Atherothrombosis in Clinical Practice 9780199976768, 9780199976751

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OX FO R D A M E R I CA N CA R D I O L O G Y L I B R ARY

Atherothrombosis in Clinical Practice

This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the conditions described in this material is highly dependent on the individual circumstances. While this material is designed to offer accurate information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical and health issues are constantly evolving, and dose schedules for medications are being revised continually, with new side effects recognized and accounted for regularly. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulation. Oxford University Press and the authors make no representations or warranties to readers, express or implied, as to the accuracy or completeness of this material, including without limitation that they make no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the material. The authors and the publishers do not accept, and expressly disclaim, any responsibility for any liability, loss, or risk that may be claimed or incurred as a consequence of the use and/or application of any of the contents of this material. The Publisher is responsible for author selection and the Publisher and the Author(s) make all editorial decisions, including decisions regarding content. The Publisher and the Author(s) are not responsible for any product information added to this publication by companies purchasing copies of it for distribution to clinicians.

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OXFO R D AMER I C AN C AR DI O L O G Y L IB R A R Y

Atherothrombosis in Clinical Practice Edited by Deepak L. Bhatt, MD, MPH Professor of Medicine, Harvard Medical School Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and VA Boston Healthcare System Senior Investigator, TIMI Study Group Boston, Massachusetts

Series Editor

Ragavendra R. Baliga, MD, MBA, FACC, FRCP Associate Director of Cardiovascular Medicine The Ohio State University Medical Center Columbus, Ohio

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Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research, scholarship, and education by publishing worldwide. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Oxford is a registered trademark of Oxford University Press in the UK and certain other countries. Published in the United States of America by Oxford University Press 198 Madison Avenue, New York, NY 10016 © Oxford University Press 2013 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Oxford University Press, or as expressly permitted by law, by license, or under terms agreed with the appropriate reproduction rights organization. Inquiries concerning reproduction outside the scope of the above should be sent to the Rights Department, Oxford University Press, at the address above. You must not circulate this work in any other form and you must impose this same condition on any acquirer. Library of Congress Cataloging-in-Publication Data Atherothrombosis in clinical practice/[edited by] Deepak L. Bhatt. p. ; cm.—(Oxford American cardiology library) Includes bibliographical references and index. ISBN 978–0–19–997675–1 (alk. paper) I. Bhatt, Deepak L. II. Series: Oxford American cardiology library. [DNLM: 1. Atherosclerosis. 2. Coronary Thrombosis. WG 550] RC692 616.1′36—dc23 2013003698

9 8 7 6 5 4 3 2 1 Printed in the United States of America on acid-free paper

Disclosures

Deepak L. Bhatt discloses the following relationships—Advisory Board: Elsevier Practice Update Cardiology, Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Other: Senior Associate Editor, Journal of Invasive Cardiology; Data Monitoring Committees: Population Health Research Institute; Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLxPharma, Takeda. Patrick Collier and Brian Griffin have no disclosure. Yousif Ahmad has no disclosure. Michelle L. O’Donoghue has received grant support through the TIMI Study Group from Astra Zeneca and GlaxoSmithKline. Amy Sarma has no disclosure. Alexandros Briasoulis has no disclosure. George Bakris-Consultant: Medtronic, Relapsya, AbbVie, Takeda, DaichiSankyo, Boeringher Ingelheim, GSK, Janssen Investigator Initiated grants-Takeda. Kathleen Yip has no disclosure. Flavio de Souza Brito has no disclosure. Renato D. Lopes has received grants, honoraria and travel expenses from Bristol-Myers Squibb. Matthew T. Roe has received grants from Eli Lilly & Company, KAI Pharmaceuticals, and Sanofi-Aventis. He is a consultant for Bristol-Myers Squibb, Eli Lilly & Company, Glaxo Smith Kline, Merck & Co., Janssen Pharmaceuticals, Daiichi-Sankyo and Regeneron. He has received honoraria for educational lectures from AstraZeneca and Janssen Pharmaceuticals. Andrew T. Yan has received research grants and honoraria from Sanofi Aventis and Bristol-Myers Squibb. Chintan Patel, Roger S. Blumenthal, and Seth S. Martin have no disclosure.

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Gregory Y. H. Lip, MD, has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, BMS/Pfizer, Daiichi-Sankyo, Biotronik, Portola and Boehringer Ingelheim and has been on the speakers bureau for Bayer, BMS/ Pfizer, Boehringer Ingelheim, and Sanofi Aventis.

To my wife Shanthala and to my sons Vinayak, Arjun, Ram, and Raj for all their love and support while I am away taking care of patients with atherothrombosis or researching new treatments for it.

