Clinical Trials in Heart Disease: A Companion to Braunwald's Heart Disease

444 Pages·2004·5.56 MB·English

by  Joann E. Manson

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Clinical Trials in Heart Disease:A Companion ISBN 0-7216-0408-0
to Braunwald’s Heart Disease
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Medicine is an ever-changing field.Standard safety precautions must be followed,but as new research
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Previous edition copyrighted 1999
Library of Congress Cataloging-in-Publication Data
Clinical trials in heart disease:a companion to Braunwald’s heart disease/[edited by]
JoAnn E.Manson...[etal.].— 2nd ed.
p. ;cm.
Companion to:Heart disease/edited by Eugene Braunwald.2nd ed.2004.
ISBN 0-7216-0408-0
1. Heart—Diseases—Research—Methodology. 2. Clinical trials. I. Manson,JoAnn E. II. Braunwald,
Eugene,1929– Heart disease.
[DNLM:1. Heart Diseases—therapy. 2. Clinical trials.WG 210 C6417 2004]
RC682.C585 2004
616.1(cid:3)2027—dc22
2003054492
Acquisitions Editor:Anne Lenehan
Editorial Assistant:Vera Ginsburgs
Publishing Services Manager:Joan Sinclair
Project Manager:Mary Stermel
Printed in The United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1
This book is dedicated to family members Christopher,Jenn,Jeffrey M.,
Joshua,Jeffrey B.,Susan,Andrew,Elena,Anne,Michaela,Dante,
andLiam,for their unfailing support and forbearance.
JEM
JEB
PMR
JMG
F O R E W O R D
Since the development of antibiotics in the middle of Department of Medicine and the Brigham and Women’s
the last century,no area in clinical medicine has moved Hospital have produced the second edition of this
forward as rapidly as has cardiology.This has resulted splendid volume—Clinical Trials in Heart Disease.The
from notable advances in cardiovascular biology and first section provides the understanding of the methods
pathophysiology, as well as from the development of involved in the design,conduct,and interpretation of tri-
several classes of important new cardiovascular drugs als.The second section consists of a systematic review
and of a variety of effective new procedures and of the key cardiovascular treatment trials of coronary
devices.The clinical impact of these new therapeutic artery disease, especially acute coronary syndromes,
modalities requires rigorous assessment in clinical trials, arrhythmias,and heart failure.The third section details
which have become the principal method of judging the growing number of trials designed to prevent or at
the efficacy and safety of interventions. Clinical trials least delay the development of cardiovascular disease.
serve as the critical interface between initial studies that This totally revised and expanded second edition pro-
have offered “proof of concept”of a therapeutic or pre- vides an up-to-date review and analysis of this very
ventive modality and its widespread clinical application. important segment of cardiology.It should be of great
Clinical trials are also required for the registration of interest not only to clinical trialists and trainees in this
new drugs and devices.It is no exaggeration to say that field, but to all physicians responsible for the care of
the randomized clinical trial now provides the key to patients with cardiovascular disease. I am proud that
rational,evidence-based cardiac care and prevention of Clinical Trials in Heart Disease is a distinguished Com-
cardiovascular disease. panion to Heart Disease:A Textbook of Cardiovascular
I am especially delighted that Drs. Manson, Buring, Medicine.
Ridker,and Gaziano,from the Preventive Medicine and Eugene Braunwald,M.D.
