The Health
Consequences
Of Smoking

CARDIOVASCULAR
   DISEASE

a report of the
Surgeon General

1983

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVCES
Ptt4icHedthService
ONiceonSmokngdHeelth
RockWe, MaryW9857


TC THE READERS OF THIS VOLUME:

  Provisions of the Public Health Cigarette Smoking Act of 1969
(P.L. 91-222) require the Secretary of Health and Human Services
to submit an annual report to the Congress on the health conse-
quences of smoking.  Attached is the 1983 report, Health Conse-
quences of Smoking: Cardiovascular Disease.   This volume is an
indepth analysis of the scientific evidence of the relationship
between cigarette smoking and multiple cardiovascular diseases.
This relationship is quantitatively the most serious of the health
consequences of smoking,  but is poorly recognized by the public.

  This report represents the consolidated work of many widely-

recognized experts known for their contribution to understanding
cardiovascular disease.   It is a scientific reference document to
serve as a state-of-the-art source for medical and behavioral
scientists and researchers.

  Smoking-related cardiovascular disease is estimated to account
for more deaths than,any other smoking-related disease, including
cancer.  This report clearly establishes that cigarette smoking
increases the risks for a number of cardiovascular diseases, partic-
ularly coronary heart disease,  the largest single cause of deaths
in the United States.  In addition,  smoking +s related to an
increased risk for stroke, atherosclerosis, and other circulatory
diseases.

  The report clearly demonstrates that cigarette smoking is a
major risk factor for coronary heart disease in the United States.
There are 55 million persons who smoke,  a larger population than
those who have hypertension or elevated cholesterol, the other
major risk factors for this disease.   Smokers '  death rates from
coronary heart disease are 70 percent greater than those of non-
smokers.  Simply by quitting smoking,  these men and women drsmati-
tally reduce their risk of premature death from this disease.

The economic and social toll these smoking-related deaths

extract from the Nation's health is immeasurable.  The report `a
findings re-emphasize the importance of this Department's continued
educational efforts to enable a fully-informed choice by indlvid-
uals on whether to begin or to continue t.o smoke.

  In my view,  this volume is a solid scientific work and a contri-
bution to the prevention efforts of this Department.

Heckler


FOREWORD

The 1983 Report is the second volume in The Health Consequences
of Smoking series that focuses on specific diseases. The 1982 Report
reviewed in depth the association between tobacco use and various
cancers; the 1983 Report is a comprehensive review of the relation-
ship between smoking and cardiovascular disease.

The ability to draw a conclusion from the scientific evidence on the
causal relationship between smoking and cardiovascular disease was
reached more recently than it was from the evidence on the
relationship between smoking and cancer. The latter relationship
was first established scientifically 30 years ago, particularly for lung
cancer. At the time the Advisory Committee on Smoking and Health
was formed in 1962, the scientific evidence linking tobacco use,
particularly cigarettes, with respiratory cancers was overwhelming.
A causal link between cigarette use and lung cancer was both clear
and compelling. A number of epidemiological studies on the relation-
ship between smoking and coronary heart disease (CHD) existed at
that time, but the Committee felt that the evidence was insufficient
to make a judgment of a causal relationship.

Nevertheless, the Committee found the evidence compelling
enough to caution that even though the causal role of cigarette
smoking in coronary heart disease was not proved, countermeasures
were warranted, and the Committee counseled against postponing
action until no uncertainty remained. The evidence was reviewed
again in the 1971 Surgeon General's Report and was, by this time,
clearly strong enough to establish cigarette smoking as a major risk
factor for coronary heart disease in men. By 1979, when the 15th
year anniversary Report of the Surgeon General was published,
there was no longer any doubt that cigarette smoking was directly
related to coronary heart disease for both men and women in the
United States.

The Importance of Cardiovascular Disease

The importance of cardiovascular disease, particularly coronary
heart disease, to the health of the American public is evident. In
1980 cardiovascular disease accounted for approximately half of all
U.S. deaths-980,000 out of 1,980,OOO total deaths. Of these, slightly

. . .
ill


over 565,000 were due to coronary heart disease; that is, approxi-
mately 30 percent of all deaths and almost 60 percent of all
cardiovascular deaths were due to CHD. The age-adjusted CHD
death rate peaked in 1963, and by 1980 had declined 30 percent. In
the period between 1968 and 1978 alone, the age-adjusted rate
declined 26.5 percent, with a greater decline noted for the younger
age groups.

In comparison, the total number of all cancer deaths was slightly
over 416,000 in 1980. Thus, deaths from CHD exceeded all cancer
deaths, and deaths from all cancers numbered less than one-half the
total of all cardiovascular deaths.

Last year this Department issued a report in which it was
estimated that tobacco use, particularly cigarette smoking, was
related to 30 percent of all cancer deaths in the United States-a
projected 129,000 premature deaths. The findings of this year's
Report, however, should be considered even more alarming, in that
the number of cardiovascular deaths that are reasonably estimated
to be cigarette related is even higher. A number of investigators'
have estimated that 30 percent, or more, of CHD deaths could be
attributed to cigarette smoking because of the higher CHD death
rates experienced by ever-smokers compared with never-smokers. If
30 percent of coronary heart disease deaths are attributed to
cigarette smoking, 170,000 Americans will die prematurely of CHD
each year. Smokers also experience increased death rates owing to
other cardiovascular diseases such as stroke, peripheral vascular
disease, aortic atherosclerosis, and other vascular problems.

Findings of the 1983 Report-Coronary Heart Disease and
Cigarette Smoking

Each of the three major risk factors poses approximately the same
increase in risk of CHD for the person with the risk factor, but
cigarette smoking is far more prevalent as a risk factor for CHD in
the American population than either hypertension or elevated
serum cholesterol. Thus, the overall finding of this Report is clear:
Cigarette smoking should be considered the most important of
the known modifiable risk factors for coronary heart disease in
the United States.

For over 25 years, cigarette smoking has been linked epidemiologi-
tally with an increased risk of dying from coronary heart disease. As
early as 1954, a strong, statistically significant association between
cigarette use and CHD was demonstrated. In the intervening years,
additional studies have confirmed this association. An examination
of only the major prospective studies, involving more than 20 million

`Report of the Royal College of Physicians. London. 1978; Sogot and Murray, Public Health Reports. 1980;
Ganinkel, Proceedings of the Fourth World Conference on Smoking and Health, Stackbolm, 1980. See Section 3 for
additional discussion.

iv


person-years of observation, indicates that smoking has been consis-
tently shown to elevate CHD mortality rates. Overall, smokers have
a 70 percent greater CHD mortality than nonsmokers. Heavy
smokers, those who consume more than two packs per day, experi-
ence CHD mortality rates almost 200 percent greater than nonsmok-

ers.

In the National Pooling Project study, a unique study that
combined data from five of the Nation's largest incidence studies on
heart disease, smokers of a pack or more per day were found to have
a greater than 2.5fold increased risk of developing a major coronary
event compared with nonsmokers. This study also found that
smokers who have other major risk factors experience a greater
increased risk than would be expected from the summation of the
independent risks. Thus, cigarette smoking interacts with the other
major risk factors in a manner that greatly increases the risk of
CHD.

The risk of developing and dying from CHD is directly related to
the total dosage of cigarette smoke exposure. A dose-response
relationship has been established for the number of cigarettes
smoked per day, the total years of cigarette smoking, and the degree
of inhalation; CHD risk is inversely related to the age of initiation.
CHD mortality ratios are also greater at the younger age groups;
thus, preventive efforts could truly have a decided impact on
extending life-expectancy-if large numbers of smokers could be
persuaded to quit smoking. The decrease in elevated CHD risk with
cessation, coupled with the prevalence of smoking as a risk factor in
the U.S. population, means that the elimination of cigarette usage
could have a greater impact on CHD morbidity and mortality than
any other preventive measure.

Sudden Cardiac Death

Smokers are at a two to four times greater risk for sudden cardiac
death @CD) than are nonsmokers. The risk for sudden death
increases with increasing daily exposure, as measured by the
number of cigarettes consumed per day.

Stroke

The association between cigarette smoking and cerebrovascular
disease (CVD) is largely confined to the younger age groups, with
little evidence of an effect after age 65. The number of stroke deaths
in 1980 totaled 170,000; even a small percentage of such deaths
represents thousands of premature deaths.

V


Women

For women who both smoke cigarettes and used oral contracep-
tives, a strong association exists between their use and one form of
stroke-subarachnoid hemorrhage. Smoking and oral contraceptive
use appear to interact synergistically to greatly increase the risk of
subarachnoid hemorrhage and of CHD, compared with the risk for
those women who neither smoke nor use oral contraceptives.

Other Cardiovascular Disease

Cigarette smoking contributes to the development of aortic
atherosclerosis and arteriosclerotic peripheral vascular disease
(APVD). Ninety percent of patients with APVD are cigarette
smokers, and the successful management of this disease includes
complete smoking cessation by such patients.

Changing Trends in Smoking Behavior and Coronary Heart
Disease

Demographers have noted a reduction in mortality rates from
heart disease for several years. However, a sharp decline in these
rates occurred in the late 1960s for reasons that are not entirely
known. Significantly, declines in cigarette smoking prevalence
among adults were first noted in 1964, the year of the first Surgeon
General's Report, with declines in prevalence accelerating between
1966 and 1970. By 1980, overall adult smoking prevalence had
declined by nearly 25 percent. While the magnitude of the impact of
these changes in smoking behavior on the decline in CHD death
rates is uncertain, the direction and nature of that impact is not. The
substantial changes in smoking beh.avior that have occurred over the
last 20 years have exerted, and will continue to exert, a substantial
beneficial effect on the incidence of CHD in the U.S. population.

We know from cohort mortality studies, incidence studies, and,
more recently, intervention trials that smoking cessation results in a
reduction in CHD mortality.

Data from the Multiple Risk Factor Intervention Trial (MRFIT)
have shown that those cigarette smokers who reported quitting at
their first-year interview (after an average of 6 years of followup)
reduced their relative risk for CHD mortality by almost half
compared with those smokers who continued to smoke. Mortality
from all causes was almost 30 percent lower among those who quit
smoking compared with those who continued to smoke. These data
correlate well with those observed in the cohort mortality studies,
which have consistently shown a decline in CHD mortality among
former smokers compared with continuing smokers. In some studies

vi


a substantial improvement in mortality within the first few years
after smoking cessation was demonstrated.

Public Perception of the Scientific Link Between Cigarette
Smoking and CHD

A recent staff report by the Federal Trade Commission revealed
that a substantial proportion of the American public is not aware of
the link between cigarette smoking and heart disease. When asked
to respond to the statement "Cigarette smoking is a major cause of
heart disease," 40 percent of adults responded "false" or "don't
know," including almost half of the adult smokers (45 percent). This
concurs with results from a 1980 Roper survey, which found that 53
percent of the population and 58 percent of smokers did not know
that smoking causes many cases of heart attack; a surprising 20
percent were not even aware that smoking causes some cases.

It is apparent that for a significant segment of the general public,
a large gap exists in its understanding of the relationship between
cigarette smoking and heart disease, a relationship that accounts for
the largest number of excess deaths of all the diseases associated
with cigarette smoking.

In last year's Report, I stated that the education of our citizens
regarding the health hazards of smoking cannot be left solely to
government. The findings of this Report and previous ones compel
me again to ask for an increased commitment by the health care
community, voluntary health agencies, schools, and other groups in
our society to join this Department and the Public Health Service in
our continuing efforts to reduce the premature death and disability
associated with cigarette smoking through renewed efforts of
education and information.

Edward N. Brandt, Jr., M.D.
Assistant Secretary for Health

vii


PREFACE

In 1982, the Public Health Service's Report on the health
consequences of smoking dealt with the relationship between
smoking and cancer. This 1983 Report turns its attention to the
relationship between cigarette smoking and cardiovascular disease,
one that imposes an even greater burden of disease and premature
death.

In preparing this Report, the Public Health Service has reviewed a
world literature that goes back more than 40 years and has
examined the results of epidemiological observations covering many
millions of person-years. This evidence permits us to affirm again
what was said in our 1979 Report and what is the consensus of other
scientific bodies here and across the world. Cigarette smoking is
causally related to heart disease; it and elevated levels of serum
cholesterol and hypertension consti.tute the major risk factors for
contracting and dying from this disease.

Since 1979, much additional information has accumulated to
support this judgment. From a public health viewpoint, the most
important is the new and further evidence presented in this volume
that when one quits smoking, the risk of dying from heart disease
begins to recede almost immediately and eventually becomes no
greater than that experienced by scmeone who has never smoked at
all. This is an encouragement to personal action and a justification
for much greater research and program effort by government and
voluntary agencies in helping people to quit smoking.

As in all previous Reports, the Public Health Service has turned to
many people and agencies within the research and clinical communi-
ty in developing this statement. On behalf of the Service, I express
my respect and gratitude to them.

C. Everett Koop, M.D.
Surgeon General

ix


ACKNOWLEDGEMENTS

This Report was prepared by the Department of Health and
Human Services under the general editorship of the Office on
Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag-
ing Editor was Dona` i R. Shopland, Technical Information Officer,
Office on Smoking and Health.

Consulting scientific editors were David M. Burns, M.D., Assistant
Professor of Medicine, Division of Pulmonary and Critical Care
Medicine, University of California at San Diego, San Diego, Califor-
nia; John H. Holbrook, M.D., Associate Professor of Internal
Medicine, University of Utah Medical Center, Salt Lake City, Utah;
and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer
Prevention Program, Division of Cancer Control, Jonsson Compre-
hensive Cancer Center, University of California at Los Angeles, Los
Angeles, California.

The editors wish to acknowledge their appreciation to the Nation-
al Heart, Lung, and Blood Institute, Claude Lenfant, M.D., Director,
for their assistance. In particular, the editors wish to acknowledge
Peter L. Frommer, M.D., Deputy Director, and Gardner C. McMillan,
M.D., Ph.D., Associate Director for Arteriosclerosis, Hypertension
and Lipid Metabolism Program, for their assistance in the planning
of the Report and for their careful review of the manuscripts. Special
recognition is due Thomas L. Robertson, M.D., Chief, Cardiac
Diseases Branch, for his substantial contribution to the Report.

The following individuals wrote portions of the Report:
Robert W. Barnes, M.D., F.A.C.S., Professor and Chairman, Depart-
ment of Surgery, University of Arkansas for Medical Sciences,
Little Rock, Arkansas

Joseph T. Doyle, M.D., Professor of Medicine and Head of the
Division of Cardiology, and Attending Cardiologist, Albany Medi-
cal Center Hospital, Albany Medical College, Albany, New York
James E. Enstrom, Ph.D., M.P.H., School of Public Health, Universi-
ty of California at Los Angeles, Los Angeles, California
Manning Feinleib, M.D., Dr.P.H., Director, National Center for
Health Statistics, Hyattsville, Maryland
Nancy J. Haley, Ph.D., Associate, Naylor Dana Institute for Disease
Prevention, American Health Foundation, Valhalla, New York

xi


Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Institute
for Disease Prevention, American Health Foundation, Valhalla,
New York

Ilse Hoffmann, Research Coordinator, Naylor Dana Institute for
Disease Prevention, American Health Foundation, Valhalla, New
York

William B. Kannel, M.D., Professor of Medicine, Chief, Section of
Preventive Medicine and Epidemiology, Boston University Medi-
cal Center, Boston, Massachusetts

Paul E. Leaver-ton, Ph.D., Acting Director, Epidemiology and Biome-
try Program, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland
Margaret H. Mushinski, M.A., American Cancer Society, Depart-
ment of Epidemiology and Statistics, New York, New York
Jeffrey Newman, M.D., M.P.H., Medical Epidemiologist, Behavioral
Epidemiology and Evaluation Branch, Centers for Disease Control,
Public Health Service, Atlanta, Georgia
Judith K. Ockene, Ph.D., Director, Division of Preventive and
Behavioral Medicine, Department of Medicine, University of
Massachusetts Medical School, Worchester, Massachusetts
Oglesby Paul, M.D., Professor of Medicine, Harvard Medical School,
Boston, Massachusetts

Thomas L. Robertson, M.D., Chief, Cardiac Diseases Branch, Division
of Heart and Vascular Diseases, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Jack P. Strong, M.D., Boyd Professor and Head, Department of
Pathology, Louisiana State University Medical Center, New
Orleans, Louisiana

Thomas J. Thorn, Statistician, Epidemiology and Biometry Program,
National Heart, Lung, and Blood. Institute, National Institutes of
Health, Bethesda, Maryland

The editors acknowledge with gratitude the followiT g distin-
guished scientists, physicians, and others who lent their support in
the development of this Report by coordinating manuscript prepara-
tion, contributing critical reviews of the manuscript, or assisting in
other ways.

Henry Blackburn, M.D., Professor ,and Director, Division of Epide-
miology, School of Public Health, University of Minnesota, Minne-
apolis, Minnesota

William Castelli, M.D., Chairman and Medical Director, Framing-
ham Heart Study, National Heart, Lung, and Blood Institute,
National Institutes of Health, Framingham, Massachusetts
Thomas B. Clarkson, D.V.M., Professor of Comparative Medicine and
Director, Arteriosclerosis Research Center, Department of Com-

xii


parative Medicine, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, North Carolina
D. Layten Davis, Ph.D., Director, University of Kentucky Tobacco
and Health Research Institute, University of Kentucky, Lexing-
ton, Kentucky

Joseph T. Doyle, M.D., Professor of Medicine and Head of the
Division of Cardiology, and Attending Cardiologist, Albany Medi-
cal Center Hospital, Albany Medical College, Albany, New York
William H. Foege, M.D., Director, Centers for Disease Control,
Atlanta, Georgia

Gary D. Friedman, M.D., Assistant Director for Medical Methods
Research, Epidemiology and Biostatistics, Kaiser-Permanente
Medical Group, Inc., Oakland, California
Peter L. Frommer, M.D., Deputy Director, National Heart, Lung,
and Blood Institute, National Institutes of Health, Bethesda,
Maryland

Michael R. Guerin, Ph.D., Section Head, Bio-Organic Analysis
Section, Analytical Chemistry Division, Oak Ridge National
Laboratory, Oak Ridge, Tennessee
Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of
Economics, Massachusetts Institute of Technology, Cambridge,
Massachusetts

Lawrence E. Hinkle, Jr., M.D., Professor of Medicine and Director,
Division of Human Ecology, Department of Medicine, The New
York Hospital-Cornell Medical Center, New York, New York
Stephen B. Hulley, M.D., M.P.H., Professor in Residence, Systolic
Hypertension in the Elderly Program Coordinating Center, De
partment of Epidemiology and International Health, School of
Medicine, University of California at San Francisco, San Francis-
co, California

Hershel Jick, M.D., Boston University Medical Center, Boston
Collaborative Drug Surveillance Program, Waltham, Massachu-
setts

Lewis H. Kuller, M.D., Dr.P.H., Professor and Chairman, Depart
ment of Epidemiology, Graduate School of Public Health, Univer-
sity of Pittsburgh, Pittsburgh, Pennsylvania
Claude Lenfant, M.D., Director, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Joseph L. Lyon, M.D., M.P.H., Department of Family and Communi-
ty Medicine, University of Utah School of Medicine, Salt Lake
City, Utah

Henry C. McGill, Jr., M.D., M.P.H., Professor, Department of
Pathology, University of Texas Health Science Center, and Scien-
tific Director, Southwest Foundation for Research and Education,
San Antonio, Texas

. . .
XIII


Gardner C. McMillan, M.D., Ph.D.,, Associate Director, Arteriosclero
sis, Hypertension and Lipid Metabolism Program, Division of
Heart and Vascular Disease, National Heart, Lung, and Blood
Institute, National Institutes of Health, Bethesda, Maryland
Kenneth M. Moser, M.D., Professor of Medicine and Director,
Division of Pulmonary and Critical Care Medicine, School of
Medicine, University of California at San Diego, San Diego,
California

Mark Novitch, M.D., Acting Commissioner of the Food and Drug
Administration, U.S. Department of Health and Human Services,
Rockville, Maryland

John A. Oates, M.D., Professor `of Medicine and Pharmacology,
Vanderbilt University School of Medicine, Nashville, Tennessee
C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine,
Department of Psychiatry, Duke University Medical Center,
Durham, North Carolina

Oglesby Paul, M.D., Professor of Medicine, Harvard Medical School,
Boston, Massachusetts

Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol-
ogy, University of Minnesota, Minneapolis, Minnesota
William Pollin, M.D., Director, National Institute on Drug Abuse,
U.S. Department of Health and Human Services, Rockville,
Maryland

James A. Schoenberger, M.D., Professor and Chairman, Department
of Preventive Medicine, Rush-PresbyterianSt. Luke's Medical
Center, Chicago, Illinois
Sam Shapiro, Professor, Health Services Research and Development
Center, Department of Health Policy and Management, School of
Hygiene and Public Health, The Johns Hopkins University,
Baltimore, Maryland

Roger Sherwin, M.D., Professor, Department of Epidemiology and
Preventive Medicine, University d Maryland School of Medicine,
Baltimore, Maryland

John A. Spittell, Jr., M.D., F.A.C.C., F.A.C.P., Mary Lowell Leary
Professor of Medicine, Mayo Medical School, and Consultant,
Cardiovascular Division, Internal Medicine, Mayo Clinic, Roches-
ter, Minnesota

Jeremiah Stamler, M.D., Chairman, Department of Community
Health and Preventive Medicine, Northwestern University Medi-
cal School, Chicago, Illinois

John F. Williams, Jr., M.D., H.H. Weiner-t Professor of Medicine,
University of Texas Medical Branch, Galveston, Texas
Robert W. Wissler, M.D., Ph.D., Donald N. Pritzker Distinguished
Service Professor of Pathology, and Senior Scientist of the
Specialized Center of Research in Atherosclerosis, Department of
Pathology, University of Chicago Medical Center, Chicago, Illinois

xiv


Robert S. Hutchings, Associate Director for Information and Pro-
gram Development, Office on Smoking and Health, Rockville,
Maryland

Margaret E. Ketterman, Public Information and Publications Spe-
cialist, Office on Smoking and Health, Rockville, Maryland
Leena Kang, Date Entry Operator, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
William R. Lynn, Program Operations Technical Assistance Officer,
Office on Smoking and Health, Rockville, Maryland
Kurt D. Mulholland, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock-
ville, Maryland

Raymond K. Poole, Production Coordinator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Roberts A. Roeder, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Linda R. Sexton, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Shari G. Simons, Clerk-Typist, Office on Smoking and Health,
Rockville, Maryland

Linda R. Spiegelman, Administrative Officer, Office on Smoking and
Health, Rockville, Maryland

Evelyn L. Swarr, Administrative Secretary, Data Processing Ser-
vices, Informatics General Corporation, Rockville, Maryland
Debra C. Tate, Publications Systems Specialist, Informatics General
Corporation, Riverdale, Maryland

Jill Vejnoska, Writer-Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Aileen L. Walsh, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Dee Whitley, Computer Operations, Data Processing Services, Infor-
matics General Corporation, Rockville, Maryland
Robert Winning, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Louise Wiseman, Technical Information Specialist, Office on Smok-
ing and Health, Rockville, Maryland

xvi


Robert S. Hutchings, Associate Director for Information and Pr+
gram Development, Office on Smoking and Health, Rockville,
Maryland

Margaret E. Ketterman, Public Information and Publications Spe-
cialist, Office on Smoking and Health, Rockville, Maryland
Leena Kang, Data Entry Operator, Clearinghouse Projects Depart-
ment, Informatics General Corporation, Rockville, Maryland
William R. Lynn, Program Operations Technical Assistance Officer,
Office on Smoking and Health, Rockville, Maryland
Kurt D. Mulholland, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock-
ville, Maryland

Raymond K. Poole, Production Coordinator, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Roberta A. Roeder, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Linda R. Sexton, Information Specialist, Clearinghouse Projects
Department, Informatics General Corporation, Rockville, Mary-
land

Shari G. Simons, Clerk-Typist, Office on Smoking and Health,
Rockville, Maryland

Linda R. Spiegelman, Administrative Officer, Office on Smoking and
Health, Rockville, Maryland

Evelyn L. Swarr, Administrative Secretary, Data Processing Ser-
vices, Informatics General Corporation, Rockville, Maryland
Debra C. Tate, Publications Systems Specialist, Informatics General
Corporation, Riverdale, Maryland

Jill Vejnoska, Writer-Editor, Information Programs Division, Infor-
matics General Corporation, Rockville, Maryland
Aileen L. Walsh, Secretary, Clearinghouse Projects Department,
Informatics General Corporation, Rockville, Maryland
Dee Whitley, Computer Operations, Data Processing Services, Infor-
matics General Corporation, Rockville, Maryland
Robert Winning, Graphic Artist, Information Programs Division,
Informatics General Corporation, Rockville, Maryland
Louise Wiseman, Technical Information Specialist, Office on Smok-
ing and Health, Rockville, Maryland

xvi


TABLE OF CONTENTS

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Preface .................................................................. ix

Acknowledgements .................................................. xi

1. Introduction, Overview, and Conclusions.. . . . . . . . . . . . . . . . . . 1

2. Arteriosclerosis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

3. Coronary Heart Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

4. Cerebrovascular Disease.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

5. Atherosclerotic Peripheral Vascular Disease and Aortic
Aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

6. Pharmacological and Toxicological Implications of
Smoke Constituents on Cardiovascular Disease.. . . . . . .203

7. Changes in Cigarette Smoking Behavior in Clinical
and Community Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ . .241

8. The Effect of Cigarette Smoking Cessation on Coro-
nary Heart Disease.............................................291

A. Trends in Cardiovascular Diseases ....................... 327

B. Trends in U.S. Cigarette Use, 1965-1980 .............. 361

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375

xvii



SECTION 1. INTRODUCTION,
       OVERVIEW, AND
        CONCLUSIONS


Introduction

Organization and Development of the 1983 Report
The content of the Report is the work of numerous scientists and
experts within the Department of Health and Human Services as
well as from outside the organization. Individual manuscripts were
written by experts nationally and internationally recognized for
their scientific contributions to the understanding of cardiovascular
diseases. These manuscripts were reviewed individually by other
experts, within and outside the U.S. Public Health Service, and the
entire Report was reviewed by a broad-based panel of distinguished
cardiovascular scientists. The 1983 Report includes a Foreword by
the Assistant Secretary for Health of the Department of Health and
Human Services and a Preface by the Surgeon General of the U.S.
Public Health Service. The body of the report consists of eight
sections and two appendices, as follows:

0 Section 1.  Introduction, Overview, and Conclusions
0 Section 2.   Arteriosclerosis
0 Section 3.  Coronary Heart Disease
0 Section 4.   Cerebrovascular Disease
o Section 5.  Atherosclerotic Peripheral Vascular Disease and
       Aortic Aneurysm
o Section 6.  Pharmacological and Toxicological Implications of
         Smoke Constituents on Cardiovascular Disease
0 Section 7.  Changes in Cigarette Smoking Behavior in Clini-
        cal and Community Trials
o Section 8.  The Effect of Cigarette Smoking Cessation on
        Coronary Heart Disease
a Appendix A.  Trends in Cardiovascular Diseases

o  Appendix B.  Trends in U.S. Cigarette Use, 1965 to 1980

Historical Perspective

Early reports linking smoking with a greater risk of developing
cardiovascular disease occurred around the turn of the century. An
early series of studies, initiated in 1904 by Erb, found a much higher
percentage of smokers than of nonsmokers with intermittent claudi-
cation; only 10 percent of his patients with claudication were
nonusers of tobacco. As early as 1934, Howard made the observation
that the increasing prevalence of coronary heart disease noted since
the first World War might be a result of the greatly increased use of
cigarettes.

By the turn of the century, numerous studies had demonstrated
clinically and experimentally that cigarette smoking or cigarette
smoke constituents, most notably nicotine, caused an elevation in
blood pressure and heart rate during smoking.

3


The first major prospective study results were made public in 1954
in the United States by Hammond and Horn and found a strong
association between cigarette use among men and coronary heart
disease (CHD). Overall, smokers were found to carry a 70 percent
greater risk of dying from CHD than nonsmokers; heavy smokers
had CHD mortality rates almost two and one-half times greater than
nonsmokers. Hammond and Horn also noted a consistent dose-
response relationship with the number of cigarettes consumed per
day.

In the intervening 30 years, numerous additional epidemiological
mortality studies were undertaken to examine this issue. These
included studies in the United Kingdom, Canada, Sweden, Japan,
and Switzerland in addition to the United States. In total, they
represent more than 20 million person-years of observation. Find-
ings from these studies have been remarkably uniform: smokers
have much higher death rates from coronary heart disease than do
nonsmokers, despite the fact that these studies were conducted in
varying populations, were geographically diverse, and involved
differing methodologies.

The first major U.S. Public Health Service review of the relation-
ship between smoking and heart disease was conducted by the
Surgeon General's Advisory Committee on Smoking and Health in
1984. Although the Committee noted that male smokers had higher
death rates from coronary heart disease, it was unable to conclude
that the association had causal significance. However, it was noted
in the report that "the causative role of these factors [risk factors
including cigarette smoking] in coronary disease, though not proven,
is suspected strongly enough to be a major reason for taking
countermeasures against them. It is also more prudent to assume
that the established association between cigarette smoking and
coronary disease has causative meaning than to suspend judgement
until no uncertainty remains."

Since the release of the original Report of the Surgeon General in
1984, additional studies dealing with. cigarette smoking and CHD
have been summarized in the series of annual reports of the Surgeon
General The Health Consequences of Smoking. By 1979, the magni-
tude of the epidemiological, pathological, clinical, and experimental
evidence had grown to the point that the Surgeon General's Report
concluded: "Smoking is causally related to coronary heart disease in
the common sense of that idea and for the purposes of preventive
medicine."

Overview

In 1980, diseases of the circulatory system were responsible for
approximately one-half of the total U.S. mortality. CHD was the

4


single most important cause of death, accounting for approximately
30 percent of all U.S. deaths.

Cigarette smoking is one of the three major independent CHD risk
factors. The magnitude of the risk associated with cigarette smoking
is similar to that associated with the other two major CHD risk
factors, hypertension and hypercholesterolemia; however, because
cigarette smoking is present in a larger percentage of the U.S.
population than either hypertension or hypercholesterolemia, ciga-
rette smoking ranks as the largest preventable cause of CHD in the
United States. Cigarette smoking also acts synergistically with the
other major risk factors to greatly increase the risk for CHD.

Arteriosclerosis is the predominant underlying cause of cardiovas-
cular disease, and atherosclerosis is the form of arteriosclerosis that
most frequently causes clinically significant disease, including CHD,
atherothrombotic brain infarction, atherosclerotic aortic disease,
and atherosclerotic peripheral vascular disease. Cigarette smoking
contributes both to the development of atherosclerotic lesions and to
the clinical manifestations of atherosclerotic vascular disease, in-
cluding sudden death. Although the precise pathophysiologic basis of
these clinical manifestations is not understood, it may be related to
several deleterious cardiovascular effects of cigarette smoking,
including production of an imbalance between myocardial oxygen
supply and demand, a decrease in the threshold for ventricular
fibrillation, and an increase in platelet aggregation. Nicotine and
carbon monoxide are the tobacco smoke constituents most closely
associated with these adverse effects; other cigarette smoke constitu-
ents such as hydrogen cyanide, oxides of nitrogen, and carbon
disulfide are being studied for possible pathogenic cardiovascular
effects.

Cigarette smoking is the most important risk factor for atheroscle-
rotic peripheral vascular disease, which usually involves the lower
extremities. Smoking cessation is probably the single most impor-
tant intervention in the management of this disorder. The effect of
cigarette smoking to aggravate and accelerate the development of
atherosclerosis is more striking in the aorta than in any other
vessels. Cigarette smoking is associated with an increased risk for
cerebrovascular disease, especially in younger age groups, but this
effect is less marked than for atherosclerotic disease at other sites.
Women cigarette smokers experience an increased risk for subarach-
noid hemorrhage; the use of both cigarettes and oral contraceptives
greatly increases this risk.

Smoking cessation is associated with decreased mortality and
morbidity from atherosclerotic vascular disease. Prospective epide-
miologic studies have shown that former cigarette smokers reduce
their CHD death risk from that of current smokers to that of
nonsmokers over approximately a 15-year period after stopping

5


smoking. The beneficial effects of quitting are not explained by
differences in baseline characteristics between quitters and continu-
ing smokers. CHD intervention trials have successfully demon-
strated the feasibility of reducing cigarette consumption; these trials
also documented a significant reduction in CHD mortality.

Conclusions of the 1983 Report

The purpose of this Report is to review in depth the many sources
of scientific evidence relating cigarette smoking to individual
cardiovascular disease entities. Listed below are the major findings
of this review.

Arteriosclerosis

1. A preponderance of evidence both from prospective studies
with autopsy followup and from autopsy studies with retrospec-
tive smoking data indicates that cigarette smoking has a
significant positive association with atherosclerosis. This evi-
dence suggests that cigarette smoking has the effect of
aggravating and accelerating the development of atherosclerot-
ic lesions in the artery wall and that its effect is not limited to
those events related to the occlusive episode. The effects are
most striking for aortic atherosclerosis; a significant positive
relationship also exists between cigarette smoking and athero
sclerotic lesions in the coronary arteries, at least for most high
risk populations. Cigarette smoking could also be associated
with other factors that precipitate thrombosis, hemorrhage, or
vasoconstriction leading to occlusion and ischemia.

2. Some evidence exists that cigarette smoke alters total serum
cholesterol concentrations and lipoprotein composition in ways
that would be expected to increase the development of athero
sclerosis. Recent studies of the effects of smoking on the
hemostatic system indicate effects on platelet function.
3. Although the specific mechanisms by which tobacco smoke
affects arteriosclerosis have not been clearly delineated, the
effects of cigarette smoking on the atherosclerotic lesions that
underlie cardiovascular disease seem well established.

Coronary Heart Disease

1. Cigarette smoking is a major cause of coronary heart disease in
the United States for both men and women. Because of the
number of persons in the population who smoke and the
increased risk that cigarette smoking represents, it should be
considered the most important of the known modifiable risk
factors for CHD.

6


2. Overall, cigarette smokers experience a 70 percent greater
CHD death rate than do nonsmokers. Heavy smokers, those
who consume two or more packs per day, have CHD death rates
between two and three times greater than nonsmokers.
3. The risk of developing CHD increases with increasing exposure
to cigarette smoke, as measured by the number of cigarettes
smoked daily, the total number of years one has smoked, and
the degree of inhalation, and with an early age of initiation.
4. Cigarette smokers have a twofold greater incidence of CHD
than do nonsmokers, and heavy smokers have an almost
fourfold greater incidence.

5. Cigarette smoking is a major independent risk factor for CHD,
and it acts synergistically with other risk factors (most notably,
elevated serum cholesterol and hypertension) to greatly in-
crease the risk of CHD.

6. Women have lower rates for CHD than do men. In particular,
CHD rates for women are lower prior to the menopause. A part
of this difference is due to the lower prevalence of smoking in
women, and for those women who do smoke, to the tendency to
smoke fewer cigarettes per day and to inhale less deeply.
Among those women who have smoking patterns comparable
to male smoking patterns, the increments in CHD death rates
are similar for the two sexes.

7. Women who use oral contraceptives and who smoke increase
their risk of a myocardial infarction by an approximately
tenfold factor, compared with women who neither use oral
contraceptives nor smoke.

8. Cigarette smoking has been found to significantly elevate the
risk of sudden death. Overall, smokers experience a two to four
times greater risk of sudden death than nonsmokers. The risk
appears to increase with increasing dosage as measured by the
number of cigarettes smoked per day and diminishes with
cessation of smoking.

9. The CHD mortality ratio for smokers compared with nonsmok-
ers is greater for the younger age groups than for the older age
groups. Although the smoker-to-nonsmoker mortality ratio
narrows with increasing age, smokers continue to experience
greater CHD death rates at all ages.

10. Cigarette smoking has been estimated to be responsible for up
to 30 percent of all CHD deaths in the United States each year.
During the period 1965 to 1980 there were over 3 million
premature deaths from heart disease among Americans attrib
uted to cigarette smoking. Unless smoking habits of the
American population change, perhaps 10 percent of all persons
now alive may die prematurely of heart disease attributable to

7


their smoking behavior. The total number of such premature
deaths may exceed 24 million.

11. Cessation of smoking results in a substantial reduction in CHD
death rates compared with those of persons who continue to
smoke. Mortality from CHD declines rapidly after cessation.
Approximately 10 years following cessation the CHD death
rate for those ex-smokers who consumed less than a pack of
cigarettes daily is virtually identical to that of lifelong non-
smokers. For ex-smokers who had smoked more than one pack
per day, the residual risk of CHD mortality is proportional to
the total lifetime exposure to cigarette smoke.

12. Epidemiologic evidence concerning reduced tar and nicotine or
filter cigarettes and their effect on CHD rates is conflicting. No
scientific evidence is available concerning the impact on CHD
death rates of cigarettes with very low levels of tar and
  nicotine.

13. Smokers who have used only pipes or cigars do not appear to
experience substantially greater CHD risks than nonsmokers.

Cerebrovascular Disease

1. Data from numerous prospective mortality studies have shown
an association between cigarette smoking and cerebrovascular
disease. This risk is most evident in the younger age groups,
and the effect diminishes with increasing age, with little or no
effect noted after age 65. No consistent dose-response effect
has been demonstrated.

2. Women cigarette smokers experience an increased risk for
subarachnoid hemorrhage. However, the use of both cigarettes
and oral contraceptives greatly increases the risk for subarach-
noid hemorrhage among women.

Atherosclerotic Peripheral Vascular Disease and Aortic
Aneurysm

1. Cigarette smoking is the most powerful risk factor predisposing
to atherosclerotic peripheral arterial disease.
2. Smoking cessation plays an important role in the medical and
surgical management of atherosclerotic peripheral vascular
disease.

3. Death from rupture of an atherosclerotic abdominal aneurysm
is more common in cigarette smokers than in nonsmokers.

Pharmacological and Toxicological Implications of Smoke
Constituents on Cardiovascular Disease
1. Over 4,000 different compounds have been identified in tobacco
   smoke.

8


2. Nicotine exerts an effect on ganglionic cells, producing tran-
sient excitation. The pharmacological effects are small, but are
reinforced several times daily in habitual smokers. The exact
mechanisms whereby nicotine might influence cardiovascular
events are unknown, but a lowering of the ventricular fibrilla-
tion threshold is dose related to nicotine levels.

3. Carbon monoxide may act to precipitate cardiac symptomatolo-
gy or ischemic episodes in individuals already compromised by
coronary disease. In addition, carbon monoxide binds to
hemoproteins, potentially inhibiting their functions.
4. Several studies have shown that smokers may alter their
smoking behavior when they switch to low-yield cigarettes.
This compensatory behavior may lead to the increased uptake
of gas phase constituents including carbon monoxide, hydrogen
cyanide, and nitrous oxides.

5. It is unlikely that a "safe cigarette" can be developed that will
reduce cardiovascular risk.

Changes in Cigarette Smoking Behavior in Clinical and
Community Trials

1. Smokers involved in intervention programs demonstrate high-
er smoking cessation rates than those in control groups.
2. In general, the success of smoking intervention programs is
related to the amount of intervention provided.

The Effect of Cigarette Smoking Cessation on Coronary
Heart Disease

1. In the four intervention trials involving mortality followup of
individual men for 5 to 10 years, the intervention groups had a
combined total of 10 percent fewer CHD deaths than did the
comparable control groups. Differences for other causes of
death or for total deaths were not significant.

2. In these trials, the amount of cigarette smoking has been
reduced 10 to 50 percent more in the intervention group than
in the control group, demonstrating that intervention can alter
smoking behavior.

3. In the two trials involving morbidity followup, the intervention
groups had 4 and 45 percent lower total CHD incidence than
did the respective control groups.
4. The relative reductions in CHD mortality in each of the four
intervention studies involving individual followup are reason-
ably consistent with the reduction in CHD risk factors, and for
a combination of all four studies, the reduction is statistically
significant.