Contents Preface ix Contributors xi 1. Atherothrombosis

1

Basem Elbarouni and Andrew T. Yan

2. Coronary Artery Disease

19

Flavio de Souza Brito, Renato D. Lopes, and Matthew T. Roe

3. Valvular Heart Disease

37

Patrick Collier and Brian Griffin

4. Cerebrovascular Disease: Ischemic Syndromes Due to Atherothrombosis

49

Mark J. Alberts

5. Atrial Fibrillation

65

Yousif Ahmad and Gregory Y. H. Lip

6. Peripheral Artery Disease

79

Amjad AlMahameed

7. Lipid-Modifying Therapy

95

Chintan Patel, Roger S. Blumenthal, and Seth S. Martin

8. Antithrombotic Therapy

111

Amy Sarma and Michelle L. O’Donoghue

9. Treatment of Primary Hypertension

129

Alexandros Briasoulis and George Bakris

10. Therapy for Type 2 Diabetes Kathleen Yip and Sangeeta Kashyap

Index 159

145

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Atherothrombosis is the coupling of atherosclerosis and thrombosis, leading to the majority of preventable deaths in the modern world. The medical, economic, social, and societal consequences of atherothrombosis are enormous. It touches upon many lives either directly or indirectly. For example, families can be devastated by the loss of a primary breadwinner at a young age from a heart attack or stroke, or by having to care for an older parent who is unable to walk due to disabling peripheral artery disease. All health care practitioners need to know about atherothrombosis, as it is so commonly encountered. Therefore, it is anticipated this book will be of interest to a wide range of audiences. Cardiologists, vascular medicine specialists, neurologists, general physicians, cardiac and vascular surgeons, physicians-in-training, and allied health professionals may all be particularly interested. This book focuses upon the many clinical manifestations of atherothrombosis and therapies that currently exist, with a focus on evolving therapeutic approaches. First, atherothrombosis is defined and the epidemiology is explored. Then, the specific manifestations of atherothrombosis (coronary artery disease, valvular heart disease, cerebrovascular disease, atrial fibrillation, peripheral artery disease) are covered by distinguished experts in the field. Next, specific medications are discussed, with an emphasis on innovative therapies and investigational agents. Novel and experimental lipid-modifying, anti-inflammatory, antiplatelet, and anticoagulant agents are covered. State-ofthe-art treatment of hypertension and diabetes is described succinctly. Lifestyle modification, medical therapies, and, where appropriate, invasive modalities are discussed. Controversies in areas such as cholesterol management and glycemic control are summarized. There is ample use of tables and figures to highlight key concepts. The emphasis is on where the field of atherothrombosis is heading, with a comprehensive review of relevant prior data. I would like to thank all the authors, who were very creative in their approaches to a complex topic. I am additionally appreciative of the fact that they were all timely in their chapter submissions—quite rare among active, busy clinician-researchers! Thus, much of the information presented is relatively new. I am very grateful to Oxford University Press and, in particular, the assistant editor Rebecca Suzan and the senior editor Andrea L. Seils. I would also like to thank the series editor, Ragavendra R. Baliga, MD, MBA, for inviting me to edit a book on the exciting and evolving topic of atherothrombosis. My hope is that readers will find this an educational and enjoyable book that is useful in both clinical practice and investigation. Deepak L. Bhatt, MD, MPH

ix

Preface

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Yousif Ahmad, MD Research Fellow University of Birmingham Centre for Cardiovascular Sciences City Hospital Birmingham, United Kingdom

Alexandros Briasoulis, MD Clinical Fellow in Hypertension ASH Comprehensive Hypertension Center, Department of Medicine The University of Chicago Medicine Chicago, IL

Mark J. Alberts, MD, FAHA, FANA Vice-Chair of Clinical Affairs Professor of Neurology Department of Neurology and Neurotherapeutics UT Southwestern Medical Center Dallas, Texas

Patrick Collier, MB, PhD Clinical Fellow, Advanced Multimodality Cardiac Imaging Robert and Suzanne Tomsich Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

Amjad AlMahameed, MD, MPH Clinical Instructor, Interventional Cardiology Division of Cardiovascular Medicine Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts

Flavio de Souza Brito, MD Clinical Research Fellow Division of Cardiology Duke University Medical Center Duke Clinical Research Institute Durham, North Carolina

George Bakris, MD Director, ASH Comprehensive Hypertension Center Professor, Department of Medicine The University of Chicago Medicine Chicago, Illinois Roger S. Blumenthal, MD Director, Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Professor of Medicine Johns Hopkins University School of Medicine Baltimore, Maryland

Basem Elbarouni, MD Division of Cardiology Department of Medicine University of Toronto Toronto, Ontario Brian Griffin, MD, FACC The John and Rosemary Brown Endowed Chair Section Head of Cardiovascular Imaging Robert and Suzanne Tomsich Department of Cardiovascular Medicine Cleveland Clinic Cleveland, Ohio

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Contributors

CONTRIBUTORS

Sangeeta Kashyap, MD Assistant Professor of Medicine Cleveland Clinic Lerner College of Medicine Department of Endocrinology, Diabetes and Metabolism Cleveland Clinic Cleveland, Ohio

xii

Gregory Y. H. Lip, MD Consultant Cardiologist and Professor of Cardiovascular Medicine Director, Haemostasis, Thrombosis & Vascular Biology Unit University of Birmingham Centre for Cardiovascular Sciences City Hospital Birmingham, United Kingdom

Chintan Patel, MD, MPH Resident, Internal Medicine, St. Agnes Hospital , Baltimore, Maryland Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Baltimore, Maryland Matthew T. Roe, MD, MHS Associate Professor of Medicine Division of Cardiology Duke University Medical Center Duke Clinical Research Institute Durham, North Carolina Amy Sarma, MD Resident, Internal Medicine Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts

Renato D. Lopes, MD, MHS, PhD Associate Professor of Medicine Division of Cardiology Duke University Medical Center Duke Clinical Research Institute Durham, North Carolina

Andrew T. Yan, MD Associate Professor Division of Cardiology Department of Medicine St. Michael’s Hospital University of Toronto Toronto, Ontario