Cardiovascular Divisions of Harvard Medical School’s Boston,MA
P R E F A C E
Cardiovascular disease (CVD) is the leading cause of even higher.11And although the prevalence of smoking,
death for adults worldwide.1 In the United States,CVD elevated serum cholesterol,and untreated hypertension
is responsible for nearly 1 million annual fatalities, or have each declined since the late 1970s,there has been
two of every five deaths.CVD kills more Americans than little or no further reduction in the frequency of these
the next seven causes combined—including cancer. cardiovascular risk factors within the last 10 years.6,12
Indeed,the average U.S.life expectancy would rise by Similarly,the proportion of adults who report no leisure
nearly seven years if major forms of CVD could be elim- time physical activity has remained relatively stable at
inated.CVD also carries a tremendous economic burden, approximately 25% over the last decade,and about 75%
with direct health care costs and indirect costs from lost have lower levels of activity than recommended.13,14
productivity estimated at $352 billion in the United Moreover,among U.S.adolescents,there are also trends
States in 2003.2 toward increasing obesity,15 smoking,16 and physical
Since the late 1960s,many developed countries have inactivity.14 In the aggregate, these secular changes, if
experienced a decline in CVD mortality,with reductions not reversed, will have far-reaching consequences for
in the United States averaging about 2% each year.This future morbidity and mortality from CVD.
favorable trend has been attributed to advances in both In developing countries,the proportion of worldwide
prevention3 and treatment4 of CVD.Despite more than deaths due to CVD is projected to climb from 28.9% to
three decades of sustained decline in mortality rates, 36.3% between the years 1990 and 2020.5 CVD is also
however, CVD is expected to remain the number-one predicted to jump from fourth to first in number of
killer in the western world well into the 21st century.5 years of life lost,and from fifth to first as a cause of pre-
Moreover, troubling recent evidence suggests that this mature death and disability.These increases are related
long-standing secular decline in CVD mortality may be principally to a decline in competing causes of death,
reaching a plateau or, in some groups such as African such as malnutrition and infectious diseases, which is
American women, even reversing. While age-adjusted allowing for population aging, as well as to a marked
death rates from coronary heart disease (CHD),which rise in cigarette smoking rates.17
accounts for nearly half of CVD deaths in the United Thus, the continuing enormous burden of CVD in
States, declined more than 3% per year between 1970 developed countries, alarming trends in cardiovascular
and 1990, the yearly rate of decline in CHD mortality risk profiles of adolescents and adults,and the emerging
slowed to 2.7% between 1990 and 1997.For stroke mor- increases in CVD in developing countries underscore
tality,the deceleration of the annual rate of decline has the crucial need to redouble treatment and prevention
been even more marked.After falling at a rate of 4.9% efforts.18
per year between 1970 and 1980, and 3.5% per year Although equally important for both genders,such pre-
between 1980 and 1990, age-adjusted stroke mortality vention and treatment efforts have lagged among women
declined a mere 0.7% per year from 1990 to 1997.6 as compared with men.Until recently,CHD was widely
Another important cause of CVD death is congestive perceived to be less of a public health problem for
heart failure (CHF). It is the only category of CVD in women than for men.While the incidence of CHD in
which prevalence,incidence,and mortality have consist- women trails the incidence in men by 10 years for total
ently increased over the past quarter-century in the CHD and by 20 years for more serious clinical events
United States.6 Currently 4.6 million Americans suffer such as myocardial infarction (MI) and sudden death,
from CHF, and there are 550,000 new cases annually.7 CHD nevertheless becomes the leading killer of U.S.men
CHF is the leading hospital discharge diagnosis of men by 45 years of age and of women by 65 years of age.2 In
and women aged 65 years and older, and 30-day read- fact, once women develop overt CHD, they have a
mission rates for individuals with this condition are markedly worse prognosis than men. Case-fatality rates
approaching 25%.6 are higher for women following both MI and myocardial
Paralleling these trends is emerging evidence of an revascularization procedures,with 38% of MIs in women
increasing prevalence of several CVD risk factors,which but only 25% of MIs in men followed by death within one
portends great difficulty in achieving further reductions year.2 Moreover, in 63% of women but in only 50% of
in the incidence of CVD.Currently,two of every three men who died suddenly from CHD,there were no previ-
U.S. adults are classified as overweight or obese, com- ous symptoms of this disease.2These gender differences
pared with fewer than one in four in the early 1960s.8,9 are not entirely accounted for by differences in age.