9


5. Numerous studies ha-.-e shown that those who quit cigarette
smoking experience a substantial decrease in CHD mortality
and an improvement in life expectancy.
6. A number of prospective epidemiological studies indicate that
former cigarette smokers substantially reduce their CHD and
total death rates from that of current smokers.

Trends in Cardiovascular Diseases

The evidence supports the conclusion that changes in smoking
habits have contributed to substantial improvement in mortality
rates from the cardiovascular diseases in the United States.

Trends in U.S. Cigarette Use, 19651980
1. The proportion of current regular smokers declined steadily
  between 1965 and 1980. The decline was steeper among males
  (from 52.1 to 37.9 percent) than among females (from 34.2 to
  29.8 percent).

2. The proportion of never smokers increased steadily from 1965
to 1980 among males (27.6 to 31.6 percent), except those 45
years old and older. Among females, only 20- to 34-year-ok%
showed an increase in proportion of never smokers.
3. The mean number of cigarettes smoked per day by current
smokers increased slightly from 1970 to 1980 (from 20 to 21.7
cigarettes).

4. Males smoked a higher mean number of cigarettes throughout
the 1970-1980 period, but the number for males and females
increased about the same amount.
5. Heaviest daily consumption was in the middle-aged group (35-
65 years). The greatest mean increase was observed among
women aged 35 to 44.

6. The proportion of current smokers who smoked less than 20
cigarettes per day decreased between 1970 and 1980 (39.8 to
33.8 percent); the proportion smoking one pack exactly (20
cigarettes) remained constant (34.9 to 34.8 percent); the propor-
tion smoking from 21 to 39 cigarettes increased slightly (13.7 to
14.5 percent); and the proportion smoking two or more packs
per day increased from 11.4 to 16.8 percent.
7. The proportion of current smokers who attempted to quit three
or more times decreased slightly from 1966 to 1980 (41.2 to 38.7
percent).

8. The proportion of former smokers having made three or more
attempts to quit increased sharply (36 to 53.2 percent) from
1966 to 1975.

9. The proportion of current smokers who had attempted to quit
during the past year increased from 1966 to 1980 (26.0 to 36.7
percent).

10


10. Among current smokers, younger persons and females were
more likely than older persons and males to have attempted to
quit during the previous 12 months.
11. The proportion of former smokers who had attempted to quit
during the previous 12 months decreased from 1966 to 1975
(13.8 to 9.8 percent).

12. Among former smokers, younger persons and females were
more likely than older persons and males to have quit during
the previous 12 months.

11


SECTION 2. ARTERIOSCLEROSIS


Introduction and Definition of Terms

Arteriosclerosis is the predominant underlying cause of cardiovas-
cular diseases, including coronary heart disease (CHD), cerebral
infarction, arteriosclerotic peripheral vascular disease, and athero-
sclerotic aortic aneurysm. The specific relationships of tobacco use
and these conditions, as well as an overview of known and suspected
risk factors for cardiovascular disease, are reviewed in other
sections.

Because arteriosclerosis is sometimes used in a broad sense to
cover a variety of arterial lesions, the nomenclature and terminology
used in this section will be defined.

Arteriosclerosis is a generic term that includes practically any
arterial disease that leads to thickening and hardening of arteries of
any size.

Atherosclerosis is a specific form of arteriosclerosis. Its most
distinctive feature is the accumulation of lipid in the intima of large
elastic arteries (aorta) and medium-sized muscular arteries (coro-
nary, femoral, carotid, and others). In addition to lipid, cells,
connective tissue fibers, and various blood components accumulate
in the lesions. A number of complications, including thrombosis,
hemorrhage into a plaque, and ulceration, can also occur in or upon
the lesions. The hallmarks of atherosclerosis are its intimal location
during the initial stage, the involvement of large- and medium-sized
arteries, and the accumulation of fat in the lesion. Atherosclerosis is
the form of arteriosclerosis that most frequently causes clinically
significant disease.

Mbnckeberg's medial calcific sclerosis, characterized by calcifica-
tion of the medial layer of muscular arteries, and arteriolosclerosis,
characterized by thickening, fibrosis, hyalinization, and narrowing
of arterioles, are other types of arteriosclerosis quite distinct from
atherosclerosis. They are beyond the scope of this section. Medial
and arteriolar lesions have sometimes caused confusion in interpret-
ing experimental studies, principally those in which rabbits and rats
have been used. Only the intimal lesions that contain lipid and
connective tissue elements in large elastic and medium-sized muscu-
lar arteries are models of human atherosclerosis.

The term atheroma has been used in several different ways,
sometimes to refer to the entire process of atherosclerosis and
sometimes to describe a specific lesion. Some pathologists use the
word to mean a large atherosclerotic plaque containing a pool of
necrotic cells, lipid, and connective tissue. Atheroma has also been
used to refer to any lesion of atherosclerosis, including fatty streaks,
fibrous plaques, or complicated or calcified lesions.

The following working definitions are offered for different types of
atherosclerotic lesions detectable grossly after staining vessels with
Sudan IV or other fat stains.

15


A fatty streak is a fatty intimal lesion that is stained distinctly by
Sudan IV and shows no other underlying change. Fatty streaks are
flat or only slightly elevated in opened fresh or immersion fmed
vessels. They do not significantly narrow the lumina of blood vessels.

A fibrous plaque is a firm, elevated intimal lesion that in the fresh
state is usually gray-white, glistening, and translucent. Human
fibrous plaques characteristically contain fat. A thick fibrous
connective tissue cap containing varying amounts of lipid covers a
more concentrated "core" of lipid. If a lesion also contains hemor-
rhage, thrombosis, ulceration, or calcification, that lesion is classi-
fied according to one of the next two categories.

A complicated lesion is an intimal plaque in which there is
hemorrhage, ulceration, or thrombosis with or without calcification.

A calcified lesion is an intimal plaque in which insoluble mineral
salts of calcium are visible or palpable without overlying hemor-
rhage, ulceration, or thrombosis.

The term raised atherosclerotic Lesion is sometimes used as a
measure of atherosclerosis to include the sum of fibrous plaques,
complicated lesions, and calcified lesions. Raised lesions are contrast-
ed with fatty streaks, which typically show little or no elevation
above the surrounding intimal surface.

Although this classification scheme implies a pathogenetic se-
quence, it can be used for descriptive purposes regardless of the
theoretical pathogenetic interrelationships among the lesions.

Certain other intimal lesions are sometimes considered as sub-
types of atherosclerosis or as lesions predisposing to atherosclerosis.
These include musculoelastic or fibromuscular intimal thickening,
gelatinous or edematous lesions, and organizing mural thrombi on
an otherwise normal intima. The pathogenetic relationship of
atherosclerosis and its clinical manifestations is less well established
for these lesions, and quantitative information related to the natural
history, topography, and geographic pathology is not available.
"Rhythmic" or periodic wrinkling of the intimal surface of the aortas
of children and adolescents is another change whose relationship to
atherosclerosis has not been established.

Clinical Significance of Atherosclerosis

Atherosclerosis is the underlying cause of coronary heart disease
(coronary occlusion, coronary thrombosis, myocardial infarction, and
angina pectoris) and of one major type of stroke (cerebral thrombosis
with infarction). Atherosclerosis also causes aortic aneurysms by
weakening the aortic media via encroachment from primarily
intimal lesions. Atherosclerosis also sets the stage for arteriosclerot-
ic peripheral vascular disease by occlusive-thrombotic disease of the

16


distal aorta and by atherosclerotic lesions in the iliac-femoral
vessels.

Previous Literature Reviews

The history of our knowledge about atherosclerosis was reviewed
by Long (39). The morphology and pathogenesis of human atheroscle-
rotic lesions were reviewed in detail by Duff and McMillan (201, and
the gross and microscopic features of typical coronary and aortic
human lesions at various ages were illustrated by McGill et al. (44).
Data on the worldwide distribution of atherosclerotic lesions among
different human populations were published in 1968 (41). Strong et
al. (72, 73) reviewed the development of atherosclerosis by age, sex,
and race, by the geographic variation in prevalence and extent of
atherosclerosis, and by the relationship of atherosclerotic lesions to
risk factors for coronary heart disease. A monograph on arterial
smooth muscle cells by Geer and Haust (22) contains an extensive
review of publications on the nature of cells in atherosclerotic
lesions, descriptions of the histologic and ultrastructural features of
arterial lesions, and electron micrographs illustrating atherosclerot-
ic lesions. The published proceedings of international symposia on
atherosclerosis (25, 34, 63, 64, 65, 86) contain review articles and
reports of investigative work in atherosclerosis.

Natural History and Topography

Atherosclerosis begins in childhood, but does not usually become
clinically manifest through its ischemic complications until later in
life. The simple fatty streak is considered to represent the earliest
lesion of atherosclerosis that can be easily recognized either grossly
or histologically. The fatty streak is gradually converted into a
fibrous plaque in which there is abundant connective tissue as well
as lipid. These more advanced intimal lesions with increased
amounts of mesenchymal tissue may enlarge to cause progressive
stenosis of the vascular lumen. These lesions may undergo sufficient
enlargement by accumulated lipid and connective tissue or superim-
nosed mural thrombus to further narrow the lumen, or the lesions
may become vascular&d and undergo intramural hemorrhage or
may become ulcerated and covered by thrombus. In these last
instances, rapid occlusion of the artery may result. Under certain
circumstances and in certain arterial segments, the lesion may so
weaken the underlying media that an aneurysm is produced, or the
lesion may become calcified-a change that may represent a healing
process, but nevertheless reflects an advanced stage of the athero
sclerotic process.

17


The strong association between cigarette smoking and the clinical
manifestations of atherosclerosis is examined in other sections of
this Report. This section examines the relationship between ciga-
rette smoking and the development of atherosclerotic lesions and
other stages of occlusive arterial disease.

A brief description of the topographic distribution of atherosclero-
sis in different arterial segments provides additional background
information for this section. The topographic distribution of athero-
sclerotic lesions was reviewed by Duff and McMillan (20) and by
Glagov and Ozoa (23). Schwartz and Mitchell (68) described selective
involvement of some arteries and areas of localization of arterial
plaques in their necropsy survey. Those studies were generally
consistent, finding that lesions occur earliest and most extensively in
the aorta. Pathologically demonstrable lesions usually develop later
and less extensively in the coronary and cerebral arteries; the renal,
mesenteric, and pulmonary arteries are the least susceptible to
atherosclerotic lesions. A diagrammatic representation of the usual
localization of arterial involvement by atherosclerosis is depicted in
Figure 1, taken from the National Heart and Lung Institute (NHLI)
task force report on arteriosclerosis (79).

Studies in the International Atherosclerosis Project (IAP) led to
the following conclusions concerning atherosclerosis in the aorta and
in the coronary, carotid, vertebral, and intracranial arteries (43).
The severity of atherosclerosis in one artery does not predict the
severity in another artery for an individual case. On a cross-cultural
basis, however, the average predilection of a population to raised
lesions in one artery is correlated with the predilection in other
arteries. The rank order of location-race groups in the IAP is
approximately the same regardless of whether the ranking is based
on raised lesions in the coronary arteries, the thoracic aorta, the
abdominal aorta, or the cerebral arteries. This finding is consistent
with the hypothesis that environmental conditions predominantly
determine the severity of atherosclerosis in a population, despite
large differences in susceptibility to lesions among individuals or
among different anatomic loci within the arteries of each person.

In general, the development of atherosclerosis follows a definite
sequence. The aorta is involved first, beginning in infancy with fatty
streaks that increase rapidly during puberty; fibrous plaques begin
in the aorta in the third decade. Fatty streaks begin in the coronary
arteries during puberty. They begin to increase significantly and
become converted into fibrous plaques in the third decade of life in
high risk populations. The carotid arteries begin to be involved with
fatty streaks at approximately the same age as does the aorta. The
other cerebral arteries begin to be involved at approximately the
same age as do the coronary arteries. Raised lesions develop in the

18


FIGURE l.-Common sites of atherosclerotic lesions
SOURCE: U.S. Public Health Service (79).

carotid arteries at roughly the same age as in the aorta, but do not
develop in the vertebral and intracranial arteries until much later.

Hypotheses of Atherogenesis

A succinct review of the major hypotheses concerning the athero
sclerotic process (47) summarized various theories of atherogenesis
with emphasis on the two major hypotheses-the lipid hypothesis,
and the hypothesis that regards atherogenesis as a process involving
the conversion of arterial mural thrombi into atherosclerotic
plaques.

The lipid hypothesis is based on the frequent occurrence of
excessive amounts of cholesterol and lipid in lesions, the positive
association between elevated serum lipids and atherogenesis in man
and in animals, the association of dietary saturated fats and
cholesterol with atherogenesis in man and in experimental animals,

19


and the association between specific diseases and genetic disorders
that affect lipid metabolism and atherogenesis.

The hypothesis concerning the conversion of mural thrombi into
atherosclerotic plaques through tissue organization of the mural
thrombi (the Duguid-Rokitansky concept) is based largely on patho-
logical observations in man that show morphological evidence
compatible with this view of atherogenesis. Such evidence is most
convincing in relation to the middle or late development of plaques
rather than to their early stages. Many investigators of atherosclero-
sis have accepted this theory as a basis for plaque progression or
complication rather than as a theory of plaque initiation. The
demonstration that platelets are capable of interacting with intimal
smooth muscle cells to stimulate them to proliferate has now
extended this theory to encompass the initiation of atherogenesis
without necessarily invoking the classical sequence of thrombosis
(59).

McMillan (47) pointed out that there has been a tendency for the
proponents of one or the other of these theories to emphasize the
rather exclusive importance of one hypothesis when considering
various factors that are thought to be of particular importance for
atherogenesis (such as cigarette smoking, hypertension, diabetes
mellitus, or hyperlipoproteinemia). That is, the atherogenic factors
often have been relegated to one or the other theory as independent
factors that promote either lipid or thrombotic atherogenesis.
Nevertheless, as McMillan (47) indicates, the two major theories are
not mutually exclusive, but may complement one another in the
initiation and progression of atherogenesis.
There is much support for the view that atherosclerosis is best
accounted for by the known facts if it is regarded as a multifactorial
disease and, in the words of McMillan, "polyetiologic and polypatho
genetic."

The finding that some individual fibrous plaques are uniform for
one or other of the sex-linked isoenzymes of 6-GPD (12, 13, 14)
suggests that each mature plaque derives from a single cell and is
the basis for a new theory of atherogenesis, the monoclonal
hypothesis. This theory suggests that plaques may result from the
transformation, genetic or otherwise, of individual cells of the vessel
wall into a cell that will react to stimulation and form a plaque.
Other observations that fatty streaks are not monotypic (55) and that
thin plaques tend to be heterotypic, while thicker ones from the
same aorta tend to be monotypic (76), suggest that the phenomenon
of cell adaptation and selection rather than that of transformation
may be the basis for plaque monotypism.

The arterial endothelium obviously has a key role in both the lipid
and the thrombotic theories. In the lipid theory, the lipoprotein
molecules traverse the endothelium in some fashion prior to being

20


accumulated in a plaque. The thrombotic theory also includes
endothelial participation as an essential phenomenon. Endothelial
damage or loss may be manifest either as increased permeability to
macromolecules or as a focus for platelet adhesion, aggregation, and
release; thus, these changes may be atherogenic stimuli. Exposure of
the intima to lipoproteins and platelets may be mitogenic for smooth
muscle cells, and can affect the arterial lesion by modulating the
cellular production of collagen and glycosaminoglycans. This se-
quence of events indicates how the lipid and thrombotic theories can
interrelate in early atherogenesis.

The most popular hypothesis to account for the accumulation of
lipid in plaques involves the introduction of excessive amounts of
plasma lipoproteins through the endothelial barrier to the intima.
The lipoproteins, particularly low density lipoproteins (LDL), are
internalized by smooth muscle and other connective tissue cells and
are not metabolized rapidly; therefore, the lipid components accumu-
late in the cells. The sterols that are liberated in the cell lysosomes of
arterial cells may become so excessive that high density lipoproteins
(HDL) are unable to remove them from the cells and from the
intima. With progressive cellular lipid accumulation, cellular necro-
sis may occur, causing lipid to be dispersed into the extracellular
portions of the arterial wall. Thus, lipid may accumulate both
intracellularly and extracellularly and may act as a local cause of
injury.

When weighing the evidence linking tobacco usage with the
development of atherosclerotic lesions, one should consider these
theories of atherogenesis as well as the natural history of atheroscle-
rosis presented earlier in order to make judgments about possible
mechanisms and the stages at which the process might be affected.

Epidemiological Evidence Linking Cigarette Smoking With
Atherosclerosis

Cigarette smoking is a major risk factor for coronary heart disease,
peripheral vascular disease, and other clinically significant sequelae
of atherosclerosis. A key question is whether cigarette smoking has
an effect on the development of the arterial lesions, the terminal
occlusive events, or both. Until the recent past, few investigators
specifically designed studies to answer questions dealing with the
association between cigarette smoking habits and the development
of atherosclerotic lesions in the aorta and coronary arteries.

In the 1971 Report of the Surgeon General The Health Conse-
quences of Smoking (801, reports of such studies were reviewed and
summarized. Since that time, a number of additional reports have
been published dealing with the relationship between cigarette
smoking and atherosclerosis of the coronary arteries, aorta and

21


peripheral arteries, arterioles within the myocardium, and cerebral
vessels. The evidence relating cigarette smoking and autopsy evi-
dence of atherosclerotic disease in each of these areas is reviewed
separately and summarized in individual tables in this section.

coronary Arteries

Table 1 summarizes the studies that have examined the relation-
ship between cigarette smoking and autopsy evidence of atheroscle-
rosis in the coronary arteries. Auerbach et al. (6) found more
coronary atherosclerosis in smokers than in nonsmokers and a
concomitant increase in the amount of atherosclerosis with the
amount of cigarette smoking. An interim report by Strong et al. (75)
concluded that atherosclerotic involvement of aortas and coronary
arteries was greatest in heavy smokers and least in nonsmokers
among autopsied men in New Orleans. A report by Vie1 et al. (81) on
accidental deaths in Chile stated that there was no relationship
between atherosclerotic lesions and the use of tobacco; however,
examination of the data indicated that heavy smokers in the 50- to
54year and 55- to 59-year age groups exhibited higher percentages of
the left anterior descending coronary intima involved by atheroscle-
rotic lesions than did nonsmokers. Apparently these differences were
not statistically significant.

A detailed study of smoking and atherosclerosis in deceased men
in New Orleans has been conducted. Several reports based on the
findings of that study, as well as various interpretations of those
findings, have been published. Strong and Richards (74) reported the
basic findings on the association of cigarette smoking and atheroscle-
rosis in 1,320 autopsied men in New Orleans, 25 to 64 years of age.
Coronary lesions were evaluated visually in coded specimens and
objectively by analysis of post mortem radiographs. Using schedules
that had been tested on pairs of living persons (49, interviewers
obtained estimates of cigarette smoking habits of the deceased men
from surviving relatives. Data were compared for black men and
white men and also were analyzed in groups according to the
presence or absence of diseases thought to be associated with
smoking or with coronary heart disease (emphysema, lung cancer,
myocardial infarction, hypertension, diabetes mellitus, stroke, etc.).
Atherosclerotic involvement of the coronary arteries was greatest in
heavy smokers and least in nonsmokers for both races in the total
sample and in the basal group (those cases least influenced by the
bias of autopsy selection). The data for these groups are presented in
Table 1.

The study by Strong and Richards (74) included approximately the
same number of autopsied subjects from New Orleans as had the
previously reviewed study by Auerbach et al. (6) in East Orange,
New Jersey. Even though the methods of evaluation of arterial

22


TABLE l.-Autopsy studies of atherosclerosis involving the coronary arteries


                       Data collection     Measure of
Study         Population       method      atherosclerosis                         Resulta


                                    Smoking     No atherosclerosis     *

Moderate    Advanced

Auerbach et al.   1,372 autopsies of   Interview with   Visual protocol      None            5.6           57.3        21.8       15.3
(6)           men who did not    relatives                   (20            2.6           30.9        37.3       29.2
           die of CND                                20-34            .8           19.7        42.1       37.4
                                              40+             .6           18.1        35.4       45.9

Avtandilov      259 males and    Not specified   Not specified   Comparative size of mean area of atherosclerotic lesions in inner coat of coronary arteries
(8)           141 female
          autopsies                                  Right coronary artery            Left coronary artery


                                                     Smoker           Nonsmoker         Smoker     Nonsmokers

3lL39     15.5 (30)'           1.3 (32)            6.3 '        2.2
40-49     23.6 (34)           11.5 (27)           15.8 '        4.4
50-59     36.3 (39)'          14.6 (39)           27.9 '        9.9
60-69     31.9 (321'          23.6 (36)           26.5 '        22.5
70-79     41.9 (16)           31.7 (36)           26.1        35.8

NOTE The results concerning aortrc athercscleroels are gwen in form of ligure Presentation Of
rid&analysis.

Vie1 et al.
(81)

1,150 males and 290 Interview with
females autopsied    relatives
following violent
death

Not specified

Graphic data presentation only. but no association noted


E   TABLE l.-Continued.

Study          Population

Data collection     Measure of
  method      atherosclerosis

ReSUlta

Strong et al.
(75)



Strong and
Richards
(74

747 New Orleans
males 20-64 years
of age at death


1,320 autopsies of
males aged 25-64

Interviews wth  IAP protocol.
next of kin    visual grading,
within 8 weeks  and optical
of death      scanning

Interview with   Visual grading     Mean percent of coronary artery intimal surface involved with raised lesions for total
next of kin    and optical       sample, males
         scanning                      Average number cigarettes smoked per day

Age                 0            l-24           25+

25-34                 3
35-44                21
4L54                32
5.%64                36

25-34                 4
35-44                12
45-54                19
55-64                32

White males
  6
  27
  37
  45
Black males
  4
  16
  31
  31

10
26
39
47

12
23
35
33


TABLE I.-Continued.


                       Data collection     Measure of
Study          Population       method      atherosclerosis                           Results



Auerbach et al.   1,056 autopsies of   Interview with   Visual and     Distribution (in percentages) of degrees of fibrous thickening, of atheroma, and of cal-
(4           male veterans      relatives      micrcacopic     cification by smoking habits standardized for age (microscopic coronary study)
                                    evaluation                       Current cigarette smokers

                                                           Never                              EX-
                                        Degree of       smoked   < pack  l-2 packs 2+ pa& Cigar/ cigarette
                                        findings      regularly per day per day per day pipe smokers

                                     Fibrous thickening
                                                  None         50.1      3.9      0.6      0.4      4.5    5.0
                                         Slight         20.1     26.5      8.0      5.1     24.4    30.6
                                                Moderate       29.0     59.1     72.6      72.3     54.8    57.4
                                                  Advanced       0.8     10.5     18.6     22.2     16.3     7.0

                                                -4theroma
                                                None         82.5     74.5     69.9     66.1     68.2    12.0
                                        Slight          4.1      4.0      3.7      3.1      4.5    3.9
                                                  Moderate       13.1     19.2     20.6     20.8     23.4    21.5
                                                Advanced       0.3      2.3      5.8      10.0      3.9     1.6

                                              Calcification
                                                None         85.8     81.5     7A.l      73.5     75.5    79.2
                                        Slight          4.5      4.1      3.8      4.3      6.2     4.3
                                                  Moderate       a.4     10.3     11.1      11.2     13.4    12.7
                                                   Advanced        1.3      4.1      7.0      11.0      4.9     3.8



TABLE I.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

Results

Distribution by percentage of degree of atherosclerosis by smoking habits standardized
for age (macroscopic study)

Current cigarette smokers

Degree of
atherosclerosis

NWW                               EX-
smoked   < pack   l-2 packs  2+ packs Cigar/ cigarette
regularly per day per day per day pipe smoker

Lif&.ic
(371

894 autopsies of
males 20-79 at
death in Yalta

Interview with
relatives

Visual grading

None or minimal   59.8     45.2      36.6      32.6    36.3    50.9
Slight          24.7     26.9      27.9      21.5    28.4    25.5
Moderate        10.2     16.2      16.0      16.5    21.0    12.6
Advanced        5.3     ii.7      lY.5      23.4     14.3    11.0
Total        100.0    loo.0     loo.0     1OQ.O    1Oil.o    loo.0
Ratio of the extent of atherosclerotic lesions in the average coronary artery between
nonsmokers and smokers


          Total               Compli-
         athero-   Fatty    Fibrous    cated    Calcified   Raised
         sclerosis   streak plaque    lesion     lesion    lesion

Nonsmoker to
heavy smoker

Nonsmoker to
smoker

1.0      1.1      1.0      1.5       0.6      1.0



1.0      1.1      1.1      1.0       0.6      1.0


TABLE l.-Continued.


                        Data collection     Measure of
Study          Population       method      atherosclerosis                           Results



Schettler      Autopsies of 89     Interview with   Visual grading                            Stenosis
et al.       males aged 60-94    relatives
(63)        at death in Tokyo                      Smoking              No            Yes          Total

                                                  No                  6              8           14
                                        Yes, daily              8             67           75
                                                 Total                14             75           89

Rhoads et al.    109 sutop&s of    Interview with   AHA panel      Mean coronary atherosclerosis grade versus selected attributes
(56)         Japanese American  subject
           male8 born 1900-                                              Regression coefficients
         1919 who parti-
         cipated in Honolulu                         Examination variables             Simple         Multiple '
         heart study

                                        Relative weight 1%)                 0.031 J           0.025O
                                        Cigarettes/day                     0.022*           0.024 3
                                      Cholesterol(mg/dl)                  0.011 3           0.0093
                                        Triglycerides(mg/dlI                 o.Oo22            NS'
                                        Glucose(mg/dl)                    0.004 2             NS'
                                            Hematirit 1%~                    o.069z            NS '

                                      `Multiple regreaxon was done by B stepw.ee ehmmatmn procedure begmnmg wth the set
                                     of vanables shown: coefficwnts are for the final step. Multiple correlation (final step1~0.46
                                                 IN- 108l
                                            ~Slgnlficant at on5 level
                                            ~S1gmficant at 0 01 level
                                      `NS. vanable included ,n timt step. deleted an not slgmficant at 0.05 level.



TABLE l.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

ReSUlti

35-44         X     4.4   a.4    x   32.2   32.1    X   60.3   62.1   2    8    12
45-54         X     5.5   0.4    x   25.1   31.4    x   65.7   70.4   2    25    12

55-64         a.1    47   7.2   31.4   31.1   20.8   60.3   57.4   62.4 11 15    9

' ATL as percent surface fatty streaks (F) plus raised lesions (Rl: FaF=F - (100 - R%E in percentage units
explained in the text; X indicates subgroups having fewer than five members

Holme et al.
(29)

129 autopsies from   Interview with   Visual grading     Correlation coefficient between number of cigarettes and raised lesions in the coronary
16,2CGC males aged  subject                  arteries = ,039, not significant.
4M9 in Oslo
prospective CHD
stwiv

Sternby
(711

60 autopaiea of 703   Interview with   Visual grading    Smoking and stenosis or atherosclerosis in the left anterior descending coronary artery
males in CHD     subject
study in Malmo.                                                           LAD        Coronary
SW&n                             Smoking category      Number       rased lesions     artery stenosis


                                     Non                3            68            33
                                     Ex                 8            52             38
                               Light               18            45            39
                              Heavy              17            54            59


TABLE l.-Continued.

Study          Population

Data collection
  method

Measure of
atherosclerosis

Results

Sorlie et al.
( 70)

139 autopsies of    Interview with   Visual grading     Association of atherosclerosis in coronary arteries with antemortem characteristics:
9,824 Puerto Rican  sub@                 simple correlation coefficients (Puerto Rico heart health program)
males aged 35-79 m
a prospective study                                                       Correlation coefficients

Characteristics
measured at exam 1

Total
(139)

Rural
(36)

Urban
( 103)

Systolic blood pressure
Diastolic blood pressure
Serum cholesterol
Age, exam 1
Relative weight
Physical activity
Blood glucose
Hematocrit
Education level
Income
Cigarettes smoked
Calories (24.hour recall)
Starch (24.hour recall)
Alcohol (24.hour recall)
Total fata (24.hour recall)
Triglycerides (fasting)
Ventricular rate
Vital capacity

0.22          0.07       0.30
0.26          0.09       0.30
0.42          0.59       0.38
0.01          0.32      4.08
0.21         JJ.15       0.25
-0.18          0.06      -0.22
0.20         4.04       0.21
0.14          0.36       0.12
0.14         a.40       0.24
0.16         4 17       0.16
4.16         xl.05      xl.22
a.14         a.43      407
-0.17         -0.29      -0.09
a.10         -9.10      a.13
-0.04         xl.53       0.03
0.23          0.49       0.19
0.13          0.20       0.08
-0.19         a.13      4.16


lesions were not identical, the findings from both of these large
studies of autopsied men in the United States were remarkably
similar. Both studies reported more extensive coronary atherosclero-
sis among the cigarette smokers than among the nonsmokers, and
for the major comparisons, with only rare exceptions, there was an
orderly progression of least extensive lesions in nonsmokers, inter-
mediate extent of lesions in light or moderate smokers, and most
extensive lesions in heavy smokers.

In the New Orleans study (741, lesions were measured not only by
visual evaluation, but also by optical electronic scanning of radio-
graphic images of the flattened arteries. The measurements of
lesions from radiographs-relative mean coronary wall thickness
and percentage of the coronary artery intima involved with calcifica-
tion-were consistently greater for the heavy smokers than for the
nonsmokers. A variety of statistical analyses on smoking measures
and atherosclerotic lesions were performed to determine the signifi-
cance of the various differences and trends. These analyses con-
firmed that the major differences between the heavy smokers and
the nonsmokers in extent of raised atherosclerotic lesions (the sum of
fibrous plaques, complicated lesions, and calcified lesions) were
significant. A one-way multivariate analysis of nine atherosclerotic
variables clearly indicated that there were statistically significant
differences among the three categories of smokers (heavy, light to
moderate, and nonsmokers) for mean coronary wall thickness, raised
lesions in the coronary arteries, percentage of cases positive for
fibrous plaques, percentage of cases positive for complicated lesions,
and percentage of cases positive for calcified lesions, with lower
values in nonsmokers and higher values in the heavy smokers.

Pate1 et al. (53) evaluated this same data on smoking and
atherosclerotic lesions to examine further the interrelationships
with measures of obesity. The confounding effects of diseases such as
hypertension and diabetes mellitus were controlled by excluding
such cases from the analysis. The confounding effects of age and
measures of smoking habits on the association between atherosclero-
sis and obesity were controlled by multivariate regression analysis.
This analysis disclosed an inverse relationship between smoking
habits and obesity. There was also a weak positive association-
when age and smoking were controlled for-between measures of
obesity and mean coronary wall thickness and raised lesions in the
coronary arteries among whites, but not among blacks. In the black
men, again with age and smoking controlled in the analysis, a weak
association between fatty streaks in the coronary arteries and
obesity was found. This analysis confirmed the previously reported
relationships between smoking habits and atherosclerosis, as mea-
sured by mean coronary wall thickness, coronary calcifications, and
raised lesions in the coronary arteries.

31


Since their first report in X65, Auerbach and his associates have
investigated the relationship of cigarette smoking to microscopic
findings in the coronary arteries (4). This study indicated that lesions
were most extensive in cigarette smokers and confirmed earlier
studies by Auerbach et al. (6) and Strong and Richards (74). The
microscopic portion of the Auerbach et al. study (4) showed that
fibrous thickening, atheroma, and calcifications of the coronary
arteries all increased with increasing number of cigarettes smoked
per day. They also found that the fibrous thickening of arteries
increased in relation to the number of cigarettes smoked per day as
the size of the artery decreased; i.e., it was least in the coronary
arteries and greatest in the myocardial arteries.
Lifsic (37) reported on the relationship of cigarette smoking to
coronary atherosclerotic lesions based on the Yalta sample from the
World Health Organization (87) autopsy study of five cities in
Europe. Information on cigarette smoking was obtained by means of
interviews with the subjects' near relatives. The prevalence and
extent of atherosclerotic lesions were evaluated in autopsies of 865
men, aged 20 to 79 years, out of the 1,220 deaths occurring in Yalta
residents of this age and sex group during the period of study. There
was a positive association of smoking with the extent of coronary
calcification; however, the author explained this association as being
related to coexisting alcohol consumption and stated that smoking
alone tended to be negatively associated with coronary calcification.
The following paragraph from Lifiic's discussion provides additional,
information from this report.

There was little significant difference between smokers and nonsmok-
ers in the prevalence and extent of atherosclerotic lesions in the
coronary arteries. Thus, of the total of 210 comparisons of different
indices of the prevalence and extent of atherosclerotic lesions between
subgroups X and W, significant differences positively correlated with
smoking were found in only 20. The tendency toward a positive
correlation of coronary atherosclerosis with smoking was found mainly
in subjects up to the age of 50, but after 60 the opposite tendency
prevailed. These age peculiarities agreed with data from other studies
showing that differences in the degree of atherosclerosis between
smokers and nonsmokers. . . are more distinct below age 60.
The author also mentioned a positive association between smoking
and coronary calcification in "strenuous workers." A note added in
proof to LifGic's article states, "Additional study of this material by
individually matched case-control analyses revealed a marked trend
toward a positive association between smoking and atherosclerotic
raised lesions in the coronary arteries" (82). Thus, while the author's
abstract does not indicate an important relationship of smoking and
coronary atherosclerosis, there are findings in the study that do

32


indicate significant relationships between smoking and coronary
atherosclerosis, especially in the younger subjects.

A subsequent study by Vikhert et al. (83) on material from five
cities in the U.S.S.R. evaluated the effect of nutritional status and
tobacco smoking on atherosclerotic changes in the coronary arteries
as measured by a visual planimetric method. This material was also
utilized for a WHO-sponsored epidemiological study of atherosclero-
sis (87). The vessels examined were from 430 men 40 to 69 years of
age. The major analyses concerning tobacco smoking were made
from 313 male heavy smokers and 82 nonsmokers. The investigators
studied both manual workers and white-collar workers and found
that tobacco smoking in combination with overnourishment had a
much more positive effect on the development of coronary athero-
sclerosis in white-collar workers than in the manual workers.

Prospective epidemiologic studies of cardiovascular disease with
autopsy followup provide additional information concerning the
relationship of smoking to atherosclerotic lesions in the artery wall.
The epidemiological studies in Oslo, Puerto Rico, and Honolulu are
characterized by careful documentation of selected major risk
factors, including cigarette smoking habits during life, and by
standardized evaluation of atherosclerotic lesions at autopsy (29, 56,
70). Each of these three studies reported findings on the relationship
of CHD risk factors to atherosclerotic lesions in more than 100
autopsies of deceased men who had been part of larger cohorts that
had been examined and followed during life. In addition, a smaller
study from Malmo, Sweden, had some of the same features as these
larger studies (71). The Oslo, Malmo, and Puerto Rico studies used
identical methods for grading the extent of atherosclerotic lesions.
These prospective epidemiologic studies with autopsy followup are in
general agreement concerning the relationship of serum cholesterol
levels and blood pressure to the extent of atherosclerotic lesions in
the coronary vasculature. The findings concerning the relationship
of cigarette smoking to the extent of coronary atherosclerosis are not
uniform. The Honolulu study (56) showed a significant relationship
between smoking habits and extent of coronary atherosclerosis. The
Oslo study (29) did not show a significant relationship between
cigarette smoking and coronary atherosclerosis. The Puerto Rico
study (70) also did not show a significant relationship between
smoking and the extent of coronary athersclerosis. A somewhat
similar study from Japan by Hatano and Matsuzaki (26) indicated a
significant relationship between cigarette smoking and coronary
artery stenosis. Thus, there is some inconsistency concerning the
association between cigarette smoking habits and coronary athero-
sclerosis in the prospective epidemiologic studies with autopsy
followup.

33


In considering this entire body of evidence, however, the prepon-
derance of evidence suggests that cigarette smoking has an effect on
the development of atherosclerotic lesions in the coronary artery
wall in the U.S. population, and that its effect is not limited to those
events immediately surrounding the occlusive episode.

Small Arteries in the Myocardium

Table 2 reviews those studies that. have examined the relationship
between cigarette smoking and lesions of the arterioles within the
myocardium. Auerbach et al. (7) found a relationship between
smoking habits and thickening of the walls of the arterioles and
small arteries of the myocardium. Auerbach et al. (4) also performed
a microscopic study of coronary artery lesions in autopsied men in
relation to previous smoking histories. In the microscopic portion of
this study, fibrous thickening, atheroma, and calcification increased
with an increased number of cigarettes smoked per day. Moderate to
advanced hyaline thickening of the arterioles in the myocardium
was strongly related to smoking. It was found in 98.6 percent of the
autopsied subjects with a two pack per day smoking habit and not
found in the group of subjects who never smoked regularly. Naeye
and Truong (51) reported essentially similar alterations in the
intramyocardial arteries, which developed more rapidly in cigarette
smokers than in nonsmokers.

The Aorta

Those studies that provide autopsy and other evidence for the
relationship between cigarette smoking and atherosclerosis of the
aorta are summarized in Table 3.

Wilens and Plair (85) found significantly more severe sclerosis of
the aorta in cigarette smokers than in nonsmokers. Sackett and
Winkelstein (61) reported that elderly cigarette smokers had signifi-
cantly higher rates of aortic calcification, detected on chest X-ray,
than did nonsmokers. Sackett et al (601, in an autopsy study, found a
significant relationship between the use of cigarettes and the
severity of aortic atherosclerosis. An interim report by Strong et al.
(75) concluded that atherosclerotic involvement of aortas was
greatest in heavy smokers and least in nonsmokers among autopsied
men in New Orleans.

Most of these studies, reviewed in the 1971 Report of the Surgeon
General The Health Consequences of Smoking (801, indicate that
differences between heavy cigarette smokers and nonsmokers are
particularly great in young individuals, and that heavy smokers
have increased surface involvement with fibrous plaques or more
advanced atherosclerotic lesions.

Since the 1971 review, a study of smoking and atherosclerosis in
deceased men in New Orleans has been completed. Several reports

34


TABLE 2.-Autopsy studies of atherosclerosis involving small arteries in the myocardium

Study   Population

Measure of
atherosclerosis

ReSUlta

Auerbach
et al
(7,

1,164 males   Records and    Biopsy of      Grade of thickness of walls of arterioles'
autopsied    family       myocardium
at VA                                                      Number of men          Percentage of men

                                                    Grade Grade Grade        Grade Grade Grade
                          Age       Smoking     Total    0     1    2. 3   Total     0     1    2. 3
                                                          -

(45

None
Cigar-pipe
ctte3 1-19
Ctte 2&39
ctte 40+

45-59

None
Cigar-pipe
ctte l-19
ctte 2cL39
Ctte 40+

60-69

None
Cigar-pipe
ctte 1-19
ctte 2&39
ctte 40+

70+

None
Cigar-pipe
ctte 1-19
ctte 20-39
ctte 40+

22     2
4     -
50     1
a5     4
29     -

15      1
13     -
33     -
99     -
50

56     4
35
92
193
67     -

32     2
40
30     -

46     -
9     -

19      1    loo.0
1      3    100.0
31     18    lc0.0
35     46    100.0
10     19    loo.0

12     2    loo.0
8     5    lc0.0
17     16    loo.0
35     64    loo.0
11     39    1Oc.o

36     16    loo.0
22     13    loo.0
44     4.3    100.0
58    135    1WJ.O
21     66    loo.0

18     12    100.0
19     21    loo.0
12     18    1lx.o
12     34    100.0
3     6    loo.0

9.1     66.4   4.5
     25.0* 75.0'
2.0    62.0   36.0
4.7    41.2   54.1
-     34.5   65.5

6.7    80.0   13.3
     61.5   38.5
-     51.5   48.5
-     35.4   64.6
     22.0   78.0

7.1    64.3   26.6
-     629   37.1
     47.0   52.2
-     30.1   69.9
-     24.1   75.9

6.3    56.2   37.5
     47.5   52.5
-     40.0   60.0
-     26.1   73.9
-     33.3'  66.71

`In the right ventrmdar wall of 1,020 men by age and smoking habits
`Percentage8 baeed on less than 10 cases
`Ctte indicates cigarettes.


TABLE 2.-Continued.