Seth S. Martin, MD Cardiology Fellow Johns Hopkins Ciccarone Center for the Prevention of Heart Disease Johns Hopkins University School of Medicine Baltimore, Maryland

Kathleen Yip, BS Cleveland Clinic Lerner College of Medicine Cleveland, Ohio

Michelle L. O’Donoghue, MD, MPH Associate Physician, Cardiovascular Division Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts

Chapter 1

Atherothrombosis Basem Elbarouni and Andrew T. Yan

Atherosclerosis is a systemic disease affecting large- and medium-sized arteries, characterized by focal or diffuse luminal narrowing due to the deposition of lipid and fibrous material (plaque) in the vessel walls. Plaque formation, originally thought to reflect merely a cholesterol storage disorder, is mediated through complex pathways, with endothelial dysfunction and systemic inflammation playing major roles.1 Atherothrombosis is characterized by acute disruption of atherosclerotic plaque leading to superimposed thrombus formation. This leads to acute narrowing or occlusion of the arterial lumen, causing acute reduction or cessation of blood flow to the supplied organ. Clinical manifestations can also result from distal embolization of the newly formed thrombus (e.g., stroke due to carotid artery atherothrombosis). Clinical syndromes of atherothrombosis vary depending on the vascular tree involved (Fig. 1.1). In particular, vascular beds at risk include the coronary arteries, cerebrovascular circulation, and peripheral circulation. The acute coronary syndrome (ACS) is the most common clinical manifestation of atherothrombosis. The spectrum of ACS, including unstable angina, non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and sudden cardiac death, depends on the degree of lumen occlusion and the myocardium at risk.2 Atherothrombosis is also a major cause of ischemic strokes and transient ischemic attacks (TIAs). The affected vessel could be either intracranial, with clinical manifestations secondary to acute artery occlusion, or extracranial, with symptoms occurring due to distal embolization of the newly formed thrombus. Atherothrombosis in the peripheral circulation is also a major cause of acute limb ischemia, defined as a sudden decrease in limb perfusion potentially threatening limb viability.3

Pathophysiology Atherosclerosis is a lifelong pathological process that primarily affects the intimal layer of large and medium-sized arteries. Early pathological changes, including intimal thickening and fatty streaks, can be seen as early as in childhood.4 As lesions progress with age, fibrous atheromatous plaques form that can lead to narrowing of the vascular lumen, causing a gradual decline in blood flow to supplied organs. For example, lesions in the coronary circulation can

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Introduction

Atherothrombosis CHAPTER 1

Acute coronary syndromes: • ST-elevation myocardial infarction • Non-ST-elevation myocardial infarction • Unstable angina Stable coronary artery disease Atrial Fibrillation Angioplasty Bare metal stent Drug eluting stent Coronary bypass surgery

2

Abdominal aortic aneurysm

Stroke Transient ischemic attack Intracranial stenosis Carotid artery stenosis Carotid endarterectomy Carotid stenting

Renal artery stenosis Renal artery stenting

Peripheral arterial disease Acute limb ischemia Claudication Amputation Endovascular stenting Peripheral bypass Abnormal ankle brachial index

Figure 1.1 Major clinical manifestations of atherothrombosis. (From Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100(9):1261–1275.)

cause stable angina, while disease in the peripheral circulation can lead to claudication. Vulnerable plaques, also called thin-cap atheromas, are lesions with a high risk of acute disruption. Histologically, they consist of a large necrotic lipid core separated from the vessel lumen by a thin fibrous cap. The fibrous cap has a paucity of smooth muscle cells and is heavily infiltrated by macrophages (Fig. 1.2).5 Atherothrombosis occurs when plaque disruption occurs, leading to superimposed acute thrombus formation. Histologically, the most common form of atherothrombosis is plaque rupture, in which there is disruption of the fibrous cap, leading to direct contact between the intraluminal blood and the lipid-rich core, triggering the clotting cascade and leading to thrombus formation (Fig. 1.3). The second most common form of atherothrombosis is plaque erosion, in which there is thrombus formation over a fibrous cap with no histological evidence of plaque rupture.6 Calcified nodules are

EL

NC

Figure 1.2 Pathological intimal thickening versus atheroma. EL, elastic lamina; NC, necrotic core. (From Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20(5):1262–1275.)

Erosion Rupture

Calcified nodule

Figure 1.3 Atherosclerotic lesions with luminal thrombi. FC, fibrous cap; NC necrotic core; Th, thrombus. (From Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20(5):1262–1275.)

the least common cause of atherothrombosis. These lesions are formed mainly of calcified nodules with little or no lipid core. The calcified nodule erodes into the lumen and comes into contact with the bloodstream, causing thrombosis.7