The prevalence of diabetes is also on the rise;between Additionally,secular declines in CVD and CHD mortality
1990 and 2000, increases averaged 49% across all have been less pronounced among women than among
racial/ethnic groups.10 The most recent estimates sug- men.Given the emerging epidemic of ‘diabesity’19 (i.e.,
gest that 7% of adults (1 in 15) have a diabetes diagnosis obesity and diabetes) and the fact that diabetes appears
and that the prevalence of undiagnosed diabetes may be to be a far more potent cardiovascular risk factor among
v
vi PREFACE
women than among men,20 boosting prevention and cessful treatments for already-ill patients, because pre-
treatment efforts among women is necessary to forestall ventive measures can be implemented broadly among a
potentially widening gender disparities in cardiovascu- much larger proportion of the population.
lar outcomes. No area of medicine has likely been the focus of more
Clinical trials are a powerful tool for evaluating large-scale,randomized clinical trials than CVD.Efforts to
the efficacy and safety of therapeutic and preventive compile listings of completed and ongoing trials in CVD
interventions in both men and women.Such trials are, have easily identified hundreds of investigations.28–30 In
however,neither necessary nor desirable in all circum- the crowded alphabet soup of trial acronyms,more than
stances. For example, the benefits of pharmacologic a few selections have wound up serving multiple trial
treatment for malignant hypertension were so large and masters, with the popular choices ranging from the
obvious in uncontrolled clinical observations that ran- predictable (e.g., CARE, five separate trials listed) to
domized trials would in fact have been unethical.Simi- the patently incongruous (e.g., BIGMAC, two separate
larly, with respect to cigarette smoking and CVD, the trials listed).30 Keeping up with the vast and seemingly
totality of evidence derived from basic laboratory exponentially expanding literature is a daunting task
research, clinical investigation, and observational epi- for increasingly busy academic researchers and clinical
demiology was clearly sufficient for the U.S. surgeon practitioners committed to applying scientifically sound,
general to declare smoking a cause of CHD—and smok- current knowledge to the care of their patients.Indeed,
ing cessation an effective preventive measure—in the in the five years since the first edition of this book was
absence of clinical trial data. However, for many other published,progress has been occurring rapidly in many
therapeutic and preventive strategies,such as drug treat- areas—for example, the efficacy and safety of post-
ment of mild-to-moderate hypertension21 or aspirin in menopausal hormone replacement therapy in the primary
the primary prevention of CVD,22 the resulting effects and secondary prevention of CHD have been called
are likely to be small to moderate (i.e.,on the order of a into question by the results of several large trials,31–38
10% to 40% difference between treatment and control andtrials of antioxidant vitamins have yielded conflicting
groups).While these differences may be very meaning- results.39
ful from a clinical or public health perspective, espe- This book,therefore,has been extensively revised and
cially for such a common and serious disease as CVD, updated so that it may continue to serve as a comprehen-
they are difficult to detect reliably in observational stud- sive and state-of-the-art resource about clinical trials in
ies.Such effect sizes may easily be obscured by uncon- CVD for those in research and in clinical practice.One
trolled or uncontrollable confounding or biases inherent third of the chapters are completely new,and the remain-
in cohort and case-control studies.23For this reason,clinical der have been substantially expanded since the first edi-
trials are the most reliable design strategy for evaluating tion to reflect the recent explosion of trials in the field.
definitively the many new promising hypotheses in the Leading authorities in more than two dozen areas of car-
treatment and prevention of cardiovascular disease. diovascular treatment and prevention research provide
Indeed, with each new advance in cardiovascular clear distillations of current knowledge gleaned from clin-
medicine,randomized clinical trials generally,and those ical trials.
of large sample size in particular, have become even While large in number,clinical trials in cardiovascular
more crucial to achieving further gains.Therapeutic tri- disease vary in quality and in their ability to provide defin-
als, which increasingly test new agents against already itive evidence that can reliably guide clinical practice.