Study   Population

Smoking data
  BO"TlX

Measure of
atherosclerosis

ResUlts

Auerbach
et al.
(4

1,056 males
autopsied
at VA

Relatives
and records

Microscopic
examination

Distribution by percentage of degree of fibrous thickening of myocardial arteries, subepicardial arteries.
and hyaline thickening of myocardial arterioles (microscopic myocardial study), by smoking habit
standardized by age

Current cigarette smokers

Demee of

findings

Never
smoked

                                Ex
~1 pack   1-2 packs   z+packB   Cigar/   cigarette

regularly   per day   per day   per day    pipe    smokers -

Myocardial arteries
None or minimal
slight
Moderate
Advanced
  Total

S&epicardial arteries
None or minimal
Slight
Moderate
Advanced
  Total

97.3      24.1
2.7      62.2
+16      12.3
-       1.4
100.0     loo.0

74.7      17.5       2.4       1.4
24.9      56.8      35.1      32.7
0.4      19.0      28.8      23.8
-       6.7      33.7      42.1
loo.0     100.0     100.0     100.0

2.9       1.1      22.0     32.0
37.1      29.6      70.6     63.2
39.0      45.0       6.7      4.2
21.0      24.3       0.7      0.6
loo.0     100.0     100.0     1rKl.o

21.5     26.2
64.8     60.5
9.9      11.6
3.8      1.7
loo.0     loo.0

Myocardial arterioles
None or minimal
Slight
Moderate
Advanced
  Total

92.0       2.1      -       -       -       3.2
8.0      28.7       2.2       1.4      39.6     40.8
-       20.8       9.6       7.9      19.6      19.1
-       40.4      68.2      90.7      40.8     36.9
100.0     100.0     loo.0     loo.0     loo.0     100.0


TABLE 3.-Autopsy studies of atherosclerosis involving the aorta

Study

      Smoking data    Measure of
Population     source     atherosclerosis                              Results

Wilens and
Plair
WI

989
consecutive
necropsea
at NY VA
hospital

Patient chart  Visual grading   Percent of subjects by smoking status and atherosclerosis

                 Severity of        Non-                             Pipe/
                    sclerosis         smoker     Heavy      Moderate     Light     cigar    Other


                    Number           161        199        288        152       70      119
                    Percent above average   9.9       25.1        26.4       19.1       10      10.9
                    Percent average      60.2       61.3        62.5       63.2       60      63.0
                    Percent below average  29.6       13.6        11.1       17.6       30      26.1

Strong and
Richards
(74)

1,320       Interview    Visual grading   Mean percent of intimal surface of abdominal aorta involved with raised lesions
autopsies    with relatives
of males                                        Average number of cigarettes smoked per day
aged 25-64
at death                     Age and race             0                   l-24             25+

White males
25-34
35.44
4554
5.%64

Black males
2534
3M4
4&54
55J34

1                    7               7
14                    33               44
33                    52               56
46                    63               71

4                    7               9
6                    20               28
14                    37               45
26                    51               56


g TABLE $-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                               Results

Sackett and 590
Winkelstein   white male
(61)        admissions
         to Powell
         Park Mem-
         orial In-
         stitute in
         1955

Patient     Chest X-ray   The relationship between smoking and calcification of the thoracic aorta
questionnaire   for calcification
         in thoracic aorta                  Nonsmokers            Smokers


                                         Percent with         Percent with   Probability
                 Age group         Number   calcification   Number   calcification     value 1    Totals


                    50-59              61       13       131        11         0.4      192
                    60-69              90       16       124        26         0.2      214
                    70 and over         116       37        63        54         0.02     164

                      Totals           267       25       323        26         -      590

                 Age-adjusted percent    -        22       -        30         -      -


                  `Chi-square of independence, twotcded.

The relationship between amount smoked and calcification of the thoracic aorta

Age group


m-59
60-69
70 and over

Totals

  Nonsmokers      Light smokers     Heavy smokers

     Percent with       Percent with       Percent with
Number calcification Number calcification Number calcification Totals


61       13      104       9      27      22      192
90      16      107      24       17      35      214
116      37      63      56       5      40      164

267      26      274      29      49      27      590

Age-adjusted percent -       22 -       29 -       32 -


TABLE S.-Continued.

Study

      Smoking data    Measure of
Population     Bource     atherosclerosis                               Results

Sackett
et al.
(60)

1,019      Standardized   Visual grading  Mean ag?+adjusted atherosclerosis ridits versus gr aded use of cigarettes and alcohol
consecutive   interview with on a numerical
autopsies of  patient on    scale                     Alcohol                      Cigarettes
white      admiwion

       patienta                    &/day                None             1 :! pack         1'2 pack+

                                      None                  ,351                  ,466             ,498
                                      0.5-1.5                 ,424                  ,570             .56l3
                                 1.6+                  ,426                 ,526             ,589

Strong et al.  Autopies    Interview    Visual grading  Mean percentage of intimal surface of aorta involved with raised lesions by age, race, and average rate
(75)        of 741      with relativea  and optical    of cigarette smoking in the last 10 years of life
         males 20-64          Bcanning

year8 at
death

Cigarettes pe r day

Age and race

White males
3-4
4654
55-64

Black males
35-44
45-54
55-64

0                  l-24             25+



16                   35              49
29                   52              54
48                   66              70



3                   22              24
12                   38              50
21                   50              49


$   TABLE 3 -4`ontinued.

Study

       Smoking data    Measure of
Population     source     atherosclerosts                              Results

Litsrc
(37)

865
autopsies

Relatives
and records

Visual gradmg  Prevalence of atherosclerotic lesions in the abdominal aorta in different subgroups (percentage)

of males
aged 2&79
at death in
Yalta

Smokrng
group


Never
Lrght
Heavy

Fatty
streak


96.5
92.8
90.7

Fibrous
plaque


96.0
96.5
97.5

Complicated
lesion


  43.0
  53.4
  60.9

Calcified
lesion


25.0
42.3
57.3

Extent of atherosclerotic lesions (percentage of surface) in the abdominal aorta

Smoking        Fatty
group           streak


Never           7.0
Light            6.1
Heavy           5.8

Fibrous
plaque


28.1
31.6
26.5

Complicated
lesion


  2.0
  5.1
  4.1

Calcified
lesion


1.2
2.2
3.4


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                              Results

Rhoads
et al.
(56-l

124
Japanese
American
males autop
sied as part
of the
Honolulu
heart study

Interview
with subject

Visual by
AHA panel
method

Correlation coefficients among selected autopsy and examination variables'

                            Aorta (N = 124). atherosclerosis grade

Age at death
Examination variables
Height (cm)
Relative wt. (%)
Cigarettes/day
Cholesterol (mg/dl)
Triglycerides (mg/dl)
Uric acid (mg/dl)
Glucose (mg/dl)
Hematocrit (%I
Vital capacity (liters)
Alcohol (pm,
Systolic pressure (mm Hg)
Diastolic pressure (mm Hgl
Mean coronary grade
Aorta grade

0.30 3

-0.12
a.10
0.14
0.243
0.14
-0.052
0.15
a.03
X1.23~
-o.08z
0.29 3
0.05
0.503 (96)'

I N= number of specimens.
sS~gniiicant at 0.05 level
a Significant at 0.01 level.

`When a correlation coeffXent is based on less than 95 percent of the ~pecmwns available (because of missing
data), the number of observations is indicated in parentheses. There were 96 autopsies with both aorta and
coronary vesel grades available. 13 wth coronary only. and 28 with aorta only


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     SO"FX?     atherosclerosis                               ReSUlta

Auerbach    1,412 males  Family      Visual grading  Percentage of selected findings by smoking habits
and Garfinkel autopsied
(5)         at VA hos-                                              Percentage of cases'
       pita1                                            "Current" cigarette smokers

Findings

Never smoked 1 pack  l-2 pack3  2+ packs  Cigar  Excigarette
regularlv per day per day per day or pipe smoker

Thoracic aorta
Many or diffuse
  distribution of plaques
Moderate or advanced
  ulceration
Moderate or advanced
  calcification
Thrombus present
Abdominal aorta
Many or diffuse
  distribution of plaques
Moderate or advanced
  ulceration
Moderate or advanced
  calcification
Thrombus present

16       26      41       37      27      29


4        6      14       12      10       8


56       63      74       74      53      67
4        7      14       11      11       9



28       54      68       79      46      53


7       19      27       27      13      22


63       76      84       88      74      81
7       23      23       31      14      23

lPercentages are adjusted to distribution by age group of all men in study.


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     source     atherosclerosis                               Results

Sternby
(71)

60        Interview    Visual grading   Smoking and atherosclerosis of the aorta
autopsies    with subject
from 703                                                                 Raised lesions in the
males enrol-                  Smoking category               Number                abdominal aorta
led in a
CHD study                        Non                         3                      26
in Malmo.                        ET.                          8                      43
Sweden                      Light                        18                      53
                             Heaw                        7                      83

Smoking and atherosclerosis m peripheral arteries

Femoral artery

Lower leg artery

Smoking

Iliac artery

Raised     Sterosis     RalSed    Stenosis

category      N      Raised lesions      lesions       (701      lesions     (70)

Non         3         17           20         0         2        0
EX         8         18           43        33        18       22
Light       18         29           29         6         3       11
Heavy       17         50           50        35        12       41


g   TABLE S.-Continued.

Study     Population

Smoking data    Measure of
  source     atherosclerosis                               Results

Tracy et al.   Autopsies    Interview     Visual exam   Means of observed minus expected raised-among-lesions GE), fatty streaks among flat surfaces (FaF),
(77)       of 1.380     with relatives          all types of lesions tATL1, and number of cases (N) by age, race, and cause of death according to
         white and                   smoking category I, abdominal aorta
         black males
       aged 2564                                         O-E                 Faf               ATL
         at death                      Age           0     l-24    25+     0     1-24    25+     0     l-24   25+

White basal
2534
3544
45-54
5.5-64

White CHD
25-34
35-44
45-54
55-64

Black basal
2634
3%44
4554
55-64

Black CHD
24-34
35-44
45.54
5564

-3.7      3.9    0.6    25.3    32.1    36.6    26.4     36.6   34.7
-7.3      5.0    12.7    22.8    30.8    35.5    27.9     48.1   64.7
77      6.1     3.6    21.3    28.9    31.4    47.3     57.3   65.8
-0.6      3.0    6.7    33.7    33.1    35.5    56.5     68.6   76.2

X      X     X      X      X     X     X      x x
-18.7     15.3    6.8    43.2    28.2    39.2    55.3     67.9   68.0
8.0      3.6     1.3    25.7    40.8    33.1    500     81.4   73.4
4.5      5.4     2.2    44.3    37.7    40.1    77.7     82.8   83.7

5.3     -3.5    -3.8    28.6    32.8    36.8    30.7     34.9   38.6
-16.9     -3.1    -3.9    26.5    31.8    33.0    27.8     43.9   45.6
-15.7     -7.3    -5.4    25.0    32.7    37.4    33.8     47.2   60.0
-9.5     a.3    -2.8    29.7    31.6    32.1    43.9     61.6   55.5

X       6.3    X      X      39.7    X     X      44.6   X
X      -2.7    9.3    X      28.0    29.9    X      55.1   61.8
X       4.6    4.8    X      34.2    386    X      72.4   73.0
-14.4     -2.8    2.5    41.9    35.8    40.7    62.5     66.2   81.4

' ATL as % fatty streaks (F) plus raised lesions (RI; FaF=F : (100 - R); O-E in percentage units explained in


TABLE 3.-Continued.

Study

      Smoking data    Measure of
Population     8oUrC.2     athercscleroeie                               ReSUlts

the text. X mdvxtes subgroups having fewer than live members

Sorlie
et al.
( 70)

139
autopsies
of 9.824

Interview     Visual
with subject   evaluation

Awxiation of atherosclerosis in aorta with antemortem characteristics. simple correlation coefficients
(Puerto Rican heart health program)

Puerto
Rican males

Correlation coefficients

aged 35-79

Characteristics
measured at exam 1

Total
(120)

Rural
(31)

Urban
(89)

Systolic blood pressure
Diastolic blood pressure
Serum cholesterol
Age, exam 1
Relative weight
Physical activity
Blood glucose
Hematcvxit
Education
Income
Cigarettes smoked
Calories (24.hour recall)
Starch (24-hour recall)
Alcohol (24.hour recall)
Total fats (24.hour recall)
Triglycerides (fasting)
Ventricular rate
Vital capacity

0.25             0.27          0.24
0.19             0.29          0.16
0.29             0.38          0.28
0.31             0.39          0.29
4.08            -0.22         4.06
-0.18            -lx21         -0.14
0.14             0.05          0.17
0.23             0.33          0.21
-0.08            a.23         a.03
0.01            -0.01         4.01
032             0.37          0.31
-0.24            -0`5.5         4 12
-0.19            a.45         -0.07
-0.18            4.39         AI 18
-0.19            4.49         a.11
0.11             0.53          0.04
0.07             0.11          0.05
-0.29            -0.28         -0.29


based on the findings in that study, as well as various interpretations
of those findings, have been published. Strong and Richards (74)
reported the basic findings on the association of cigarette smoking
and aortic atherosclerosis in 1,320 autopsied men in New Orleans, 25
to 64 years of age. Aortic lesions were evaluated visually in coded
specimens and objectively by analysis of radiographs. Interviewers
obtained estimates of cigarette smoking habits of the deceased men
from surviving relatives. Data were compared for black men and
white men, and also were analyzed in groups according to the
presence or absence of diseases thought to be associated with
smoking or with coronary heart disease (emphysema, lung cancer,
myocardial infarction, hypertension, diabetes mellitus, stroke, etc.).
Atherosclerotic involvement of the aorta was greatest in heavy
smokers and least in nonsmokers for both races in the total sample,
as well as in the basal group (those cases least influenced by the bias
of autopsy selection). The lesions were measured not only by visual
evaluation, but also by optical electronic scanning of radiographic
images of flattened arteries. Atherosclerotic lesions in the abdominal
aorta were more extensive in the heavy smokers than in the
nonsmokers, and there was an orderly trend of increased lesions
with increased smoking. In general, the magnitude of difference in
extent of lesions between nonsmokers and heavy smokers was
greater in the abdominal aorta than in the coronary arteries. A
variety of statistical analyses of smoking measures and atheroscle-
rotic lesions was applied to determine the significance of the various
differences and trends. All of the analyses confirmed that the
differences between the heavy smokers and the nonsmokers in
extent of raised atherosclerotic lesions were significant. A one-way
multivariate analysis of nine atherosclerotic variables indicated that
there were statistically significant differences among the three
categories of smokers (heavy, light to moderate, and nonsmokers) for
lesions in the abdominal aorta.

Following the initial report of Strong and Richards (74), there were
three additional publications from this study. Two of these were
directed toward interpretation of findings in regard to the effect of
cigarette smoking on fatty streaks (the earliest grossly visible lesions
of atherosclerosis) and raised atherosclerotic lesions (the more
advanced stage of the atherosclerotic process). The other study was
directed toward the interrelations of obesity, smoking, and athero-
sclerotic lesions in these same cases.

The original report by Strong and Richards (74) indicated that
raised lesions, the more advanced lesions, were greater in heavy
smokers than in nonsmokers. They also reported statistically
significant differences for fatty streaks in the abdominal aorta and
for fatty streaks in the coronary arteries, with the highest values in
the nonsmokers and lowest values in the heavy smokers. The well-

46


recognized problem of evaluating fatty streaks when more advanced
lesions of atherosclerosis are present made it difficult to interpret
the findings on fatty streaks. Pate1 et al. (54) approached this
problem by using a simple two-parameter model of fatty streaks
arising from a normal intimal surface at a constant rate and with
subsequent conversion to raised lesions at a constant rate. They
concluded that in the abdominal aorta, smoking enhances the
formation of fatty streaks as well as the subsequent conversions to
more advanced lesions, and in the coronary arteries, smoking seems
only to enhance the conversion of fatty streaks to fibrous plaques.
Tracy et al. (77) evaluated the same data from the New Orleans
study on smoking and atherosclerotic lesions. They approached the
problem using a different model: N = F -+ R, where N denotes
normal intima, F denotes fatty streaks, and R denotes raised lesions.
In this model, class A causes are viewed as promoting the process
from beginning to end, while class B agents act at the first or the
second step, but not at both. Their analysis and interpretation
suggest that cigarette smoking has a large class B effect. They
concluded that the target tissue of smoking is the fatty streak, and
the slowly progressing or regressing fatty streak (formed alike in
smokers and nonsmokers) is caused to progress more rapidly or to
cease to regress by smoking. Both of these studies, Pate1 et al. (54)
and Tracy et al. (73, agree that smoking has a role in the progr&ion
of fatty streaks to a more advanced stage of the atherosclerq$c
process.

Auerbach and Garfinkel in 1980 (5) published findings on smoking
habits and atherosclerotic lesions in over 1,400 aortas collected at
autopsy from male patients. The extent of atherosclerotic lesions
(plaques, ulcerations, and calcification) increased with number of
cigarettes smoked, and was also greater in excigarette smokers and
pipe smokers than in nonsmokers. The findings were more striking
in the abdominal aorta than in the thoracic aorta. Aortic aneurysms
were found eight times more frequently among those who smoked
one to two packs of cigarettes per day than in nonsmokers.

LifSc (37) reported on the relationship of cigarette smoking to
aortic lesions based on the Yalta sample from the World Health
Organization (WHO) autopsy study of five cities in Europe (87).
Information on cigarette smoking was obtained by means of inter-
views with the subjects' near relatives. The prevalence and extent of
atherosclerotic lesions were evaluated in autopsies of 865 men, aged
20 to 79 years, out of 1,220 deaths occurring in Yalta residents of this
age and sex group during the period of study. There were significant
positive relationships between smoking and the extent of fibrous
plaques, complicated lesions, and calcified lesions in the abdominal
aorta.

47


Aortic atherosclerosis has also been evaluated using autopsy
followup of prospective epidemiologic studies of cardiovascular
disease. Epidemiological studies in Puerto Rico and Honolulu
documented selected risk factors, including cigarette smoking habits,
during life and had standardized evaluation of atherosclerotic
lesions at autopsy (56, 70). Each of these studies reported findings on
the relationship of risk factors and aortic atherosclerotic lesions in
more than 100 deceased men from large cohorts that had been
examined and followed during life. A smaller study from Malmo,
Sweden, had some of the same features as these larger studies (71).
All of these studies found a significant positive relationship between
cigarette smoking and aortic atherosclerosis.

The prospective epidemiologic studies with autopsy followup
confirmed the relationship between smoking and atherosclerotic
aortic lesions found in earlier autopsy studies. The preponderance of
evidence suggests that cigarette smoking aggravates or accelerates
aortic atherosclerosis, and this effect on atherosclerosis may be more
pronounced in the aorta than in the coronary arteries.

Cerebral Vasculature

The relationship between cigarette smoking and atherosclerosis in
the cerebral vasculature has not been extensively evaluated. Two
studies that have examined this question are summarized in Table 4.
Sternby (71) reported that cigarette smokers had more extensive
raised lesions in the basilar artery than had nonsmokers. This study
was based on 60 autopsy subjects from 703 men born in 1914 who
participated in a study of cardiovascular disease in Malmo, Sweden.
Holme et al. (29) reported a positive correlation coefficient between
raised lesions in the cerebral vessels and the number of cigarettes
smoked; this relationship was not statistically significant, however.

The limited amount of information available on the relationship
between cigarette smoking and atherosclerosis in the cerebral
vasculature does not allow a clear conclusion to be drawn at this
time.

Pathophysiologic Mechanisms of Tobacco Smoke
Studies of Components of Tobacco Smoke

The possible pathophysiologic mechanisms for the atherogenic
influence of cigarette smoking were reviewed in the 1971 Report of
the Surgeon General The Health Consequences of Smoking (80). The
major components of cigarette smoke considered in that review were
nicotine and carbon monoxide. Numerous investigators have studied
the effect of nicotine administration, either subcutaneously or
intravenously, upon experimentally induced changes in the aorta
and coronary arteries of animals. When administered alone, nicotine

48


TABLE 4.-Autopsy studies of atherosclerosis involving cerebral vasulation

Study            Population

Smoking data
  8ource

Measure of
atherosclerosis

Result.6

Sternby
(711

60 autoplied
subjects from
703 male8 in
CHD study in
Malmo. Sweden

Interview
with subject

Visual
inspection

Smoking and atherosclerosis m the basilar arteries

Smoking
category     Number   Basilar artery raised lesions


Non         3              1
EX          8              6
Light        18              3
Heavy       17              7

Holme et al.
(29)

129 autopsies
out of 16,200
men aged
4049 in
Oslo CHD
study

Interview
with subject

Visual grading

Correlation coefticlent between raised lesions in the cere-
bra1 vessels and number of cigarettes smoked per day is
0.090 (not statistically signifxantl.


induces certain degenerative or necrotic changes in the arterial wall,
but these are characteristically medial changes rather than the
intimal changes that characterize atherosclerosis. When nicotine is
administered in combination with a high cholesterol diet, it seems to
aggravate arterial damage, according to a preponderance of studies.
Some studies, however, do not report this synergism between
cholesterol feeding and nicotine (16, 84).

Schievelbein and associates (66) reported the effect of long-term
nicotine exposure on the development of arteriosclerosis in rabbits.
They administered nicotine to rabbits not being fed an atherogenic
diet. All animals had arteriosclerotic lesions in the aorta and
coronary arteries at the end of the experiment, but there was no
difference between the control group and the experimental animals
administered nicotine. They reviewed the experiments of several
authors who studied nicotine and their own animal experiments and
concluded that the evidence did not establish a causative role for
nicotine in the etiology of arteriosclerosis.

A recent report by Liu et al. (38) on experimental arterial lesions
in rhesus monkeys with various combinations of dietary hypercho-
lesterolemia, hypervitaminosis D(2), and nicotine indicated that the
combination of these three factors produced high scores for various
measures of arteriosclerotic changes in aorta, coronary, and limb
arteries of the monkeys. When the factors were administered singly,
however, very little arterial disease was demonstrated over the
period of the experiment. The group with all three factors was the
only group with significant coronary arteriosclerosis as well as
complicated lesions of the arteries of extremities.

Dooyse et al. (15) reported the effects of chronic oral consumption
of nicotine on the rabbit aortic endothelium. They found that fasting
serum levels of glucose, triglyceride, total cholesterol, and LDL
cholesterol were elevated in nicotine-treated rabbits as compared
with controls. They found no significant differences between the
experimental group and the controls for leukocyte, erythrocyte, and
platelet counts, or for hematocrit and hemoglobin. Endothelial cells
from the aortic arch of the nicotine-treated animals showed exten-
sive changes, such as increased cytoplasmic silver deposition, in-
creased formation of microvilli, and numerous focal areas of
"ruffled" endothelium. The authors concluded that nicotine adminis-
tered orally to rabbits has a demonstrable morphologic effect on
endothelial cells in the aortic arch.

While the evidence for and against a primary role for nicotine in
the development or acceleration of atherosclerosis is not conclusive,
nicotine is certainly one of the components of tobacco smoke for
which there are both some supporting data and a rational conceptu-
alization for a role in the pathogenesis of atherosclerotic lesions.
There is little doubt that nicotine alone or in combination with other

50



factors, such as hypercholesterolemia or excessive doses of vitamin
D, can damage the arterial wall, and arterial injury is widely
accepted as one mechanism for predisposing to or accelerating
lesions in animal models of atherosclerosis.

Carbon monoxide is another major component of cigarette smoke
for which there are some data supporting a possible atherogenic role;
however, a review of recent literature on the role of carbon monoxide
in arterial injury and atherogenesis leads to no consensus. Early
studies by Astrup and coworkers (3) on the effect of carbon monoxide
in rabbits suggested the theory that carbon monoxide causes
endothelial damage, which might promote atherogenesis. Later
studies by Astrup's group (2, 32) indicated that the duration of
exposure of rabbits to carbon monoxide did not influence the intimal
morphology of the coronary arteries or the aorta. They felt that
these new data contradicted the theory of carbon-monoxide-mediated
endothelial damage as a cause of atherosclerosis.

Recent experimental studies have produced a variety of results
regarding the effects of carbon monoxide on the development of
arterial lesions. Malinow et al. (40) exposed cynomolgus monkeys,
fed a standard laboratory diet or a semipurified high cholesterol diet,
to carbon monoxide or to room air for 14 months. None of the
animals developed a myocardial infarction, and there was no
difference in plasma cholesterol levels or in aortic or coronary
atherosclerosis attributable to carbon monoxide exposure. Davies et
al. (17) studied the effect of intermittent carbon monoxide exposure
on experimental atherosclerosis in the rabbit and found there was an
increase in coronary artery atherosclerosis in the carbon-monoxide-
exposed animals, but they did not find significant differences in the
lipid content of the aortas. Armitage et al. (1) studied the effect of
carbon monoxide on the development of atherosclerosis in the White
Carneau pigeon and found that the severity of coronary atherosclero-
sis was significantly greater in birds exposed to carbon monoxide
than in nonexposed birds after 52 weeks of exposure, but not after 84
weeks. The severity of atherosclerosis was related to the degree of
hypercholesterolemia. They suggested that in the White Carneau
pigeon, exposure to carbon monoxide elevates plasma cholesterol
levels, and thereby increases the extent of experimentally induced
atherosclerotic lesions. They further suggested that compensatory
mechanisms may reduce the effect of carbon monoxide exposure on
hypercholesterolemia over time.

Two reviews in 1979 came to different conclusions concerning the
relationship of carbon monoxide and arteriosclerosis. Astrup and
Kjeldsen (2) surveyed the cardiovascular effects of exposure of
animals to carbon monoxide and concluded that carbon monoxide
produces myocardial effects that can lead to decreased myocardial
oxygen tension with compensatory increases in coronary blood flow.

51


They stated that their previous findings of arterial intimal changes
had not been confirmed. Turner (78) reviewed studies involving
carbon monoxide, tobacco smoking, and the pathogenesis of athero-
sclerosis, and concluded that carbon monoxide exposure enhances
the extent of coronary atherosclerosis in pigeons that have been
made hypercholesterolemic by adding dietary cholesterol. Carbon
monoxide was without effect on normocholesterolemic birds. They
indicated that the level of carbon monoxide exposure, the duration of
exposure, and the level of dietary cholesterol are critically interde-
pendent factors that can influence the pathogenesis of the disease.

Studies by Sarma et al. (62) on the effect of carbon monoxide on
lipid metabolism of human coronary arteries provide some support
for the idea that carbon monoxide increases endothelial permeabili-
ty. They perfused human coronary arteries under sterile conditions
in vitro with blood containing high and low concentrations of carbon
monoxide. They found no effect of carbon monoxide on lipid
synthesis in the arterial wall; however, the arteries that were
exposed to carbon monoxide showed a higher uptake of cholesterol
from the perfusate as compared with their corresponding controls.
Thus, the results of Sarma et al. (62) were in agreement with those of
other investigators who have found that carbon monoxide signifi-
cantly increases the permeability of endothelial membranes.

Schneiderman and Goldstick (67) used a computer simulation of
the oxygen transport system of the arterial wall to evaluate the
extent of carbon-monoxide-induced hypoxia of the arterial wall
under various conditions; the results suggested that the moderate to
high carboxyhemoglobin levels found in some smokers may result in
a significant reduction in the oxygen tension of the arterial wall.

Hugod (31) reported no morphological change in the coronary
arteries and aortas of rabbits exposed to low doses of hydrogen
cyanide, alone or in combination with 200 ppm carbon monoxide,
and nitric oxide for 2 weeks.

McMillan (46) reviewed the many substances that may enter the
body from tobacco smoke and that have been conjectured as having a
role in cardiovascular disease. He concentrated on those substances
other than carbon monoxide and nicotine, such as cadmium, zinc,
chromium, carbon disulfide, carbon dioxide, tobacco antigens, hydro-
gen cyanide, nitric oxide, and polonium-210. He concluded that these
substances provide interesting ground for speculation as to their
possible role in cardiovascular disease, but that only carbon monox-
ide and nicotine offer both data and a rational conceptualization for
a role in cardiovascular disease.

Studies of Whole Tobacco Smoke
McGill (42) reviewed potential mechanisms for the augmentation
of atherosclerosis and atherosclerotic disease by cigarette smoking.

52


On the basis of his review of the evidence concerning smoking and
serum lipid and lipoprotein concentrations, he suggested that
cigarette smoking often causes a slight to moderate elevation of total
serum cholesterol concentration, and that smoking may depress
HDL concentrations and elevate LDL concentrations. These changes
might have the effect of increasing atherosclerosis because increased
levels of LDL and decreased levels of HDL have been shown to be
related to increased amounts of atherosclerosis as well as to an
increased risk of coronary heart disease.

Hojnacki et al. (28) studied the effect of acute inhalation of
cigarette smoke and consumption of dietary cholesterol on plasma
lipoprotein composition in atherosclerosis-susceptible White Car-
neau pigeons. They concluded that cigarette smoking can mediate
alterations in lipoprotein composition independent of changes in-
duced by dietary cholesterol and saturated fat.

Sieffert et al. (69) demonstrated endothelial damage and focal
platelet aggregation after exposing Sprague-Dawley rats to tobacco
smoke for l&minute periods three times a day for 6 and 12 weeks.
Scanning electron microscopic examination of perfusion-fixed the
racic aortas disclosed elongation of endothelial cells, uplifting of
endothelial cells from the basement membrane, areas of endothelial
loss, pitting, crater formation, and white blood cell invasion of the
underlying intima. They also found platelet aggregation on damaged
intima. They did not indicate which one of the constituents of
tobacco smoke they suspected as being the cause of these changes.

Rogers et al. (58) recently completed an investigation of cigarette
smoking, diet-induced hyperlipidemia, and experimental atheroscle-
rosis in baboons. The design of the study and interim results are
contained in a report by Rogers et al. (57). The baboons in this
controlled experiment consumed a diet enriched in cholesterol and
saturated fat for 3.3 years and puffed on lighted cigarettes or shams
for 2.8 years. The study was designed to determine whether cigarette
smoking interacts with diet-induced hyperlipidemia to accelerate the
development of atherosclerosis. This hypothesis was based on a
report by Keys (35), who found that populations with high total
serum cholesterol concentrations and a high incidence of atheroscle-
rotic disease have a dose-related relationship between cigarette
smoking and the incidence of atherosclerotic disease. However, in
populations with low total serum cholesterol levels and a low
incidence of atherosclerotic disease, cigarette smoking is not associ-
ated with the incidence of atherosclerotic disease. Thus, cigarette
smoking might augment atherosclerosis cnly when it interacts with
an atherogenic diet. The investigation by Rogers et al. (57, 581, used
nonhuman primates-baboons-as experimental animals, and the
animals were trained by operant conditiuning techniques to smoke
cigarettes in a human-like manner. The diet induced a moderate

53


hypercholesterolemia, which attained a peak of 235 mg/dl 5 months
after initiation and declined thereafter to 160 mg/dl at termination.
The early report of Rogers et al. (57) disclosed no significant
differences in serum lipids or lipoproteins between smokers and
shams after 1.6 years of smoking; however, there were some
differences that would be expected to accompany the augmentation
of atherosclerosis, namely higher LDL/HDL ratios in smokers than
in shams. At the completion of the experiment, these trends of
differences in lipoprotein concentrations were not present, and the
mean serum total cholesterol, serum triglyceride, LDL cholesterol,
and HDL cholesterol concentrations of smokers and shams were not
significantly different. The LDL/HDL cholesterol ratios of smokers
and shams were almost identical. Their observations on LDL/HDL
cholesterol ratios in the midcourse of the experiment and again at
the end suggested that cigarette smoking either increases the
LDL/HDL cholesterol ratio only during hypercholesterolemia or
increases the LDL/HDL ratio only in some animals.

At autopsy of these baboons, the mean extent of fatty streaks was
not significantly different for smokers versus shams in the aorta,
femoral, iliac, and innominate arteries. The mean extent of fatty
streaks in smokers was significantly greater than in shams for the
carotid arteries. The variability in extent of lesions was greater in
smokers than in shams, suggesting the possibility that a subset of
smokers may have responded positively to smoking by developing
increased lesions. This difference in variability of lesions was
statistically significant for the thoracic aorta, carotid, and innomi-
nate arteries. The authors suggest that the "compensatory" decline
in mean serum cholesterol concentration that occurred in the latter
part of the experiment could have led to regression of experimental-
ly induced lesions.

The authors indicate that their results do not support the
hypothesis that cigarette smoking, at a level approximately equiva-
lent to that of the average human cigarette smoker, augments
experimental atherosclerosis in the presence of a moderate level of
diet-induced hypercholesterolemia. They did, however, find a signifi-
cantly greater extent of fatty streaks in the carotid arteries for the
smokers and significantly more variability in the extent of lesions in
the smokers. Also, among the small number of animals that died
during the course of the experiment, the smoking animals had more
extensive involvement with lesions than did the shams. Neverthe-
less, there were no dramatic, clear-cut, across-the-board differences
between the smoking and nonsmoking animals. The authors con-
clude that this experiment cannot be regarded as a conclusive test of
the hypothesis that cigarette smoking can augment the formation of
fatty streaks associated with dietary-induced hyperlipidemia.

54


McGill's review (42) indicated that smokers have slightly increased
erythrocyte counts, hematocrit, and hemoglobin concentrations, but
he doubted that the slight changes observed would increase the risk
of atherosclerosis. In the experiments with baboons, smokers also
had elevated leukocyte counts owing to both increased polymorpho-
nuclear leukocytes and increased lymphocytes. These changes might
be one manifestation of an altered immune system that might
deserve attention as a possible mechanism for accelerating athero-
genesis. The smoking baboons had slightly elevated blood glucose
levels; it is not known if this change would contribute to atheroscle-
rosis. Body weight and blood pressure are slightly lower in smokers
than in nonsmokers, and this response to smoking is in the opposite
direction with regard to risk of atherosclerotic disease.

Smoking and the Hemostatic System

McGill indicated that the limited number of recent studies of the
effects of smoking on the hemostatic system show little or no effect
on clotting action, but marked effects on platelets. Platelet counts
are not different in smokers and nonsmokers, but smokers have a
decrease in survival time and an increase in platelet turnover (50),
increased adhesiveness (49), and increased tendency for aggregation
(24,27,36).

Ogston et al. (52) found that chronic smoking led to an increased
plasma fibrinogen concentration, but acute smoking did not. Janzon
and Nilsson (33) found that chronic smoking was associated with
increased librinolytic activity of the blood.

Davis and Davis (18) studied the effect of cigarette smoking on
circulating platelet aggregates as detected by the platelet-aggregate
ratio in volunteer subjects. The platelet-aggregate ratios were lower
in the smokers, indicating increased circulating platelet aggregates.
The authors indicated that the decrease in platelet-aggregate ratio
was not mediated through the elevation of plasma nonesterified
fatty acid concentration.

Fuster et al. (21) found a shortened platelet survival half-life in
apparently normal persons who smoked and in persons with a strong
family history of coronary disease. Their study suggested a possible
relationship among cigarette smoking, strong family history of
coronary disease, and platelet activation in the process of coronary
atherogenesis in the young adult.

Smoking and the Immune System

McGill (42) suggested that the leukocytosis observed in smokers
may represent in part a manifestation of an immune disorder.
Immune complex disease markedly aggravates atherogenesis in
rabbits (48) and in baboons (30). Becker and Dubin (10) and Becker et
al. (II) have identified a low molecular weight glycoprotein in

55


tobacco smoke that is highly antigenic in man. McGill (42) suggests
that differences in sensitivity to antigenic materials could account
for the great variation in response to cigarette smoking. He also
suggests endothelial injury and increased endothelial permeability
as a mechanism for cigarette smoking effects on cardiovascular
disease. Becker (9), in summarizing a workshop on immunologic
injury and the thrombotic process in atherogenesis, postulated that
the capacity of tobacco glycoprotein to activate the intrinsic pathway
of coagulation might contribute to the growth of arteriosclerotic
plaques and to more lethal complications by initiating thrombus
formation. Denburg et al. (19) studied the reactivity of 164 patients
with peripheral vascular disease to purified tobacco glycoprotein;
they suggested that reactivity to tobacco glycoprotein may he
causally related to the development of atherosclerotic vascular
disease.

Conclusions

1. A preponderance of evidence both from prospective studies with
autopsy followup and from autopsy studies with retrospective
smoking data indicates that cigarette smoking has a significant
positive association with atherosclerosis. This evidence suggests
that cigarette smoking has the effect of aggravating and
accelerating the development of atherosclerotic lesions in the
artery wall and that its effect is not limited to those events
related to the occlusive episode. The effects are most striking for
aortic atherosclerosis; a significant positive relationship also
exists between cigarette smoking and atherosclerotic lesions in
the coronary arteries, at least for most high risk populations.
Cigarette smoking could also be associated with other factors
that precipitate thrombosis, hemorrhage, or vasoconstriction
leading to occlusion and &hernia.

2. Some evidence exists that cigarette smoke alters total serum
cholesterol concentrations and lipoprotein composition in ways
that would be expected to increase the development of athero-
sclerosis. Recent studies of the effects of smoking on the
hemostatic system indicate effects of smoking on platelet
function.

3. Although the specific mechanisms by which tobacco smoke
affects arteriosclerosis have not been clearly delineated, the
effects of cigarette smoking on the atherosclerotic lesions that
underlie cardiovascular disease seem well established.

56


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(74) STRONG, J.P. RICHARDS, M.L. Cigarette smoking and atherosclerosis in
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  RY, M.T. On the association of cigarette smoking with coronary and aortic
  atherosclerosis. Journal of Athemsclerosis Research 10: 303-317, November-
    December 1969.

(76) THOMAS, W.A., JANAKIDEVI, K.. REINER, J.M., LEE, K.T. Glucose-6
  phosphate dehydrogenase (G-6-PD) monotypism in atherosclerotic lesions of
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(77) TRACY, R.E., TOCA, V.T., STRONG, J.P., RICHARDS, M.L. Relationship of
  raised atherosclerotic lesions to fatty streaks in cigarette smokers. A thero-
   sclerosis 38(3/4): 347-357, February-March 1981.
(78) TURNER, D.M. Carbon monoxide, tobacco smoking, and the pathogenesis of
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   and Welfare, Public Health Service, Health Services and Mental Health
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(82) VIKHERT, A.M., ZHDANOV, V.S., LIPSHITS, A.M. Atherosclerosis in males
   doing manual and brain work. Kardiologija 16(3): l&123,1976.
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(85) WILENS, S.L., PI&R, CM. Cigarette smoking and arteriosclerosis. Science
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62


SECTION 3. CORONARY HEART
        DISEASE

63


Introduction

Higher rates of disease and earlier mortality in cigarette smokers
than in nonsmokers have been documented in a large number of
investigations. Of the several disease manifestations that account for
the excess disability and death in cigarette smokers, coronary heart
disease (CHD) is the leading cause in North America and northern
Europe (18, 40,43,45, 67, 94,96, 134, 143, 189,214,224,257). CHD is
related to several risk factors, including cigarette smoking. Esti-
mates indicate that up to 30 percent of all CHD deaths in the United
States are attributable to the cigarette smoking habit (189).

Three of the major prospective studies have reported estimates of
cigarette-related CHD mortality based on the number of observed
versus expected CHD deaths in smokers and nonsmokers. In the ACS
25State study, involving more than 1 million men and women,
Garfinkel(73) estimated that of the 12,724 CHD deaths that occurred
among all males followed prospectively for 6 years, 5,358 (46 percent)
would not have occurred if all male cigarette smokers had the same
CHD death rates as did nonsmoking males. Among females, a similar
percentage of excess deaths (40 percent) attributed to smoking was
noted; however the total number of CHD deaths was not large. Rogot
and Murray (224) followed 290,000 U.S. veterans over a period of 16
years. During this time 13,845 CHD deaths were observed among
cigarette smokers, whereas only 8,787 were expected. This repre-
sents an approximately 40 percent greater observed-toexpected
ratio. In the British physicians study, in which 34,000 male British
physicians were followed for 22 years, it was reported that cardiovas-
cular disease accounted for 52 percent of all excess deaths in
smokers, including 31 percent arising from CHD. By contrast, lung
cancer was responsible for 19 percent of the cigarette-related excess
deaths (232).