Atherothrombosis CHAPTER 1

Fibrous cap atheroma

3

Pathologic intimal thickening

Atherothrombosis CHAPTER 1

4

Epidemiology Since the early 20th century, rising living standards, along with unprecedented advances in medical knowledge and health care, including improved prevention and treatment of infectious disease, have led to a significant increase in life expectancy. For example, life expectancy at birth has increased globally from 46 years in 1950 to 68 years in 2009.8,9 This has led to a significant global change in the causes of death, with a shift from predominantly infectious diseases and nutritional deficiencies to chronic non-communicable diseases, such as cardiovascular disease and cancer. This shift has been dubbed the “epidemiologic transition.”9 Different societies can be considered to be at different stages of this transition: developed countries are at an advanced stage of this transition, while developing countries are undergoing the early stages of this transition.10 As a consequence of this shift, cardiovascular disease, including atherothrombosis, is the most common cause of death globally. In developed countries, atherothrombosis is a major cause of morbidity and mortality. For example, in the United States, the prevalence of coronary heart disease (CHD) among the adult population is estimated at 7 percent, with close to half (3.1 percent) of these patients having suffered a myocardial infarction. The prevalence of stroke among the same population is 3 percent. Each year, an estimated 785,000 Americans will have a new ACS, while 470,000 will have a recurrent attack. An estimated 795,000 people will experience a new or recurrent stroke.11 Projections show that by 2030 an additional 8 million people could have CHD, a 16.6 percent increase in prevalence from 2010.12 In 2008, CHD caused 1 of every 6 deaths, while stroke caused 1 in 18 deaths.11 Peripheral artery disease (PAD) affects an estimated 12 to 20 percent of Americans more than 65 years of age.13 Despite the high prevalence and incidence of atherosclerosis, there has been a significant decline in mortality rates attributable to CHD. In the Framingham Heart Study, there was a 59 percent decline in CHD deaths from 1950–1969 to 1990–1999. This decline is true for both sudden and non-sudden cardiac death.14 This trend in declining mortality has continued over the last decade, with a 36 percent decline in the rates of death attributable to cardiovascular disease from 1998 to 2008. Globally, similar declines in cardiovascular and cerebrovascular mortality were seen in industrialized countries, including Canada, Australia, Japan, and Western Europe.15 This decline in mortality is probably due to a combination of improvements in early and long-term management strategies for patients with atherothrombosis, and the reduction and improved control of atherothrombosis risk factors.16 This could be considered akin to a later stage of the epidemiologic transition, in which adoption of healthier lifestyle habits, better control of risk factors, and improved secondary prevention lead to a reduction in mortality rates. Cardiovascular disease is also a major health burden in developing countries. In 2004, approximately 80 percent of the 16.7 million deaths attributed to cardiovascular disease occurred in low- and middle-income countries.17 These countries could be considered at earlier stages of the epidemiologic transition, where increasing life expectancy and “westernization” of lifestyle habits, including decreasing physical activity, urbanization, dietary changes, and increasing

Atherothrombosis CHAPTER 1

rates of tobacco use combine, leading to an epidemic of cardiovascular disease. Unfortunately, contrary to the trends seen in industrialized countries, the mortality rates from cardiovascular disease in developing countries continue to rise. For example, China has witnessed a doubling of the number of deaths attributed to cardiovascular disease over the past two decades.18 It is estimated that disability-adjusted life years lost attributable to cardiovascular disease between 1990 and 2020 will rise by 55 percent in the developing countries, compared to a 14.3 percent reduction in industrialized countries.19 This indicates that the future burden of cardiovascular disease will be shouldered mainly by emerging economies. Another disturbing observation is that, in developing countries, deaths due to cardiovascular disease tend to occur a decade or two earlier than they do in Western countries. Nearly half of cardiovascular deaths in developing countries occur before 70 years of age, compared to only a fifth in industrialized countries.20 The potential impact of cardiovascular disease burden falling mainly on society’s “breadwinners” can lead to major economic constraints at both individual and societal levels.

Several risk factors are known to increase the risk of atherosclerosis and atherothrombosis (Table 1.1). While the majority of studies identifying these risk factors focus on coronary heart disease, atherosclerosis is a systemic disease, and there is general acceptance that they promote atherosclerosis in all vascular beds. Risk factors can be divided into non-modifiable, such as age, gender, and family history, and modifiable, such as smoking, diabetes, dyslipidemia, and hypertension. Age is a major risk factor for atherothrombosis, with the majority of heart attacks in men occurring after the fourth decade.21 The age-adjusted risk of atherothrombosis is higher in men than in women, although this difference disappears after the age of 75. On average, there is a 10-year delay in the onset of atherothrombosis in women compared to men, and this difference holds widely across the globe.22 An interesting finding, however, is that modifiable risk Table 1.1 Major Atherothrombosis Risk Factors Non-modifiable Risk Factors • Age • Gender • Family history of premature coronary artery disease

Modifiable Risk Factors • Hypertension • Diabetes • Dyslipidemia • Smoking • Obesity • Chronic kidney disease