established treatments rather than inactive placebos, Critically reviewing and synthesizing the results of such
must be designed to detect ever decreasing benefit dif- studies requires an understanding of their design and
ferences.Progress in treating acute MI,for example,has analysis.Section I provides an overview of these issues.
led to substantial decreases in short-term mortality fol- The opening chapter places the contributions of clinical
lowing hospitalization for this condition,from approxi- trials within a larger research context, emphasizing the
mately 20% in 1970 to 10% in 1995.24–27 As a importance of complementary evidence from basic labo-
consequence,although a 20% mortality benefit in 1970 ratory research and observational epidemiology in arriving
would have yielded an absolute reduction of four per- at sound clinical and public health policy decisions.The
centage points (from 20% to 16%), a new treatment following chapters cover the basics of trial methodology,
today that confers a comparable 20% benefit would including the role of data monitoring boards,which are
yield an absolute mortality reduction only half as great critical to the management of randomized trials.
(a 2-percentage-point decrease,from 10% to 8%).Thus, Sections II and III provide substantive,critical assess-
the reliable detection of such a benefit today requires ments of clinical trials for the treatment and prevention
clinical trials of even larger sample sizes to rule out the of CVD. Section II reviews treatment trials for three
statistical possibility that the play of chance accounts common conditions:acute coronary ischemia,arrhyth-
for any observed treatment effect.Clinical trials of large mias,and congestive heart failure.The latter two topics
sample size are also crucial in evaluating promising pri- receive greatly expanded coverage here as compared
mary prevention strategies,because participants in such with the first edition of the book. Prospects for the
trials are,by definition,at lower baseline risk of disease effective treatment of serious ventricular arrhythmias
and will accrue outcomes at a much slower rate than have recently brightened with the development of
those with a previous history of disease.Nevertheless, strategies that combine drug therapy with surgery and
the discovery of effective primary prevention measures antiarrhythmic devices, such as implantable defibrilla-
can have an even larger public health impact than suc- tors. And, although the prognosis for heart failure
PREFACE vii
patients remains poor,major therapeutic advances have and changes in lifestyle. Annals of Internal Medicine 1984;
been achieved in this area during recent years.Section 101:825–836.
4. Hunink MGM,Goldman L,Tosteson ANA,etal:The recent decline
III focuses on primary and secondary prevention trials.
in mortality from coronary heart disease,1980–1990.JAMA 1997;
Primary prevention trials evaluate whether an agent or
277:535–542.
procedure can reduce the risk of developing CVD 5. Murray CJL,Lopez AD:The global burden of disease:A comprehen-
among those without prior CVD—either healthy indi- sive assessment of mortality and disability from diseases,injuries,
viduals at usual risk or those already recognized to be and risk factors in 1990 and projected to 2020.Cambridge,MA:
Harvard University Press,1996.
at high risk of CVD. Secondary prevention trials, con-
6. Cooper R,Cutler J,Desvigne-Nickens P,etal:Trends and disparities
ducted among those with preexisting cardiovascular in coronary heart disease,stroke,and other cardiovascular diseases
disease,determine the ability of an agent or procedure in the United States:Findings of the National Conference on Car-
to ameliorate symptoms, prevent recurrence, or diovascular Disease Prevention.Circulation 2000;102:3137–3147.
7. National Heart Lung and Blood Institute:Morbidity & Mortality:
decrease CVD-related mortality. Secondary prevention
2000 Chart Book on Cardiovascular, Lung, and Blood Diseases.
trials can be distinguished from treatment trials in that,
Bethesda,MD:National Heart,Lung,and Blood Institute,National
whereas treatment trials often take place in acute set- Institutes of Health,2000.
tings (e.g., thrombolytic therapy initiated immediately 8. Flegal KM, Carroll MD, Ogden CL, Johnson CL: Prevalence and
following myocardial infarction among hospitalized trends in obesity among US adults, 1999–2000. JAMA 2002;
288:1723–1727.