Whyte (277), using the "attributable fraction" method as advocat-
ed by Miettinan (179), reanalyzed data from the Pooling Project
study and estimated that 24 percent of first major coronary events
were cigarette related and independent of other risk factors. When
all three major risk factors were considered together, the proportion
of attributable risk increased to 70 percent.

Both Lute and Schweitzer (163, 164) and Boden (21) attributed 25
percent of all circulatory diseases to smoking. Both used data derived
from estimates provided by the NIH Task Force Report on Preven-
tive Medicine (63). These estimates are in close agreement with that
published by Richter and Gori (219) that attributed 30 percent of
heart disease to smoking; they also estimated that 33 percent of all
arteriosclerosis was cigarette related. The latter estimate is identical
to those published by the National Cancer Institute and the National
Heart, Lung, and Blood Institute in the final report on the program
to reduce the risk of disease in smokers (189).

65


In young people-including young women who are otherwise at
very low risk for CHD-as many as threequarters of the cases may
be attributable to the cigarette smoking habit (244, 257). During the
period 1965-1977, there were an estimated 2.8 million premature
deaths from heart disease, primarily CHD, in American men and
women attributable to the use of tobacco. Furthermore, unless
smoking habits of Americans change, over 10 percent of all those
now alive may die prematurely of heart disease that will be
attributable to the use of tobacco. The number of such deaths may
exceed 24 million (189).

Annually during recent years, more than one and a quarter
million Americans have suffered fatal or nonfatal heart attacks (2,
101, 198). The deaths from CHD have numbered over 500,000 and
have exceeded the deaths from any other cause; half or more of these
deaths are sudden (139). In addition to these acute manifestations of
CHD, more than 5 million Americans are under treatment for
chronic manifestations of CHD (2, 198). Millions of others have
significant CHD that is undiagnosed. Of those currently undiag-
nosed, approximately one-quarter will manifest sudden, unantici-
pated death as the first clinical indication of CHD (110, 137, 153).

Scientific Investigation of the Relationship Between Coronary
Heart Disease and Smoking: Objectives of the Present Review

The scientific basis for the judgment that cigarette smoking is a
major contributor to CHD in Americans has been presented in the
Reports of the Surgeon General beginning in 1971 (264l and
emphasized recently in the Reports of 1979 (263) and 1980 (261). A
large number of epidemiologic, clinical, and experimental studies
using a variety of methods and research designs have accumulated
overwhelming evidence of the strong relationship between cigarette
smoking and CHD. The possibilities of sample selection bias or
confounding of this association by other factors as explanation for
this association have been examined exhaustively and do not explain
the relationship between cigarette smoking and CHD.

In this section, emphasis is placed on critical examination of the
relationship between cigarette smoking and CHD incidence and
mortality. The independence of cigarette smoking as a predictor of
CHD is considered in the context of those other risk factors that also
predict the occurrence of CHD. This includes evaluation of the
consistency of the relationships between risk factors and subsequent
CHD, including those mathematical models for prediction of CHD
that have been applied widely among diverse population groups. The
examination takes into account sample size, effects of multiple risk
factors acting simultaneously, and secular trends in risk factor

66


prevalence. Areas of opportunity for expansion of knowledge are
discussed.

Mortality studies are summarized with respect to the relationship
of smoking and CHD. The large prospective mortality studies provide
evidence of the influence of cigarette smoking in large and varied
populations, and they provide sufficient numbers of cases for
detailed analyses of the influence of smoking intensity and duration,
age, sex, race, and smoking cessation on CHD.

Coronary Heart Disease Manifestations

The major clinical manifestations of CHD are myocardial infarc-
tion (MI), which may be fatal or nonfatal; other death from CHD,
which may be sudden or not; and angina pectoris, which is the first
clinical manifestation in about one-third of new cases (40).

In most cases, obstruction to blood flow in the coronary arteries is
caused by arteriosclerotic narrowing (34, 39). Some cases are
associated with coronary artery spasm with or occasionally without
atherosclerotic change in the coronary arteries (39, 87, 174, 202).
When there is thrombosis superimposed on the coronary narrowing,
myocardial infarction typically results (34). The aggregation of
platelets and formation of fibrin thrombi are related tc the acute
clinical manifestations of coronary heart disease, and may also play
a role in the development of coronary atherosclerosis (187, 230).
Several autopsy studies in the United States and elsewhere have
shown that atherosclerosis of the coronary arteries is more common
in cigarette smokers than in nonsmokers (3, 7, 8, 9, 220, 245, 247).
This topic is discussed elsewhere in this Report.

Clinical Manifestations and Epidemiologic Criteria for Coronary
Heart Disease Events

Myocardial Infarction

Myocardial infarction (MI) denotes necrosis of a discrete volume of
heart muscle resulting from prolonged, severe ischemia following
interruption of coronary blood flow. The characteristic symptom is
unremitting chest pain that may be associated with sweating,
nausea, shortness of breath, dizziness, or loss of consciousness. The
role of coronary thrombosis in the evolution of acute myocardial
infarction (AMI) has been debated in the past; recently, coronary
angiography has been performed in large numbers of patients with
AMI. In the majority, coronary thrombosis has been found to be
superimposed upon preexisting arteriosclerotic narrowing. In a
small proportion of cases, but more commonly in young men and
women, MI has been observed in patients with little or no coronary

67


atherosclerosis who have had coronary artery spasm or coronary
thrombosis or both (I).

Loss of consciousness in acute myocardial infarction is an ominous
sign because it often reflects inadequate pumping action of the heart
owing either to catastrophically abnormal cardiac rhythm or to
severe deterioration of cardiac muscle function. A broad range of
cardiac rhythm disturbances may occur, but the most characteristic
catastrophic one accompanying myocardial infarction is a chaotic
irregularity of muscle fiber contraction (ventricular fibrillation) that
results in a cessation of effective pumping by the heart. In such
instances, death occurs within several minutes after cessation of
blood flow to the brain if the rhythm disturbance is not reversed.

In patients who survive long enough to be admitted to the hospital,
the diagnosis of AM1 may be made from changes in the electrocardio-
gram and increases in serum enzymes (I). In comprehensive clinical
epidemiologic studies, the criteria for identifying cases of MI include
specific presenting symptoms, electrocardiographic changes, and
serum enzyme elevations (40,214).

Death from CHD

In fatal cases, evidence of CHD may be provided by clinical or
autopsy information (40, 214). In the absence of adequate clinical or
autopsy evidence, diagnosis of death from CHD is based on documen-
tation of a sufficiently short interval from onset of symptoms until
death and the absence of another potentially lethal condition (153).

Sudden Cardiac Death

A large proportion of deaths certified as due to CHD have been
sudden, and a significant fraction of these sudden cardiac deaths
@CD) have occurred in persons with no prior history of CHD (68, 109,
139, 152, 154, 220). The incidence of SCD increases with age, and it is
substantially more frequent in men than in women; in women the
incidence of SCD lags behind that of men by 20 years (139).

Epidemiologic investigations have shown that the majority of
deaths in ambulatory adults that are sudden and unanticipated are
associated with severe CHD. In the Baltimore study by Kuller et al.
(1531, 71 percent of the deaths (excluding trauma) that occurred
within 24 hours of the onset of terminal illness in individuals who
had been able to function in the community were from CHD. In those
with other causes, more than half were associated with fatty liver.
Alcohol consumption appears to have a complex relationship to
CHD, and heavy alcohol consumption has been identified as a factor
in sudden death in several studies. This relationship has been shown
to be independent of the relationship with cigarette smoking (38, 64,
148, 158, 173, 188, 209, 216). Although some difficulty may arise in


appropriate designation of unwitnessed deaths, the less frequent and
rare conditions are usually differentiated easily from SCD.

Criteria for SCD have varied in different studies. Among ambula-
tory adults considered to be well who die suddenly, the probability of
severe CHD has been shown to be very high both by autopsy data
and by clinical data (40, 109, 139, 157, 200, 248). In large population
studies, however, information for some cases is often not available to
determine the exact interval from onset of symptoms until death;
therefore, criteria for sudden death have often included intervals up
to 24 hours (153, 156, 200). In a high proportion of such cases, severe
CHD has been observed by autopsy examination (10, 12, 50, 68, 109,
153, 160, 200, 208).

The physiologic disorders responsible for sudden collapse and
cardiac arrest in ambulatory adults have been well documented. In
the overwhelming fraction, ventricular fibrillation is the terminal
ventricular rhythm disorder; however, profound cardiac bradycardia
or cardiac standstill can be the mechanism as well. Ventricular
fibrillation may further degenerate into cardiac standstill (33, 47,55,
56, 145, 202). Among patients resuscitated following cardiac arrest,
AM1 has been documented during the subsequent hospital course in
one-quarter toone-half of the cases; in the others, severe, multivessel
coronary atherosclerosis, with or without old MI, has been observed
by coronary angiography in three-quarters or more (33, 56,273).

Ascertainment of CHD From Death Certificates

In large-scale mortality studies the underlying cause of death on
death certificates has usually been used to identify the deaths from
coronary heart disease. [In recent editions of the International
Classification of Diseases, the term ischemic heart disease is
preferred over the older term coronary heart disease. Some authors
prefer the term arteriosclerotic heart disease. For uniformity,
coronary heart disease (CHD) is used throughout this section
regardless of the usage in the publications reviewed.] The accuracy of
death certificate data has been evaluated through review of avail-
able clinical data and retrospective analyses and from available
pathological data. Coronary heart disease has been confirmed as
probable or likely in the vast majority of cases (183, 184, 236, 284).

In a random sample of 1,362 U.S. death certificates in 1960,
pertinent clinical and pathological information to determine the
cause of death was investigated by Moriyama et al. (182). In the 87
percent of cases for which responses from medical certifiers were
obtained, only 7 percent of those certified to be CHD were judged to
be incorrect or probably incorrect. The information for diagnosis of
CHD was judged to be reasonable or well established in 74 percent
and inadequate to determine the cause of death in 19 percent.

69


In recent years, cardiac evaluation has become more prevalent
with widespread use of objective diagnostic tests. This should result
in even greater accuracy of CHD case ascertainment from death
certificates.

Angina Pfxtoria

Angina pectoris is the first clinical manifestation in about one-
third of the new cases of CHD (1331. In the typical form, observed in
about 90 percent of clinically diagnosed patients, chest pain or
tightness occurs with exertion or excitement and is relieved prompt-
ly by rest or nitroglycerin. Such patients usually have fixed
obstruction to blood flow due to arteriosclerosis in one or more of the
coronary arteries (34, 174,237). Patients with typical angina pectoris
are at increased risk for the more serious manifestations of CHD,
myocardial infarction, and death from CHD (34, 133, 174, 175, 241).

In the atypical form, chest discomfort usually occurs at rest,
although it may also occur with exertion, and it is usually relieved
by nitroglycerin (87, 174, 175,237,241). This atypical or variant form
of angina pectoris has been shown to result from coronary artery
spasm that occurs at the site of atherosclerosis in many cases, but in
otherwise normal-appearing coronary arteries in others (87, 175,
202). Sudden death is a rather common complication of variant
angina (39, 110, 175,202, 241).
Conditions other than CHD may cause symptoms that mimic
angina pectoris, and definitive diagnosis may require clinical obser-
vation over time and the performance of ancillary diagnostic
procedures (34, 40). However, in large-scale epidemiologic studies,
complete diagnostic evaluation is usually not feasible, and the
proportion of cases with underlying severe coronary atherosclerosis
has probably varied among the different studies (40, 121, 273).

In addition to those in the population who have symptoms of CHD,
there are many with significant coronary atherosclerotic obstruction
who are undiagnosed. The frequency of clinically silent but physic
logically significant coronary artery disease is unknown; it is
estimated that in one-quarter of the cases with a new myocardial
infarction, the infarction is silent and detected only on followup by
electrocardiographic (ECG) examination (I 72).

In prospective epidemiologic studies with clinical followup, cases
may be classified only by the most severe CHD manifestation, in this
order: death from CHD, nonfatal myocardial infarction, and angina
pectoris. Thus, the cases classified as angina pectcris are those
remaining who have not experienced a more serious CHD event, and
as noted above, this diagnosis may lack sensitivity and specificity for
coronary atherosclerotic disease. Variation in the strength of
association between smoking and angina pectoris may be influenced
by these methodological considerations (48,49, 121, 135,229).

70


A number of well-documented, clinical series of patients with
angina pectoris and severe CHD confirmed by coronary angiography,
surgery, or post-mortem examination have been reported (4, II, 32,
42, 97, 98, 118, 171, 201, 253, 268, 272). These studies provide
important information for clinical management and add insights
into relationships with risk factors. However, causal inferences must
be made with caution when measurements of risk factors have been
made after the onset of clinical disease and data from appropriate
comparison groups are not available.

Epidemic CHD and the Application of Epidemiologic
Methodology

CHD was thought to be uncommon in the early part of this century
when most deaths were caused by infectious disease. Before the mid-
century, however, CHD had become the leading cause of death, and
year to year increases were large (101, 159). Neither the cause of
CHD nor the reasons for the rising epidemic could be explained.
Nevertheless, pioneering efforts in cardiovascular epidemiology
revealed that certain characteristics were observed more often in
CHD cases, and epidemiologic investigations were begun to obtain
data with which to make causal inferences (4486, 143).

Prospective Cohort Studies: Intensive Population Studies of
Risk Factors and CHD

In several early investigations, cigarette smoking and several
other characteristics were observed to be strongly associated with
CHD (60, 136, 276). To clarify the nature of these relationships,
defined population samples were examined for personal characteris-
tics that could be related to CHD. Intensive observation for
subsequent incidence of CHD through reexamination and surveil-
lance activities in members of population samples that were free of
disease at the baseline examination provided a substantial part of
the data from which causal inferences relating to smoking and CHD
were made. A number of these are briefly described in the following
pages. In each study, smokers were found more likely to develop
CHD than nonsmokers.

studies in U.S. whites

Within the U.S. population, CHD mortality has been highest in
white men, and they were investigated most intensively in the early
prospective studies. To provide a sufficiently large number of cases
for detailed analyses of the relationship of CHD to cigarette smoking
and other risk factors, several of the long-term epidemiologic studies
agreed to pool their data in the National Cooperative Pooling Project

71


sponsored by the Council on Epidemiology of the American Heart
Association and supported by the American Heart Association and
the National Heart Institute, now designated the National Heart,
Lung, and Blood Institute (168, 214). Five of the studies participating
in this effort had used comparable methodology in data collection so
that the data from each of these five cohorts could be pooled for
analysis. In Table 1, analyses for the pooled data are referred to as
"Pool 5." The five cohort studies contributing to the pooled data will
be characterized briefly individually, and then analysis of the pooled
data will be summarized.

Fmmingham Heart Disease Epidemiology Study

The Framingham study was initiated by the Public Health Service
in 1948. The members of the prospective cohort were 2,282 men and
2,845 women who were aged 29 through 62 and free of CHD at initial
examination (40, 86, 133). The cohort was based on a random
subsample of the residents of Framingham, Massachusetts; the
response rate was 69 percent. The respondents were supplemented
by volunteers who had similar characteristics. A standardized
cardiovascular examination at entry included information on habits,
physical characteristics, and blood chemistries. Reexamination has
been carried out biennially for ascertainment of cardiovascular
disease and changes in characteristics. Cardiovascular disease case
ascertainment has included community and mortality surveillance
activities (86, 136). Analyses through 24 years of followup have
shown that cigarette smoking is strongly related to MI and death
from CHD (40, 133, 135). In Table 1, Framingham data analysis is
shown with that of the other cohorts participating in the National
Cooperative Pooling Project. The excess risk of MI and death from
CHD was found to increase progressively with the number of
cigarettes smoked (Table 1).

The relationship to angina pectoris has been less clear. In the 12-
year and the 24-year followup data analyses, however, male cigarette
smokers were observed to experience a higher incidence of angina
pectoris than were nonsmokers (40, 135). The effect was stronger at
younger ages; after 24 years of followup, the incidence of angina
pectoris in those 30 to 39 years old at entry to the study was twice as
high in smokers as in nonsmokers (Figure 1).

Albany Cardiovascular Health Center Study

In 1952 the New York State Health Department established at the
Albany Medical College a prospective study of male civil servants
working in Albany. Participation was obtained from 87 percent of
eligible men aged 40 through 54, of whom 1,823 were free of CHD at
initial examination. After 6 years, the incidence of MI and death
from CHD was significantly higher in cigarette smokers in compari-

72


TABLE l.-National Cooperative Pooling Project. Analysis
      of the incidence of CHD by smoking behavior
      in five participating cohorts individually and in
      the data pooled for the five cohorts with
      comparable methodology (Pool 5). Standardized
      incidence ratio, risk ratios, number of men,
      person-years of experience, and number of first
        events

smoking behavior

Pool 5

Standardized incidence ratio by study group

ALB    CHGAS   CH-WE FRAM   TECUM

All

Nonsmokers
Never smoked
Past smoker
<l/2 pack/day

1M)     100

55      48
45     (53)
67      56
(67)

Cigar and pipe only

78

68)

59
44
89
(431

98

Cigarette smokers
About l/2 pack/day
About 1 pack/day \
>l pack/day

104
120
183

(521     (64      139     106      (151)
108     125      128     119       117
200     190      162     174       151

Risk ratio
21 pack/day
Nonamokera
95% confidence interval
Low
High

2.5

2.7      3.3       2.4      2.2      ( 1

2.1       1.8      2.1       1.6      1.5      ( )
3.1       4.3      6.2       3.7      3.4      ( 1

Risk ratio
>l pack/day
Nonsmokers
95% eonfdenoe interval
g

3.2       3.7      4.0       2.6      2.6      ( )

2.6       2.4      2.5       1.2      1.8      ( )
4.2       6.1      8.4       5.5      4.5      ( )

Number of men at risk    G332     1.796    G=     1,926
Person-years of experience  70,970    17,240   11,017    16,072
Number of fti eventa      644      154     123      140

100      100

67      (53)
77      60)
(4%     (50)
76     (43)

57      (61)

2,162
19,756

1,140
6,885
49

NOTE: ALB: Albany Gardiovaacular Health Center Study
   CHGAS Chicago Peoples Gas Company Study
   Cl+WE: Chicq?o Western Ehctric Company Study
   FRAMz Fnmiiham Heart Dimaw Epidemiology Study
   TECUM:T ecumaeh Health Study
NOTE: (  k haed on fewer than 10 first eventa.
SOURCE: Pooling Project Raearch Group (214.

son with nonsmokers (48). Subsequent analysis after 10 years of
followup confirmed these findings (Table 1).

Chicago Peoples Gcs Company Study
Beginning in 1958, the Chicago Peoples Gas Company medical
department examined 1,264 white men aged 40 to 59 (92 percent of

73


I m Corrected rate
a Crude rate    Men

Smokers   2fi5 I
       174 I     Nonsmokers

30-39

40-49  50-!j9  30-39

    AGE AT ENTRY

  151
  134
II
40-49

211

150
3.
50-59

FIGURE l.-Twenty-four-year incidence of angina pectoris
      in men, by cigarette smoking status

NOTE: Tbe crude rata have been mrrected to take into account those members of the population who are no
longer at risk by reasan of having developed the disorder in question or having been lost to observation by death.
SOURCE: Dawber (40).

those eligible) who were free of CHD (161, 214). Analysis of the data
obtained during an average of 8.8 years of followup revealed a higher
incidence of MI and death from CHD in cigarette smokers than in
nonsmokers (Table 1).

Chicago Western Electric Company Study

Beginning in 1957,67 percent of male Western Electric Company,
Chicago, employees aged 40 to 55 were examined; 1,98l` were free of
CHD (161, 206, 214). After an average followup of 8.3 years, the
incidence of MI and death from CHD was higher in cigarette
smokers than in nonsmokers (Table 1).

Tecumseh Health Study

The Tecumseh health study began examination of the entire
community of Tecumseh, Michigan, in 1959; participation was
obtained from 90 percent (61, 214). Included was a cohort of 1,240
white men aged 40 to 59 who were free of CHD at initial
examination. During an average followup of 8.05 years, the incidence
of MI and death from CHD was higher in cigarette smokers than in
nonsmokers (Table 1).

Minnesota Business and Professional Men Study

Selected Minnesota business and professional men were first
examined in 1948; 284 men aged 40 to 59 years were free of CHD
(144, 214). During an average followup of 14.1 years, those who

74


smoked cigarettes experienced a higher incidence of MI and death
from CHD than did nonsmokers.

Minnesota-Based Railroad Worker Study

Among eligible railroad men working in the northwest sector of
the United States, 65 percent participated in the Minnesota-based
railroad worker study examinations beginning in 1958 (143, 214). Of
these men, who were white, aged 40 to 59 years, and free of CHD at
first examination, 2,571 were followed for an average of 4.9 years.
Those who smoked cigarettes experienced a higher incidence of MI
and death from CHD than did nonsmokers.

National Coopemtive Pooling Project

As indicated above, the data from five of the cohorts participating
in the National Cooperative Pooling Project were pooled for those
white men who were aged 40 to 59 years, were free of CHD at initial
exam, had comparable baseline examinations, and were followed for
up to 10 years with comparable case ascertainment (Table 1). The
demographic and other characteristics of these cohorts were similar
to the characteristics of middle-aged white men in general living in
the United States during the same period (190-196).

Subjects contributing to the pooled data numbered 8,422; during
an average followup of 8.5 years (72,011 person-years), 688 cases of
major CHD were observed (214). Major CHD was defined as nonfatal
or fatal MI or sudden death from CHD (death in less than 3 hours
from the onset of illness).

Risk of CHD With Smoking

According to the pooled data for men aged 40 to 59, those who
smoked a pack or more of cigarettes per day at initial examination
experienced a risk for a first major coronary event that was 2.5 times
as great as the risk of nonsmokers (Table 1). In these analyses,
nonsmokers included those who never smoked, cigar and pipe only
smokers, past smokers, and those who smoked less than half a pack
per day. Those smoking less than half a pack per day consisted
largely of those who smoked occasionally or only two or three
cigarettes per day. For each of the five cohorts separately, the
relative risks varied from 2.2 to 3.3.
The risk was greatest in those with the heaviest smoking habits in
all age groups (Table 2), and excess incidence attributable to smoking
more than one pack of cigarettes per day tended to increase with
increasing age up to age 60; however, with increasing age, relative
risk declined. This apparent paradox is due to the rapid rise of CHD
incidence with age. The excess incidence in heavy smokers (more
than one pack per day) was large and statistically significant for

75



TABLE 2.-National Cooperative Pooling Project. Analysis
      of the risk of CHD by smoking behavior from
      the pooled data of the five cohorts* observed
      with comparable methodology (Pool 5). Average
      annual risk of first major coronary event,
      standardized incidence ratio (SIR), risk ratio >l
      pack per day/nonsmokers, and number of first
      events, by age group

smoking pattern

              Age @-UP

4cM4     45-49     iti&     5.5-59     60-64     40-64

Average annual risk (per 1,000 man-years)

All                3.1       6.4       8.0      22.6      19.9

Nonsmoker          (1.5)       3.0       3.6       7.3      15.5
Never smoked         (1.9)     (0.7)     (2.5)       8.7      11.4
Past smoker          (0.9)       5.5       4.3       6.1      15.5
<l/2 pack/day        (1.7)     (4.7)     (5.9)     (6.4)     (7.5)

Cigar and pipe only     (2.1)     (2.21      (2.1)      12.1      19.5

Cigarette amokera
About l/2 pack/day    (3.1)      (5.0)     (6.2)      15.5      24.3
About 1 pack/day      3.9       8.4      10.3      13.8      22.0
>l pack/day         4.9      12.2      17.4      22.5      26.8

Riik ratio
> pack/day/nonsmokers  ( 1       4.1       4.8       3.1       1.7

SIR

100

58
54
63
55

71

104
120
183

3.2'

Number of fti events                SIR

All

Never smoked
Paat smoker
<l/2 pack/day
Cigar and pipe only
About l/2 pack/day
About 1 pack/day
>1 pack/day

34       113      158      194      145

3        2        8       21       21
1       11       10       13      * 18
1        4        6        6        4

2        4        5       26       33

3        7        9       19       15
14       49       64       61       42
10       36       56       48       22

644

55
53
21

60

53
230
172

o See footnote of Table 1 for names of the five study group.
' Approximate 95% confidence interval: 2.642.
NOTE: (  ): bad on fewer than 10 first events.
SOURCE: Pooling Project Research Group (2I4.

each !5-year age group between 45 and 64, and the differences were
progressively greater with age up to 60. For those smoking about one
pack per day and about one-half pack per day, the excess risks were
sizable, but of a lower magnitude. Because of the relatively smaller
numbers, the data were not sufficient for evaluation of differences in
risks among those who had never smoked, those who had smoked
less than one-half pack per day, and former smokers.

In the Pooling Project data, the risk for cigar and pipe smokers
was not significantly different from either the nonsmoker group or

76


the half-pack per day smokers, but it was significantly lower than
that for men who smoked a pack of cigarettes per day (Table 2).
However, the position of cigar and pipe smokers on the continuum of
risk could not be adequately evaluated from these data because of
small numbers.

In summary, detailed prospective studies of the incidence of CHD
in white males in the U.S. population have demonstrated a clear,
strong, dose-related relationship between cigarette smoking and
acute myocardial infarction and death from CHD. This cigarette
smoking effect was proportionally greater in younger populations,
but was present in all age groups examined in these studies.
Cigarette smokers in the Framingham study had a high incidence of
angina pectoris among the younger age groups, but this relationship
was not as strong as the relationship between smoking and myocar-
dial infarction. Pipe and cigar smokers had a risk that was not
statistically different from the risk of nonsmokers.

Ethnic Groups in the United States With Lower Risk of
CHD -

CHD mortality in blacks is lower than in whites in the United
States (75, 76, 197, 225, 236, 259). A case-control study of the
incidence of CHD during World War II in young Army men observed
a risk ratio of 0.61 in black men relative to white men (120). Reasons
for lower rates in black men are not adequately understood,
although the smoking habits of blacks have been found to differ from
those of whites. Blacks have tended to smoke cigarettes with higher
tar and nicotine content, but they have also tended to smoke fewer
cigarettes (262). Hypertension is also more prevalent in blacks than
in whites (142). On the other hand, plasma lipid levels were reported
to be more favorable; high density lipoprotein cholesterol levels
(HDLC) were higher and low density lipoprotein cholesterol levels
(LDL-C) were lower in black men than in white men aged 20 to 49
(259). HDLC has been negatively associated with CHD, and LDL-C
has been positively associated with CHD @Q&4,21 7).

The Evans County, Georgia, study was initiated in 1960 to
investigate differences in coronary heart disease incidence and risk
between blacks and whites for an entire community in a rural,
principally agricultural setting (107). All residents of Evans County
over age 40 and a 50 percent subsample of those aged 15 to 39 years
were eligible; 92 percent of those eligible were examined between
1960 and 1962. Followup examinations from 1967 through 1969
provided a mean followup period of 7 l/4 years. Reexamination for
evidence of new CHD was obtained in 91 percent of the 3,102
initially examined members of the population, including 537 black
males and 947 white males (83 percent and 93 percent, respectively,
of those initially available). In addition, community and mortality

77


surveillance was used to ascertain the incidence cases of fatal and
nonfatal CHD.

During the 7 l/4 years of followup, 13.6 percent of the black males
and 12.7 percent of the white males died. The onset of CHD was
observed in 6 surviving and 7 decedent black men and in 40
surviving and 32 decedent white men. The age-adjusted incidence
rate for white men was 3.5 times the rate in black men. There were
few cases in women, but the incidence rates in black women and in
white women appeared to be similar. CHD incidence was higher in
smokers than in nonsmokers for the black and the white popula-
tions.

Beginning in 1965, 9,824 men aged 45 to 64 years who were
residents of four rural and three urban areas of Puerto Rico were
examined at a clinic in San Juan. The methods used were compara-
ble to those used by the Framingham study (85). Of the targeted
population samples, over 80 percent attended the medical examina-
tion, and over 90 percent of the examined cohort participated in four
followup examinations at 2 l/2-year to Syear intervals. The average
followup was 8 l/4 years (246).

In comparison with men in Framingham, fewer men in Puerto
Rico were smokers, and the Puerto Rican smokers consumed fewer
cigarettes per day (85). After 2 l/2 years of observation, the
incidence of CHD in Puerto Rican men was only half that observed
in Framingham, and the difference between smokers and nonsmok-
ers was not significant (222). However, after 8 l/4 years of
observation and the accumulation of approximately four times as
many cases, cigarette smokers had a significantly higher incidence of
MI than did nonsmokers; this was true both for those living in the
rural areas and for those in the urban areas when considered
separately (246').

Japanese Americans have an incidence and mortality from CHD
that is intermediate between the very low rates in Japan and the
high rates in white Americans (X$222,284). The explanation for this
gradient of CHD with migration has been investigated by the Ni-
Han-San study centering on a cohort of Japanese Americans living
in Hawaii (14, 222).
The target cohort of the Honolulu heart study was all noninstitu-
tionalized men of Japanese ancestry born between 1900 and 1919
who were living on the Island of Oahu in 1965 (130). Initial
examinations were conducted between 1965 and 1968, and participa-
tion was obtained from 72 percent of the identified men who were
eligible (7,705 men aged 45-69 years and free of CHD). CHD
incidence was observed by followup examination (at 2 and 6 years)
and by intensive community and mortality surveillance activities.
The 2-year incidence of MI and death from CHD was only half of that
observed in Framingham men, but was significantly higher in

78


cigarette smokers (85). The relative risk for those smoking 21 or
more cigarettes per day was six times higher than for nonsmokers
(221). At 6 years of followup, the risk of MI and death from CHD, but
not of angina pectoris, was strongly related to cigarette smoking, and
the risk increased in proportion to the number of cigarettes smoked
per day (130).

CHD death rates are lower in Great Britain than in the United
States by about one-fourth, and those in Norway are substantially
lower than either. In 1962 the National Heart Institute and the
National Cancer Institute in the United States, the London School of
Hygiene and Tropical Medicine, and the Norwegian Cancer Registry
undertook a study to examine differences in death rates among
migrant populations to the United States (223). Native-born Ameri-
cans were included in the study for comparison. Approximately
32,000 British migrants and 18,000 Norwegian migrants aged 30 to
74, residing in 12 States, were sent questionnaires. For native-born
Americans, similar questionnaires were sent to a subsample of
23,CKKl white persons drawn from a 1961 National Health Survey
sample covering the same geographic areas. A total of 7,895 CHD
deaths occurred (3,193 British, 1,213 Norwegian, and 3,489 native-
born deaths). Norwegian migrants exhibited the lowest CHD death
rates. British migrants' rates were about equal to those for native-
born Americans.

The decedent's cigarette smoking status as of October 1962 was
requested from the next of kin, Smoking status from October to the
end of the study period (1963-1966) was presumed not to be altered.
Mortality ratios for CHD were significantly elevated among smokers
compared with nonsmokers, particularly at the younger ages. The
ratios were 1.9 or greater for both males and females at age 45 to 54
years and decreased somewhat with age. CHD death rates among
smokers demonstrated little difference between the three groups,
and ratios were greater for female than male smokers in all but two
instances. Table 3 provides a summary of these mortality ratios by
migrant class, age, and sex.
In summary, a number of ethnic groups in the United States have
lower rates of CHD, but even in these populations, the risk of MI and
CHD death are significantly higher in smokers than in nonsmokers.

Studies in Other Countries

Cigarette smoking has been found to be related to the incidence of
CHD in other countries where long-term followup of large, defined
cohorts has been performed. For some cohorts, early data analyses
with relatively few cases have not shown significant differences, but
later followup analyses with large numbers of cases have usually
demonstrated a positive relationship between cigarette smoking and
CHD.

79


TABLE 3.4ronary heart disease mortality ratios (smoker
      versus nonsmoker) of British and Norwegian
      migrants to the United States and native-born
      Americans by age, sex, and cigarette smoking
        stahll3

Aae and mortality ratio (smoker vs. nonsmoker)

Group                 45-54         55-64       65-74


British migranb

Malea                 1.9           1.3         1.3
Females               2.9           2.4         1.7

Norwegian migrants

Males                 2.3           1.5         1.6
Females               -1           2.3         2.0

    Native-born Americana

     Males
     Females


NOTE: All nonsmoker ratice are 1.0.
`Les.thm 1odeaths.
SOURCE Ra@ WZ0.

2.3           2.7         1.4
2.6          2.0         1.3

An international study conducted in seven countries observed
large differences in CHD incidence and mortality among 16 cohorts
of men aged 40 to 59 at baseline examination in the United States,
Europe, and Japan (143). The United States cohort was the railroad
men described above in the Pooling Project (214). This cohort
experienced a relative risk of CHD with cigarette smoking that was
similar to that of other U.S. cohorts of white men (Table 1). The
other cohorts of men were residents of Yugoslavia (Dalmatia,
Slovenia, Velika Krsna, Zrenjanin, and Belgrade), Japan (Ushibuka
and Tanushimaru), Finland (districts in the east and west), Italy
(Crevalcore, Montegiorgio, and railroad men in Rome), the Nether-
lands (Zutphen), and Greece (Crete and Corfu). In all, 12,763 men
were examined, of whom 12,509 were free of evidence of coronary
heart disease at baseline examination. During the 10 years of
followup, 1,512 deaths occurred from all causes, and 413 were
attributed to coronary heart disease.

Ten-year CHD death rates were less than 75 per 10,000 for the
cohorts living in Crete (Greece) and in Croatia (Yugoslavia) and for
the two cohorts in Japan; however, for the cohorts of east and west
Finland, the U.S. railroad men, Zutphen (the Netherlands), and
Belgrade (Yugoslavia), the CHD death rates were 250 per 10,000 or
higher. Although the cohorts participating in the Seven Countries
study were not selected as representative of their countries, the CHD
death rates of cohorts grouped by country were highly correlated


with the CHD death rates for men of the same ages reported in the
vital statistics of these countries.

Cigarette smoking was strongly related to CHD mortality in those
cohorts with both high CHD death rates and relatively large
numbers of cases for analysis. For example, among U.S. railroad
men, CHD death rates were about three times as high in men who
smoked 20 or more cigarettes per day compared with men who had
never smoked or men who had stopped smoking. Furthermore, the
association between CHD and number of cigarettes smoked daily was
stronger in the cohorts with high CHD mortality than in the cohorts
with low CHD mortality. Among northern European men as well as
United States railroad men, the lo-year age-standardized CHD death
rates increased significantly with the level of cigarette smoking, and
the risk for northern European men smoking 20 or more cigarettes
per day was more than four times greater than for men who had
never smoked (Figure 2). For the southern Europeans, however,
differences were only twofold and not statistically significant. Age-
standardized rates for death from all causes, respiratory tract
cancer, and neoplasms were also more closely related to the number
of cigarettes `consumed in northern Europe than in southern Europe,
and for all deaths the differences were significant in both regions.

The lO-year incidence date provide a larger number of cases for
analysis, as deaths from CHD represented only about 20 percent of
the total CHD incidence in the Japanese and European cohorts.
Definite CHD was observed in 351 of the 9,780 men during the
followup period. The highest rate (11 percent) was observed in east
Finland, and the lowest (0.3 percent) was observed in Crete (Table 4).
Rates within countries were similar in general, but in Greece the
rates were higher in Corfu than in Crete; in Finland the rate in the
eastern district was double that in the western district; in Yugosla-
via, the Serbian cohorts in Belgrade and Zrenjanin were similar, but
in the farming village of Velika Krsna the rate was only half as high.
The Japanese cohorts were small and the incidence too low for
evaluation of the influence of smoking. Only 19 men in the two
Japanese cohorts were observed to develop definite coronary heart
disease during the 10 years of followup.

To provide greater stability in analyses, the European cohorts
were grouped together by region: the three cohorts in Finland and
the Netherlands, the five cohorts in Yugoslavia, and the three
Italian cohorts with the two Greek cohorts. The lO-year CHD
incidence in Finland and the Netherlands was significantly related
to the number of cigarettes currently smoked, and former smokers
had a CHD incidence that was twice that of those who had never
smoked (Figure 3). In Yugoslavia, the CHD incidence in smokers was
nearly twice that of those who had never smoked. Also in Yugosla-
via, the CHD incidence was nearly three times higher for those

81


16.2%

NEVER   STOPPED     10/d        10-19/d

N--357    N- 416    N-436        N=712

                SMOKING HABIT

  5.6%
gg
> 20/d

N=446

CHD

DEATHS

FIGURE 2.-Age-standardkd N-year death rates from all
       causes and from coronary heart disease of
      men in northern Europe (east and west
      Finland and Zutphen), classified by smoking
      habit at entry; all thee of cardiovascular
      disease at entry
SOURCE Keys U4.9.

smoking 20 or more cigarettes per day at entry compared with those
who had never smoked, but no significant differences were observed
between former smokers and never smokers (Figure 4). In the Italian
and the Greek cohorts, the contrasts were less marked (Figure 5).
The incidence of CHD was significantly higher in those northern
Europeans and Yugoslavs smoking 10 or more cigarettes per day
compared with lighter smokers, never smokers, or ex-smokers. The
rates were also higher in the Italian and Greek cohorts, but were not
statistically significant.

Observation of the Italian cohorts has continued, and 20-year
followup data were recently reported (126). With the substantially
larger number of cases, a significantly higher incidence of CHD was
observed in cigarette smokers than in nonsmokers. The 20-year
incidence of CHD increased from 90 per 1,000 in those who had never
smoked to 159 per 1,000 in those smoking 10 to 19 cigarettes per day.
The incidence in the highest smoking category (20+ cigarettes per
day) was slightly lower (140 per 1,000) than the rate in those
smoking from 10 to 19 cigarettes per day.

A number of prospective studies of CHD have been performed in
the United Kingdom. Those with mortality followup-for example,

82


TABLE 4.-Ten-year incidence of coronary heart disease
      among men free of cardiovascular disease at
      entry (age-standardized rate per 10,000)

Cohort

            Hard CHD             Any CHD

N       N      Rate      SE       N      Rate     SE

JMmatia       662       13     165       52       40     629      94
Slav&a        880       18     253       60       40     561       88
Tanusbimaru     504        8     148       5-4       20     354      82
East Finland     728       71   1,074      115      201    2,868      166
West Finland     808       45     539       80      129    1,582      129
CEValCOre      956       43     450       67       105    1,080      100
M0hgi0rgi0     708       22     353       69       64     986      111
Zutphen        845       45     513       76       91    1.066      106
Ushibuka       496       11     204       63       23     458      94
ClFk         655        2     26       20       13     210      56
corfu         525       17     337       79       37     688      110
Rome railroad    736       z-5     357       68       57     786       99
Velikn Krsna     487        6     132       52       21     452      94
Zrenjanin       476       12     239       70       37     715      118

TOti       . 9,780      351     369.9 '     19.1      913     943.8 '     29.6

' Mean of the cohort rate weighti by the number at rink in each cohort.
8OlJRCE Keyn (143).

the British physicians study and the Whitehall study-are reviewed
below under the heading Prospective Mortality Studies.

Morris and Kagan and associates (185) investigated differences in
CHD in drivers and conductors working on London buses. Among
other positive associations, those who smoked were found to have a
higher 5year incidence of CHD than those who did not smoke.

In 1977 Morris, Marr, and Clayton (186) reported followup on
workers who were 30 to 67 years of age at examination. The sample
was of 337 men living in London and in southeast England who had
participated in a `I-day individual dietary survey. By 1976, 45 of
these men had developed clinical CHD. Among the CHD cases,
cigarette smoking was significantly more frequent than expected,
and this was true for each occupational group: bank staff, bus
drivers, and bus conductors. Estimated relative risks (compared with
nonsmokers) were 3.5 for those smoking 11 to 20 cigarettes and 4.7
for those smoking more than 20 cigarettes (88).