5

Cardiovascular risk factors

Atherothrombosis CHAPTER 1

6

factors seem to operate with greater power among women. For example, the incidence of myocardial infarction is increased six-fold in women and three-fold in men who smoke at least 20 cigarettes per day compared to non-smokers.23 A family history of premature cardiovascular events in a first-degree relative has been shown to be associated with an increased risk of CHD, with most cohorts showing a 40 to 60 percent increase in risk.24,25 While variable definitions of premature coronary artery disease are used in different studies, a commonly used definition is CHD or sudden death in a first-degree male relative younger than 55 years of age or a first-degree female relative younger than 65 years of age.26 The risk of atherothrombotic events seems to be higher when more than one first-degree relative has a positive history of premature heart disease.27 When assessing patients, however, it is important to note that selfreported family history can be inaccurate, which might reduce its usefulness in patient risk assessment.28 Diabetes is a major risk factor for atherothrombosis. Patients with diabetes and no prior myocardial infarction have as high a risk of cardiovascular mortality as nondiabetic patients with prior myocardial infarction.29,30 As such, major guidelines recommend classifying diabetes as a CHD equivalent.26,31 Hemoglobin A1c, which reflects average blood glucose levels over a period of 3 months, is a useful indicator of diabetes control and has been shown to be a predictor of cardiovascular events.32 When compared to conventional glucose control, intensive lowering of blood glucose led to a significant reduction in rates of myocardial infarctions, albeit with no impact on all-cause mortality.33 Hypertension is also a major risk factor for cardiovascular disease. In the INTERHEART study, hypertension accounted for 18 percent of the population-attributable risk of a first myocardial infarction.22 The association of blood pressure levels with cardiovascular events seems to be continuous, with a progressive increase in risk with incremental increases in blood pressure above a threshold of 115/75 mmHg.34 In a meta-analysis of trials of blood pressure lowering using pharmacologic strategies, a 10-mmHg systolic and a 5-mmHg diastolic reduction in blood pressure was estimated to reduce the risk of stroke by 38 percent and the risk of coronary disease by 16 percent, regardless of the drug class used.35 There is a clear relationship between serum cholesterol levels and cardiovascular risk, established by several epidemiologic studies.36–38 The causal role of cholesterol in CHD is corroborated by clinical trials that demonstrate reduction of cardiovascular death with lowering cholesterol levels.37,39 A high level of low-density lipoprotein (LDL) cholesterol, a fraction of total cholesterol, is a particularly important risk factor for atherosclerosis40 and is the primary target of lipid-lowering strategies.26,31 On the other hand, high-density lipoprotein (HDL), generally referred to as “good” cholesterol, is cardioprotective, with HDL levels inversely related to cardiovascular events.41,42 Unfortunately, despite the well-documented protective effects, attempts to raise HDL with pharmacotherapy have met with disappointing results.43,44 Cigarette smoking is a major cause of cardiovascular disease.45,46 The population attributable risk of smoking in the INTERHEART study was 35 percent, double that for hypertension. Unfortunately, active smokers, even heavy smokers, seem to underestimate the cardiovascular risks of smoking.46 Smokers who

Polyvascular disease Given the systemic nature of atherosclerosis, it is not surprising that a significant portion of patients with atherosclerosis develop disease in several vascular territories. The prevalence of polyvascular disease (atherosclerosis in more than one vascular bed) seems to be around 15 to 30 percent of all patients with atherothrombosis.58,59 Furthermore, patients with polyvascular disease are at a much higher risk of atherothrombosis events compared to patients with single-territory disease or patients with multiple risk factors but no documented

Atherothrombosis CHAPTER 1

7

had a myocardial infarction should be strongly encouraged to quit, as the risk for recurrent events decreases to 50 percent by 1 year and to nonsmoker levels in 2 years.47 Obesity, defined by a body mass index of 30 kg/m2 or greater, is associated with a higher CHD risk.48 It is unclear whether this association is purely due to the higher prevalence of classic cardiovascular risk factors among obese patients,49 or if obesity per se is an independent risk factor for atherosclerosis.50 Nevertheless, from a clinical perspective, obesity should be a trigger for global risk factor assessment and modification, and weight reduction should be strongly encouraged for obese patients. Chronic kidney disease has been shown in several studies to be associated with atherosclerosis.51 While the association of end-stage renal disease and atherothrombotic events is well established,52 even less severe forms of chronic kidney disease are associated with an increased risk of atherothrombosis.52 Furthermore, chronic kidney disease is associated with more severe CHD and with higher mortality after atherothrombotic events.53 Patients with documented atherosclerosis or prior atherothrombosis in one vascular bed are at high risk for future atherothrombotic events and should be managed aggressively. The presence of PAD seems to be a particularly strong predictor of disease in other territories, and is probably a marker of advanced systemic atherosclerosis. Furthermore, the functional limitation of patients with PAD might mean they do not exert themselves to the point of angina, leading to delayed presentations with extensive CHD.54 In a prospective Canadian study of ambulatory patients at high risk for or with established atherosclerosis, patients with PAD were at increased risk of cardiovascular events at 6 months compared to patients without PAD (7.3 percent versus 4.1 percent, p < 0.001). PAD remained an independent predictor in multivariable analysis (odds ratio 1.54, 95 percent confidence interval 1.18–2.01).55 In the ARIC study, after adjusting for age and risk factors, patients with an ankle–brachial index (ABI) of less than 0.9 were two to three times more likely to develop coronary events during the follow-up period. This association was particularly high among patients of African descent.56 A meta-analysis of studies of ABI in the general population found that the 10-year cardiovascular mortality was 18.7 percent in men with an ABI of less than 0.9, compared to 4.4 percent in men with a normal ABI. Furthermore, after stratifying patients according to Framingham risk category, patients with a low ABI (less than 0.9) had twice the 10-year event rate of patients with a normal ABI in the same Framingham risk category.57

Atherothrombosis CHAPTER 1

8

atherosclerosis. In the REACH registry, the 1-year rates of atherothrombotic events (cardiovascular death, nonfatal myocardial infarction, stroke, or hospitalization for atherothrombotic events) increased significantly with the higher number of vascular beds with symptomatic atherosclerosis (5.31 percent in patients with risk factors only, 12.58 percent in patients with one, 21.14 percent in patients with two, and 26.27 percent in patients with three disease locations, p for trend 20 min) ongoing rest pain • Angina at rest with dynamic ST depression >0.5 mm or new bundle branch block • Angina with new or worsening MR murmur • Angina with S3, new or worsening rales, or pulmonary edema • Angina with hypotension, bradycardia, or tachycardia • Age >75 years • Elevated cardiac troponins (>0.1 ng/mL) • Sustained ventricular tachycardia