patients),secondary prevention trials evaluate chronic,
9. Flegal KM,Carroll RJ,Kuczmarski RJ,Johnson CL:Overweight and
long-term therapies, such as cholesterol reduction, obesity in the United States:Prevalence and trends,1960–1994.
antioxidant vitamin supplementation, physical activity, International Journal of Obesity 1998;22:39–47.
or weight loss.(Some agents,such as aspirin,are useful 10. Mokdad AH,Bowman BA,Ford ES,etal:.The continuing epidemics
of obesity and diabetes in the United States. JAMA 2001;
in both treatment and prevention settings,and are thus
286:1195–1200.
discussed in both Sections II and III.) Preventive strat-
11. Harris MI, Flegal KM, Cowie CC, etal: Prevalence of diabetes,
egies are assuming increasing importance in the face of impaired fasting glucose,and impaired glucose tolerance in U.S.
constraints on health care resources in developed adults:The Third National Health and Nutrition Examination Sur-
countries and the severely limited medical care avail- vey,1988–1994.Diabetes Care 1998;21:518–524.
12. Arnett DK,McGovern PG,Jacobs DR,Jr.,etal:Fifteen-year trends
able in developing countries now confronting the CVD
in cardiovascular risk factors (1980–1982 through 1995–1997):
pandemic. The Minnesota Heart Survey.American Journal of Epidemiology
2002;156:929–35.
13. Barnes PM,Schoenborn CA:Physical Activity among Adults:United
ACKNOWLEDGMENTS States,2000.Advance Data No.333.Hyattsville,MD:U.S.Depart-
ment of Health and Human Services,Centers for Disease Control
and Prevention,2003.
Collaboration and teamwork are critical elements in 14. U.S.Department of Health and Human Services:Physical Activity
clinical trials of heart disease.So,too,were they vital in and Health:A Report of the Surgeon General.Atlanta,Georgia:U.S.
the preparation of this companion text to Braunwald’s Department of Health and Human Services,Centers for Disease
Control and Prevention,National Center for Chronic Disease Pre-
Heart Disease. The majority of chapter authors gra-
vention and Health Promotion,1996.
ciously accepted our initial invitation and provided out- 15. Ogden CL,Flegal KM,Carroll MD,etal:Prevalence and trends in
standing comprehensive summaries of the current state overweight among U.S. children and adolescents, 1999–2000.
of knowledge on clinical trials in their areas of expert- JAMA 2002;288:1728–1732.
16. Johnson LD, Bachman JG, O’Malley PM: Cigarette smoking con-
ise. Our medical editor, Shari Bassuk, ScD, performed
tinues to rise among American teenagers in 1996.Ann Arbor,Michi-
yeoman’s work.Her expert editing and superb organiza-
gan:University of Michigan News and Information Services,1996.
tional skills were crucial to the success of this project. 17. Murray CJL,Lopez AD:The global burden of disease:Summary.
At Elsevier, publisher Anne Lenehan and her assistant Cambridge,MA:Harvard University Press,1996.
Vera Ginsburgs also provided invaluable assistance at all 18. Hennekens CH:Increasing burden of cardiovascular disease:Cur-
rent knowledge and future directions for research on risk factors.
stages of production.Finally,we thank our families (in
Circulation 1998;97:1095–1102.
particular, Chris, Jenn, Jeffrey M., Joshua, Jeffrey B., 19. Astrup A,Finer N:Redefining type 2 diabetes:‘Diabesity’or ‘obesity
Susan,Andrew,Elena,Anne,Michaela,Dante,and Liam) dependent diabetes mellitus’? Obesity Reviews 2000;1:57–59.
for their unfailing support and forbearance. 20. Manson JE,Spelsberg A:Risk modification in the diabetic patient.