The Belfast practitioner's study was initiated in 1964, using
experienced, self-selected practitioners to observe the operation of
risk factors in middle-aged men who were community residents (88).
The sample comprised all men born in the lo-year period 1909-1918
(age 45 to 54 at the beginning of the study) who were registered in six
cooperating group practices. Examinations were performed in 69
percent of the designated population sample. Among the 1,202
subjects free of CHD at the initial examination, 104 developed CHD


19.1%

14 6%

NEVER   STOPPED

N 357    N 418

10/d        10-19/d

N -- 436        N 712

SMOKING HABIT

  9 7%
1
  ? 20/d
N = 446

OTHER
CHD

HARD
CHD

FIGURE 3.-Age-standardized lo-year incidence rate of

      coronary heart disease of 2,369 men in
     northern Europe (east and west Finland and
     Zutphen), classified by smoking habit at entry
      and then free of cardiovascular disease
SOURCE: Keys (14.3).

during the &year period of followup. MI occurred in 55 (15 fatal),
cardiac ischemia in 5, and angina pectoris in 49. Current tobacco
consumption, total years of smoking, and total tobacco consumption
were significantly higher in the cases with CHD than in the overall
population sample.

The Stockholm prospective study examined and followed men and
women attending a health survey center in 1961 and 1962 (26). This
sample was not a randomly selected population sample of Stockholm,
but the incidence of myocardial infarction was similar to that of the
Stockholm county population (27). A principal objective was to
examine the relationships of fasting plasma triglyceride and choles-
terol values to the future development of CHD. In analysis of g-year
followup data for 3,168 men, the incidence of MI and death from
CHD with all ages combined was about fourfold higher for smokers
than for nonsmokers (26). The difference was statistically significant.
Risk factors for MI were evaluated in 3,189 men, among whom 130
experienced myocardial infarction during 14 years of followup;
cigarette smokers experienced nearly three times the incidence of

84


6.0% r

OTHER
CHD

HARC
CHD

NEVER

N-881

STOPPED 10/d    lo-1916

N 367 N=213    N- 771

   SMOKING HABIT

,20/d

N = 565

FIGURE 4.-Age-standardized lo-year incidence rate of
      coronary heart disease of 2,797 men in
     Yugoslavia (Dahnatia, Slavonia, Velika Krsna,
     Zren@.nin, and Belgrade), classified by smoking
      habit at entry and then free of cardiovascular
        disease
SOURCE: Keys u4.3.

MI experienced by nonsmokers (27). In analysis of risk factors and
death during 14.5 years of followup of 3,466 men and 2,738 women,
death due to ischemic vascular disease (principally CHD and stroke)
was significantly related to smoking in men and in women (22).

The Section for Preventive Medicine at the University of Goteborg
has observed the relationship of smoking and other risk factors to
the incidence and the mortality from CHD in several studies of the
Giiteborg population (278). In 1963 a 30 percent sample of men born
in 1913 was examined (at age 50) and followed; 88 percent participa-
tion was obtained, and 834 were found to be free of CHD. In 1970 a
primary prevention trial was begun for examination of 10,000
intervention and 20,000 control subjects 47 to 54 years of age.

The 1913 birth cohort experienced a markedly excessive risk of MI
with smoking during its first 4 years of observation (275); more than
90 percent of those who had myocardial infarctions were current
smokers in comparison with 55 percent of those who did not.
Subsequent analyses with Byear followup have confirmed this
strong relationship between smoking and CHD; the incidence of fatal


  5 1 %








  2 4%
~

6 9%          7 0%     6.9%
1 I

OTHER

Cl-ID

HARD

CHD

NEVER STOPPED   1 O/d   10-19/d    > 20/d

N-849   N=521 N=5a2   N-830    N=769

          SMOKING HABIT

FIGURE 5.-Age-standardized IO-year incidence rate of
       coronary heart disease of 3,551 men in Italy
      and Greece (Crew&ore, Montegiorgio, Rome
       railroad, Crete, and Corfu), classified by
       smoking habit at entry and then free of
        cardiovascular disease
SOURCE: Keys W~J.

and nonfatal MI increased with the quantity of daily tobacco
consumption. Pipe and cigar smokers experienced an increased risk
similar to cigarette smokers (278). No significant difference was
observed for angina pectoris by smoking status.

Prospective data obtained in the Norwegian Vegetable Oil workers
study beginning in 1965 have been analyzed with respect to risk
factors measured at the baseline examination and the incidence of
CHD during the following year (199). The defined sample comprised
16,608 men born between 1905 and 1916 who were employed in
industries throughout Norway. Randomization to a control group or
to a group receiving linolenic acid was performed in 13,000 men 50 to
59 years of age who were well and agreed to participate. Industrial
physicians participated in the provision of baseline data and in the
ascertainment of cases.

Fewer than the expected number of deaths occurred, but the
number of deaths from CHD was intermediate between that
expected on the basis of the Oslo and the total Norwegian popula-
tions. MI was observed in 162 men during the followup; there were
no significant differences in CHD incidence attributable to treat-
ment with linolenic acid.

86


TABLE 5.-First diagnosed myocardial infarction (probable
      + possible) in relation to cigarette consumption

Rates percentage

     5 percent sample                      Adjusted for age and
                 MetI   Infarctions
Cigarettes       MtWl     at   diagnmedin          Weight/height Elevated sedi-
per &Y   No. choleateml risk'   otx3el-v. yr   Unadjusted     ratio    mentation rate

None    228    239.6   5,693      37
l-4      40    244.1   1,094

5-14     162    245.2   3,679

15-24     47    240.7   1,214 f

25+      9    236.3    191       a 4.19 :~~~~l.% 4.15 :I~;;~..., ;f$l.m
Unknown  126    237.0   4.304      42      96

612   241.0 16,175     162     1.00

' Men with no previous infarction diagnwia
SOURCE:Natvigetal.(199).

The incidence of MI increased markedly with the level of cigarette
smoking; the relative risk of MI for men smoking 25 cigarettes or
more per day was over six times that of nonsmokers (Table 5).
Smoking was less strongly related to angina pectoris (199).
The Oslo study examined and followed 14,000 men aged 40 to 49
who were free of cardiovascular disease and diabetes mellitus at
examinations in 1972 and 1973. During 4 2/3 years of followup,
searches of discharge records of Oslo hospitals and of death
registration by the Oslo health department were used to identify
nonfatal and fatal first MIS; sudden deaths without confirmation of
MI were excluded (117). The incidence of MI in nonsmokers (never
and ex-smokers) was only 40 percent of that in cigarette smokers
(117).

A ICyear prospective study of men examined in 1964 at age 50 in
Glostrup County, Denmark, was reported by Schroll and Hagerup
(240). Out of a total population sample of 514 men, 436 were
examined; followup for mortality and myocardial infarction was
obtained in virtually all patients. This population resided in a
middleclass suburb in the western part of Copenhagen and was
thought to reflect the change in Danish society from principally
agricultural to industrial and to be representative of the total
Danish population in 1964. During the l&year followup, 31 men
developed first myocardial infarctions, an incidence of 7.1 percent.
Fatal MI occurred in 16, and 15 experienced a nonfatal MI. A
significantly higher risk of myocardial infarction was observed in
those who smoked tobacco at baseline examination. The incidence
was as follows: nonsmokers, 6 percent; smokers of 1-14 g per day, 6
percent; smokers of 15-24 g per day, 14 percent; smokers of 25 g or

87


TABLE 6.-Seven-year incidence of fatal and nonfatal first
      myocardial infarction in 3,772 smokers by
      category of smoking habit and 440 men who
       have never smoked

   Never smokera

   Cigarette smokera
     Total
    > IO/day

   Cigar smokem
     T&d
    > 3/&y

   Cheroot amokera
     Total
    >wday

   Pipe smokers
     Total
    >6ldaY

SOURCE: GynteIberg et al. (91).

Myocardid infarction
per 1,cao men


     17



     36
     43



     42
     35



     48
     72



     26
     34

Relative risk



  1.0



  2.1
  2.5



  2.4
  2.1



  2.8
  4.2



  1.5
  2.0

more per day, 19 percent. Thus, the heavy smokers experienced an
incidence of MI that was three times that of nonsmokers.

The incidence of fatal and nonfatal first myocardial infarctions in
men was observed in 3,772 smokers and 1,440 nonsmokers who had
baseline examinations in 1970 and 1971, were aged 40 to 59, and
were employed in public and private Copenhagen combanies (91).
The initial response rate was 87 percent. Fatal MI was ascertained
during 7 years of followup from death certificates; nonfatal MI was
ascertained from 5-year followup by questionnaires (79 percent
response rate) and from hospital records. Myocardial infarction
among t.he nonresponders was included if recorded in the Copenha-
gen heart register, which registered all inpatient cases of myocardial
infarction in the Copenhagen area.

During the followup period, 41 men free of coronary heart disease
at baseline examination died from a first myocardial infarction and
129 men had a nonfatal first myocardial infarction. Overall, the
relative risk of myocardial infarction was twice as high in smokers
as in nonsmokers. The relative risk of fatal and nonfatal first MI in
smokers compared with never smokers was as follows: cigarette
smokers of more than 10 per day, 2.5; cigar smokers of more than 3
per day, 2.1; cheroot smokers of more than 6 per day, 4.2; and pipe
smokers smoking more than six times per day, 2.0 (Table 6). In this
study heavy cheroot smokers experienced the highest risk of MI.
Finnish men aged 50 to 53 years, insured for 10 or more years with
a large Finnish life insurance company, were examined in 1965 and


1966; the examined cohort (1,648 men) consisted of 40 percent of
those respondents who had complete data (207). Risk factor data
included serum lipids after a 1Zhour overnight fast. A smoker was a
person who smoked cigarettes regularly every day; pipe and cigar
smokers as well as ex-smokers were excluded from the analysis of
smoking effects. With these criteria, 567 men were smokers and 982
were nonsmokers. During 7 years of followup, all deaths were
identified, and cause of death was determined from death certificate
files. Cardiovascular deaths included those due to coronary heart
disease, heart failure, cardiac arrhythmia, cerebrovascular acci-
dents, and sudden deaths. Cigarette smoking was associated with
increased cardiovascular mortality independently of other risk
factors.

The North Karelia, Finland, project was started in 1972 to
mobilize community intervention for health promotion and disease
prevention (235). Substantial risk factor data were obtained from
random population samples of two rural counties in eastern Finland.
Analysis showed a strong relationship between the major risk factors
at the baseline examination (smoking, hypertension, and serum
cholesterol) and the subsequent development of CHD. The relation-
ship of smoking to the incidence of acute myocardial infarction was
independent of the other risk factors (235). Eastern Finland had the
highest incidence and mortality from CHD in the world, but the
rates have declined substantially coincident with decreasing preva-
lence of these risk factors (235).

A large defined cohort of men aged 42 to 53 years, born in France
and employed in the Paris civil service, was observed for an average
of 4 years (range, 2-7 years) following a baseline examination for risk
factors in 1965 (218). Those with definite Q waves on initial
examination were excluded, leaving 7,453 men at risk. Criteria for
CHD were based on those of the Pooling Project and the London
Whitehall study (51,218).

The overall incidence of CHD was 5.1 per 1,000; MI and CHD
deaths accounted for 60 percent of the cases, while 40 percent of the
cases were due to angina pectoris. Cigarette consumption, hyperten-
sion, hypercholesterolemia, and clinical diabetes mellitus were
independently related to the incidence of coronary heart disease.
Men in their fifties had a strikingly lower incidence of CHD than
men in the United States; this is consistent with French mortality
statistics. In univariate analysis, the incidence of CHD was progres-
sively higher with increasing number of cigarettes smoked per day
among inhalers; noninhalers had an intermediate risk (Figure 6)
(218).

A defined cohort of 10,232 Israeli civil servants and municipal
workers (86 percent of the defined sample) aged 40 years and above
were first examined in 1963 and followed for fatal and nonfatal MI

89


w
Y
w
0
0
g
2
2                         22
5    51   -a---

TOBACCO         NON -    EX-   NON-

CONSUMPTION    SMOKERS SMOKERS INHALERS INHALERS

c       Tobacco Smokers : 61 8%
      16.2 Cigarettes per day

NON -     NONINHALERS         INHALERS

SMOKERS (  ' < 10   10-15   215  I  c 10   10-19   220  I

1 3.4 1 4.3 1 4.5 1 4.6 1 5.0 1 6.9 1 86 1

21.1     8.0    5.8    11.3    4.3    12.7    197
                                    ,
14.0     7.7    5.6    108    4.0    17.3    30.7


and sudden cardiac death (177). Reexaminations were performed in
1965 (97.5 percent reexamination rate) and again in 1968 (98 percent
reexamination rate). After 5 years of followup, 9,794 were found to
be free of myocardial infarction and there were 427 incidence cases
(44 per 1,000). Of these 170 (40 percent) were unrecognized myocardi-
al infarctions, half of which had been asymptomatic. The incidence
of CHD was significantly related to the daily use of cigarettes, and
the relative risk was greater at younger age (81, 176). In multivariate
analysis the relationship of smoking to CHD became stronger when
other variables were taken into account (81).

In summary, there were marked differences in CHD rates for the
populations in different countries and different geographic locations.
The relationship between cigarette smoking and CHD was more
pronounced in those countries with high CHD rates. However, even
in those countries with low CHD rates the evidence increasingly
suggests a relationship between cigarette smoking and CHD.

Cigarette Stoking and Other Risk Factors

The strong relationship between cigarette smoking and CHD has
been shown to be independent of the other major risk factors in a
number of well-designed epidemiologic studies. A number of other
factors have also been described as having an influence on CHD risk
(119, 124, 133, 159, 214, 251). The magnitude of excess risk observed
with these minor risk factors has usually been small in comparison
with the excess risk observed with the major risk factors (44 68,143,
214).

The independence of the relationship between cigarette smoking
and CHD risk has been observed in a straightforward fashion. The
excess risk of CHD in smokers compared with nonsmokers exists at
both high and low levels of the other risk characteristics associated
with CHD. Also, extensive experience has shown that confounding
influences can be separated out with multiple logistic analysis (147).
Such analyses with adjustment for potentially confounding influ-
ences have been made for many characteristics in many of the
studies cited in this Report. They include hypertension, elevated
serum cholesterol, obesity, family history of CHD, diabetes mellitus,
physical inactivity, certain personality characteristics, psychological
stress, socioeconomic status, and intake of alcohol and coffee. When
the data have been sufficient for adequate analysis, excess risk of
CHD has been observed in cigarette smokers independent of the
presence (or absence) of other CHD-risk-conferring characteristics.
Such observations, made in a very large number of studies, indicate
that it is the cigarette smoking habit itself that confers high risk of
CHD rather than an associated characteristic (18, 40, 43, 45, 67, 94,
96,143,214,244,257).

91


Behavioral characteristics other than cigarette smoking have been
considered important in relation to CHD, but relatively few studies
of behavioral characteristics have been conducted in the context of
standardized examinations of defined cohorts with consideration of
potentially confounding variables. The Western Collaborative Group
Study (WCGS) in California met these conditions, and therefore this
study will be considered in some detail (24, 66, 71).

In the WCGS (229), 3,154 employed men examined in 1960-1961
and found to be free of CHD were characterized for behavioral
pattern by a structured interview developed for this purpose and
administered by trained interviewers. From tape recordings of
interviews, reviewers who had no knowledge of the subjects' history
or other characteristics classified the men as Type A personalities
according to their manifestation of enhanced aggressiveness, ambi-
tiousness, competitive drive, and chronic sense of time urgency. The
men were classified as Type B personalities if they manifested less of
the Type A characteristics and were more calm and relaxed. The
Type A pattern was determined in 1,067 and the Type B pattern in
1,182 of the subjects at risk. Previously recognized risk factors were
also measured. Mortality surveillance was obtained, and final
followup examinations were performed for this population in 1969.

With an average followup of 8.5 years, there were 140 deaths; 31
were attributed to an initial CHD event, 19 to a recurrent CHD
event, and 90 to non-CHD causes, including 7 who had developed
CHD prior to the onset of the non-CHD terminal illness. CHD
incidence was observed in 257 cases. Autopsy examination was
performed in 24 of 31 decedent cases; acute coronary thrombosis or
acute myocardial infarction was obse~ed in 23, and severe diffuse
coronary atherosclerosis was observed in 1 case.

CHD death was ascertained in 34 Type A and 16 Type B subjects.
The CHD death rate per 1,090 person-years was 2.92 for Type A and
1.32 for Type B subjects.

As would be expected from other studies, the CHD incidence cases
were older, smoked more cigarettes, were heavier, and had higher
systolic and diastolic blood pressures, higher serum cholesterol and
triglyceride levels, and higher ratios of beta to alpha lipoproteins.
Other positive associations were a history of diabetes mellitus,
parental history of CHD, low level of education, and low level of
leisure time activity. Occupational physical activity and annual
income were not significantly related to CHD incidence.

Cigarette smoking was significantly related to the incidence of
CHD, and the risk was higher with increasing numbers of cigarettes
smoked at the time of the baseline examination; the relative risk
with smoking in older men was as great as in the younger men.
By personality patterns, those who had been characterized as Type
A had an incidence of CHD that was twice as high as the incidence in

92


those who had been characterized as Type B. This difference
persisted after adjustment for the other risk factors. In both deciles
of age at entry (3M9 and 50-59), the relative risks for current
cigarette smokers were higher than for nonsmokers in both Type A
and Type B personalities (Table 7) (229).

A multiple logistic equation describing the relationships of the
conventional risk factors to the incidence of CHD in this study was
similar to the Framingham study equation (25). The coefficients for
the two studies were not significantly different. Cigarette smoking,
serum cholesterol, and systolic blood pressure were independent risk
factors and were significantly related to the CHD incidence. The
total number of cases and the number by decile of risk were similar,
using the equation developed from the WCGS data and the equation
from the Framingham study, indicating good relative agreement in
risk prediction. In the WCGS analysis, the Type A behavior pattern
was found to predict the incidence of CHD independently of the
other risk factors. The additional predictive power of the Type A
characteristic in the multiple logistic equation was related to some
extent to higher levels of the conventional risk factors in Type A
individuals.

Evidence for the importance of personality characteristics was also
observed in the Framingham cohort and in studies by the French-
Belgian Collaborative Group (66, 104). In these studies as well, the
effect of cigarette smoking on CHD remained independent of
personality characteristics.

In summary, the evidence from studies with adequate data have
clearly demonstrated that cigarette smokers experience higher risk
of CHD regardless of their other behavioral characteristics.

Interaction of Cigarette Smoking and Other Risk Factors

A number of pharmacologically active substances are present in
tobacco smoke, and a number of direct physiologic effects have been
observed (262) and are reviewed elsewhere in this Report. Recently,
evidence has accumulated of an effect of smoking on lipoproteins.
Recent population studies have demonstrated an inverse relation-
ship between high density lipoprotein cholesterol (HDL-C) and the
incidence of CHD (80, 84, 217). Population groups known to be at
lower risk for CHD have been observed to have relatively high levels
of HDL-C. Thus, HDLC levels have been higher in women in
comparison with men, in black men in comparison with white men,
and in men in Japan in comparison with men in the United States (5,
106, 146, 260). An adverse influence of cigarette smoking on the
levels of HDL-C and other plasma or serum lipoprotein components
has been observed in a number of populations. The several classes, or
fractions, of these lipid-protein complexes have different functions

93


$  TABLE 7.-Prospective history and findings by behavior pattern


                                    Age 39-49 years                         Age 50-59 years
                          Subjects       Subjects         Rate of        Subjects       Subjects        Rate of
                                 at risk        with CHD'         CHD =           at risk         with CHD         CHDP

                         Type 5w     Type Type     Type  Type     Type Type     Type  Type     Type Type
                                A     B        A     B        A     B        A     B        A     B        A B


   Number of subjects              1,067   1,182      95 50       10.5    5.0       522 383       83 29       18.7    8.9

   Parental history of CHD
     YW                         214    197      23 15       12.6    9.0       103    64       20     1       22.8   12.9
      No                         a53    935      72    35        9.9    4.2       419    319       63 22       17.7    8.1

   Smoking habits
     Never smoked                   221    315      11     8        5.9    3.0        90 89       10     5       13.1    6.6
    Pipe or cigar                   191    216       11     6        6.6    3.3        81 78       17     2       24.7    3.0
     Former cigarette                 110 129      11     5       11.8    4.6        91 41       10     2       12.9
    Current cigarette                                                                           5.1
                                545    522      62 31       13.4    7.0       260    175       46 20       20.8   13.4

   Current cigarette usage
     None                       522 660      33 19        7.4    3.4       262 208       37     9       16.6    5.1
     I-15/day                      95    119       3     8        3.7    7.9        65 43        8     1       14.5    2.7
    2 16/day                      450    403      59 23       15.4   11.4       195    132       33 19       22.9   16.9

   Systolic blood pressure, mm Hg
      <I20                        264    328       17     4        7.6    1.4        95 80        7     4        a.7    5.9
      120-159                       771 826      69 43       10.5    6.1       381 283       64 21       19.8    8.7
     2160                        32 28      9. 3       33.1   12.6        46 20       12     4       30.7   23.5

   Diastolic blood pressure, mm Hg
     c95                        970  1,100      81    45        9.8    4.8       448 344       64 25       16.8    8.5
     295                         97 82      14     5       17.0    7.2        74 39       19     4       30.2   12.1


TABLE 7 .-Continued.

                                Age 39-49 years                           Age 50-59 years
Serum cholesterol, mg/lOO ml
< 220                       486    607      24    11        5.6    2.1        211    146       20     6       11.2    4.6
22cL259                       352    376      32    20       10.7    6.3        179    142       36    10       23.7    8.3
2260                        226    195      39    19       20.3   11.5        130    90       27    13       24.4   17.0

Fasting serum triglycerides, mg/lOfl ml
<loo                       252    346       12     I        5.6    2.4        151    99       16     5       12.5    5.9
loo-176                       500    536      48    22       11.3    4.6       236    170       37    11       18.3    7.6
2 177                        247    249      30    20       14.3    9.6        114    98       26     9       26.8   10.6

Serum &la-lipoprotein ratio
<2.36                        733    836      57    24        9.1    3.4       323    263       43    18       15.7    8.1
> 2.36                        331    343      38    26       13.5    8.9        196    117       39    11       23.4   11.1


I Coronary heart disease
`Average annual rate/l.000 subjects at risk. Difference in rates between type A and type B was tested fur significance by Mantel.Haenszel ye, wth adlustment for factors indicated For each factor,
the adjusted asswiatwn between behavior pattern and CHD inadence is aignficant at p < .OOl.
SOURCE: Rosenman et al. (2291.


in lipid metabolism (41, 78, 213). Most of the cholesterol in the
plasma is complexed in the low density lipoprotein cholesterol
(LDLC) fraction, which appears to have atherogenic properties,
while a lesser proportion of cholesterol is complexed with high
density lipoprotein cholesterol (HDL-C), which appears to have
antiatherogenic properties (82, 100, 180,230).

The HDLC levels in the cigarette smokers in the studies cited
above have been found to be significantly lower than in nonsmokers,
and in some studies the concentration of HDL-C has been found to
correlate inversely with daily cigarette consumption. This relation-
ship does not appear to be confounded by other factors. Thus, HDGC
is inversely correlated with indices of obesity, such as relative
weight, and positively correlated with alcohol intake; adjustment for
these characteristics increases the difference in HDLC between
cigarette smokers and nonsmokers (79, 99, 105, 212). Additional
studies are needed to investigate the complex mechanisms whereby
cigarette smoking depresses HDL-C levels and increases the risk for
CHD.

Blood pressure increases transiently after smoking, mediated by
an adrenergic mechanism (37); however, most surveys have demon-
strated a small negative association between smoking and blood
pressure (263). Recent investigations of this relationship have
adjusted for the covariables of weight and alcohol.

In an examination of the offspring of Framingham heart study
patients and their spouses, multivariate analysis demonstrated a
negative correlation between smoking and blood pressure, especially
diastolic blood pressure, that was similar to the original Framing-
ham cohort (102). A cross-sectional survey of employed men in
Australia also demonstrated that, adjusted for weight and alcohol,
diastolic blood pressures were slightly lower in smokers (5). In the
cohort of the Lipid Research Clinics prevalence study, the small
negative correlation between smoking and blood pressure was more
apparent for systolic blood pressure (3s). In the cross-sectional and
prospective analyses of several study populations in Chicago, how-
ever, smoking was associated with higher blood pressure, especially
systolic blood pressure (52, 53). Alcohol consumption was not
included in these multivariate analyses.

If smoking is associated with a slightly lower blood pressure, a rise
in blood pressure might be predicted after smoking cessation,
especially if smoking cessation is followed by weight gain, but recent
studies have not supported this concern. In the Kaiser population,
smoking cessation has been associated with only a small weight gain
(70). Effects on blood pressure were also small and inconsistent
among subgroups. In the Multiple Risk Factor Intervention Trial,
smokers who quit lost less weight than those who did not quit (239);
controlling for weight, there was no increase in blood pressure with

96


smoking cessation. These studies show that there is little, if any,
adverse effect on risk factors following smoking cessation. The
benefits of smoking cessation for health in general, and cardiovascu-
lar health in particular, far outweigh any objectively observed
disadvantageous effect.

Although epidemiologic studies do not suggest that smoking
causes high blood pressure, concern has been expressed that it may
exacerbate the clinical course. Two casecontrol studies in Great
Britain (20, 125) and one in New Zealand (57) compared smoking
patterns in patients with malignant or accelerated hypertension
with those with benign hypertension. In all three, statistically
significant associations between smoking and the more severe
manifestations of hypertension were demonstrated.

A recent clinical study directly observed the blood pressure effects
of smoking in mild hypertensives (65). When 16 habitual smokers
abstained from cigarettes, their blood pressure was significantly
lower than usual. Smoking two cigarettes resulted in a blood
pressure increase of 10/8 mm Hg that lasted approximately 15
minutes. Combining coffee drinking with smoking led to an increase
in blood pressure to their usual levels that lasted 2 hours.

For the most part, recent surveys have supported the traditional
finding of a small negative association between smoking and blood
pressure. Smoking cessation is not associated with a significant
increase in blood pressure, especially if weight gain is avoided.
Preliminary studies suggest that smoking increases the likelihood of
developing malignant hypertension. Prospective and intervention
studies are indicated to further investigate this phenomenon.

These findings can be translated into clinical recommendations: (1)
nonhypertensive smokers can be assured that smoking cessation will
not lead to high blood pressure, especially if weight gain is avoided,
and (2) hypertensive smokers should be warned that these two risk
factors are synergistic for cardiovascular disease and that the need
for risk reduction is increased. Smoking cessation will not complicate
the management of high blood pressure, and may reduce hyperten-
sive complications. Concomitant monitoring of weight during and
after smoking cessation is indicated.

Synergistic Effects of Cigarette Smoking When Associated
With Other Risk Factors

Evidence that the increase in CHD risk associated with smoking
may be greater when other risk factors are present than when they
are absent has been observed in several investigations. Figure 7
presents the data from the Framingham 12-year followup. The CHD
risk increases with increasing levels of blood pressure or serum
cholesterol, and at each level of these two risk factors the risk in

97


m Nonsmoker of cigarettes

0 Cigarette smoker       287
1

207

All
Frammgham
-
men

88-120 120-139140-159160-179180-300 96-193 194-220221-249250-534

SYSTOLIC BLOOD PRESSURE       SERUM CHOLESTEROL

FIGURE `I.-Cigarette smoking at levels of blood pressure
      and serum cholesterol, X-year incidence

NUlE Tbe contribution of cigarette amoking to risk of coronary beart diaeae appears to be independent of
other demonstrated rimk factors. At any level of blood pressure or enam cholesterol, cigarette smokers had an
excess risk, E-year ineideoce.
SOURCE: Knnnel(J3Zl.

smokers is greater than the risk in nonsmokers. However, the
increment of risk with smoking is not constant, but rather increases
with increasing levels of blood pressure or cholesterol. For example,
in Figure 7 the increment in risk in smokers with a systolic blood
pressure of 80-120 mm Hg is 32 (49 minus 17), while the increment
for smokers with a systolic blood pressure of 140-159 is 101 (150
minus 49). These data suggest that cigarette smoking interacts with
the other two major risk factors to produce a combined risk that is
greater than the sum of the risks that would have been produced by
the same risk factors acting separately.

Pooling Project data are also consistent with a synergistic effect of
cigarette smoking with hypertension and hypercholesterolemia
(Figure 8) (19). Evidence of synergism has been found in other studies
as well. In the Ni-Hon-San study, the effect of cigarette smoking on
CHD incidence in the presence of high serum cholesterol appeared to
be more than additive in Japanese Americans living in Hawaii. The
same effect was not observed in Japanese men living in Japan, who
in general had substantially lower serum cholesterol levels (221).
Evidence of synergism was observed in the Stockholm prospective
study and the Goteborg studies (Figure 91(27,278).

The synergistic interaction between the major risk factors may
also explain the observation that the actual incidence of CHD in

98


170

160

150

140

130

z   120

;   110
a
F   100

P   90
2   80

70

60

50

40

30 i     23

        54       54
I
           - 1
None    SM only    c or H   SMBC     C&H
of 3             only   Sh!?. H    (no SM)

103
-
        92

RISK FACTOR STATUS AT ENTRY'

-

FIGURE 8.-Major risk factor combinations, N-year

       incidence of first major coronary events, men
      age 30-59 at entry, Pooling project
' Definitiona of the three major risk factors and their symbols: hypercholestemlemia (0. 2 250 mg/dh; elevated
blood pressure (H). diastolic pressure 290 mm H&C; cigarette smoking (SW, any current use of cigar&tea at entry
NOTE: All rates were age adjusted by lo-year age groups to the U.S. white male population, 1980.
SOURCE: The Pooling F'mject Reseereh Gmup (214).

populations with low levels of serum cholesterol is substantially
lower than the incidence predicted by the multiple logistic equations
derived from the Framingham population (85, 91, 124, 143, 146). If
the synergistic interaction is present at low levels of the major risk
factors to the same degree as at high levels of risk factors, then the
impact of cigarette smoking on blood pressure in a low cholesterol
population would he expected to be smaller than that measured in
high cholesterol populations such as in the United States and
Western Europe. The multiple logistic equations do not separate out
effects that are due to synergistic interactions, and they distribute
the synergistic effects to the separate risk factors as though there
were no interaction among the risk factors in producing CHD. These
equations treat the risk factors as though the effects of the risk

99


FIGURE 9.-Risk factors for disease according to
      population studies

NOTE P = probability of nonfatal and fatal myocardial mfarction for a Sayearsld man during 13 years'
followup. 85.5 men bon in 1913
SOURCE: Wdhelmsen (278)

factors were additive. This limitation of the multiple logistic
equation technique leads to an overprediction of the number of CHD
cases to be expected in a population on the basis of smoking habits
when that population has very low levels of another major risk
factor such as serum cholesterol levels. Therefore, the very low levels
of CHD observed in cigarette smokers from populations with very
low serum cholesterol levels may reflect the synergistic nature of the
interaction among the major risk factors rather than the absence of
a CHD risk associated with cigarette smoking in those populations.
The possibility also exists that the cigarette smokers in some of these
populations have not been smoking for a sufficient duration or with
a sufficient intensity to manifest an effect on coronary artery
disease.

Analytical and methodological refinements appear to be needed
for better understanding of the biological significance of synergism
(147). Nevertheless, the evidence is clear that cigarette smoking
greatly increases the risk of CHD in individuals already at increased
risk because of other risk factors.

100



Risk of CHD in Women

Young and middle-aged women experience only one-fifth the
incidence and mortality from CHD of men (16, 40, 94, 102, 139, 244,
255, 283). These rates are steeply age dependent, and rates in young
and middle-aged women lag behind those in men by about 10 years.
Reasons for the sex-dependent. differences are incompletely under-
stood, but this protective influence of female sex is partly due to
differences in cigarette smoking and other behavioral variables (6,
58, 103,127, 128, 150, 151, 166, 170,203,204,210,227,234,243,244,
255, 267, 270, 280).

During the 1950s and 196Os, when the previously reported large-
scale investigations of smoking and CHD were conducted, relatively
few women smoked, and on the average, those who did began at an
older age,.smoked fewer cigarettes, and inhaled less than men (261).
During the past two decades, women have begun to smoke cigarettes
at younger ages, and their cigarette smoking habits have become
more like those of men (261). Observations by a number of
investigators have shown that the incidence of CHD in recent years
in women who smoke cigarettes is far greater than the very low rates
that are observed in women who do not smoke, and the incidence of
CHD in women who smoke heavily may be similar to the incidence
in men.

To observe the effect of cigarette smoking in women more
specifically, studies have been performed to take account of poten-
tially confounding influences on the occurrence of CHD. Slone et al.
(244) in Boston observed cases and matched controls from a large
number of U.S. hospitals between July 1976 and December 1977.
During this l&month period, 55 cases of nonfatal MI were identified
in women under age 50 who had not used oral contraceptives within
the month prior to admission and who had not been under treatment
for heart disease or related disorders. The estimated relative risk for
smokers compared with nonsmokers was 6.8 (p <O.OOl). In light
smokers (1 to 14 cigarettes per day) the relative risk was 4.4, and in
heavy smokers (more than 35 cigarettes per day) the relative risk
was 21. The relative risk appeared as great in those who had not
experienced menopause as in those who had experienced menopause.
In those young women with no known risk factors other than
cigarette smoking, the data indicated that the smoking habit
accounted for 76 percent of the risk of nonfatal MI (244). This
magnitude of relative and attributable risk with smoking in other-
wise healthy young women is consistent with similar observations in
young men.

A subsequent report included cases observed through August 1978
with and without the following characteristics: obesity, diabetes
mellitus, abnormal blood lipids, hypertension, angina pectoris,
history of preeclampsia, coffee consumption, and oral contraceptive

101


(CC) use (227). Smoking was confirmed as a singularly strong risk
factor (Figure 10). Relative risk increased exponentially with the
number of cigarettes smoked, and the relative risk in younger
women was greater than in older women. A gradient of risk with
increasing level of cigarette smoking was also observed in subjects
who had one or more of the other risk factors. In those at the highest
level of risk, women smoking 35 or more cigarettes per day who had
one or more predisposing risk factors, the relative risk was 31.

A number of investigations have been performed to observe the
effects of OC use, and there is substantial evidence for interaction of
the smoking effect with OC use as well as other risk factors. These
data suggest that the biological effect of multiple risk factors,
particularly when combined with OC use, may be multiplicative for
the risk of CHD. Shapiro et al. (242) found that women who smoked
more than 25 cigarettes per day but did not use OCs experienced a
relative risk of MI of 7 in comparison with nonsmoking women who
did not use OCs. Nonsmokers who used OCs experienced a relative
risk of MI of 4.5. The women who combined both behaviors had a
relative risk of MI of 39. In a case-control study of factors related to
MI in nurses in the United States, Rosenberg et al. (226) reported
relative risks with OC use, smoking, and hypertension of 3,5, and 8,
respectively; however, in nurses with all three characteristics the
relative risk was 170.

Comparable results were observed in England by Mann, where the
relative risk for MI in women with major cardiovascular risk factors
(including cigarette smoking) who used OCs was up to 128 times that
of women free of these characteristics (169). The importance of
cigarette smoking to the incidence of MI in women has been
confirmed by other studies in England (211, 270), Sweden (16, 2791,
Scotland (2031, Finland (234, and elsewhere.

In addition to the excess risk of nonfatal MI and death from CHD,
sudden cardiac death in women has been observed to be strongly
related to the cigarette smoking habit (249, 254). However, the
relationship of angina pectoris to cigarette smoking is uncertain. As
in men, some studies have shown a positive relationship with
smoking (271), but other studies have found no significant difference
in the occurrence of angina pectoris between female smokers and
nonsmokers (16,40,203).

CHD incidence and mortality in women increase remarkably after
the menopause. Before the menopause, cases of CHD may be limited
largely to women who smoke (15, 16, 138). Furthermore, there is
evidence that the menopause occurs at an earlier age in women who
smoke than in women who do not smoke (129,270). Willet et al. (282)
observed a progressive increase in the risk of early menopause with
an increasing level of daily use of cigarettes, and cigarette smoking
was more closely related to early menopause than any other factor

102


0 Observed RR estimate. 30-44 yr
A Observed RR estamate, 45-49 y
0 Fltted RA estrnate

  20 -









   15 -
co
F
%
b
s
::   IO-
??
Y
F
4
E



  50 -








  10 -

30-44yr 0
/ B



8

0      1      2     3      4      5
Never    Ex-     1-14   15-24   25-34    -35
smoked   smoker

          CIGARETTES PER DAY

FIGURE lo.-Relation to relative risk of myocardial
       infarction to cigarette smoking, according to
         we

NOTE: DilTerence in slopea:x~~= 2.7,~ = 0.10.
SOURCE: Rceenbeg et al. wn.

considered. The evidence that a combination of cigarette smoking
with the use of oral contraceptives potentiates (multiplies) the
occurrence of CHD is strong, but the mechanisms are not adequately
understood. The use of noncontraceptive estrogens was not associ-
ated with an excess risk of MI (228). Furthermore, menopausal
estrogen therapy has been associated with a protective effect from
CHD death (231). There is evidence that both cigarette smoking and


progestins in oral contraceptives depress high density lipoprotein
cholesterol (HDL-C), and HDL-C appears to protect from CHD (13,
23, 35, 41, 59, 62, 74, 78, 122, 123, 213, 215, 265, 266, 269, 281). Those
with low levels of HDLC have been shown to suffer higher rates of
CHD than those with high levels of HDGC (see Interaction of
Cigarette Smoking and Other Risk Factors above).

Whatever the mechanism, it must be concluded that women who
decide to smoke assume a substantially increased risk of CHD, and
that the risk for women who smoke heavily approaches the risk of
CHD for men. The relative risk of cigarette smoking is greater in
younger women than in older women, and the relative risk increases
progressively with the number of cigarettes smoked. Women who
smoke have been observed to experience menopause earlier than
women who do not smoke, and this may also increase the CHD risk
for women who smoke. A synergistic interaction between cigarette
smoking and other risk factors for CHD has been demonstrated for
women, particularly for oral contraceptive use. More investigation is
required to evaluate this phenomenon; an astonishingly high rela-
tive risk of CHD occurs in women who smoke cigarettes and also
have other risk factors, including use of oral contraceptives.

Risk of Sudden Cardiac Death

The definition of sudden cardiac death @CD) is discussed in the
introduction to this section. In a number of studies, severe CHD has
been observed in a large proportion of the cases that have succumbed
toSCD (10,12,139,153,154,156,157,160,162,200,208,248).

In several epidemiologic studies, cigarette smoking has been even
more closely related to SCD than to CHD in general. After 24 years
of followup in the Framingham study (40, 1391, the risk of SCD in
cigarette smokers was found to be three times that in nonsmokers,
and a comparable relative risk was observed in the five-cohort
Pooling Project data (124, 251). Although the relative risk in young
men was greater than in older men, the relative risk was 2 even in
men aged 7@ to 79 in the Framingham cohort (40). In the Pooling
Project data, the IO-year incidence of SCD increased progressively
with the number of cigarettes smoked per day, analogous to the
relationships with the first major coronary event or with all CHD
deaths (124, 251). Other studies confirming the importance of
cigarette smoking in SCD include members of the Kaiser-Perman-
ente health plan in the San Francisco Bay area (681, black and white
men and women in Baltimore (156), men employed in the telephone
industry throughout the United States (llO), and men living in
Scandinavia (72, 220).

Other risk factors used to predict the occurrence of SCD include
hypertension, high relative weight, high serum cholesterol, left
ventricular hypertrophy by electrocardiogram, and alcoholism (50,

104


64, 68, 109, 137, 139, 149, 152, 153, 156, 173, 188, 209, 216). In
multivariate analysis of the combined Framingham and Albany data
for men aged 45 to 64, cigarette smoking emerged with the highest
level of statistical significance among five risk factors predicting
SCD (137).

Approximately half of those who experience SCD have preexisting
clinical evidence of CHD (109, 139, 153, 154, 220). In a study by the
Health Insurance Plan of Greater New York it was found that in
comparison with patients who stopped smoking, those who continued
to smoke after myocardial infarction or after the onset of angina
pectoris experienced twice the risk of death over the subsequent 4
l/a-year period of followup (242). Results supporting this observation
have been observed in some other studies (69, 141,155,233,238,250).

