient with heart failure with reduced ejection fraction (Owens AT, Brozena SC, Jessup M. New management strategies in heart failure. Circ Res. 2016;118:480–495. Copyright © American Heart Association, Inc. All rights reserved.)

Note: ACE, angiotensin converting enzyme; ARB, angiotensin-­receptor blocker; ICD, implantable cardioverter-­defibrillator; NYHA, New York Heart Association.

optimal management of hypertension, lipid dis- PREVENTION OF orders, and diabetes along with other conditions CHEMOTHERAPY-­INDUCED that may contribute to HF (e.g., obesity, smoking) is highly recommended. ­Unless contraindi- CARDIOMYOPATHY cated, all patients with reduced LVEF should be Many studies have attempted to identify risk treated with beta-­blockers (with preference for ­factors and to develop less toxic agents. However, carvedilol, metoprolol succinate, and bisoprolol) ­there is no consensus on the best approach to preas well as with ACE inhibitors or angiotensin-­ vent chemotherapy-­induced cardiomyopathy (27). receptor blockers (ARBs) (55,56). ­These agents The first approach is to use less cardiotoxic derihave been shown to improve morbidity and mor- vates (for example, in anthracyclines, treatment tality and to impede and even reverse LV remod- with epirubicin or idarubicin) and to administrate eling. Mineralcorticoid receptor antagonists the drug via continuous infusion. Continuous ­ ere should be added in patients with LVEF of less infusion and increasing infusion duration w than 40% and diabetes or HF symptoms (New found to reduce anthracycline cardiotoxicity withYork Heart Association [NYHA] functional out affecting oncological efficacy (27,58). The second strategy in anthracycline use is classes II to IV). In African American patients with reduced LVEF, adding hydralazine and iso- liposomal encapsulation (liposomal doxorubicin), sorbide dinitrate is recommended. Primary pre- which modifies the tissue distribution without vention with an implantable cardioverter-­ affecting oncological efficacy. However, this ­ ecause of high defibrillator (ICD) is recommended for patients method is not commonly used b with reduced LVEF, but the appropriateness of cost; its use has received approval by the Food and this recommendation in patients with advanced Drug Administration (FDA) only for ovarian cancancer needs to be individualized. Further details cer, multiple myeloma, and Kaposi sarcoma (27). Dexrazoxane, a topoisomerase II (Top2) beta on the management of HF with reduced LVEF inhibitor and iron chelator, is the only FDA-­ are depicted in Figure 8-2.

References / 85 approved drug for the prevention of anthracycline-­ induced cardiotoxicity. The mechanism is not clear and may involve reduction in the formation of oxygen radicals. Recent studies showed that this drug changes Top2’s configuration, which prevents anthracyclines from binding to Top2 complex (59). However, b ­ecause of concerns about increased risk of secondary malignancies, the FDA has restricted its use to adult patients with cancer who have received high doses of anthracyclines (more than 300 mg / m2 doxorubicin or more than 540 mg / m2 epirubicin) (60,61). The third strategy is to use beta-­blockers and ACE inhibitors or ARBs. Randomized ­trials have shown that carvedilol and nebivolol have a protective effect in this population. The mechanism is unclear and may be related to the antioxidative effect of ­these drugs (62–64). ACE inhibitors and ARBs have similar protective effects. One study revealed that in high-­ risk patients (who ­ were treated with high-­dose chemotherapy and had positive troponin posttherapy), treatment with enalapril resulted in improved LVEF compared with control (65). The recently published Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) study showed that in patients with breast cancer, treatment with candesartan provided protection against early LV dysfunction (66). Statin therapy may have an additional role in preventing cardiotoxicity in this population as well (67,68).

CONCLUSION With the advances in oncology and improvement in patient survival, an increasing number of cancer patients ­ will suffer from early and late chemotherapy-­induced cardiomyopathy. ­Future studies are needed to improve the safety profile of chemotherapy agents and to prevent the occurrence of this severe complication as well as to determine the optimal medical therapy for this growing population.

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CHAPTER 9

Iatrogenicity of Blood Pressure Mea­sure­ment in the Diagnosis of Hypertension Thomas D. Giles, Gary E. Sander, and Camilo Fernandez