In:Manson JE,Ridker PM,Gaziano JM,etal,eds.Prevention of
JoAnn E.Manson Myocardial Infarction. New York: Oxford University Press,
Julie E.Buring 1996:241–273.
21. Hebert PR,Fiebach NH,Eberlein KA,etal:The community-based
Paul M.Ridker
randomized trials of pharmacologic treatment of mild-to-moderate
J.Michael Gaziano hypertension. American Journal of Epidemiology 1988;
127:581–590.
22. Hennekens CH,Buring JE,Sandercock P,etal:Aspirin and other
antiplatelet agents in the secondary and primary prevention of
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dence of myocardial infarction and in mortality due to coronary replacement therapy in postmenopausal women with ischaemic
heart disease,1987 to 1994.New England Journal of Medicine heart disease:The Papworth HRT atherosclerosis study. British
1998;339:861–867. Journal of Obstetrics and Gynaecology 2002;109:1056–1062.
27. Goldberg RJ,Yarzebski J,Lessard D,etal:A two-decades (1975 to 34. Writing Group for the Women’s Health Initiative Investigators:
1995) long experience in the incidence,in-hospital and long-term Risks and benefits of estrogen plus progestin in healthy post-
case-fatality rates of acute myocardial infarction:A community- menopausal women:Principal results From the Women’s Health
wide perspective.Journal of the American College of Cardiology Initiative randomized controlled trial.JAMA 2002;288:321–333.
1999;33:1533–1539. 35. Waters DD,Alderman EL,Hsia J,etal:Effects of hormone replace-
28. Astra AB:What’s what:A guide to acronyms for cardiovascular ment therapy and antioxidant vitamin supplements on coronary
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29. Parmley WW:TOTAL ABC CHAOS.Journal of the American College trolled trial.JAMA 2002;288:2432–2440.
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31. Hulley S,Grady D,Bush T,etal:Randomized trial of estrogen plus 37. Manson JE,Hsia J,Johnson KC,etal:Estrogen plus progestin and
progestin for secondary prevention of coronary heart disease in the risk of coronary heart disease.New England Journal of Medi-
postmenopausal women.Heart and Estrogen/progestin Replace- cine 2003;349:523–534.
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32. Grady D,Herrington D,Bittner V,etal:Cardiovascular disease out- sal of fortune.Circulation 2003;107:1830–1833.
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Estrogen/progestin Replacement Study follow-up (HERS II).JAMA tion prevent cardiovascular events? Journal of Women’s Health
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C O N T R I B U T O R S
ROBERT ALLAN,PhD JEFFREYA. CUTLER, MD
Clinical Assistant Professor of Psychology in Psychiatry, Senior Scientific Advisor,Division of Epidemiology and
Weill Medical College of Cornell University; Assistant Clinical Applications, National Heart, Lung, and Blood
Attending Psychologist in Psychiatry,New York Presby- Institute,Bethesda,Maryland.
terian Hospital,New York,New York. Comparative Features of Primordial, Primary, and
Cardiac Psychology:Psychosocial Factors Secondary Prevention Trials
ELLIOTT M. ANTMAN, MD
Associate Professor, Department of Medicine, Harvard DAVID L. DEMETS, PhD
Medical School;Director,Samuel A.Levine Cardiac Unit, Professor and Chair, Department of Biostatistics and
Department of Medicine,Cardiovascular Division,Brigham Medical Informatics, University of Wisconsin, Madison,
and Women’s Hospital,Boston,Massachusetts. Wisconsin.
Direct Thrombin Inhibitors Principles of Data and Safety Monitoring Boards in
Randomized Trials
SHARI S. BASSUK, ScD
Epidemiologist,Division of Preventive Medicine,Brigham
JOHN P. DIMARCO, MD, PhD
and Women’s Hospital,Boston,Massachusetts.
Professor of Medicine,Internal Medicine,Cardiovascular
Antioxidant Vitamins
Division, University of Virginia, Charlottesville,Virginia.