The results of numerous studies have consistently identified
cigarette smoking as a leading factor in SCD. This is true for men
and women, and the risk increases with the number of cigarettes
smoked per day.

Prospective Mortality Studies

The detailed epidemiologic studies of CHD incidence described
elsewhere in this section establish the close association between
cigarette smoking and the subsequent development of coronary
heart disease. The possibility that this association can be confounded
by other characteristics with which smoking is associated has been
intensively examined in these studies. The relationship between
cigarette smoking and CHD has been demonstrated to exist indepen-
dent of the presence of other risk factors.

Studies using CHD mortality as an end point can be performed at
a lower cost than can studies of the incidence of the disease. This
allows the inclusion of larger numbers of individuals in order to
examine the effects of smoking in larger segments of the population.
It also provides sufficient numbers of cases for detailed analyses of
the effects of dose, age, smoking cessation, and other variables of
interest. Studies examining the relationship between cigarette
smoking and subsequent CHD mortality are now available for a
variety of populations and include over 20 million person-years of
observation. In the 10 largest studies the results are remarkably
similar. Whether in the United States, Canada, the United Kingdom,
Scandinavia, or Japan, smokers as a group experience excess CHD
mortality that is approximately 70 percent above that of the
nonsmokers.

In the following paragraphs, the major studies that have prospec-
tively examined the relationship between cigarette smoking and
CHD mortality are discussed. The number of individuals followed in
these studies allows a detailed examination of the nature of this

105


relationship, including the changes in risk that occur with age, the
relationship between dose of cigarette exposure and CHD risk, the
effects of low tar and nicotine cigarettes, the risk of pipe and
cigarette smoking, and the benefits of cessation.

Overall CHD Risk for Men and Women

A number of major prospective studies have examined the
relationship between cigarette smoking and CHD mortality in men
and women. Under this heading, a description of the populations
studied and the findings for overall CHD risk in those populations
are presented. Under subsequent headings, the questions of the
differences in risk that occur with age, increasing dosage of cigarette
exposure, low tar and nicotine cigarettes, pipe and cigar smoking,
and the effects of cessation are examined on the basis of the evidence
from these prospective studies.

In the United States, Dorn initiated a study of U.S. veterans who
had served in the Armed Forces between 1917 and 1940 and who had
U.S. Government life insurance policies in force in December 1953.
This initial cohort of 293,658 persons was mailed a questionnaire in
1954, and the nonrespondents were followed up again in 1957.
Responses were obtained from 248,046 veterans, with an overall
response rate of 85 percent. Reports for 2 l/2 years (46') and 8 l/2
years (131) of followup were reviewed in detail in prior reports of the
Surgeon General. The N-year followup has been completed by Rogot
and Murray (224). Death certificates were located for 85,323 (98
percent) of those original questionnaire respondents who died.
Confirmation of the cause of death shown on the death certificate
was investigated by Dorn (46). Whenever a death occurred in the
United States, clinical confirmation concerning cause of death was
sought from the physician who signed the death certificate. A
response was obtained in 99 percent, and after review of the cause of
death based on clinical data, only 6 percent of the deaths were
reassigned to a cause different from that originally indicated on the
death certificate. This degree of confirmation is considered good.
Coronary heart disease mortality was 58 percent higher in cigarette
smokers than in nonsmokers (Table 8), and CHD accounted for more
excess deaths than any other cause of death.

In 1952, the 9-State study by the American Cancer Society was
initiated; 187,783 white males, aged 50 to 70, were followed for an
average of 44 months. There were 11,870 deaths. Of these deaths,
5,297 were due to coronary heart disease (96'). A highly significant
excess mortality was observed in smokers as compared with non-
smokers. The death rate for coronary heart disease was 70 percent
higher in smokers compared with nonsmokers (Table 8).

In late 1959 and early 1960, the American Cancer Society enrolled
1,078,894 men and women from 25 States in a prospective study that

106


TABLE 8.-Coronary heart disease mortality ratios, major
      prospective studies

Population/
Study

Size

         Mortality ratio

No. of          fzigarette
CHD deaths Nonsmoker   smoker

Comments

U.S.
veterans

ACS 9-&&e
study

Japanese in
29 health
districta

ACS 2SState
study

Canadian
veterans

British
physicians

Swedish
study

California
malesin

290,000 males    34,874       1.00      1.58


188,ooo males     5,297       1.00      1.70


122,000 males     3,351       1.00      1.71
143.000 females    2,653       1.00      1.78


358,@30 males    10,771       1.00     1.90-2.55
483,000 females    4,048       1.00       o

~78,OCKl males     3,405       1.00


34,000 malee     3,191       1.00
6,195 females     179       1.00

1.60

1.62

27,ium males      916       1.00      1.70
28,000 females     457       1.00      1.30

68,cQo males     1,718       1.00      1.60

Male data for two
levels of smoking
intensity, see Table
12; `female data
available by age and
amount smoked only,
see Tables 9 and 14

`Female data avail-
able by amount
smoked only, see
Tables 9 and 12

Swiss
physicians

3,149 males      280       1.00     xX3-2.18

Data available by
amount smoked only,
see Table 12

was the largest of its kind ever conducted. All segments of the
population were included, with the exception of groups that could
not be easily traced. An initial demographic questionnaire recorded
height, weight, detailed information concerning smoking (types of
tobacco used, number of cigarettes smoked per day, inhalation, age
at which smoking began, brand of cigarettes used), and other
variables that might influence mortality. Hammond reported cause-
specific mortality for the initial followup through September 1963
(97.4 percent successfully traced) on all those aged 35 to 84 at the
time of enrollment (93). In men, 1,639,211 person-years of experience
were observed, and in women, 2,125,360 person-years of experience
were observed. Death certificates were obtained in 97.9 percent of
the 25,895 deaths. CHD mortality ratios in male cigarette smokers

107


compared with those who never smoked regularly varied from 2.81
in men aged 45 to 54 to 1.24 in men aged 75 to 84 (Table 9). Ratios for
women were 2.00 and 1.19 for age 45 to 54 and 75 to 84, respectively.
In the 6year followup reported by Hammond and Garfinkel (94),
there was a total of 28,446 deaths. Using the death rates of
nonsmokers as the standard, over 11,590 excess deaths were
attributable to smoking. Coronary heart disease accounted for 46
percent of the excess deaths in men and 40.6 percent of the excess
deaths in women.

A study of California men in various occupations was begun in
1954, and 68,153 men aged 35 to 64 were followed for mortality
through December 1962 (234). Smokers included current as well as
ex-smokers. Nonsmokers were all men who had never regularly
smoked cigarettes for even 1 year, and pipe and cigar smokers were
included in this group. A total of 4,706 men were identified. The
mortality ratio for CHD was 1.6 (60 percent excess CHD mortality) in
smokers as compared with nonsmokers.
San Francisco longshoremen were studied by Paffenbarger et al.
(205); 3,686 men aged 35 to 74 were examined in 1951 and followed
for 22 years. A total of 1,270 deaths were observed during 55,635
person-years of observation. After adjusting for difference in age,
systolic blood pressure, and level of activity, the CHD mortality ratio
for those smoking 20 cigarettes or more per day was 2.09 relative to
those subjects who smoked fewer cigarettes or none.

Gillum and Paffenbarger reported CHD mortality from followup of
13,728 university students examined between 1939 an< 1950 (77).
CHD morbidity followup was observed in 8,852 who had returned
self-administered questionnaires in 1962, 1966, or 1972. Four control
subjects were randomly assigned to each of the 98 cases of fatal CHD,
78 cases of myocardial infarction, and 49 cases of angina pectoris.
Fatal CHD, MI, and angina pectoris were strongly associated with
smoking history; relative risks were near 2.5. Association with fatal
CHD, or with MI, or both, was also apparent for a family history of
CHD, weight, height, and systolic blood pressure.

The Canadian Department of National Health and Welfare
initiated a study in 1955 of smoking and health in disability
pensioners, principally veterans of World Wars I and II. Best
reported the results of a 6year followup in 1966 (17). The 78,000
Canadian men were aged 30 to 90 at the onset of the study. Smoking
habits were determined at the start of the study. Nonsmokers were
respondents who had never smoked. Ever smokers were those who
had smoked at least 100 cigarettes during their lifetime or 10 cigars
or 20 pipefuls of tobacco. Current smokers were those who reported
smoking at the start of the study. Ex-smokers were those who had
smoked previously, but had stopped smoking at the start of the
study. During the (i-year followup, 9,491 deaths were observed, of

108


TABLE 9.4ronary heart disease mortality ratios and
      rates, by age and smoking habit, prospective
       studies

Study

Mortality ratio and (rate)' by age

AC% 25.Stat.e

Male nonsmoker
Male smoker
Female nonsmoker
Female smoker

35-44      45-54      5.5-64      65-74      7&&34
- -    - ___
l.oo-1'     1.oowio~     l.ow42)    1.ooC1400)    Loo(3132)
- (148)    2.81(422)    l.a4@96)    1.45@25)    1.24@71)
1.00       l.WW     l.oow3)    1.00(653)     1.00(19733
-      2.00(66)     1.6%275)    1.44041)    1.19@49)

U.S. veterans

Nonsmoker or
occasional only
fzigarettes only

Japanese in 29 health
diitricts

Male nonsmoker
Male smoker
Female nonsmoker
Female smoker
ACS 9-E%.& *

Nonsmoker
Smoker

35-44

Loowl)
4.44@0)

1.W~)     l.Cux501)    1.0@1015)
7.00(353)     1.60@601    1.6of1659r

1.01X2216)
1.20(2683)

4049        50-m        60-69        70+
1.oc@.0)       l.OOw3.3)      l.OO(105.5)     l.OO(189.6)
3.09a4.7)      1.4268.8)      1.62U70.7)     1.71t323.8)
l.OLX6.1)       l.OOC?3.6)      l.oo(79.5)      l.OO(lc9.4)
1.46@.9)       1.7X41.2)     1.54w2.5)     1.44(157.9)

45-54      5.564      65-74

75-M

50-54

1.00@71)
1.92@21)

55-59        60-64

Loowl)      1.00(733)
1.650301)      1.66(1219)

65-69

l.oow?47)
1.41(1759)

British physicians, male
Nonsmoker
currenf cigarettee only

British physicians, female
Nonsmoker
Smoker 1-14 cigarettes
     15-24 ci&B
     25+ cigarettes

<65                 265
l.ow39)               l.ax1655)
2.19(413)                1.37(2259)


1.00(31)                 l.ooC511)
1.41(44)                0.78@02)
2.54(79)                2.1&1117)
2.74@5)                2.76(1411)

Canadian veterans        55-59      60-64      6569      70-74      75-79
                         ~ ~   ~ -

Nonsmoker            1.00       1.00       1.00       1.00       1.00
CigaFettes OdY         1.90       1.61       1.36       1.79       1.45

Swedish pmepective         16-39        40-49        50-59        6@69
Nonsmoker             1.00         1.00         1.00         1.00
Male smoker, cigs only      -          2.60         1.70         1.70
Female smoker           -          -          2.60         1.10

Swiss physicians          35-54        5.5-G        66-74        75+
Nonsmoker            1.00         1.00         1.00         1.00
Heavy smoker *          2.30         2.20         1.90         1.00

C!difomia males in 9        3&u      4ti51        5s64        6549
OCCUpatiOnS

Nodmoker             1.00
Smoker               6.24


' Bate per 100,COO. anlam otherwIse stated.
n Number of deaths tna small to compute a ratio.
' Heavy smoker: one or more path per day.

1.00         1.00         1.00
2.95         1.56         1.24

which approximately 2,000 were attributed to coronary heart
disease. Smokers experienced a death rate 68 percent higher than

109


that of nonsmokers. The excess mortality was due mainly to
cardiovascular disease, with coronary heart disease alone accounting
for 36 percent of the excess. The death rate due to coronary heart
disease in smokers was 60 percent higher than the death rate in
nonsmokers (Table 8).

In 1951, a study of mortality in British physicians was initiated.
The results were reported by Doll and Hill (44) and subsequently by
Doll and Pete (45) and by Doll et al. (43). A total of 34,400 men
responded to the questionnaire (69 percent response rate). Followup
questionnaires were sent in 1957, 1966, and 1972. Twenty-year
mortality through October 1971 was reported in 1976 (45). Virtually
all of the sample had been traced, and 10,072 deaths were identified.
Nonsmokers were defined as those who had never smoked as much
as one cigarette per day for as long as 1 year. Smoking status was
updated using the information from followup questionnaires. Coro-
nary heart disease accounted for 3,191 of the deaths. Information
from the first questionnaire was related to the deaths occurring in
the first 7 years, information from the second questionnaire to
deaths in the next 8 years, and information from the third
questionnaire was related to deaths in the last 5 years of the
followup period. The death rate for smokers of all forms of tobacco
was 37 percent higher than the death rate for nonsmokers.

Results of the 22-year mortality followup of female British
physicians were reported recently (43). Among 6,194 respondents
there were 1,094 deaths. Coronary heart disease was the underlying
cause of death in 179. Among smokers, excess mortality was
observed only for those smoking 15 or more cigarettes per day, but
for these women the relative risks exceeded 2. The coronary heart
disease mortality of all female smokers was only 35 percent of that of
all male smokers. Those women who smoked more heavily (15 or
more cigarettes per day) experienced CHD mortality that was 67
percent of that of men who smoked more than 15 cigarettes per day.
Further analyses indicated that these female smokers had a lower
cumulative smoking exposure than the male smokers; the female
smokers had begun smoking at later ages and smoked fewer
cigarettes, and fewer reported inhaling cigarette smoke. The CHD
deaths among the female smokers were too few for more detailed
analysis of the risk at levels of smoking behavior comparable to the
most intense male smokers.

Examinations were given and questionnaires administered to
18,403 British civil servants working in London (205). Blood pres-
sure, plasma cholesterol, blood glucose, height, weight, and relevant
data were collecfecl in a standardized fashion. During the U&year
followup there were 1,657 deaths, of which 704 were due to coronary
heart disease. Grade of employment was significantly related to
death from coronary heart disease; those at the highest grades

110


(administrators and professionals) experienced the lowest rates.
However, at each grade of employment cigarette smokers experi-
enced higher mortality than nonsmokers. The mortality of ex-
smokers was similar to that of nonsmokers.

Grundy (89) reported the relationships of smoking habit and
worksite exposure to carbon monoxide for 4,924 steelworkers in
Ebbwvael, Wales, who were examined in 1964. After 10 years, 99
percent of the population surveyed was traced and 740 deaths were
recorded. The total mortality and CHD mortality were higher than
average for England and Wales. The smokers (73 percent of the
sample) experienced a coronary heart disease mortality that was 80
percent higher (relative risk 1.8) than that of nonsmokers. Occupa-
tional exposure to carbon monoxide appeared to play a negligible
role, in comparison with the importance of cigarette smoking, for
coronary heart disease mortality. The high smoking rate in this
population explained a substantial part of the excess mortality of
this population compared with the average mortality for England
and Wales.

In 1963, a probability sample of Swedish men and women aged 18
to 69 was surveyed by Cederlof et al. (31), and mortality was observed
during the subsequent 10 years through December 1972. There were
25,444 male respondents (93 percent) and 27,342 female respondents
(95 percent). In 1969, a followup questionnaire of a subsample
indicated that smoking habits had not changed substantially since
1963 in the majority of those surveyed; for example, 78 percent of
men and 63 percent of women who reported smoking 16 or more
cigarettes per day in 1963 reported the same cigarette habit in 1969.
During the N-year followup, a total of 5,655 deaths were ascer-
tained. Overall coronary heart disease mortality was 70 percent
higher in male cigarette smokers and 30 percent higher in female
cigarette smokers than in nonsmokers (Table 8). The possibility of
confounding by other factors was evaluated. For univariate analysis,
lower income and listing with the Swedish Alcohol Registry were
associated with significantly higher CHD mortality. (In Sweden,
violators of laws related to the use of alcohol, e.g., public drunken-
ness, drunk driving, illegal alcohol sales, are required to be
registered.) However, cigarette smokers in each of these groups had
significantly higher CHD mortality than never smokers, and the
differences were particularly marked at higher levels of cigarette
consumption. The CHD relative risks were also significantly higher
for cigarette smokers within the high income group, among rural
residents, and among those not listed in the Alcohol Registry.

In the Stockholm prospective study, risk factors for ischemic heart
disease were evaluated in 3,486 men and 2,738 women who were first
examined in 1961 through 1962 (22). During a 14 l/2-year followup,
a total of 694 deaths were observed, of which 43 percent in men and

111


31 percent in women were attributed to ischemic heart disease. Of
235 ischemic vascular deaths in men, 189 were attributed to
myocardial infarction. In univariate and multivariate analyses,
cigarette smoking was signiticantly and independently related to the
risk of ischemic vascular death in both sexes.

In 1955, a survey on the smoking habits of 3,749 Swiss physicians
was initiated. The first reported findings (252) after 9 years of
observation were similar to the findings in the British physicians
study of Doll and Hill (44). More recently published data, baaed on 18
years of followup (90), recorded 1,212 deaths among those physicians
who completed questionnaires during the original survey and for
whom complete information concerning cause of death was avail-
able. A total of 280 coronary heart disease deaths (59 nonsmokers
and 221 smokers) were reported. CHD mortality ratios increased
with increasing number of cigarettes per day. Light smokers (10 or
fewer cigarettes per day) had a mortality ratio of 1.33, increasing to
2.18 with the heaviest amount smoked (35 or more cigarettes per
day). Mortality for CHD among smokers tended to be greater in the
younger age groups than in the older age groups.

Hirayama has reported followup at 8,10, and 13 years for 122,261
men and 142,857 women over 40 years of age who were residents in
29 health districts in Japan (111-126). There was an overall 95
percent participation rate, and ascertainment of cause of death was
virtually 100 percent. In the 13year followup, over 3 million person-
years of risk and 39,127 deaths (22,946 in men and 16,181 in women)
were observed. Heart disease was certified in 3,351 men and 2,651
women. At the time of the baseline survey, the proportion-of smokers
was 76 percent in men and 10.5 percent in women. Mortality ratios
for smokers were 1.7 for men and 1.8 for women. The possibility of
confounding by other factors was evaluated through crossclassifica-
tion of smoking by social class, consumption of meat and milk, and
alcohol consumption. Higher coronary heart disease mortality was
observed with higher social class and among those consuming more
meat and milk. Alcohol intake was inversely related to coronary
heart disease mortality. At both high and low levels of these
characteristics, however, the risk of death from CHD among smokers
remained higher than among nonsmokers. The proportion of coro-
nary heart disease mortality attributed to cigarette smoking in this
population was 34.3 percent for men and 9.5 percent for women.

CHD mortality, as well as CHD incidence, is clearly much higher
in cigarette smokers than in nonsmokers. This excess mortality
occurred uniformly in each of the major prospective studies. It also
occurred in populations of markedly different ethnic background
and geographical location. The relationship also persisted when a
number of other confounding variables were taken into account. The
risk was somewhat lower for women, but in those groups of women

112


whose smoking habits approximated those of men, the CHD death
rates were much closer to those of men.

Impact of Cigarette Smoking on Coronary Heart Disease
Mortality With Increasing Age

Coronary heart disease mortality increases with increasing age in
both cigarette smokers and nonsmokers. The question of the
magnitude of the CHD risk due to smoking for different age groups is
one that has important public health impact for advising individuals
at different ages about the risks of smoking and the benefits of
cessation. In several of the prospective mortality studies, the
question of the magnitude of the risk of dying of coronary heart
disease at different ages in smokers and nonsmokers has been
examined.

Table 9 details the coronary heart disease death rates and
mortality ratios for different age groups of smokers and nonsmokers
in each of the prospective studies reporting these data. As can be
seen from this table, the CHD mortality ratios for cigarette smokers
compared with nonsmokers decline with increasing age. However,
the decline in the ratio is the result of the rapid rise in CHD
mortality rates with age in nonsmokers, and the absolute difference
between the death rates of cigarette smokers and nonsmokers
increases with increasing age. Thus, the excess risk is actually
numerically greater in older populations than in younger popula-
tions, and the reduction in mortality ratio is an artifact of the fact
that coronary heart disease is responsible for such a large part of the
mortality of the older age groups in the United States.

Figures 11 (men) and 12 (women) present the relationships of CHD
mortality and age for nonsmokers and smokers of various number of
cigarettes per day. The risk for the nonsmoker increases steadily
with increasing age, but with each increment in number of cigarettes
smoked per day, there is a clear increase in CHD risk prior to age 70.
The shape of the curve with increasing age remains similar with
increasing number of cigarettes smoked per day, and the net effect is
consistent with cigarette smoking increasing the apparent "CHD
risk age" of the individual by 5 to 15 years.
The decline in the mortality ratio with increasing age found in the
prospective mortality studies is consistent with the risk factor
relationships found in the incidence studies. In these studies,
cigarette smoking is responsible for a relatively larger proportion of
the coronary heart disease occurring in younger populations and a
smaller percentage of the total coronary heart disease occurring in
older populations.

113


5ooo





45OQ





4000





3500





3000





2500





2ooo





1500





1000





500

No. of cigarettea
smokedperday

10-1s

None

t          I          I          I          1
40         50         60         70         60

                 YEARS

FIGURE ll.-CHD death rates (per 100,000), by age and
       number of cigarettes smoked per day, males
SOURCE: Derived from the ACS 25-Stat.e study (93.

Dose-Response Relationships

The large number of deaths observed in the prospective mortality
studies allow a detailed examination of the relationship between the
"dose" of smoke exposure and subsequent coronary heart disease
mortality. The simplest measure of dose is the number of cigarettes
smoked per day; however, the dose of smoke received by a person

114


No. of cigarettes
smoked per day

2000




1400


1300


1200


1100


1000


900


600


700


600


500

NOIW









2s39









lo-19

40         50         60         70         60

                 YEARS

FIGURE lZ.-CHD death rates (per lOO,OOO), by age and
       number of cigarettes smoked per day, females
SOURCE Derived fmm the ACS %-State study WY.

would also be increased in those persons who inhaled deeply
compared with those individuals who did not. The duration of the
cigarette habit is also a measure of the dose of exposure; those
persons who began to smoke earlier in life would have a greater
cumulative exposure to cigarette smoke at any given age than those
persons who began to smoke later in life. Several of the major
prospective studies have examined these questions; the data are

115


TABLE lO.-Coronary heart disease mortality ratios by
      inhalation characteristic, prospective studies

Study

sex

Nonsmoker

Inhalation characteristic

Light

None

Swedish       Male                 1.00        1.8       1.6      1.2
           Female                1.00        1.6       1.2      1.7'

                                          YeS         NO

British        Male       <65        1.00          2.2         1.4
physicians              >65        1.00          1.5          1.3

None-alight   Moderate-deep

ACS          Male       4534
25-.%&e               55-64
                    65-74
                    n-84

Female      4.544
         5544
        65-74
         75.84

1.00
1.00
1.00
1.00

1.00
1.00
1.00
1.00

2.67         3.17
1.83         2.01
1.31         1.63
1.29         1.20

1.82         2.15
1.61         1.89
1.30         1.78
1.13         -2

L Number of deaths too small for statistical reliability.
`Number of deaths tax small to compute.

presented in Tables 10, 11, and 1`2. Table 13 provides data from two
studies that examined the risk of coronary heart disease mortality
by length of time smoked. In general, they show that the more total
years of smoking exposure the greater the overall risk of CHD
mortality.

In the study of Canadian veterans, a progressive dose-response
relationship was observed with number of cigarettes smoked per day.
The CHD mortality ratio increased from 1.55 in those smoking 1 to 9
cigarettes per day to 1.78 among those who reported smoking 20 or
more cigarettes per day. A similar relationship was found in the
American Cancer. Society 9-State study, where the excess CHD
mortality rate varied from 29 percent in smokers of 1 to 9 cigarettes
per day to 140 percent in smokers of 41 cigarettes or more per day.

In the American Cancer Society 25-State study, the number of
CHD deaths was large enough to conduct a detailed examination of
the relationship between the dose of cigarette smoke exposure and
the subsequent coronary heart disease mortality. The mortality
ratios for males in the group 45 to 54 years of age increased from
2.35 in those who smoked 1 to 9 cigarettes per day to 3.35 in those
who smoked 40 or more cigarettes per day. In the next oldest age
group, those 55 to 64 years of age, the mortality ratio increased from
1.54 in those who smoked 1 to 9 cigarettes per day to 2.13 in those
who smoked 40 or more cigarettes per day (Table 14). The mortality
ratio also increased with depth of inhalation. In the 45- to 54-year-old

116


TABLE il.-Coronary heart disease mortality ratios by age
      began to smoke, prospective studies

Study          Age

Nonsmoker
ratio

        Smoker
Mortality ratio by age of initiation

us. veterans                        5 14     1519      W24    2%

              55-64        1.00       1.96      1.64       1.65     1.56
              65-74        1.00       2.03      1.66       1.54     1.55

ACS 2.5State                       <14       15-24      2%

Males          45-54        1.00        3.47        3.11        2.37
            55-64        1.00        2.08        1.99        1.70
            6&74        1.00        1.54        1.62        1.17

FemallX3         45-54        1.00        -'        2.03        2.00
            55-64        1.00        -         1.64        1.74
            65-74        1.00        -         -        1.36

Males                    1.00        3.65        1.90        1.67

Swedish                          516       17-16       219

M&9                    1.00
          .
Females                   1.00


' Number of deaths tao small to calculate ratio.

1.90        1.70        1.70
2.00        1.10        1.30

age group, the mortality ratio increased from 2.67 in those who
inhaled not at all or only very slightly to 3.17 in those who inhaled
moderately or deeply (Table 10). There was also a consistent dose-
response relationship when the age at which the individual started
smoking was considered. The younger the age at which regular
smoking began, the greater the mortality ratio. In the 45-54 age
group the mortality ratio increased from 2.37 in those who began
smoking at age 25 or older to 3.47 in those who began smoking prior
to age 15 (Table 11).

For women, the excess mortality in the American Cancer Society
25State study generally paralleled the dose-response relationship
observed in men, but the CHD deaths were too few for evaluation of
the risk related to the age at which smoking was begun.

A similar relationship was demonstrated in the study of California
men in various occupations. The mortality ratio increased from 1.39
for those men who smoked half a pack per day to 1.74 for those who
had smoked 1 l/2 packs or more per day. Mortality ratios increased
with the duration of smoking from 1.05 in those who had smoked
from 1 to 9 years to 1.77 in those who had smoked 20 years or more.
The study of British physicians also examined the question of a
dose-response relationship. They found a steady increase in CHD
mortality with increasing number of cigarettes smoked per day. The
death rate from ischemic heart disease increased from 501 per
100,000 in those who smoked 1 to 14 cigarettes per day to 677 per

117


TABLE 12.-Coronary heart disease mortality ratios by
      amount smoked, prospective studies

Study

      M&S                   Females

cigs/bY         Ratio       cigs/bY       Ratio

U.S. veterans

Nonsmoker        1.00
l-9             1.24
l&20           1.56
2139           1.76
40+           1.94

ACS 9-State






JapeSe

Nonsmoker        1.00
l-9             1.29
lo-20           1.89
21-40           2.15
41+            2.41

Nonsmoker        1.00
1-14            1.59
15-24           1.79
25-49           2.11
50+            2.82

(For female data,
see Table 9)

ACS 25State

Nonsmoker
1-19
20+

1.00
1.90
2.55

(For female data,
see Tables 9 and 14)

Canadian veterans

Nonsmoker        1.00
l-9             1.55
10-20           1.58
21+            1.78

British physicians






Swedish






California
mupationa



Sti physicians

Nonsmoker        1.00        Nonsmoker        1.00
1-14            1.47         1-14            0.96
15-24           1.58         1624 f        2.20
25+            1.92        25+            2.12

Nonsmoker        1.00         Nonsmoker        1.00
1-7             1.50         l-7             1.20
8-15            1.70         l&15            1.60
16+            2.20        16+            3.00

Nonsmoker        1.00
about 112 pk       1.39
about 1 pk        1.67
about 1 l/2 pk      1.74

Nonsmoker        1.00
l-10            1.33
l&19           1.42
29-34           1.77
350rmOlV        2.18

100,000 in those who smoked 25 or more cigarettes per day. Depth of
inhalation was analyzed after adjusting for age and amount smoked.
Those responding that they did inhale experienced a 57 percent
higher mortality rate than those responding that they did not inhale.
A dose-response relationship was also reported in the U.S.
veterans study, the study of mortality in northeast England, the

118


TABLE 13.-Coronary heart disease mortality ratios by
     number of years having smoked, prospective
        studies

Study

             Number of years having smoked

Nonsmoker  < 5         5-9   lo-14       15-19  2&29  3cM9  240

Canadian
veterans    1.00     1.4         1.7    1.5         1.7    1.6    1.5    1.6

                    l-9             lo-19           20+

California
occupations   1.00         1.05             1.13             1.77

TABLE 14.-Coronary heart disease mortality ratios, males
      and females, by age and amount smoked, ACS
      %-State study

Number oi       4.544       55-64       65-74       75-64

cigarettes/day    M F     M F     M F     M F

Nonsmoker     1.00   1.00    1.00   1.00    1.00   1.00    1.00  1.00
l-9         2.36   9.94    1.54   1.26    1.26   1.10    1.17  -'
E-19        3.09   2.00    1.92   1.64    1.61   1.42    1.39   -
2%39        3.11   2.67    2.04   2.01    1.56   1.65    1.11   -
40+         3.35   -    2.13   -     -    -     -   -

' Number of deaths too small to wmpute.

Swedish probability sample study, the Stockholm prospective study,
and the study of 29 health districts in Japan. Mortality from CHD in
the Whitehall study was higher in inhalers than in noninhalers, but
the relative risk was reduced after adjusting for cigarette consump
tion and tar yield. Among inhalers, the risk increased with the
amount smoked; this trend was less evident in those not inhaling.

Thus, in those studies that have had an adequate number of deaths
to examine the question of a dose-response relationship between
cigarette smoking and death from coronary heart disease, a clear
dose-response relationship has been demonstrated for the number of
cigarettes smoked per day, depth of inhalation, age at initiation of
the smoking habit, and total duration of the smoking habit. The risk
of coronary disease mortality is lower with fewer cigarettes smoked
per day, but the evidence presented in the prospective mortality
studies does not suggest a threshold for this effect. There is no
evidence to suggest that any level of cigarette smoking is safe with
regard to coronary heart disease risk.

119


Low Tar and Nicotine Cigarettes

There has been a major change in the tar and nicotine yield of the
cigarettes being smoked by the U.S. population over the last 30
years. The impact of this decline in tar and nicotine yield on the risk
of developing coronary heart disease in individuals smoking lower
yield cigarettes has been examined in detail in the 1981 Report of the
Surgeon General The Health Consequences of Smoking: The Chang-
ing Cigarette (262). There are essentially no epidemiological data on
the risk of very low yield cigarettes (those below 5 mg of tar). The
American Cancer Society 25-State study did, however, address the
relative risk of those who smoked cigarettes with varying yields of
tar (95). Groups were matched for age, race, number of cigarettes
smoked per day, age at which smoking began, place of residence,
occupational exposures, education, and history of lung cancer or
heart disease. CHD mortality was calculated for two 6-year periods
(196CL1966 and 1966-1972) for those smoking low, medium, or high
tar and nicotine cigarettes. The men and women (both in early and
late periods) who smoked cigarettes with high tar and nicotine yield
experienced higher CHD death rates than those who smoked low tar
and nicotine cigarettes (Table 15). Additional analyses were per-
formed after further matching of the groups with respect to history
of stroke; diabetes mellitus; hypertension; usual amount of exercise;
obesity; consumption of aspirin, tea, coffee, and alcohol; and occupa-
tion. Although this procedure resulted in fewer matched subjects,
the results were comparable to the analyses above; CHD mortality in
the low tar and nicotine cigarette smokers was 86 percent of that of
the high tar and nicotine cigarette smokers. However, this slight
reduction in CHD mortality associated with smoking low tar and
nicotine cigarettes disappeared if an increase in the number of
cigarettes smoked per day occurred. Those smokers of low tar and
nicotine cigarettes who smoke between 20 and 30 cigarettes per day
experienced a 10 percent higher coronary heart disease mortality
than did smokers of 1 to 19 high tar and nicotine cigarettes. In
addition, a comparison of matched subjects who never smoked
regularly with those who smoked low tar and nicotine cigarettes
revealed that the low tar and nicotine cigarette smokers experienced
a 66 percent higher coronary heart disease mortality rate.

Data from the Framingham study on the incidence of coronary
heart disease (30) have not shown a lower CHD risk among filter
smokers compared with nonfilter smokers.

Data from the Whitehall study have been published that examine
tar yield by number of cigarettes smoked per day in inhalers and
noninhalers for CHD mortality. This is presented in Table 16. While
no clear pattern is evident for noninhalers, among inhalers there
was a tendency for the highest CHD rates to be seen in those
smoking cigarettes with the highest tar yield (108). In a recent study

120


TABLE 15.-Adjusted number of coronary heart disease
      deaths and mortality ratios during each of two
      periods of time, by sex and by tar and
      nicotine content of cigarettes usually smoked

sex

Period '

High tar      Medium tar     Low tar
and nicotine     and nicotine    end nicotine

Male
Female
Female

Total

Male
Male
Female
Female

Total .

Adjusted number of CHD deaths

696.5         632.5         645.6
336.0         345.6         274.2
318.7         277.5         257.4
265.6         228.0         215.5

1.616.8        1,#3.3        1.392.7

      Mortality ratios

1.00          0.91          0.93
1.00          1.03          0.82
1.00          0.87          0.81
1.00          0.86          0.81

1.00          0.92          0.86

`Period 1: 1960-1966; Period 2: 1966-1972
SOURCE: Hammond et al. wh

TABLE le.-Ten-year coronary heart disease mortality per
       hundred (and number of deaths) standardized
      for age and employment grade, according to
      cigarette consumption and tar yield, Whitehall
       study

                 Inhalers                     Noninhalers

        l-S/day   1@19/day   > m/day     I-9/day   1&19/day   > 2O/day
         ~ ___ ___ ___ ___ ~

Tar (m&i@ Rate No.   Rate No.   Rate No.    Rate No.   Rate No.   Rate No.

18-23      2.68  (14)   5.63  (71)   6.60  (101)    3.94  (14)   4.91  (17)   6.05  (20)
24-32      3.81   (7)   6.57  00)   6.23  (36)    1.78   (3)   9.03  (10)   4.27   (6)
2%       7.42  CD)   6.47  (37)   7.84  (10)    5.06   (4)   4.75   (4)   0.00   (0)

Total      4.29  (44)   5.98  (138)   6.56  (147)    3.46  (21)   5.73  (31)   5.16  (26)

NOTE: Rate for lifelong nonsmokers of cigarettes = 2.75 (70).
SOURCE: Higgenbottam et al. (108.

(240), tar and nicotine content of the cigarettes was documented;
those men who smoked low yield cigarettes did not have a lower risk
for myocardial infarction than those smoking higher yield cigarettes.
The relative risk of developing coronary heart disease in persons
smoking low yield cigarettes and persons smoking high yield
cigarettes is further confounded by the possibility that those who

121


TABLE 17.-Coronary heart disease mortality ratios for
     male cigarette, pipe, cigar, and mixed pipe
     and/or cigar smokers, prospective studies

Study            Nonsmoker


U.S. veterans'         1.00

    Mortality ratios
Cigarette    pipe    aw   Mixed pips and/
smoker     smoker   smoker  or cigar smoker


1.58       1.02      1.12

ACS 9-Stat.e          1.00         1.70        -      1.28

Swedish

1.00         1.70       1.40

ACS 25State'         1.00       1.90-2.55      1.08

British physicians       1.00

' Smoker group are "pure" smokers only.
' Age 5664 only.

1.62                        1.03

smoke low yield cigarettes may smoke greater numbers of cigarettes
per day or may alter the manner in which they smoke those
cigarettes to increase the yield from the cigarette. The available data
are conflicting concerning a possible reduction in risk of CHD for
those smoking the lower yield cigarettes; further evidence is needed
before this question can be definitively answered.

Pipe and Cigar Smoking

A number of studies have addressed the question of.the relative
risk for CHD from smoking pipes and cigars compared with
cigarettes. Those prospective mortality studies containing data that
address this question are presented in Table 17. In general, the risk
for coronary heart disease mortality of smoking pipes and cigars is
substantially lower than the risk of smoking cigarettes. This is
generally felt to be due to the tendency of pipe and cigar smokers not
to inhale smoke into the lung. If this is the mechanism of this lower
risk, then the tendency of those who switch from cigarettes to pipes
and cigars to continue to inhale the smoke may minimize or
eliminate the reduction in risk for coronary heart disease that might
be expected after switching to pipes and cigars from cigarettes.

Cessation

Whether the excess coronary heart disease mortality that occurs
with cigarette smoking decreases over time following cessation of
cigarette smoking is a question of great importance for those
individuals who are currently smoking cigarettes. Data from the
prospective mortality studies that have examined this question are
presented in Table 18.

122


TABLE 18.-Cessation of smoking and coronary heart
     disease mortality ratios, prospective studies

Study             Continuing smoker

Eksmoker

U.S. veterana

Swedish males
     females

ACS 25&&e

Canadian veterans

British physicians
males

Japanese males in
29 health dietricte

  1.58              1.16

  1.70              1.50
  1.30              1.50

l-19' 20+        1-19 2O+
1.87   2.06         1.26    1.62

  1.60              1.46

1.62              1.29

1.71

1.34

TABLE 19.-&essation of smoking and CHD mortality
      ratios, by length of time off cigarettes and
      number of cigarettes smoked daily, ACS 2!5-
      State study, 6year followup

Years stopped smoking

Amount smoked per day

l-19          20+

None, current smoker                1.87          2.06
Le3sthan1                      2.00          2.13
1-4                           1.43          2.00
5-9                          1.44           1.45
10 or more                      0.99          1.35
All ex-emokers                    1.26          1.62

In the American Cancer Society 25-Stat.e study, the mortality
ratios in former smokers compared with continuing smokers were
progressively lower with increasing intervals of smoking cessation.
For those who had smoked less than 20 cigarettes per day, the CHD
mortality after 10 years of cessation was comparable with that of
those who had never smoked regularly. However, for those who had
smoked 20 or more cigarettes per day, the CHD mortality rate
remained 35 percent higher even after 10 years (Table 19).
The British study of physicians also conducted a detailed analysis
of the effects of cessation. The relative risk for males 30 to 54 years
of age was 1.9 for those who had discontinued smoking for less than 5
years, but it was 1.3 for those who had discontinued smoking for 5 or
more years. Those who discontinued smoking for 15 years or more
had a relative risk that remained slightly above 1. Those aged 30 to

123


TABLE 20.PHD mortality ratios by length of time off
       cigarettes

Study

           Mortality ratios

"ke   Nonsmoker      Yeare off cigarettes         comments

                       <5    5-9   l&14 5+

British        3s54    1.00     1.9     1.3     1.4     1.3
phyaiciam     5544    1.00     1.9     1.4     1.7     1.3
e@yr foump)  85+     1.00     1.0     1.3     1.2     1.1

                        <IO        >lO

Swedish m&n          1.00       1.50         1.00
(l@yr followup)

Japanese males
in29health
dietrict3
(1Csj-r folbJwup)

1.00





1.00

54        25

1.15         0.90





2.10         1.82

Smokers who consumed
<2oo,ooo cigaretteal
lifetime


Smokers who consumed
>2wloo cigarew/
lifetime

64 had a relative risk of 1.3 after 15 years, while those 65 and over
had a relative risk of 1.1 (Table 20).

The Swedish national probability sample study examined former
smokers who had stopped in the 10 years prior to 1963. A relative
risk of 1.6 existed for those who had smoked 20 years or more prior to
quitting, but the relative risk was 0.9 for those who had-smoked less
than 20 years before quitting. Those at younger ages had greater
residual relative risks than those in the older age groups. Among
those who had stopped smoking 10 or more years prior to the
beginning of the study, no significant excess risk of coronary disease
was observed. The results in women were consistent with those in
men, but the cases were too few for detailed analysis (Table 20).

In the Japanese study of 26 health districts, former smokers
exhibited relative risks that were related inversely to the time since
smoking cessation; the residual risk was directly proportional to the
number of cigarettes smoked prior to quitting.