CHAPTER 2

High Risk

25

Table 2.2 Short-Term Risk of Death or MI in Unstable Angina

Coronary Artery Disease CHAPTER 2

Table 2.3 Risk Scores for UA/STEMI TIMI

GRACE

PURSUIT

ACTIONRegistry- GWTG

• Age >65 years • >3 CAD risk

• Age • Heart rate

• Age • Sex

• Age • Creatinine

• Systolic BP

• Worst

factors • Known CAD

(>50% stenosis • Prior aspirin • >2 anginal

episodes in prior 24 hours • ST deviation >0.5 mm of presenting ECG • Elevated cardiac markers

• • • •

•

(mmHg) Creatinine (mg/dL) Killip class Cardiac arrest at admission Elevated cardiac markers ST-segment deviation

CCS class in previous 6 weeks • Signs of heart failure • ST depression on presenting ECG

(mg/dL) • Systolic BP

(mmHg) • Troponin • Heart rate • Heart failure or

shock • ST-segment

changes • Prior peripheral

arterial disease

26

Adapted from references 36 and 37.

Ticagrelor, prasugrel, and clopidogrel (platelet P2Y12 inhibitors) are recommended for all patients at moderate-to-high risk of ischemic events. According to the CURRENT–OASIS 7 trial, in patients with ACS, there was no significant difference between a 7-day double-dose regimen of clopidogrel (600 mg loading dose followed by 150 mg for 6 days, followed by standard dosing) and standard-dose clopidogrel (300 mg loading followed by daily 75 mg) with respect to the primary outcome of cardiovascular death, MI, or stroke, although in those receiving PCI, stent thrombosis was reduced. There was also no significant difference between aspirin doses of 300 to 325 mg daily and doses of 75 to 100 mg daily with respect to the same outcome.38 The 2012 ACC/AHA guidelines suggest clopidogrel (Class I/LOE: B), ticagrelor (Class I/LOE: B), and prasugrel (Class I/LOE: B—only at the time of PCI) for patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected. In patients in whom an initial conservative strategy is selected, clopidogrel or ticagrelor (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 months. (Class I/LOE: B).22,39,40 Anticoagulation is recommended for all patients in addition to antiplatelet therapy. In comparison with unfractionated heparin (UFH), enoxaparin has a more predictable anticoagulant effect and a lower incidence of thrombocytopenia and does not require serum monitoring. In patients with ACS treated with a conservative strategy, enoxaparin is superior to UFH in preventing in-hospital death or MI with similar rates of bleeding complications. In patients treated invasively, enoxaparin therapy is associated with a higher rate of bleeding than UFH, with a similar rate of death or MI. In conservatively treated patients at high risk for bleeding, fondaparinux is the preferred antithrombotic agent, but because of an excess of catheter-related thrombosis, it is infrequently used in patients in whom an early invasive approach is planned. Bivalirudin is an

STEMI Reperfusion therapy (PCI and fibrinolytic therapy) It is well established that use of rapid reperfusion therapy with primary PCI or fibrinolysis reduces infarct size, preserves left ventricular function, and

Coronary Artery Disease CHAPTER 2

Early invasive versus conservative approach to revascularization (and timing of intervention) Many publications have assessed the effects of a routine invasive versus conservative or selective invasive approach in the short and long term, but there is no clear evidence regarding very early angiography for UA/NSTEMI patients managed invasively versus delayed angiography.22 The TIMACS trial was a milestone in this issue because it showed that early intervention (coronary angiography 24 hours or less after randomization) did not differ greatly from delayed intervention (coronary angiography 36 hours or more after randomization) in preventing the primary outcome, but it did reduce the rate of the composite secondary outcome of death, MI, or refractory ischemia and was superior to delayed intervention in high-risk patients.44 A recent meta-analysis, based on the FRISC-2, ICTUS, and RITA-3 studies comparing a routine invasive versus a selective invasive strategy, showed benefit for early invasive management through 1 year.45 Therefore, in the high-risk patients for developing recurrent ischemia or infarction despite intensive medical therapy, an early invasive strategy is usually recommended; cardiac catheterization is performed (within 24 to 48 hours of admission) and coronary revascularization is accomplished percutaneously or surgically, if indicated. Clinical factors that favor an invasive approach include old age, diabetes, previous MI, ST-segment depression, recurrent angina at rest despite maximal medical therapy, elevated cardiac biomarkers, signs and symptoms of heart failure, hemodynamic instability, sustained ventricular tachycardia, recent percutaneous coronary intervention, history of coronary bypass surgery, and depressed left ventricular systolic function.22,23 Patients at very high risk, such as those with ischemic pain that is refractory to the usual antiischemic therapy, as well as those with hemodynamic or electrical instability should have arteriography performed immediately, with a view to proceeding with coronary revascularization within 2 hours of presentation (urgent invasive strategy). It is important to state that early invasive management ensures only early angiography and that revascularization decisions after early angiography are complex and individualized based upon patient comorbidities and medical history, coronary anatomy, and other aspects.44