MALCOLM R. BELL, MBBS, FRACP Drug Therapy for Ventricular Tachycardia and Ventricu-
Professor of Medicine,Mayo Medical School;Consultant lar Fibrillation
in Cardiovascular Diseases and Internal Medicine,Mayo
Clinic and Mayo Foundation,Rochester,Minnesota.
ERIC J. EICHHORN, MD
Coronary Artery Bypass Surgery
Adjoint Professor of Medicine, Department of Internal
Medicine,University of Colorado Health Science Center,
JOHN A. BITTL, MD
Denver,Colorado;Staff Physician;Director of Heart Fail-
Interventional Cardiologist,Ocala Heart Institute,Munroe
ure Services,Medical City Dallas Hospital;Medical Direc-
Regional Medical Center,Ocala,Florida.
tor,Cardiopulmonary Research Science and Technology
Direct Thrombin Inhibitors
Institute,Dallas,Texas.
JULIE E. BURING, ScD, FACE Beta Blockers
Professor of Ambulatory Care and Prevention,Harvard
Medical School; Deputy Director, Division of Preven-
MARGARET C. FANG, MD
tive Medicine,Brigham and Women’s Hospital,Boston,
Clinical and Research Fellow in Medicine,Clinical Epi-
Massachusetts.
demiology Unit,Massachusetts General Hospital,Boston,
Contributions of Basic Research,Observational Studies,
Massachusetts.
and Randomized Trials
Anticoagulant and Antiplatelet Drug Therapy in Atrial
Fibrillation
CLAUDIAU. CHAE, MD, MPH
Instructor in Medicine,Harvard Medical School;Associ-
ate Physician,Division of Preventive Medicine,Brigham GARYS. FRANCIS, MD
and Women’s Hospital; Assistant in Medicine, Cardi- Director, Coronary Intensive Care Unit, Cardiology
ology Division,Massachusetts General Hospital,Boston, Department, Cleveland Clinic Foundation; Professor of
Massachusetts. Medicine,Ohio State University,Cleveland,Ohio.
Postmenopausal Hormone Replacement Therapy Drugs Blocking the Renin-Angiotensin-Aldosterone
System
DAVID E. CHIRIBOGA, MD, MPH
Fellow,Preventive Medicine,Department of Family Medi-
cine and Community Health,University of Massachusetts LAURENCE S. FREEDMAN, PhD
Medical School,Worcester,Massachusetts. Professor of Statistics,Department of Mathematics and
Prevention Strategies:From the Office to the Community Statistics,Bar Ilan University,Ramat Gan,Israel.
and Beyond Methodology of Randomized Trials
ix
x CONTRIBUTORS
LAWRENCE M. FRIEDMAN, MD JUHANAKARHA,MD
Assistant Director for Ethics and Clinical Research,National Clinical Fellow,Internal Medicine,Department of Medi-
Heart,Lung,and Blood Institute,Bethesda,Maryland. cine, Brigham and Women’s Hospital, Boston, Massa-
Comparative Features of Primordial, Primary, and chusetts.
Secondary Prevention Trials Angioplasty:Primary, Rescue, and Adjunctive Mechan-
ical Interventions
J. MICHAELGAZIANO, MD, MPH, FACC
Associate Professor of Medicine,Harvard Medical School; CHARLES R. KERR,MD, FRCPC, FACC
Chief,Division of Aging,Brigham and Women’s Hospital; Professor; Head, Division of Cardiology, Department of
Director, Massachusetts Veterans Epidemiology Research Medicine,University of British Columbia;Head,Division
and Information Center,Boston,Massachusetts. of Cardiology, Department of Medicine, St. Paul’s Hos-
Cholesterol Reduction;Aspirin,Other Antiplatelet Agents, pital,Vancouver,British Columbia,Canada.
and Anticoagulants;Antioxidant Vitamins Pacing
TOBIAS KURTH, MD, ScD
BERNARD J. GERSH, MB, ChB, DPhil
Instructor in Medicine,Department of Medicine,Harvard
Professor of Medicine,Department of Internal Medicine,
Medical School; Associate Epidemiologist, Divisions of
Mayo Medical School;Consultant,Department of Internal
Preventive Medicine and Aging,Department of Medicine,
Medicine,Mayo Medical Center,Rochester,Minnesota.