Data from the X-year followup of U.S. veterans provides informa-
tion on CHD mortality for ex-smokers by the number of cigarettes
smoked per day (Table 21). Those ex-smokers with the lowest
smoking exposure levels as measured by the number of cigarettes
consumed per day had the lowest CHD mortality ratios. When all ex-
smokers were analyzed by the length of time since cessation (Figure
13), ex-smokers who had been abstinent for 20 or more years had a
CHD mortality ratio virtually identical to lifelong nonsmokers (1.00
versus 1.05). Friedman et al. (69) found that the benefits of quitting

124


TABLE 21.~ssation of smoking and CHD mortality ratios
      of current smokers versus ex-smokers, by
      number of cigarettes smoked daily, U.S.
      veterans study, M-year followup

No. cig/daily              Current smoker

Ex-smoker

Nonsmoker                  1.00               1.00
l-9                       1.24               1.02
lo-20                     1.56               1.14
2139                     1.76               1.31
40+                      1.94               1.30
AU smokers                  1.66               1.16

SOURCE: Begot and Murray (224).

A   8 C D E

FIGURE lb-Coronary heart disease mortality rates by
       number of years stopped smoking, U.S.
       veterans study, N-year followup

NOTE: A = Btopped b than 5 years: B = stopped 5-9 years; C = stopped 10-14 years; D = tipped 15-19
years; E = stopped 20 or more years.
SOURCE: Begot and Murray GW.

smoking could not be explained by differences in other risk factor
levels between continuing smokers and quitters.

Thus, cessation of cigarette smoking resulted in a reduction in the
risk of CHD in each of the mortality studies that have examined the
question. There appears to be some residual excess CHD risk in those
ex-smokers who smoked heavily for extended periods of time prior to

1%



quitting, and the magnitude of this residual risk is proportional to
the total lifetime exposure to cigarette smoke.

Populations With Low Rates of Smoking

Mortality has been studied in several population groups that have
abstained from cigarette smoking for religious reasons. These
include Seventh Day Adventists in California, Mormons living in
Utah, members of the Reorganized Church of Jesus Christ of the
Latter Day Saints living in Missouri, and Old Order Amish living in
Indiana, Ohio, and Pennsylvania.

Seventh Day Adventists in California prohibit the use of tobacco
and alcohol and advocate a well-balanced diet that includes a
relatively large grain and fruit content. As reported by Wynder and
Lemon (285), the Seventh Day Adventists have experienced excep-
tionally low coronary heart disease as well as low cancer mortality.

Cardiovascular mortality from 1969 to 1971 in Mormons and non-
Mormons living in Utah was studied by Lyon et al. (165). Utah has
the lowest per capita consumption of cigarettes and alcohol of the 50
States, and this is attributable to the Mormon Church's position
against the use of tobacco and alcohol. Below the age of 65, both
Mormons and non-Mormons in Utah had significantly lower core
nary heart disease mortality than the average for U.S. whites, but
above the age of 65 only Mormons had significantly lower rates.
Mormon men and women in comparison with non-Mormon men and
women living in Utah experienced 25 percent and 29 percent fewer
deaths, respectively, from coronary heart disease. The rates were
lower in Mormons than in non-Mormons at all ages. Below the age of
65, Mormon men and women experienced CHD mortality rates only
66 percent and 51 percent, respectively, of the rates for coronary
heart disease that were experienced by U.S. whites.

The mortality of Missouri residents who were members of the
Reorganized Church of Jesus Christ of Latter Day Saints (RLDS) was
compared with the mortality of other white Missouri residents and of
Utah residents for the period 1971-1978 (167). The RLDS advocates
abstinence from the use of tobacco, alcohol, and hot drinks. A well-
balanced diet is recommended, with ample whole grains, fruits, and
vegetables but with moderate intake of meat. The total mortality
rate for Missouri RLDS residents was 22.6 percent lower than that of
other Missouri white residents and 14.4 percent lower than that of
Utah residents. CHD mortality was 17.4 percent lower than CHD
mortality for other Missouri whites. The CHD mortality of RLDS
members appears to be intermediate between that of Mormons living
in Utah and that of U.S. whites.

Mortality among Old Order Amish living in Ohio (1960-1975),
Indiana (1967-1972), and Pennsylvania (1970-1975) was reported by

126


Hamman et al. (92). This unique population group is rooted in a rural
lifestyle reminiscent of 19th century America. Their diet has been
incompletely characterized, but probably is relatively high in fats
and carbohydrates. Tobacco use has been widespread among men,
but principally limited to pipe and cigar smoking and tobacco
chewing. Alcohol intake is thought to be limited to consumption at
home, and excessive intake is uncommon. Mortality of the Amish
was compared with mortality of the non-Amish residents in the
study counties. The non-Amish residents included an unknown
proportion of those who were former members of the Amish faith
and members of other conservative religious groups who shared
components of the Amish lifestyle. Amish men, but not women, 40 to
69 years of age had significantly lower total mortality (61 percent
and 98 percent, respectively) and cardiovascular mortality (65
percent and 89 percent) than did the non-Amish residents living in
the same counties. Lower cardiovascular disease mortality for the
Amish men was highly significant in all three States.

Conclusions

1. Cigarette smoking is a major cause of coronary heart disease in
the United States for both men and women. Because of the
number of persons in the population who smoke and the
increased risk that cigarette smoking represents, it should be
considered the most important of the known modifiable risk
factors for CHD.

2. Overall, cigarette smokers experience a 70 percent greater
CHD death rate than do nonsmokers. Heavy smokers, those
who consume two or more packs per day, have CHD death rates
between two and three times greater than nonsmokers.
3. The risk of developing CHD increases with increasing exposure
to cigarette smoke, as measured by the number of cigarettes
smoked daily, the total number of years one has smoked, and
the degree of inhalation, and with an early age of initiation.
4. Cigarette smokers have a twofold greater incidence of CHD
than do nonsmokers, and heavy smokers have an almost
fourfold greater incidence.

5. Cigarette smoking is a major independent risk factor for CHD,
and it acts synergistically with other risk factors (most notably,
elevated serum cholesterol and hypertension) to greatly in-
crease the risk of CHD.

6. Women have lower rates for CHD than do men. In particular,
CHD rates for women are lower prior to the menopause. A part
of this difference is due to the lower prevalence of smoking in
women, and for those women who do smoke, to the tendency to
smoke fewer cigarettes per day and to inhale less deeply.

127


Among those women who have smoking patterns comparable
to male smoking patterns, the increments in CHD death rates
are similar for the two sexes.

7. Women who use oral contraceptives and who smoke increase
their risk of a myocardial infarction by an approximately
tenfold factor, compared with women who neither use oral
contraceptives nor smoke.

8. Cigarette smoking has been found to significantly elevate the
risk of sudden death. Overall, smokers experience a two to four
times greater risk of sudden death than nonsmokers. The risk
appears to increase with increasing dosage as measured by the
number of cigarettes smoked per day and diminishes with
cessation of smoking.

9. The CHD mortality ratio for smokers compared with nonsmok-
ers is greater for the younger age groups than for the older age
groups. Although the smoker-to-nonsmoker mortality ratio
narrows with increasing age, smokers continue to experience
greater CHD death rates at all ages.

10. Cigarette smoking has been estimated to be responsible for up
to 30 percent of all CHD deaths in the United States each year.
During the period 1965 to 1930 there were over 3 million
premature deaths from heart disease among Americans attrib
uted to cigarette smoking. Unless smoking habits of the
American population change, perhaps 10 percent of all persons
now alive may die prematurely of heart disease attributable to
their smoking behavior. The total number of such premature
deaths may exceed 24 million.

11. Cessation of smoking results in a substantial reduction in CHD
death rates compared with those of persons who continue to
smoke. Mortality from CHD declines rapidly after cessation.
Approximately 10 years following cessation the CHD death
rate for those ex-smokers who consumed less than a pack of
cigarettes daily is virtually identical to that of lifelong non-
smokers. For ex-smokers who had smoked more than one pack
per day, the residual risk of CHD mortality is proportional to
the total lifetime exposure to cigarette smoke.

12. Epidemiologic evidence concerning reduced tar and nicotine or
filter cigarettes and their effect on CHD rates is conflicting. No
scientific evidence is available concerning the impact on CHD
death rates of cigarettes with very low levels of tar and
  nicotine.

13. Smokers who have used only pipes or cigars do not appear to
experience substantially greater CHD risks than nonsmokers.

128


Appendix: Prediction of CHD

The probability of developing CHD may be accurately predicted
within populations that are stratified by risk scores based on daily
use of cigarettes and the levels of the other major risk factors. This
may be accomplished efficiently using the multiple logistic equation,
which provides for simultaneous consideration of multiple risk
factors (40, 80, 84, 85, 88, 91, 126, 130, 133, 135, 137, 139, 143, 159,
168, 214, 221, 246). Furthermore, the reproducibility of the relation-
ship between risk factors and the subsequent development of CHD
may be tested among different population samples. As demonstrated
in the investigations cited above, the risk of CHD in white
populations in the United States and northern Europe has been
shown to be predictable based on a knowledge of cigarette smoking,
blood pressure, and serum cholesterol. In other population groups
with lower incidences of CHD, relative risk has been predicted well,
although the magnitude of risk has been overestimated. Such
predictability confirms the importance of the major risk factors to
the development of CHD.

Pooling Project

The relationships among a number of characteristics measured at
baseline examinations and the subsequent development of CHD was
studied intensively in the Pooling Project, in which the experience of
five major prospective studies of defined cohorts were compared and
combined. From these analyses it was concluded that the levels of
the three major risk factors-cigarette smoking, blood pressure
(systolic or diastolic blood pressure), and serum cholesterol-ac-
counted for most of the risk predicted by the variables considered;
the other variables were relative weight and ECG abnormalities.
Furthermore, the relationships of the risk factors to CHD were
similar among the cohorts considered.

Ranking of Risk

On the basis of the observed relationships among the levels of the
major risk factors and the subsequent incidence of CHD in the pooled
data, the men in each of the cohorts could be ranked by order of
expected risk. With the men thus ranked in quintiles of estimated
risk from low to high, the incidence of CHD was found to be nine
times higher for the men in the uppermost quintile than for the men
in the lowermost quintile.

Genemlizability

To test the generalizability of the relationship between these risk
factors and the subsequent incidence of CHD (in other words, the
prediction of future CHD events from given individual characteris-

129


tics), the multiple logistic equation describing the relationship of risk
factors to subsequent events in the combined data from the cohorts
contributing to the pooled data were applied to other cohorts. In the
cohort of U.S. railroad men, there was good correspondence between
the number of first major coronary events predicted and the
numbers observed by quintile of risk; 45 percent of CHD events were
observed in the highest quintile and 74 percent were observed in the
upper two quint&s. The total number of estimated cases was 133 as
compared with 112 actually observed in the cohort of U.S. railroad
men (`Table 22).

Comparability of Framingham Study Results With the
Results in the Other cohorts

The mathematical relationships between the risk factors and the
subsequent incidence of CHD for the Framingham study men were
near the averages observed for the other four cohorts in the Pooling
Project (Tables 23 and 24). The Framingham study results have been
compared with the results of other cohort studies in the United
States and elsewhere (25, 77, 85, 182); therefore, it is of interest to
consider in some detail the closeness of agreement between the
prediction of CHD by Framingham data and by the other cohort data
in the Pooling Project. In univariate analyses for each study by CHD
event and risk factor, it was found that the Framingham coefficients
were not significantly different from those of the other cohorts,
except for a higher coefficient for serum cholesterol in the Tecumseh
cohort and a higher coefficient for cigarette smoking in the Chicago
Gas Company cohort (Table 23). The Framingham coefficient for
smoking was slightly lower than the average for the other cohorts.

Risk Indices for Individual Use

Multivariate risk-scoring indices for estimating the risk of CHD
based on daily use of cigarettes and the levels of other characteristics
have been developed for prediction of the risk of CHD in individuals.
These include RISKO, developed by the Michigan Heart Association,
the Framingham Risk Index, based on the Framingham study
experience, and the Self-Scoring Risk Test, based on the experience
of the Chicago Western Electric Company cohort (54,138,178).
The discriminative power of RISK0 and the Framingham Risk
Index to identify individuals who would develop CHD was evaluated
in the experience of Los Angeles County safety personnel (256).
Personnel who were free of symptoms (4,066 individuals) were
examined and followed in the 1971 to 1979 time frame with a less
than 3 percent loss to followup (256). Subsequent to initial examina-
tion, 71 developed CHD, these symptomatic cases were characterized
by a higher proportion of cigarette smokers (60 percent compared
with 37 percent), higher systolic blood pressures, higher serum

130


TABLE 22.-Prediction of lo-year risk of a first event for men of two studies (Minnesota business and
      professional men and Minnesota-based railroad workers) from parameters of the
      multivariant logistic analysis for Pool 6, age 40-59 at entry

Quintilea of
expected or
predicted risk

       Pool 5             Minnesota business and professional men            Minnesota-based railroad workers
     (6,875 men)                      G!SO men)       ,                  (2,422 men)
                               Predicted,                          Predicted,
                                 mrrected for                            corrected for
                                 duration of                            duration of
Expected       OtWlWd       Predicted      followup '      ObSWWd       Predicted      followup'     OlXWWd

I
::I
N
V
All
V/I
V-I
Percentage of
event.9 in V
Percentage of
events in
VI + v

41.3' 30.0'    29    21.1      1.0   18.4     2.0 37.6     3    53.6     16.9 34.8     6.3 17.0     8    16.5
101.1 71.2 51.8 73.5  106 71  51.6 77.1   2.2 1.6  27.9 39.6   3.3 4.5 57.0 80.9   4 7  125.0 71.4  30.6 44.2 91.3 63.2  21.7 15.0 31.0 44.7  15 5  31.0 12.4
145.5 106.8    164    119.3      3.1   55.3     6.3 113.0     6    107.1     64.7 133.7     31.7 65.5     33    68.2
264.0 192.0    251    182.5      5.5   97.4     11.2 199.1     12    214.3     115.2 237.0     56.4 116.1     50    102.9
623.1 90.6    621    90.3     13.4   47.7     27.4 97.5     32    114.3     271.5 112.1    133.0 54.9    112    46.2
   6.4          8.7           5.3           5.3          4.0           6.8          6.8         6.3
222.7 162.0    222    161.4      4.5   79.0     9.2 161.5     9    160.7     98.3 202.2     48.1 99.1     42    36.4

  42.4          40.4          40.8          40.8          37.5          42.2          42.4         44.6



  65.7          66.8          64.0          64.0          56.3          66.3          66.3         74.1

`Mean durstion of followup for Pool 5 men wae sirably leee then for Minnesota bueineee end pmfasional men. Since the relationship between ege end incidence of major coronary events is
curvilineer (exponential). not linear. a correction factor wee derived from the 1970 U.S. life table for white men startmg et ege-predicted numbers of even@ rates were multiplied by this correction
factor-2.044--to obtain the numbera of events and rata for different duration of followup.
`Mean duration of followup for Pool 5 men wee sizably greeter then for Minnmota-based railroad workers. A correction factor-O. i WI--wan derived by the method deecribed in the footnote above.
`Number of events.
`Rate per Loco.
SOURCE: Pooling Project Reaeerch Gmup W4.


TABLE 23.-Standardized univariate logistic coefficients for
      deaths from myocardial infarction, CHD, and
       all causes, by study and risk factor

Flnminghem Aumny    Chicago Gee    Chicago W.E.    Tecunueh

Myccardial infarction or CHD death

SBP            0.3373      0.2695      0.3123        0.2511        0.5633
DBP            0.3126      0.2645      0.3169         0.2797        0.5059
chol~ml        0.3433      0.3614      0.2665        0.3271        0.7KIl'
Relative weight     0.2775      0.2365      0.1496         0.0703        40136
Smoking         0.3115      0.1450      0.6964'        0.3049        0.5133

Death all cauwa

SBP            0.4671      0.4671
DBP            0.3664      0.4006
ChOleetelUl        0.1155      0.1321
Relative weight     0.0540     -0.1452
Smoking         0.3676      0.3745

0.4102
0.2426
0.1615
-0.0921
0.5606

CHD death

SBP            0.4860      0.3103      0.3663
DBP            0.4136      0.3394      0.2816
Cholesteml        0.2872      0.2550      0.2474
Belative weight     0.3223      0.0490      0.1967
SmOlKing         0.3327      0.4612      0.6060

0.4166
0.3362
0.0796
0.1645
0.3226

0.3212
0.4056
0.2344
0.0765
0.2311

0.2926
0.4906
0.4533 '
Am214
0.5546

0.5331
0.5518
0.6566'
0.0453
0.4623

' Differs signifiaratly from Framingham (p< .cw.
`DiEfee eigdicmtly from Fmmi&am (p < .01X

NOTE: The coeff~cienta here are given in leas precision for eae ofcomparim~. For each oxfikient in the atudien
other than Fmmingham. a teat statistic was calculated ta teat whether it differed significantly from the
compmable mefftient for Fnunii. Thaw that did were appropriately marked. The test etatidic in the
differma between the coeficients divided by the atanderd error of the differenm. The standard error of tbe
difference in calcul&ed by taking the quare root of the sum of the variance of the meffkienta. Under appropriate
nolwllity aLlmmption0, tlh statietic in B standard normel deviat.e.
SXJRCE: Mccee end Gordon w93.

cholesterol, slightly greater prevalence of excess body fat, and less
frequent regular exercise. The risk scores of cases in comparison
with noncases were significantly higher with RISK0 and with the
Framingham Risk Index. In stepwise discriminant analysis, the
Framingham Risk Index and RISKO, separately and in combination,
identified the group with elevated levels of risk factors that
experienced a higher incidence of CHD than the group with low
levels of the risk factors.

Blacks and Whites in Evans County, Georgia

In looking for an explanation of the large difference in CHD
incidence rates between black and white men in the Evans County
study (see above), the incidence at different levels of risk factors was
evaluated (28, 107, 258). Although cigarette smoking and other risk
factors were strongly related to the incidence, differences in baseline
characteristics did not appear to explain the higher rates of CHD in
white men. However, white and black sharecroppers and farm

132


TABLE 24.-Standardized multivariate logistic coefficients
       for deaths from myocardial infarction, CHD,
      and all causes, by study and specified set of
        risk factors

Mb   MbY    Chicago Gas    Chicago W.E.    Tecumaeh

Myoaudkl infarction or CHD death

SBP            0.3432      0.2426      0.3376         0.2342        0.5524
Cholenteml        0.2905      0.3534      0.2187         0.3056        0.7989'
smo!&lg         0.3374      0.4227      0.7010 '        0.2820        0.5509

DBP           0.3022      0.2725      0.3694         0.2680        0.5222
Choleateml        0.2893      0.3462      0.2176         0.2979        0.7705 '
Smoking         0.3352      0.4359      0.7240 '        0.2934        0.5647

Death all caueea

SBP
Choleeteml
Smoking

DBP
Choleateml
Smoking

CHD death

SBP
ChOk.BtMO\
Smok@

DBP
Cholesteml
Smoking

0.5483      0.4254      0.4495         0.275 '        0.4742
0.0209      0.0992      0.1307         0.0260        0.4617 '
0.4845      0.3453      0.6033         0.3206        0.5614

0.4306      0.3983      0.2855         0.3382        0.4971
0.0279      0.0937      0.1339         0.0145        0.4391'
0.4855      0.3638      0.6012        0.3372        0.5880

0.5292      0.2897      0.3936         0.2981        0.5720
0.2033      0.2406      0.1661         0.2025        0.9164'
0.4027      0.4107      0.8076        0.2092        0.4989

0.4200      0.3126      0.3309         0.3799        9.5752
0.2038      0.2324      ox@3         0.1995        0.8918'
0.3806      0.4273      0.8200        0.2273        0.5140

' Differs signiicantly from Framingham (p < .06).
`Differs migniticantly from Framingham (p< .Ol).

NOTE The coefficients here are given in less precision for ease of comparison. For each coeffkient in the studies
other than Framingham, a test statistic wan calculated ta teat whether it differed significantly from the
comparable coefkient for Framingham. Thana that did were appropriately marked. The test statistic in the
differma, between the coeffacienta divided by the ntandanl error of the difference. The standard error of the
difference ia calculated by taking the equare root of the sum of the variance of the coeffkients. Under appropriate
aormatity assumptions, this stabtic is a standard Norma deviate.
SOURCE: Mccse and Gordon wm

laborers had similarly low incidences, but the numbers of cases were
too few for more definitive analysis of the influence of occupation
(29). At all levels of the major risk factors, the incidence of CHD was
higher in white than in black men, but some differences were
smaller in the higher ranges of the risk factors. The absolute rates
for white men were higher than for black men whether they were
smokers (including ex-smokers) or nonsmokers, but the relative risk
for white male smokers compared with nonsmokers was 2, whereas
the relative risk in black male smokers compared with nonsmokers
was 3 (107).

Multivariate analyses were performed to evaluate differential risk
between the black and the white men in Evans County (146). A
multiple logistic model for the white men was developed using as

133


explanatory variables smoking, diastolic blood pressure multiplied
by age, abnormal electrocardiogram, and cholesterol multiplied by
age. This predicted the total incidence and the cases by decile of risk
quite well among the white men. When this model was applied to the
risk factor levels of the black men ranked by decile of relative risk,
four times as many cases were predicted as had been observed (54
predicted, but only 13 actually observed). However, when the
multiple logistic model was constrained by an appropriate constant,
the number of cases fit the black data satisfactorily. This is
consistent with the view that cigarette smoking and the other risk
factors are as important in the blacks as in the whites, but that the
blacks were protected by some factor that was not accounted for in
the analysis (146).

The Seven Countries Study

In the Seven Countries study, the risk of CHD in U.S. railroad men
resident in the northwest sector of the United States was compared
with the risk of CHD in men living in contrasting environments in
Europe and Japan. In the Pooling Project, the U.S. railroad men
were found to have levels of risk factors comparable to the other
principal cohorts, but the total number of cases was 16 percent lower
than the number predicted by average parameters of the Pooling
Project data.
`I'he relationships of risk factors measured at entry to the
subsequent incidence of CHD were less uniform in those cohorts of
the Seven Countries study with a low incidence of CHD events, and
the absolute incidence at specified levels of the risk. factors was
significantly different.
With parameters developed from the data of the U.S. railroad
cohort and using the risk factors cigarette smoking, systolic blood
pressure, serum cholesterol, body mass index, pulse rate, and age,
226 CHD deaths were predicted for the northern European cohorts,
whereas 272 CHD deaths were actually observed. Although the
predicted number of cases based on the experience of U.S. railroad
men underestimated the number observed in the northern European
cohorts by 20 percent, there was excellent correlation between
predicted and observed cases by decile of risk. Furthermore, the
absolute rate in the northern European cohorts was close to that
predicted by average U.S. experience as observed in the Pooling
Project.

In contrast to the northern European cohorts, the southern
European cohorts had substantially fewer CHD deaths than were
predicted by the multiple logistic equation based on the experience of
the U.S. railroad cohort. As shown in Figure 14, 66 percent more
cases were predicted than observed; however, rank order by decile of
risk correlated closely (r = 0.92). Consistent with these differences,

134


E
z 25

2 20
8
g 15,

Total number of cases of
myocardlal ~niarct~on
or coronary death
   Predlcled = 69 2
   Observed = 151

0     5    10    15    20 25    30    35
     X= "HARD" CASES PREDICTED IN DECILE

FIGURE 14.-Ten-year incidence of coronary death or
myocardial infarction (hard CHD) in northern Europe, in
the deciles of probability estimated from the logistic
coefficients from the data on the men in southern Europe
and the number of such incidence cases actually observed
in those deciles
SOURCE: Keys (14.3.

Predicted = 35.9
Observed = 91

0  2  4  6  8  10 12 14 16 16 20
x=CHD DEATHS PREDICTED IN DECILE

FIGURE 15.-Ten-year deaths from coronary heart disease
in northern Europe, predicted in the deciles of probability
estimated from the logistic coefficients from the data on
the men in southern Europe and the number of coronary
deaths actually found in those deciles
8om Keya w3l.

135


multivariate equations for CHD incidence and for CHD deaths based
on southern European experience underpredicted CHD incidence
and death rates for the cohorts in northern Europe by a factor of 2.5
(Figures 14 and 15). Nevertheless, by rank order of risk, correlation
between predicted and observed events was excellent (r = 0.98).

These detailed comparisons of the results from major epidemiolog-
ic investigations of CHD incidence do indicate that there is excellent
agreement in the relationships of cigarette smoking and the other
risk factors to the subsequent development of CHD in white men
living in the United States and northern Europe. The agreement is
close enough so that risk of CHD may be predicted well by the level
of the major risk factors, using equations that are largely inter-
changeable among widely separated cohorts living in these different
regions.

136


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156


SECTION 4. CEREBROVASCULAR
        DISEASE

157


Introduction

Death rates from stroke have been declining in developed coun-
tries since the 1920s (28). Between 1968 and 1975 there was a sharp
decline in the age-adjusted mortality rates from coronary heart
disease, cerebrovascular diseases, and all major cardiovascular
diseases among U.S. white and nonwhite males and females (50). As
shown in Table 1, the decrease is close to 33 percent for stroke.

Additional major reductions in disability and death from stroke
can come largely from preventive measures, not from further
innovations in treatment of the completed catastrophe. Formulation
of a preventive program is greatly aided by an understanding of the
epidemiology of cerebrovascular disease, including the chain of
circumstances leading to its occurrence, the identity of vulnerable
subgroups of the population, the existence of modifiable predisposing
factors, and the natural history of the disease.

Magnitude of the Problem

Cerebrovascular diseases, both ischemic and hemorrhagic, are a
public health problem of major proportions. They constitute the
third leading cause of death, after coronary heart disease and cancer,
and are responsible for 9 percent of all deaths in the United States
(33). There are about 1.8 million stroke victims in the United States,
and about a half-million new events occur each year; there are
approximately 200,000 deaths annually in the United States from
strokes. In the Framingham study it was estimated that the chances
of suffering a stroke before age 70 are 1 in 20. The incidence was
found to double in each successive decade after age 45. Although
stroke incidence becomes substantial only after age 65,20 percent of
strokes occur before that age. In men, the average annual incidence
of atherothrombotic brain infarction is only one-third that of
myocardial infarction, with stroke incidence lagging behind myocar-
dial infarction by more than 10 years. In women, on the other hand,
brain infarction incidence and myocardial infarction incidence are
virtually identical (56). The reasons that brain infarction is manifest-
ed later in life than CHD in men and exhibits little male predomi-
nance are unclear. In the United States, stroke mortality is higher
among blacks than among whites, and the difference decreases with
age.

The Stroke Entity

There are three major specific forms of cerebrovascular diseases:
(1) cerebral insufficiency associated with transient blood flow
deficiencies; (2) cerebral infarction caused either by the blocking of a
vessel by an embolism or by thrombosis; and (3) cerebral hemor-
rhage, including parenchymal and subarachnoid. The terms "stroke"


TABLE l.-Percentage of change in mortality rates of
      causes of death in persons aged 35 to 74, by
      sex and color, United States, 1966-1976

Percentage of change

Cause of death

white
men

white     Nonwhite
women      men

NOklWhit.+
women

All

Coronary heart disease        -21.0     -26.5      -30.7       -39.1     -24.3
Cerebrovascular diseases        -30.6     -30.4      -43.7       -47.1     -32.7
Major cardiovascular diseasea     -20.9     -26.1      -33.2       -40.7     -24.6

All causes                -15.3     -16.4      -24.0       -32.7     -17.3

SOURCE: Stamler Go).

and "cerebral vascular accident" are nonspecific; they refer to a
variety of clinical entities and are usually used in reference to
syndromes accompanying ischemic or hemorrhagic lesions.

The underlying process of a stroke may be an atheroma (i.e., fatty
deposit in the inner lining of an artery wall), thrombosis, embolism,
a bleeding disorder, a developmental anomaly, an aneurysm, inflam-
mation, failure of flow, or increased blood viscosity. The chief causes
of cerebral ischemia are atherothrombosis and embolism. Intracrani-
al hemorrhage is generally due to hypertensive intracerebral
hemorrhage, rupture of a saccular aneurysm, or bleeding from an
arteriovenous malformation. A cerebral embolism usually originates
in the heart, particularly when atria1 fibrillation, rheumatic valvu-
lar deformity, myocardial infarction with a mural thrombus, or a
valve prosthesis is present; it may also arise from ulcerated
atheroma in the carotid, vertebrobasilar, or middle cerebral arteries.
The main trunk of the middle cerebral artery and its branches are
the most common sites for the formation of intracranial thrombosis.

The reliability of stroke diagnoses and case ascertainment in
diverse populations has presented problems for epidemiological and
clinical research. With the fairly recent development of new
technology such as computer-assisted tomography, however, the
accuracy and the quality of differential diagnosis as to type of stroke
are improving. It is unlikely that any single etiology or set of risk
factors applies equally to all types of stroke. Atherothrombotic brain
infarction is the most common variety of stroke, accounting for
about 59 percent of the total number of strokes in the Framingham
population (56).

Cardiovascular Risk Factors

Since the underlying pathologic features of atherosclerosis in the
cerebral, cardiac, and peripheral circulation are virtually identical,

160


it is not unexpected to find that they share a number of precursors.
Although some significant differences in their impact exist, there are
a number of modifiable risk factors common to brain and myocardial
infarction (22). In fact, when five major cardiovascular risk factors
(systolic blood pressure, serum cholesterol, glucose intolerance,
cigarette smoking, and electrocardiogram-left ventricular hypertro
phy (ECG-LVH)) are considered jointly as a cardiovascular risk
profile, they are actually more highly predictive of brain infarction
than of coronary heart disease (24). The top decile of multivariate
risk using this profde identifies half the strokes evolving in the
Framingham population, compared with only 25 percent of the
coronary events (22). However, for cerebrovascular @isease, systolic
blood pressure and ECG-LVH were the chief determinants of this
multivariate predictive capacity. In addition to these risk predictors,
various cardiac impairments such as coronary heart disease, cardiac
failure, and atria1 fibrillation are major predisposing factors (55).
Cigarette smoking, which is a major predictor for coronary heart
disease, has been less consistently predictive for cerebrovascular
disease; but nevertheless appears to play a significant role among
men at younger ages.

Hypertension

A consistent finding in epidemiologic studies is that elevated blood
pressure is the most important risk factor for stroke. This seems to
apply for virtually all varieties of stroke (56). It is the key risk factor
for intracerebral hemorrhage, occlusive cerebral vascular disease,
and perhaps subarachnoid hemorrhage (28). About 50 to 60 percent
of strokes occur in the 20 percent of the population with definite
hypertension. Hypertension predisposes powerfully to stroke at all
ages and in both sexes, and even mild elevations in blood pressure
double the risk. The stroke risk for isolated systolic hypertension is
substantial, and the exclusive use of diastolic pressure to judge the
risk in the elderly with systolic hypertension can be misleading. No
component of blood pressure, including the pulse pressure, mean
arterial pressure, or diastolic pressure, is more closely related to
stroke incidence than systolic pressure (25). Also, lability of the
pressure has not been shown to reduce the risk, and it is not safe to
use the lowest pressure recorded to determine whether treatment is
indicated.

Blood Lipids

Lipids and their lipoprotein vehicles, closely linked to coronary
disease incidence, are of uncertain importance for stroke. Neither
cholesterol nor triglyceride levels have any predictive value beyond
age 55, when strokes are common, and partition of the serum total
cholesterol into its atherogenic low density lipoprotein (LDL) and

161


protective high density lipoprotein (HDL) components does not
clarify the role of cholesterol in stroke as it does for coronary heart
disease in advanced age (II). In women there is actually a paradoxi-
cal, strong negative association of brain infarction incidence with
LDL cholesterol. This inverse relationship to atherogenic cholesterol
has also been noted in Japanese men and for intracerebral hemor-
rhage (19). Hence, further clarification is needed.

Glucose

Atherothrombotic brain infarction incidence is increased threefold
in diabetics. In contrast to coronary heart disease, the impact of
impaired glucose tolerance does not diminish with advancing age
and is not greater for women than for men. The effect of diabetes
mellitus is independent of other risk factors, but is greatly influ-
enced by coexistent hypertension or cardiac disease (23).

Cardiac Disease

Even if asymptomatic, cardiac changes such as EC!G-LVH, cardiac
enlargement on X-ray, atrial fibrillation, coronary disease, cardiac
failure, or rheumatic heart disease powerfully predispose to the
occurrence of strokes. ECG-LVH is the most powerful EZG predictor.
Atrial fibrillation, chronic as well as intermittent, increases stroke
risk sixfold, and when accompanied by rheumatic heart disease,
seventeenfold (55). Although each contributes independently to risk,
coexistent hypertension further augments the risk associated with
any cardiac impairment.

Environmental Factors

Few modifiable environmental contributors to stroke incidence
have been convincingly demonstrated. The demonstrated association
of obesity with stroke incidence appears to derive mainly from the
higher blood pressure and glucose intolerance that it promotes.
Physical activity is weakly and inconsistently related to stroke
incidence (55). The apparent influence of coffee intake disappears on
adjustment for coexistent alcohol and cigarette use. Alcohol seems to
be associated with an increased risk of stroke in some studies,
possibly because of higher blood pressure in alcohol users.

Cigarette Smoking

The contribution of cigarette smoking to the incidence of stroke
may vary depending on the type of stroke or clinical manifestation of
cerebrovascular disease. The evidence for such a relationship
suggests that smoking is more strongly associated with premature
(i.e., before age 55) and nonfatal strokes than with fatal strokes (22).

162


With 16 years of followup data on 293,000 insured U.S. veterans,
Rogot and Murray (43) reported that 653 excess stroke deaths were
associated with cigarette smoking, producing a mortality ratio of
1.47. Earlier, with 8.5 years of followup, Kahn (21) had found stroke
mortality to be 1.4 times higher in smokers and rates to increase
with amount smoked. In the more recent study, a slight dose-
response relationship was found for both current and ex-smokers,
with mortality ratios lower among former smokers than among
current smokers. Mortality ratios for stroke were near unity for
smokers of only cigars or pipes-l.07 and 0.99, respectively (43). A
study of 54,460 men employed in British industries revealed no
relationship between the cigarette habit and stroke mortality over 3
years, but demonstrated a threefold excess coronary mortality (3).
Kuller (28), in a review of the epidemiology of stroke, concluded
that there was no consistent evidence of a relationship of cigarette
smoking to stroke in several population and casecontrol studies.
Data after 24 years of followup in the Framingham study showed no
overall statistically significant relationship between the incidence of
atherothrombotic brain infarction (ABI) and cigarette smoking
among males. The stroke incidence was lower in nonsmoking males
only between the ages of 45 and 54, and no clear dose-response was
evident (56'). In a comparison of stroke prevalencenot specified as
to type-among Japanese in Japan, Hawaii, and California, prelimi-
nary analyses revealed positive correlations between stroke and
increased blood pressure, ECG-LVH, and cigarette smoking for all
ages (20). Paffenbarger et al. (37) found no relationship between
cigarette smoking and stroke in a 22-year followup of 3,666 long-
shoremen.
In an earlier study of chronic diseases among male former
students at Harvard, Paffenbarger and Wing (38) noted a slight
excess of nonfatal stroke among those who had smoked during
college. They also found that hypertension, overweight, and short
stature were predisposing characteristics for stroke in later life. The
data must be interpreted with some caution, however, because they
were abstracted from existing school records and the smoking
information was not collected in a standardized manner. In a
Canadian retrospective study (I), a relative risk of 2.4 (p < 0.001) was
found for stroke and smoking, but these results are also subject to
potential bias in the recording of the smoking history.
Hammond and Horn (15) studied the relationship between smok-
ing and disease among 187,783 white men, 50 to 69 years old,
followed from May 1952 through October 1955. Of the 11,870 deaths
during this period, 1,050 were from cerebral vascular lesions. A
statistically significant mortality ratio of 1.30 was found for smokers
and a dose-response relationship was apparent.


TABLE 2.-Mortality ratioa for cerebrovascuhr disease
      related to smoking, United &a* 19691

Mortality ratioa (iV=4,099), by age

M/daY         40-49        50-a        60-69        70-79

Never emoked
1-9
lo-19
20-30
>a

Never emoked          1.00
l-9               1.60
lo-19               2.60
m-30              2.90
>m               5.70'

1.00
2.79

1.14
2.21

1.94

Males
   1.00
   1.96
   1.48
   2.03
   2.40

Femalea
    1.00
    1.26
    2.70
    2.37
    3.62'

1.00         1.00
1.90         0.95
1.44'         0.92.
1.62         1.22
1.72         0.63'

1.00
126
2.16
1.83

1.00
0.83
0.67 a
1.29
-

In a large-scale prospective study of male British physicians, Doll
and Hill (8) found that the results differed somewhat between the
10th and 20th year of followup. A stroke mortality ratio of 1.2 was
found for smokers at the lO-year followup, with no dose-response
relationship evident. After 20 years of followup, a relative risk for
cerebral thrombosis of 1.52 was found for heavy smokers and a
strong dose-response relationship was apparent (9).

In an analysis of the 1,094 deaths that occurred among female
British physicians who had been followed for 22 years, Doll et al. (7)
found no effect of smoking on mortality from cerebral thrombosis;
however, there were only 66 such deaths.

The American Cancer Society studied prospectively more than a
million men and women enrolled in 1959, following them for 13
years. With 6 years of followup, mortality ratios for cerebral
vascular disease were found to be increased among male and female
smokers compared with nonsmokers, with the highest ratios evident
among the 40- to 49-year-olds (Table 2). The excess risk was not
present in either sex past age 70. There was no significant dose-
response relationship (13, 14).

A study of the differences in mortality ratios by the type of
cigarette smoked (29) and a later analysis of data from the American
Cancer Society study indicated lower mortality ratios from stroke
among males who smoked low tar and nicotine or filtered cigarettes
than among smokers of higher tar and nicotine cigarettes or of
"plain" cigarettes (6). No such differences were found among

164


females. A study conducted by the Tobacco Research Council in
England showed mortality ratios that were lower, but not signifi-
cantly so, among smokers of lower tar and nicotine cigarettes (s).

In 1965, Ostfeld began a prospective study among random samples
of the elderly in Cook County, Illinois, to determine variables
associated with stroke. They found that stroke-prone persons can be
identified even among the elderly. Stroke risk was higher among the
blacks and among persons with preexisting cardiovascular disease,
transient ischemic attacks (TIAs), diabetes mellitus, or hypertensive
cardiovascular disease. Cigarette smoking was, however, unrelated
to any class of stroke in the elderly, with or without preexisting
cardiovascular precursors (36).

Kimura (26) reviewed the results of six prospective studies of
cardiovascular disease in Japan and found a correlation of cigarette
smoking with myocardial infarction when accompanied by abnor-
malities in serum cholesterol and blood pressure; no relationship of
cigarette smoking to stroke was noted. Okada et al. (34) studied
stroke prospectively in Japanese men 40 years old or older residing
in two rural communities and found relative risks of intracerebral
hemorrhage and brain infarction among nonsmokers that were not
statistically significantly lower than those in smokers.

In an &year prospective study of a random sample of 35- to 59-
year-olds in two counties in eastern Finland, age, blood pressure,
diabetes mellitus, and previous stroke were found to be predictive of
stroke incidence in both men and women. Cigarette smoking and
serum triglyceride levels were found to be positively associated with
stroke among men, but not among the women (47). In an effort to
predict coronary heart disease and other mortality rates, Menotti et
al. (32) analyzed 14 CHD risk factors using a multiple logistic
function model. The study included 1,524 men between 40 and 59
from two rural areas in Italy who were measured for all 14 risk
factors upon entry. After 15 years, 37 men had had a stroke. Of the
14 risk factors considered, age and blood pressure were the only
factors found to be significantly associated with stroke risk, ranking
1 and 2, respectively. Smoking ranked third for predicting stroke,
but was not statistically significant.

In a retrospective study (16') of 126 stroke patients and 212
matched controls in Tilburg, Holland, a significantly increased risk
of stroke associated with cigarette smoking was not found. Hyperten-
sion was found to be related to stroke, and the risk was age
dependent, being strongest among the younger patients.