27

acceptable antithrombotic option for patients treated with an invasive strategy, particularly those considered at high risk for having a bleeding complication, but is not recommended to patients conservatively treated.19,22,34,41,42 An intravenous GP IIb/IIIa inhibitor is an option in patients in whom an invasive strategy is planned before PCI (ACC/AHA—2012 Class I/LOE: A—intravenous eptifibatide and tirofiban are preferred) or at the time of PCI (ACC/AHA—2012 Class I/LOE: B). Abciximab should not be administered to patients in whom PCI is not planned (ACC/AHA—2012 Class III/LOE: A).22,43

Coronary Artery Disease CHAPTER 2

28

improves survival in patients with STEMI when administered within 12 hours of symptom onset.19 Primary PCI is the recommended reperfusion therapy over fibrinolysis if performed by an experienced team within 120 minutes of first medical contact.24 In the National Registry of Myocardial Infarction, which compared primary PCI to fibrinolytic therapy, PCI was associated with 37 percent lower mortality at highvolume interventional centers.19 At facilities without PCI capability, patients with STEMI may be treated with fibrinolytic therapy if not contraindicated or transferred to a facility with PCI capability.24,35 All hospitals participating in the care of patients with STEMI must record and monitor delay times and work to achieve the following quality targets: • First medical contact to first ECG, 10 minutes or less • First medical contact to reperfusion therapy: • For fibrinolysis, 30 minutes or less (“door to needle”) • For primary PCI, 90 minutes or less (60 minutes or less if the patient presents within 120 minutes of symptom onset or directly to a PCI-capable hospital [“door to balloon”])24 Fibrinolytic drugs approved for the treatment are streptokinase, alteplase, reteplase, and tenecteplase (Table 2.4).19,24,35 The main absolute contraindications to thrombolytic therapy are any prior intracranial hemorrhage, known structural cerebral vascular or malignant intracranial lesion, ischemic stroke within 3 months, intracranial or intraspinal surgery within 2 months, suspected aortic dissection, active bleeding or diathesis, significant closed-head or facial trauma within 3 months, severe uncontrolled hypertension, and, for streptokinase, prior treatment with streptokinase within the previous 6 months.24 Management of STEMI Patients undergoing primary PCI should receive a combination of aspirin and a P2Y12 inhibitor, as early as possible before angiography, and a parenteral anticoagulant. The preferred P2Y12 inhibitors are ticagrelor or prasugrel. They have been shown to be superior to clopidogrel in large outcome trials.43 Anticoagulant options for primary PCI include unfractionated heparin (UFH), enoxaparin, and bivalirudin. Use of fondaparinux in the context of primary PCI was associated with potential harm in the OASIS-6 trial and is therefore not recommended. The existing data suggest that if bivalirudin is chosen as the anticoagulant, there is no benefit of routine addition of GP IIb/IIIa blockers, and a strategy of bivalirudin alone leads to lower bleeding rates and reduced mortality. If UFH or enoxaparin is chosen as the anticoagulant, the role of routine use of GP IIb/IIIa blockers remains contentious.30,32 In patients undergoing fibrinolytic therapy there is a good case for the routine use of clopidogrel as an adjunct to lytic therapy. Prasugrel and ticagrelor have not been studied as adjuncts to fibrinolysis and should not be given. Parenteral anticoagulation has been used extensively during and after fibrinolysis and should preferably be given until revascularization or at least 48 hours or for the duration of hospital stay, up to 8 days. Enoxaparin was associated with a reduction in the risk of death and reinfarction at 30 days when compared with a weight-adjusted UFH dose, but at the cost of a significant increase in noncerebral bleeding complications. Finally, fondaparinux was shown in the large

Table 2.4 Guideline Recommendations and Level of Evidence for Antithrombotics in Non-ST-Elevation ACS by Management Strategy and for Antithrombotics in STEMI by Management Strategy NSTEMI Initial Conservative

Early Invasive

Therapy Clopidogrel Prasugrel Ticagrelor GP IIb/IIIa UFH LMWH Fondaparinux Bivalirudin Clopidogrel Prasugrel Ticagrelor GP IIb/IIIa UFH LMWH Fondaparinux Bivalirudin

ACC/AHA 2012 Class I (LOE: B) No Recommendation Class I (LOE: B) Class IIa (LOE: A) Class I (LOE: A) Class I (LOE: A) Class I (LOE: B) Not Recommended Class I (LOE: A/B) Class I (LOE: B) Class I (LOE: B) Class I (LOE: A/B) Class I (LOE: A) Class I (LOE: A) Class I (LOE: B) Class I (LOE: B)

ESC 2011 Class I (LOE: A) No Recommendation Class I (LOE: B) Class III(LOE: A) Class I (LOE: C) Class I (LOE:B) Class I (LOE:A) No Recommendation Class I (LOE: B) Class I (LOE: B) Class I (LOE: B) Class I (LOE: B) Class I (LOE: C) Class I (LOE: B) Class I (LOE: B) Class I (LOE: B)

ACCP 2008/12 Grade 1A No Recommendation Grade 1B Grade 2B Grade 1A Grade 1B Grade 1A No Recommendation Grade 1A Grade 1B Grade 1B Grade 1A Grade 1B Grade 1B Grade 1B Grade 2B (continued)

29

CHAPTER 2

Coronary Artery Disease

30

CHAPTER 2

Coronary Artery Disease

Table 2.4 Continued STEMI Primary fibrinolytic

Primary PCI

Clopidogrel Prasugrel Ticagrelor GP IIb/IIIa UFH LMWH Foundaparinux Bivalirudin Clopidogrel Prasugrel Ticagrelor GP IIb/IIIa UFH LMWH Fondaparinux Bivalirudin