HISTORICAL PERSPECTIVE The man who coined the term “blood pressure” almost 300 years ago was an En­glish scientist, the Reverend Stephen Hales (1, 2). Hales first mea­sured blood pressure (BP) in a series of famous experiments during the first quarter of the eigh­teenth ­century. He assessed arterial BP directly and invasively, first in dogs in 1708 and l­ater in ­horses in 1714, by vertically inserting a long glass tube directly into an incision made in the carotid artery and recording the height of blood in the tube (3). In 1628, the En­glish physician William Harvey introduced the theory of blood circulation, in which the arterial pulse was first understood to be a pressure wave originating from the heart’s contractions (4). By the eigh­teenth ­century, pulsus magnus durus et tardus—­a hardness of the pulse—­was well associated with increased arterial pressure (5). The sphygmometer, or sphygmograph, was introduced in 1834 by the French physician Jules Hérisson to display and rec­ord the arterial pulse wave (6), and his countryman, physiologist Etienne-­Jules Marey, performed the first proper analy­sis of the pulse wave in h ­ umans (7). In 1896 and 1897, an Italian doctor, Scipione Riva-­ Rocci, described a s­imple mercury sphygmomanometer that was the forerunner of the modern device (8,9). In 1905, Nicolai Korotkoff, a Rus­sian physician, described the auscultatory sounds that t­ oday bear his name and provide the basis for modern noninvasive BP mea­sure­ment (10,11,12).

Misunderstanding of the Use of Blood Pressure in Diagnosing Hypertension Soon a­ fter the sphygmomanometer was introduced into medical practice, observations based on case studies documented the association of high levels of arterial pressure with renal, vascular, and cardiac diseases (13,14). Recommended upper limits of normal BP w ­ ere based on arbitrary values, depending on the opinions of individual medical prac­ti­tion­ers (15,16). Yet, in the opinion of some eminent prac­ti­tion­ers, high BP was considered beneficial (17). In an address given in 1912 before the Glasgow Southern Medical Society, Sir William Osler made the following statement about high BP

Role of Drugs in Producing Hypertension  /  89 associated with atherosclerosis: “In this group of cases it is well to recognize that the extra pressure is a necessity—as purely a mechanical affair as in great irrigation system with old encrusted any ­ mains and weedy channels. Get it out of your heads, if pos­si­ble, that the high pressure is the primary feature, and particularly the feature to treat” (17). ­These two opposing points of view should have alerted early investigators that blood pressure levels alone could not be used to define the disease hypertension.

respond with the value of the BP recordings that he obtained in his office. He then arranged for the recording of BP outside of the office and reported the discordance (22). This has since been termed “white-­coat effect” (23). Unfortunately, no conclusive agreement exists on ­whether WCH individuals have shown more pronounced subclinical organ damage and a less favorable cardiovascular prognosis than their true parts (24,25,26). Cross-­ normotensive counter­ sectional studies aimed at investigating organ damage (as assessed by markers with proven prognostic value such as left ventricular hypertrophy, carotid intima-­media thickness [IMT], and microWHITE-­COAT albuminuria) in patients with WCH compared HYPERTENSION: with normotensive and sustained hypertensives THE ULTIMATE IN have yielded equivocal findings (25,27,30). MoreIATROGENIC DISEASE over, in some studies the risk of cardiovascular Currently, hypertension is defined as diastolic BP events in the WCH group has been shown to be (DBP) equal to or greater than 90 mmHg and an similar to that in the masked hypertension group increase equal to or greater than 10 mmHg from (28,29,30). baseline, and/or systolic BP (SBP) equal to or greater than 140 mmHg and an increase equal to or greater than 10 mmHg. White-­coat or isolated ROLE OF DRUGS IN clinic (or office) hypertension is commonly used to define individuals with elevated BP values in PRODUCING HYPERTENSION the doctor’s office and normal out-­of-­office val- Drugs, as well as herbal preparations and indusues including self-­measured or ambulatory BP trial chemicals, may elevate BP or impair (18). White-­coat hypertension (WCH) accounts responses to antihypertensive medi­cations; thus, for a relevant fraction of the hypertensive popu- elevated blood pressure in individuals exposed to lation, and the clinical and prognostic signifi- such molecules may artificially suggest chronic cance of this condition has been investigated cardiovascular disease (31,32,33). This “hypercades (19,20). tension” is iatrogenic and can be cured simply by extensively in the past two de­ Depending on age, sex, and race, 10% to 25% of removing the offending substance (31). It is individuals have a white-­coat effect large enough imperative to consider the role of such substances to render the BP reading of no value (20,21). in the evaluation of BP, particularly hypertension In years to come, historians w ­ ill remark on of recent-­onset and resistant hypertension, as has what a shameful occurrence resulted when mil- been emphasized in the Seventh Report of the lions of individuals ­were diagnosed as having a Joint National Committee on Prevention, Detecdisease, hypertension, when in fact they did not tion, Evaluation, and Treatment of High Blood suffer from the disease at all. Thus labeled, ­these Pressure (JNC 7) (34). The so-­called iceberg effect individuals suffered loss of self-­esteem, endured refers to a very common situation in which a were denied some drug may significantly increase BP, but the resulhigher insurance premiums, ­ classifications of employment, and, perhaps worst tant BP still remains within the normal range of all, ­were started on a drug regimen that they according to JNC 7 (34) or JNC 8 (35) criteria. ­were told would last a lifetime. This has resulted Clinical trial data and adverse drug report­because clinic blood pressures are used instead of ing most often describe only new hypertension ambulatory blood pressure monitoring (ABPM). (equal to or greater than 140/90 mmHg), rather In 1962, the cardiologist and pioneer in the than significant increases within the normal field of hypertension Maurice Sokolow observed range (e.g., 20/10 mmHg). ­These small but sigthat the clinical course of his patients did not cor- nificant increases within the normal range elevate