Brigham and Women’s Hospital,Boston,Massachusetts.
Coronary Artery Bypass Surgery
Aspirin, Other Antiplatelet Agents, and Anticoagulants
C. MICHAELGIBSON, MS, MD
J. MICHAELMANGRUM,MD
Associate Professor of Medicine, Harvard University;
Assistant Professor of Medicine,Department of Internal
Associate Chief of Cardiology, Beth Israel Deaconess
Medicine,Cardiovascular Division,University of Virginia,
Medical Center;Director,TIMI Angiographic Core Labora-
Charlottesville,Virginia.
tory and Data Coordinating Center,Brigham and Women’s
Drug Therapy for Ventricular Tachycardia and Ventricu-
Hospital,Boston,Massachusetts.
lar Fibrillation
Angioplasty:Primary, Rescue, and Adjunctive Mechan-
ical Interventions
JOANN E. MANSON, MD, DrPH, FAHA, FACP
Elizabeth F. Brigham Professor of Women’s Health and
HEATHER L. GORNIK, MD, MHS
Professor of Medicine, Harvard Medical School; Chief,
Cardiology Fellow,Cardiovascular Division,Brigham and
Division of Preventive Medicine and Co-Director of the
Women’s Hospital,Boston,Massachusetts.
Connors Center for Women’s Health and Gender Biology,
Adjunctive Medical Therapy
Brigham and Women’s Hospital,Boston,Massachusetts.
Postmenopausal Hormone Replacement Therapy;Anti-
ERMINIAM. GUARNERI, MD, FACC
oxidant Vitamins
Medical Director, Integrative Medicine, Department of
Cardiovascular Disease,Scripps Clinic,La Jolla,California.
ELIZABETH MCNEILL,MD, MBChB, BSc (Hons), MRCP
Multiple Risk-Factor Intervention Trials
Clinical Fellow in Electrophysiology,Department of Car-
diology, University of British Columbia; Clinical Fellow
JACQUELINE A. HART, MD in Electrophysiology, Department of Cardiology, St.
Co-Medical Director,C.A.L.M.Program,Division of Cardi-
Paul’s Hospital, Vancouver, British Columbia, Canada;
ology,Newton-Wellesley Hospital,Newton,Massachusetts.
Specialist Registrar in Cardiology,Bristol Royal Infirmary
Multiple Risk-Factor Intervention Trials
(South West Deanery),Bristol,United Kingdom.
Pacing
JIANG HE, MD, PhD
Professor of Epidemiology and Medicine,Tulane Univer- SHAMIR R. MEHTA, MD, MSc (Epi), FRCPC, FACC
sity School of Public Health and Tropical Medicine,New Assistant Professor, Department of Medicine, McMaster
Orleans,Louisiana. University;Staff Cardiologist (Interventional Cardiology),
Blood Pressure Reduction Hamilton Health Sciences, General Division, Hamilton,
Ontario,Canada.
ELAINE M. HYLEK, MD, MPH Aspirin and Thienopyridines
Assistant Professor, Harvard Medical School; Associate
Physician; Associate Chief, General Internal Medicine DAVID A. MORROW,MD, MPH
Division/Clinical Epidemiology Unit,Massachusetts Gen- Instructor in Medicine, Harvard University; Associate
eral Hospital,Boston,Massachusetts. Physician,Cardiovascular Division,Brigham and Women’s
Anticoagulant and Antiplatelet Drug Therapy in Atrial Hospital,Boston,Massachusetts.
Fibrillation Heparin and Low–Molecular-Weight Heparin