ACC/AHA 2013 Class I (LOE: A) No recommendation No recommendation No recommendation Class I (LOE: C) Class I (LOE: A) Class I (LOE: B) Not recommended Class I (LOE: B) Class I (LOE: B) Class I (LOE:B) Class IIa (LOE:A/B) Class I (LOE: C) No recommendation Not recommended Class I (LOE: B)

ESC 2012 Class I (LOE:A) Not recommended Not recommended Not recommended Class I (LOE: C) Class I (LOE: A) Class IIa (LOE:B) Not recommended Class I (LOE:C) Class I (LOE:B) Class I (LOE:B) Class IIa (LOE:B/C) Class I (LOE:C) Class IIb (LOE: B) Not recommended Class I (LOE: B)

ACCP 2008/12 Grade 1 A No recommendation No recommendation Grade 2B Grade 1 Grade 1B Grade 1B Not recommended Grade 1A Grade 1B Grade 1B Grade 1B Grade 1C Grade 2A Not recommended No recommendation

ACC, American College of Cardiology; ACCP, American College of Chest Physicians; AHA, American Heart Association; ESC, European Society of Cardiology; LMWH, low-molecular-weight heparin; LOE, level of evidence; UFH, unfractionated heparin. Adapted from reference 41.

Various clinical issues of the management of patients with stable coronary disease are being addressed in many ongoing clinical trials. In the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA),15 investigators are scheduled to enroll 8,000 patients with highrisk noninvasive vascular testing results to a strategy of OMT (with coronary angiography and revascularization when clinically indicated) or to a strategy of revascularization. The results of this trial probably will determine the treatment strategy for patients with high-risk myocardial imaging (stress perfusion or echocardiographic) test results, by testing for differences in the composite end point of time to first occurrence of cardiovascular death or nonfatal MI.46 The use of hematopoietic stem cells to boost bone marrow function and blood vessel formation has been tested in the phase II Autologous Cellular Therapy CD34—Chronic Myocardial Ischemia (ACT34-CMI) trial and in phase III, Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina (RENEW).47 Finally, among the emerging platforms for CAD biomarkers discovery, perhaps none has garnered more recent attention than proteomics and metabolomics. The identification of new biomarkers of coronary artery diseases will depend on the complementary power of genetics, transcriptional profiling, proteomics and metabolomics.48 Taken together, these new lines of research discovery for patients with symptomatic coronary disease will help to evolve the diagnosis and management of these patients in an effort to better control patient symptoms and further improve short-term and long-term outcomes. Table 2.5 Dosing of Antithrombotic Therapies for the Treatment of Acute Coronary Syndromes Drug Class

Dose

Comments

• Initial dose 160–325 mg, then 75–325 mg daily for both STEMI and NSTEMI

Indefinitely

Aspirin Aspirin

Platelet P2Y12 Inhibitors

Clopidogrel

Recommend for up to 12 months for patients with STEMI and NSTEMI, regardless of whether PCI is performed • Loading dose: 300–600 mg, then 75 mg/day

There may be an interaction of proton pump inhibitors with clopidogrel treatment so caution is recommendation is using this concomitant medication.

(continued)

Coronary Artery Disease CHAPTER 2

Future directions in CAD

31

OASIS-6 trial to be superior to placebo or UFH in preventing death and reinfarction, especially in patients who received streptokinase. Bivalirudin has not been studied with fibrin-specific agents. Tenecteplase, aspirin, enoxaparin, and clopidogrel are the antithrombotic combination that has been most extensively studied as part of a pharmacoinvasive strategy (Tables 2.4 and 2.5).19,24,33,35

Coronary Artery Disease

Drug Class

Dose

Comments

Prasugrel

• Loading dose: 60 mg, then 10 mg/day

There are no recommendations for treatment with prasugrel before PCI and no recommendations for use in patients who do not undergo PCI

Ticagrelor

• Loading dose: 180 mg, then 90 mg twice a day

The recommended maintenance dose of Aspirin to be used with ticagrelor is 81 mg daily

Glycoprotein IIb- STEMI: to support IIIa Inhibitors reperfusion with primary PCI in conjunction with UFH or bivalirudin, in selected patients, or in High-risk UA/NSTEMI patients Abciximab

• 0.25 mg/kg IV bolus, then 0.125 mcg/kg/min (maximum 10 mcg/min)

Duration:12 hrs

Eptifibatide

• 180 mg/kg bolus followed 10 mins later by second IV bolus of 180 mg/kg, then 2.0 mg/kg/ min, started after first bolus

Duration: 18–24 hours In patients with CrCl Intermittent bolus to achieve activated clotting time of 200–250 secs • PCI without GPIIb/IIIa: 70–100 U/kg IV > Intermittent bolus to achieve activated clotting time of 250–300 sec

Duration: 2–5 days, discontinue after successful PCI

Discontinue after successful PCI

Discontinue after successful PCI

(continued)

Comments

• Use with fibrinolysis: IV bolus of 60 U/kg (maximum 4000 U) followed by an infusion of 12 U/kg/h (maximum 1000 U) initially, adjusted to maintain aPTT at 1.5 to 2.0 times control (approximately 50 to 70 s) for 48 h or until revascularization.

Duration: 48 hours after fibrinolysis

Enoxaparin

• If age