90  /  Iatrogenicity of Blood Pressure Measurement in the Diagnosis of Hypertension ­TABLE 9-1 ​Oral agents that increase blood pressure Category

Examples

Alcohol

beer, whiskey, wine

Anabolic androgenic ste­roids nandrolone, oxymetholone, oxandrolone Antidepressants

venlafaxine, tricyclics (imipramine, nortriptyline), MAO (phenelzine, tranylcypromine)

Chemicals

bisphenol A, lead

Erythropoietin

rHuEPO, darbepoetin

Herbal preparations

see ­Table 9-2

Immunosuppressants

cyclosporine, tacrolimus

Corticosteroids

Mineralocorticoids: licorice (glycyrrhizic acid), carbenoxolone, fludrocortisone, 9α-­fluoroprednisolone Glucocorticoids: prednisone, prednisolone, triamcinolone

NSAIDs/coxibs

ibuprofen, piroxicam, indomethacin

Oral ­contraceptives

estrogen-­containing preparations

Stimulants

methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine, modafinil, atomoxetine, dihydroergotamine, catecholamines

Sulfonylureas

glybenclamide

Sympathomimetic amines

catecholamines and amine analogs such as phenylpropanolamine

Angiogenesis Inhibitors   Monoclonal antibodies   Tyrosine kinase inhibitors

(see ­Table 9-4) bevacizumab sunitinib, sorafenib

cardiovascular risk, as has been demonstrated in several studies. An example is the increased cardiovascular risk between high normal and optimal BP groups (36,37). Many clinical ­trials mea­ sure BP not as a primary end point but rather as a safety pa­ram­e­ter; such mea­sure­ments are less carefully performed and generally qualitative rather than quantitative and without carefully matched control data. Yet another consideration is that accentuated BP responses are observed in the presence of older age and cardiovascular or renal disease (38). The more impor­ tant oral agents categories and individual drugs that increase BP are listed in ­Table  9-1. Categorization is sometimes difficult ­because certain agents may be represented in multiple categories; for example, catecholamines may be considered stimulants and sympathomimetic amines. Very importantly, not all agents within a category have the same BP effects. The major categories are discussed below.

Nonsteroidal Anti-­Inflammatory Drugs Perhaps the best examples of drugs causing hypertension are nonsteroidal anti-­inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) specific inhibitors. ­There has been considerable discussion about the effects of dif­fer­ent drug classes as well as drugs within each class on BP elevation. As early as 1994, a meta-­analysis using eight databases from 50 randomized controlled ­trials demonstrated that NSAIDs elevated supine mean BP by 5  mmHg (95% confidence interval [CI], 1.2  mmHg to 8.7  mmHg) and antagonized the antihypertensive effect of beta-­ blockers (BP elevation, 6.2  mmHg; 95% CI, 1.1 mmHg to 11.4 mmHg) more than vasodilators or diuretics did (39). Among NSAIDs of COX-1 class, piroxicam produced the most marked elevation in BP (6.2  mmHg; 95% CI, 0.8 mmHg to 11.5 mmHg), whereas sulindac and

Role of Drugs in Producing Hypertension  /  91 aspirin had the least hypertensive effect. The observed BP increases ­were sufficient to antagonize the BP-­lowering effect of antihypertensive medi­cation to an extent that could potentially increase hypertension. Among 19 randomized controlled t­rials of 45,441 participants, COX-1 and COX-2 inhibitors increased SBP and DBP compared with placebo (3.85/1.06 mmHg) and nonselective NSAID (2.83/1.34 mmHg) (40). COX-2 inhibitors ­were associated with a nonsignificantly higher relative risk (RR) of causing hypertension compared with placebo (RR, 1.61; 95% CI, 0.91 to 2.84; P = 0.10) and NSAID (RR, 1.25; 95% CI, 0.87 to = 0.23). Rofecoxib increased SBP by 1.78; P  2.8 mmHg and caused a nonsignificantly higher risk of developing clinically impor­tant SBP elevation (RR, 1.50; 95% CI, 1.00 to 2.26; P = 0.05) compared with celecoxib. When the BP effects of rofecoxib and celecoxib w ­ ere compared in 1,092 subjects ages 65 years or older with osteoarthritis and receiving a fixed antihypertensive regimen, significantly more patients in the rofecoxib group developed increased SBP (change greater than 20 mmHg plus absolute value equal to or greater than 140 mmHg) at any time point (14.9% versus 6.9%, p