An investigation in Finland (10) of 128 men and 85 women under
50 years of age with ischemic stroke revealed 1.5 times as many
cigarette-smoking men and three times as many cigarette-smoking
women in the stroke group as in the Finnish population of the same
age. Hypertension, abnormal electrocardiographic findings, and oral

165


contraceptive use in women were also shown to increase risk. In a
large prospective study (40) of women under 55 years of age in
California who were followed for 6.5 years, cigarette smoking
increased the risk of subarachnoid hemorrhage 5.7 times and use of
oral contraceptives increased it 6.5 times. The relative risk was 21.9
among women who both smoked and used the pill compared with
nonsmoking nonusers. In a case-control study (4) involving 12
university hospitals, 598 nonpregnant women with strokes between
age 15 and 44 were identified. Compared with controls, current use
of oral contraceptives was considerably higher in women with
thrombotic strokes (ninefold) and somewhat higher in women with
hemorrhagic strokes. It was also found that 74 percent were current
or past smokers. In an investigation of 75 hemiplegics aged 18 to 50
years, Steinmann (51) found that cardiac disease and hypertension
were the predominant risk factors. In men, but not in women, heavy
smoking was a risk factor.

Further confirming the general impression that cigarette smoking
is a stroke risk factor in young men are the results of three cas+
control studies. Among 100 male stroke patients, aged 40 to 69, Koch
et al. (27) found a relative risk of 11.2 for smokers of more than 20
cigarettes a day. In a study (30) of 56 male and 34 female patients
under 66 years of age with cerebral hemorrhage or infarction,
significantly more stroke patients than their matched controls were
found to be smokers, and more smoked at least a pack of cigarettes a
day. Other factors predisposing to stroke in this study population
were high blood pressure, oral contraceptive use, and a family
history of stroke, plus cerebral neoplasm and thrombocytopenia. In
another study (521, among 39 male and 28 female ischemic stroke
patients, cigarette smoking was found significantly more frequently
among male cases than among matched controls. In the young
females, use of oral contraceptives was the predominant risk factor.

Haberman et al. (12) summarized mortality and incidence studies
dealing with smoking and stroke (Tables 3 and 4). They pointed out
that the relationship between smoking and cerebrovascular disease
is not a uniform finding of the epidemiologic studies of this disease
process. The authors cautioned that the studies are not strictly
comparable because of variations in methodologies, but they suggest-
ed that an association between smoking and stroke may exist but be
age dependent. An age dependency is suggested by the Framingham
and Paffenbarger studies.

Transient Ischemic Attacks

Some evidence connects cigarette smoking with transient ischemic
attacks (TIA). In a 6year followup for TIA of 7,895 men aged 45 to 68
years in the Honolulu heart study (411, prior cigarette smoking was

166


TABLE 3.-Results of stroke incidence studies

Study      Type'

Date

Relationship between
stroke and smoking'

Approximate
relative risk

HiX&ii
WaShiIlgtOll

Framingham
Manitoba
Rural Japan
Harvard
Walnut Creek
Bu- sg-

P
P

195a64
1961-71

194%73
197c-71
1964-70
1916-66
196%76
1965-78

CI
Stroke
CI
ABI
CI
Stmke
Nonfatal CI
SAH

None
None
None
Yes. Not Sip
Yea. Sig?
Yea. Not sig
Yes. SLg
Yes. sii
Yes. Sig?

0.9
0.8-1.1
1.1-2.7 (males)
2.4
1.9-2.7
1.6
5.7
3.8

' P denoted prospective; R denotes retmspxtive.
`CL oerebml infarction; AEU: atbemthrombotic brain infarction; SAH: subarachnoid hemorrhage
`? denotes doubt about the 8tudy de&x
SOURCE: Haberman et al. uzl.

TABLE 4.-Results of stroke mortality studies

NaUh?

Type'

Date

Relationship between
stroke and smoking

Approximate
mortality ratio

LQ*0Mll&?Il
WaShillgtOll
Harvard
rkml
British doctora
(10 year)
British docton,
(20 year)
American Cancer
Swiety

P       196149         None             1.1
P, R      1962-71         None             0.9
P       1916-66         YeS              2.1
P       1964-62         Yea             1.3-1.9


P        1961-61         None             1.2


P'       1961-71         Yes             1.1-1.5


P       1959-65         Yes            1.3-2.8

' P denota pmnpective; R denotea retrcapective
`Baaed on cerebral thmmlmia ody.
SOURCEz Ii&m- et d. (Ia).

associated with TIA, even in multivariate analysis taking other risks
into account. However, Ostfeld et al. (3s) found conflicting results.

Subarachnoid Hemorrhage

A retrospective study (2) of patients with subarachnoid hemor-
rhage demonstrated an association with cigarette smoking. In this
study, smoking was estimated to increase the risk of a subarachnoid
hemorrhage almost fourfold in both sexes. In the Walnut Creek
contraceptive study this was confirmed, with a 5.7-fold increased risk
compared with nonsmokers (39). Also, in a 6.5year followup of this
cohort of 16,759 white middle-class women aged 18 to 54, cigarette
smoking was associated with a fivefold to sevenfold relative risk of
subarachnoid hemorrhage and also with a 4.8fold risk for other
strokes (40).

167


Smoking Cessation

Controlled clinical trial data measuring the effect of smoking
cessation on cerebrovascular disease are not available; observational
studies have been published. In the 16year followup of 293,000
insured veterans (43), specific causes of death were studied in
relation to smoking status. Mortality ratios for ex-smokers were
found to be much lower than for current smokers. For stroke, the
mortality risk for the ex-smoker rapidly returned to the nonsmoker
rate after the cessation of smoking. Koch et al. (27) found an
increased risk of stroke in young patients that was not detectable in
ex-smokers after 1 year.

Oral Contraceptives

Oral contraceptives (OCs) have been widely used for more than 20
years, and many reports suggest that women who use them are at
increased risk of stroke (4, 5, 18, 44, 53, 54). Firm, undistorted
prospective data on the risk of cigarette smoking in women taking
OC!s are sparse, owing to the generally low incidence of stroke in
women of childbearing age. Reliance is placed chiefly on retrospec-
tive data subject to unavoidable selective bias or on multicenter
prospective data based on small numbers of events. Such data as
exist strongly suggest a synergistic effect of smoking and oral
contraceptives that may be related to "hemorrhagic stroke" (42, 46).

In 1969, the Walnut Creek Contraceptive Drug Study began a long-
term study of the effects of OC use on the health of women aged 18 to
54 at study initiation. After 6.5 years of followup, Petitti and
Wingerd (39) analyzed the data from 15,260 women. The authors
found relative risks associated with OC use of 6.5 and 7.6 for
subarachnoid hemorrhage and thromboembolism, respectively. The
risk of subarachnoid hemorrhage for smokers was 5.7 times that for
nonsmokers; the relative risk of subarachnoid hemorrhage for
women who smoked and used oral contraceptives was 21.9. Among
the small number of ex-users, past use significantly increased the
risk of subarachnoid hemorrhage, but not of other vascular diseases
(39). In another study, cigarette smoking in itself was evidently not a
demonstrable risk factor for stroke among women, even at an early
age (42).

In a two-part review article, Stadel(48, 49) indicates that CC use
multiplies, rather than adds to, the risk of age and other factors in
the development of myocardial infarction (MI) and stroke. On the
basis of a total of only 31 cases reported in two studies and 134
reported in a third, Stadel (49) further indicates that current and
past use of OCs appears to increase the risk of subarachnoid
hemorrhage in women near age 35 or older (17). Stadel suggests that
the risk of cardiovascular disease among current users of oral

168


TABLE B.-Annual death rate for oral contraceptive users
     related to age, duration of use, and smoking
       habits

User characteristic                 Annual death rate

       AgegrouP

         1634 years
        MY-
         4549 year8


         Duration of use

        <By--
         >5years

       Smoking habit

          Nonsmoker
          Smoker

SOURCE: McQusen (31); Royal college ofoemml Ractitionen (II).

1 per 20,GOo
1 per 3,ooo
1 per 700



1 per S,ooo
1 per 2,ooo



1 per 10,ooo
1 per 3,ooo

contraceptives is related to the estrogen and progestogen content of
the pill.

A large prospective study in England (46,000 British women) found
that both the incidence and the mortality rates of a variety of
diseases, including cerebrovascular disease, were increased among
users of oral contraceptives versus nonusers (4s). The number of
stroke deaths in the Royal College of General Practitioners (RCGP)
study was small; thus, risk estimates were subject to error. Women
over 35 and women who smoked and took oral contraceptives were
found to be at substantially higher risk than were nonsmokers and
nonusers of GCs.

Additional analysis of the RCGP study including followup through
1976 showed that current or previous users of oral contraceptives
had a standardized mortality rate for cerebrovascular disease 4.7
times that of controls. Increases in total death rates were found
among older women, women who had used the pill for 5 or more
years, and women who smoked cigarettes (44) (Table 5).

Results from a c ase-control study conducted by the Collaborative
Group for the Study of Stroke in Young Women (5) showed that
cigarette smoking and the use of oral contraceptives were indepen-
dent risk factors for subarachnoid hemorrhage; the relative risk was
2.6 for smokers and 4.1 for users of GCs. When a heavy smoker also
took oral contraceptives, the risk increased to 6.1 or 7.6, depending
upon the control group used for comparison. In an earlier report, the
same group (4 reported that risk of cerebral ischemia or thrombosis
was approximately nine times greater among women using oral
contraceptives than among nonusing controls. They also reported

169


lower incidence rates among black women than among white women
and that more of the cases than of the controls were or had been
regular smokers.
The data suggest that cigarette smokers who use oral contracep
tion are at significantly increased risk of stroke and that this risk
may result from a synergistic interaction between cigarette smoking
and the use of oral contraceptives.

Preventive Implications

Declining trends in stroke mortality and the marked geographic
variation suggest that cerebrovascular disease may not be an
inevitable consequence of aging or of genetic makeup. High risk
candidates can be identified using a general cardiovascular risk
profile. There is as yet no conclusive evidence that intervening to
lower lipids, reduce overweight, provide exercise, treat diabetes
mellitus, or stop cigarette smoking will in fact reduce stroke risk.
However, former cigarette smokers appear to have a lower risk of
stroke than do continuing smokers.

The key to stroke prevention is early, vigorous, sustained control
of hypertension and the cardiac impairments that escalate the risk.
Cigarette smoking cessation may also play a role, particularly in
young male stroke candidates or in women using oral contraceptives.

Summary

A preventive approach to stroke is imperative because central
nervous system damage often leads to an irreversible functional
deficit. Less than a third of stroke victims have symptoms warning of
the impending stroke. The similarity of factors predisposing to
stroke and those increasing susceptibility to coronary heart disease
and congestive heart failure indicates that vascular disease of the
brain is part of a larger problem of cardiovascular disease. The
measures indicated for prevention of stroke include those recom-
mended for prevention of coronary heart disease, occlusive peripher-
al arterial disease, and congestive heart failure. Hypertension is
clearly the major contributor to stroke incidence. Cigarette smoking
also contributes, especially in younger populations, and may be
important because of its demonstrated relationship to coronary
heart disease and congestive heart failure, which powerfully contrib-
ute to stroke risk. Cigarette smoking cessation is indicated as part of
a comprehensive program of risk factor modification to avoid
atherosclerotic cardiovascular disease, including stroke.

Women cigarette smokers experience an increased risk for sub-
arachnoid hemorrhage; the use of both cigarettes and oral contracep-
tives appears to synergistically increase this risk.

170


Conclusions

1. Data from numerous prospective mortality studies have shown
an association between cigarette smoking and cerebrovascular
disease. This risk is most evident in the younger age groups, and
the effect diminishes with increasing age, with little or no effect
noted after age 65. No consistent dose-response effect has been
demonstrated.

2. Women cigarette smokers experience an increased risk for
subarachnoid hemorrhage. However, the use of both cigarettes
and oral contraceptives greatly increases the risk for subarach-
noid hemorrhage among women.

171


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(48) STADEL, B.V. Oral contraceptives and cardiovascular disease (First of two
   parts). New England Journal of Medicine 30X11): 612-618, September 10,
    1981.

(49) STADEL, B.V. Oral contraceptives and cardiovascular disease (Second of two
   parts). New England Journol of Medicine 30X12): 672-677, September 17,
    1981.

(50) STAMLER, J. What is happening with coronary heart disease in the United
   States? In: Hayaae, S., Murao, S., MacArthur, C. (Editors). Cardiology.
   Proceedings of the VIII World Congress of Cardiology, Tokyo, September 17-
   23,1978.

(51) STEINMANN, B. Zur Pathogenese der Apoplexie im Alter unter 50 Jahren.
   [On the pathogeneeis of apoplexy in pereons below 50 years of age.]
   Schweiterische Medizinieche Wochemchrift 99(31): 109%1196,1969.
(52) TURNHEIM, M., HAVELEC, L., HEISS, W.-D., SUMMER, K. Eigenarten
   iachaemischer insulte bei jungen Emachsensen. [Characteristic features of
   ischemic strokes in young adults]. Weiner Klinische Wochenechrifl 89(4):
   106110,1977.

(53) VESSEY, M.P., DOLL, R. Investigation of relation between use of oral
   contraceptives and thromboembolic disease. British Medico1 Journal
   2(6599): 199-295, April 27,1966.

(54) VESSEY, M.P., DOLL, R. Investigation of relation between use of oral
   contraceptives and thromboembolic disease. A further report. British
   Medico1 Joumol2@658): 651657, June 14,1969.
(55) WOLF, P.A., DAWBER, T.R.. KANNEL, W.B. Heart disease as a precursor of
   stroke. In: Schoenberg, D.S. (Editor). Neurological Epidemiologv Principles
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   Raven Press, 1978, pp. 667677.
(56) WOLF, P.A., DAWBER, T.R., THOMAS, H.E., Jr., KANNEL, W.B. Epidemic
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   Framingham study. NeuruZogy 28(10): 973-977. October 1978.

175



SECTION 5. ATHEROSCLEROTIC
        PERIPHERAL
        VASCULAR DISEASE
        AND AORTIC
        ANEURYSM

177


Atherosclerotic Peripheral Vascular Disease

Introduction

The peripheral arteries include those branches of the aorta
supplying the upper and lower extremities and the abdominal
viscera. Most peripheral arterial occlusive disease is due to athero-
sclerosis, although other conditions such as fibromuscular dysplasia,
muscular entrapment, cystic adventitial degeneration, and arteritis
may cause obstruction of the peripheral arteries. Symptomatic
atherosclerotic peripheral vascular disease (ASPVD) occurs most
often in the vessels of the lower extremities. The anatomic location
of such disease is usually classified according to the major arterial
segments involved, including aortoiliac, femoro-popliteal, and tibio-
peroneal artery occlusive disease. Occlusive lesions of the origins of
visceral arteries commonly involve the renal arteries and the
mesenteric arteries, including the celiac and superior and inferior
mesenteric arteries.

With many asymptomatic patients, peripheral arterial occlusive
disease can be detected on physical examination. Symptomatic
patients are usually classified according to the severity of presenting
complaints; for example, patients may be classified as suffering
intermittent claudication (leg pain brought on by exercise and
relieved by rest), ischemic rest pain, or, the most severe complaint,
tissue necrosis, including gangrene or ischemic ulceration. Patients
with renal artery occlusive disease may present with severe and
uncontrollable hypertension, although such patients may respond to
medical treatment for hypertension. Patients with arterial occlusive
disease of the mesenteric arteries may present with acute ischemia
of the intestine, due to thrombosis or embolization, or with more
chronic symptoms of pain aggravated by eating and weight loss.

The diagnosis of peripheral arterial occlusive disease can usually
be made from the history and physical examination, including the
evaluation of peripheral arterial pulsations and detection of arterial
bruits. However, more accurate and objective diagnosis of peripheral
arterial occlusive disease is possible with noninvasive diagnostic
techniques, particularly Doppler ultrasound or plethysmography.
Arteriography is reserved for patients with symptoms sufficient to
make them candidates for surgery, and is not usually required for
the diagnosis of peripheral arterial occlusive disease.

The majority of patients with peripheral arterial disease may be
candidates for medical therapy such as exercise regimens and
reduction of known risk factors through cessation of smoking,
control of diabetes mellitus, dietary measures to control hyperlipide
mia and obesity, and medical management of hypertension. Inten-
sive foot hygiene and avoidance of trauma are additional important
medical measures for patients with lower extremity ASPVD. The

179


newly developed treatment of balloon dilatation (percutaneous
transluminal angioplasty) may be used to restore pulsatile flow for
severely symptomatic patients. Surgical therapy is required in only
about 10 percent of the patients with advanced arterial occlusive
disease. One surgical approach is arterial reconstruction, usually
involving endarterectomy or bypass with vein or prosthetic grafts of
diseased segments. Sympathectomy is infrequently used, but it may
be helpful in patients with cutaneous ischemia, for whom restoration
of pulsatile flow is not possible. Amputation of limbs with advanced
arterial occlusive disease that cannot be remedied by surgical
reconstruction remains in use, but it is required by only about 5
percent of all patients presenting with peripheral arterial occlusive
disease.

Risk Factors for Peripheral Arterial Occlusive Disease

The most powerful risk factor predisposing to atherosclerotic
peripheral arterial occlusive disease is cigarette smoking (47); in fact,
the rarity of peripheral arterial occlusive disease in patients who
have never smoked was noted by Eastcott as early as 1962 (23). The
epidemiologic evidence linking cigarette smoking to atherosclerotic
peripheral arterial occlusive disease is discussed in detail below.

Several studies have suggested hyperlipoproteinemia as a risk
factor contributing to atherosclerotic peripheral arterial occlusive
disease. The type of hyperlipoproteinemia and the degree of associa-
tion with peripheral vascular disease appear to be different, how-
ever, from the hyperlipoproteinemia associated with coronary artery
disease. Zelis et al. (92) reported that patients with Type III
hyperlipoproteinemia are particularly susceptible to the develop
ment of peripheral vascular disease, and they noted objective
improvement in the peripheral circulation with medical treatment
of this disorder. Greenhalgh et al. (30) reported that fasting serum
lipid concentrations were abnormally high in 44 percent of a
consecutive series of 116 patients with proven peripheral vascular
disease. In 39 percent of the patients the serum triglyceride level was
raised, and in 15 percent the serum cholesterol level was increased.
Ballantyne and Laurie (5) evaluated 353 consecutive patients with
peripheral vascular disease and showed a predominance of Type IV
hyperlipoproteinemia in males, but a predominance of Type IIa
hyperlipoproteinemia in females. Patients with peripheral vascular
disease and Type IIa or Type Ilb hyperlipoproteinemia were more
likely to have associated coronary artery disease. Eighty-four
percent of the patients were cigarette smokers, with the majority
smoking more than 10 cigarettes daily. There was no relationship
between cigarette consumption and the occurrence of hyperlipopro
teinemia. However, Farid et al. (25) found that in 122 patients with
angiographically proved peripheral arterial occlusive disease, heavy


smoking seemed to be associated with an unexpectedly high propor-
tion of an abnormal lipid pattern: 43 percent of the males exhibited
Type IV hyperlipoproteinemia. Lawrie et al. (51) surveyed 4,477
healthy males and females in the west of Scotland and found a high
prevalence of hyperlipoproteinemia of Type II and Type IV. Hyperli-
poproteinemia occurred more frequently in survivors of myocardial
infarction, but also occurred, though to a lesser extent, in patients
with peripheral vascular disease.
Olsson and Eklund (57) evaluated 160 men and 123 women with
digit plethysmoraphy and found that most atherogenic lipoprotein
abnormalities associated with disease of the lower extremities
involved the relatively triglyceride-rich part of the low density
lipoprotein (LDL) fraction and the relatively cholesterol-rich part of
the very low density lipoprotein (VLDL) fraction. These authors
found a deleterious influence of smoking even in the preclinical
stage of peripheral vascular disease. Davignon et al. (18) evaluated
114 French Canadian patients with angiographically proved periph-
eral vascular disease. The severity of atherosclerosis correlated
positively with plasma triglyceride concentration, but cigarette
smoking was the risk factor most frequently found in patients with
peripheral vascular disease. In contrast, Erikson et al. (24) did not
find a positive correlation between arteriographic changes in 30
patients with intermittent claudication and serum concentrations of
lipids and lipoproteins. Trayner et al. (80) compared 32 patients with
peripheral vascular disease to control subjects. The vascular disease
study group had a significantly higher incidence of hypertriglycerid-
emia, more marked for the males, and had lower levels of high
density lipoproteins (HDL) than did the control subjects. The study
group also had a twofold higher prevalence of cigarette smoking
than control subjects. Control patients who smoked also had lower
levels of HDL than those who did not smoke. Phillips et al. (61) also
established a relationship between an increase of VLDL triglyceride
and cigarette smoking, while HDL cholesterol decreased with
cigarette smoking.
Hypertension is associated not only with coronary and cerebrovas-
cular disease, but also with peripheral arterial occlusive disease (46).
Larson et al. (50) established an interaction of hypertension and
hypercholesterolemia in an experimental study of mongrel dogs,
suggesting that the combination of these two risk factors produces
alterations in lipid composition in the canine aorta that appears to
be geometric rather than arithmetic in nature. However, Stehbens
(74) claimed that epidemiologic studies are less conclusive than
experimental studies in establishing the relationship of risk factors
in atherosclerosis. He postulated that local hemodynamics associated
with hemodynamic stress, rather than the level cf lipid intake, is the


principal factor governing the accumulation of lipid in the vessel
wall.

It is clear that multiple risk factors have been associated with
atherosclerosis not only in the coronary and cerebrovascular arterial
beds but also in the peripheral circulation. Ftosen et al. (6.5) evaluated
the association of risk factors in 109 patients with peripheral arterial
occlusive disease. The arterial disease was established by clinical and
arteriographic examination and classified into three anatomic
groups-aortoiliac, combined aortoiliac and femoropopliteal, and
femoropopliteal disease. Type IV hyperlipoproteinemia and glucose
intolerance were significantly more common in patients with
isolated femoropopliteal disease. Cigarette smoking was the most
prominent risk factor in all groups, occurring in 90 percent of
patients with aortoiliac or combined disease and in 75 percent of
patients with femoropopliteal artery disease. The onset of clinical
symptoms occurred at an average of 8 to 10 years earlier in smokers
than in nonsmokers. Heyden et al. (35) established that smoking and
coffee drinking interact in affecting LDL and total cholesterol, but
coffee drinking alone did not appear to affect blood lipids. Criqui et
al. (16') reviewed the relationship between cigarette smoking and
HDL cholesterol in 2,663 men and 2,553 women aged 20 to 69 years
in 10 North American populations of the Lipid Research Clinics
Program Prevalence Study. Cigarette smoking was associated with
substantially lower levels of HDL cholesterol; this association was
dose related. Hulley et al. (37) found the same association in a
longitudinal study of 301 high-risk males 35 to 57 years of age. After
1 year's intervention on diet, hypertension treatment, and smoking
counseling, both smoking frequency and serum thiocyanate were
significantly and independently associated with the changing plasma
HDL-cholesterol concentration. A relationship linking cigarette
smoking and abnormal lipoprotein metabolism comes from the
report of Topping et al. (78), which found that patients with both
Type III hyperlipoproteinemia and cigarette smoking suffer abnor-
malities of liver metabolism of cholesterol-rich "remnants." Such
impaired hepatic metabolism may result in hyperlipoproteinemia
and subsequent peripheral vascular disease.

Sllmmary of Epidemiologic Studies

Because peripheral arterial occlusive disease does not pose as
severe a mortality threat as coronary artery disease does, there have
been fewer major epidemiologic studies of peripheral vascular
disease. However, the underlying pathologic lesion, atherosclerosis,
remains the same in the two conditions, and there is increasing
evidence of an association between peripheral vascular disease and
similar lesions in the coronary or cerebrovascular beds. Both clinical
and angiographic correlates of peripheral arterial disease with


concomitant coronary artery disease were suggested by the reports of
Friedman et al. (281, Kuebler et al. (49), Silvestre et al. (72), and
Hertzer et al. (34). These reports not only suggest a clinical
relationship between peripheral and coronary artery occlusive
disease, but also indicate that the perioperative and long-term risks
of treatment for peripheral vascular disease are strongly influenced
by the presence of concomitant coronary artery disease.

Several publications have extensively reviewed the evidence
associating cigarette smoking with peripheral arterial occlusive
disease (81, 82, 83). Early studies by Juergens et al. (44), Begg (7),
Schwartz et al. (71), and Widmer et al. (87) documented a much
higher prevalence of cigarette smoking (usually exceeding 90 per-
cent) in patients with peripheral arterial occlusive disease, when
compared with control patients without vascular disease. Data from
the Framingham study (4s) suggest that cigarette smoking is one of
the major risk factors in the development of intermittent claudica-
tion (Table 1). Over a X-year period of followup, a higher total
incidence and a higher annual incidence of intermittent claudication
were noted in smokers as compared with nonsmokers. This differ-
ence was statistically significant for all age groups of both sexes.
Using multivariate analysis to control for other risk factors, this
relationship of smoking to intermittent claudication became stron-
ger.

Many other investigators have noted a high prevalence of ciga-
rette smoking in patients with peripheral arterial occlusive disease.
Tomatis et al. (77) found that 98 percent of patients with aortoiliac
disease and 91 percent of patients with femoropopliteal disease were
cigarette smokers. Astrup et al. (3) found a significant correlation
between the frequency of severe intermittent claudication and the
consumption of more than 15 cigarettes a day in nondiabetic patients
with peripheral vascular disease. A significant difference between
heavy smokers and other smokers was not found, however, for the
development of gangrene. Further, the development of claudication
did not vary with the number of years of smoking or the total
number of cigarettes consumed in a lifetime. Weinroth and Herz-
stein (84) noted a 50 percent greater incidence of peripheral arterial
occlusive disease in diabetics who smoked than in those who did not,
Juergens et al. (44) followed 520 patients with nondiabetic peripheral
arterial occlusive disease, approximately 50 percent of whom contin-
ued to smoke despite medical advice to quit. Of those who continued
to smoke, approximately 10 percent eventually required amputation,
but no amputations were necessary in patients who successfully
stopped smoking.

Horowitz et al. (36) reported that age was a significant factor in the
prevalence of arterial disease, with nearly half of the cases occurring
in patients over the age of 70. A higher percentage of patients with

lQ!!


TABLE L-Average annual incidence (over 16 years) of
     intermittent claudication according to cigarette
       habit at examination

Age at examination
and cigarettes
smoked per day

Subjects
at risk'

Men

Rate per 10,coO


Actual   Smoothed

Subjects
at risk'

Women

Rate per 10,OQO


Actual  Smoothed *

MY-         6290       16      15.9       7933       4      3.8

None            2342       6       9.8       4514       3      2.4
Under 20          903       17      13.4       1876       0      4.0
20              1466      30      16.3       1090       9      6.5
over 20          1523       16      24.9       422       12      10.6


55-64 years         4484      51      51.3       5959      19      19.3

None            2170      28      27.6       4276       19      17.5
Under 20          743      61      43.6       1030       19     21.6
20              a79      40      66.7       434       0     26.7
Over 20           670      in     107.9       197      76     33.1


65-74 years          1326      57      56.6       1924      31      31.2

None             190      44      55.2       1541       19     23.6
Under 20          254      98      51.3       266      94     45.3
20              167      90      59.5        I9       0     66.5
over20           111       0      61.7        29      172     164.2

' Numhen of subjecta at rislr according to cigar&em smoked do not add to tot& shown because same subjecta
a?eintheunkn~category.
`The "amwthed" rates an based on the mean of the individual probabilities of development of intermittent
ckudication in ti 2 yeam following examioa tion. where individual probability h calculated awarding to cigar&e
we at examination using the values of the parameten atiited in Wing the logistic function to the oavmnee of
intermittent claudication in the sex-age group.
NOTE: The trend is aigniticantly Merent from zao at the 0.05 level for women 65 to 74 yearn of age and at the
0.01 level for men 65 to 64.
SOURCE lbumel and Shurtleff (481.

arterial disease smoked than did patients without arterial disease. A
higher percentage of males than of females had peripheral arterial
occlusive disease. De Backer et al. (21) likewise noted an increase in
intermittent claudication with increasing age, but also found a
significant correlation of serum cholesterol, systolic blood pressure,
blood glucose, and cigarette smoking in patients with intermittent
claudication.

Future epidemiologic studies of peripheral vascular disease must
take into account the merits and limitations of the clinical diagnosis
of peripheral arterial occlusive disease. Horowitz et al. (36) suggest
that the judgment of trained paramedical personnel compares
favorably with that of physicians in screening large numbers of
patients for peripheral vascular disease.

De Backer et al. (21) emphasized the importance of using ankle
systolic blood pressure measurement with Doppler ultrasound to

184


objectively screen patients for peripheral arterial occlusive disease.
Such useful techniques have been emphasized by Marinelli et al. (54)
in a large epidemiologic study of vascular disease in patients with
diabetes mellitus.
In addition to clinical studies, several autopsy surveys have
reported an association between smoking and peripheral atheroscle-
rosis (59, 60, 66, 67, 75, 89). Such studies have supported a direct
association between smoking and the formation of abdominal aortic
fatty streaks, as well as their subsequent conversion to raised lesions.
Most reports of peripheral vascular disease emphasize the predom-
inant occurrence of this disorder in males (88). However, diabetes
mellitus may predispose females to peripheral arterial occlusive
disease in a frequency similar to that of males. Broome et al. (12)
reported on 15 women with aortoiliac occlusive disease, all of whom
were cigarette smokers (mean, 20 cigarettes a day), and none of
whom had diabetes mellitus. The temporal trend toward increased
smoking by women may significantly increase their risk of peripher-
al arterial occlusive disease. The Framingham heart study (47) found
that the incidence of peripheral vascular disease was increased
among smokers and that cigarette smoking was as strong an
independent risk factor in women as in men. Heavy smokers had a
threefold increase in the incidence of peripheral arterial occlusive
disease. Weiss (86) evaluated 245 women with peripheral arterial
occlusive disease. The risk in ex-smokers who had not smoked for 5
years or more was nearly normal, with a risk ratio of 1.06. Patients
who had not smoked for 1 to 5 years had a risk ratio of 1.70. Patients
who continued to smoke, but smoked less than one pack a day, had a
risk ratio of 11.53, and those who smoked more than a pack a day
had a risk ratio of 15.56. The risk for arterial occlusive disease was
particularly associated with the proximal aortoiliac segment and
was less associated with distal or femoral-popliteal artery disease.
This study described both a dose-response effect and a benefit
following cessation of smoking.
There have been few studies of the association of visceral arterial
occlusive disease and cigarette smoking. Mackay et al. (53) reported
on the correlation of smoking and renal artery stenosis. They found
that smoking was nearly twice as common in patients with nonma-
lignant hypertension associated with renal artery stenosis as in
those patients with hypertension of comparable severity without
renal artery disease. Previous studies documented that a higher
proportion of smokers was noted in patients with malignant
hypertension (IO, 39). Cigarette smoking was present in 20 of 22
patients with malignant hypertension and associated renal artery
stenosis (53).
Cigarette smoking appears to be the only form of tobacco
consumption associated with an increased risk of developing periph-


era1 arterial occlusive disease. Smith (73) reported that no cases of
intermittent claudication were found in patients who used only
smokeless tobacco (snuff, chewing tobacco), provided that patients
with a history of diabetes mellitus, heavy ethanol intake, or dietary
problems were excluded.

Frishman (29) reviewed the effects of involuntary smoking on the
cardiovascular system. Although levels of carbon monoxide common-
ly found in cigarette-smoke-filled environments have been demon-
strated to decrease exercise tolerance in patients with existing
angina pectoris and intermittent claudication, studies are not
available to document the role that passive smoking might play in
the etiology of atherosclerotic cardiovascular disease (69).

Clinical Investigations in Humans

In several studies, the effect of cigarette smoking or the constitu-
ents of cigarette smoke on the human peripheral vascular system
has been investigated. Cryer et al. (17) studied the effects of cigarette
smoking, sham smoking, and smoking with adrenergic blockade in
10 subjects. There was a significant increase in the mean plasma
norepinephrine and epinephrine levels associated with smoking. The
smoking-related increase in pulse rate, blood pressure, blood glycer-
ol, and blood lactate-pyruvate ratio was prevented by adrenergic
blockade. These findings were attributed to local norepinephrine
release from adrenergic axon terminals within tissues rather than to
increments in circulating catecholamines. In experiments comparing
cigarettes of varying nicotine content, the subjective recognition of
different cigarette brands may influence the results of clinical
experiments. Ossip et al. (58) have suggested that nicotine extraction
filters be used to minimize the within-subject differences due to the
recognition of cigarette brand. The influence of the type of beta
blocker used in therapy of patients who are cigarette smokers was
investigated by Trap-Jensen et al. (79). These authors found that the
use of a nonselective beta blocker, propranolol, during smoking
caused a marked rise in diastolic and mean blood pressure and
forearm vascular resistance, due to the blockade of adrenaline-
induced vasodilatation, which is mediated by beta-2 receptors in the
resistance vessels. Selective beta-l blockade with atenolol attenuated
the systolic blood pressure and the tachycardiac responses induced
by cigarette smoking.

Several studies have suggested an association between cigarette
smoking and the level of circulating hemoglobin. Castleden et al. (14)
evaluated 61 male nondiabetic smokers with peripheral artery
disease and compared them with age-matched nondiabetic male
smokers and nonsmokers admitted for routine inquinal herniorrha-
phy. They found a significant association between smoking and
hemoglobin levels and a highly significant correlation between


smoking and peripheral vascular disease. In addition, the carboxy-
hemoglobin generated by smoking was associated with increased
platelet adhesiveness, decreased fibrinolytic activity, and increased
plasma fibrinogen. Yamori et al. (91) suggested that the hematocrit
was increased in proportion to the number of cigarettes smoked and
that this may be a mechanism for increased mortality rate from
cardiovascular diseases in smokers.

Other hematologic effects of cigarette smoke have been observed
in blood platelets and with fibrinolysis. Davis and Davis (19) studied
18 volunteers to assess the effect of cigarette smoking on platelet
aggregation. The smoking of two unfiltered tobacco cigarettes during
a 2Cminut.e period resulted in a significant increase in the platelet
aggregate ratio. During this time, the mean plasma nonesterified
fatty acid concentration remained unchanged. These same authors
(20) subsequently reported that the increase in the platelet aggregate
ratio resulting from smoking two unfiltered cigarettes could be
prevented with pretreatment with one aspirin tablet. Janxon and
Nilsson (43) evaluated the fibrinolytic activity in vein walls among
71 randomly selected heavy smokers and 41 nonsmokers from a
population of men born in 1914 residing in Malmo, Sweden. After 12
hours' abstention from tobacco, the smokers were found to have the
same fibrinolytic activity as nonsmokers. Smoking six cigarettes
during 3 hours increased the fibrinolytic activity in the blood,
presumably hecause of the combined effects of nicotine and carbon
monoxide.

Several studies of the effects of smoking on the peripheral
circulation have involved noninvasive measurement of limb blood
flow using plethysmographic techniques. Janzon (40) used a water-
filled plethysmograph to study 71 randomly selected heavy smokers
and 41 nonsmokers from the study group of men born in 1914 and
residing in MalmS, Sweden. The smokers were found to have lower
systolic and diastolic arm blood pressure and lower systolic blood
pressure in the big toe with greater pressure gradients from the arm
to the big toe compared with nonsmokers. During reactive hyper-
emia, smokers had decreased blood flow and increased peripheral
vascular resistance. This same author (42) studied the acute effect of
smoking on heart rate, blood pressure, and calf blood flow in 20
randomly selected 59-year-old male heavy smokers (more than 15 g
of tobacco per day). After smoking two cigarettes, there was a
significant increase in blood pressure and heart rate. Blood flow and
resistance to blood flow in the calf did not change at rest, but during
reactive hyperemia, the resistance to blood flow decreased and calf
blood flow increased, an effect attributable to the peripheral
vascular effects of nicotine. Janzon (41) evaluated 51 randomly
selected 59-year-old heavy smokers for changes in peripheral vascu-
lar function after smoking cessation of 8 to 9 weeks. He noted an

187


increase in blood flow during reactive hyperemia in patients who
stopped smoking and a decrease in blood flow in patients who
continued to smoke. Isacsson (38) performed venous occlusion
plethysmography on the calf of 809 randomly selected 55-year-old
men residing in Malmij, Sweden. Sixty-two percent of the total
population examined were cigarette smokers. A history of intermit-
tent claudication was present in 20 subjects, but arterial insufficien-
cy could be clinically demonstrated in only 6 of the 20. Ilio-femoral
occlusive disease was found in another eight patients. These patients
had a higher prevalence of systolic hypertension, hypercholesterol-
emia, hypertriglyceridemia, and lipoprotein abnormalities. The
amount of smoking was inversely related to the magnitude of the
arterial flow capacity in the legs and directly related to the presence
of occlusive arterial disease. More ex-smokers had high blood flow
capacity than had a low flow capacity. The arterial flow capacity in
the legs was reduced in direct proportion to the tobacco consumption
per day. Coffman (15) used plethysmographic and isotope methods to
document cutaneous vasoconstriction, increased skeletal muscle
blood flow, and decreased venous distensibility in human subjects
after tobacco smoking or nicotine injection.

Recent studies have employed Doppler ultrasound to document
changes in blood velocity and transit time following cigarette
smoking. Sarin et al. (68) noted a reduction in mean digital artery
blood flow velocity of 42 plus or minus 6 percent following the
smoking of a single cigarette in 10 male volunteers. Lusby et al. (52)
evaluated the effects of cigarette smoking on hemodynamics in the
large and small vessels of patients with peripheral arterial occlusive
disease. Using Doppler probes, large vessel response to smoking was
evaluated by measurement of pulse transit time delay. Patients with
occlusive arterial disease had significant shortening in transit time
delay, suggesting a stiffening in the main vessels in response to
smoking. Such changes were not seen in control patients without
peripheral arterial occlusive disease. A digit pulse volume recorder
was used to measure the amplitude of digit pulsation, a measure of
small vessel hemodynamics. The digit pulse amplitudes decreased
significantly in response to both low and high nicotine cigarettes,
and patients tended to self-titrate their nicotine intake. Due to this
maintenance of nicotine level, the study failed to demonstrate a
benefit on small vessel hemodynamics accompanying a switch from
high to low nicotine cigarettes.

Recent studies suggest that tobacco allergy may play a role in the
development of the cardiovascular effects of cigarette smoking.
Becker and Dubin (6) reported that approximately one-third of
healthy smoking and nonsmoking volunteers exhibited immediate
cutaneous hypersensitivity to a glycoprotein antigen purified from
cured tobacco leaves and found in cigarette smoke. Denburg et al.

188


(22) skin-tested 164 peripheral vascular disease patients with puri-
fied tobacco glycoprotein. The authors also performed basophil
degranulation tests to assess in vitro reactivity to tobacco glycopro-
tein. Immediate skin-test hypersensitivity to tobacco glycoprotein
was found in 11 percent of patients with angiographically demon-
strable peripheral vascular disease; a control group of normal
patients was not skin tested. The basophil degranulation test was
positive in 60 percent of smokers compared with 24 percent of
nonsmokers (p < 0.01). Forty-three percent of skin-test-negative and
91 percent of skin-test-positive patients with peripheral vascular
disease had a positive basophil degranulation test. Only 3 percent of
patients with negative basophil degranulation tests had a positive
skin test. The percent of patients with positive skin tests increased in
proportion to the severity of angiographic peripheral vascular
disease. What role tobacco hypersensitivity may play in the develop
ment of peripheral atherosclerosis remains to be elucidated.

A final area of clinical epidemiologic study is the relationship of
maternal smoking to the fetal cardiovascular system. Asmussen (2)
studied the umbilical artery, umbilical vein, and vessels of the
placental villi of newborn children in relation to the maternal
smoking history. His studies documented that severe damage to
vessel walls is associated with maternal tobacco smoking during
pregnancy. These fetal vascular changes may lead to vascular lesions
later in life.

Experimental Studies in Animals

In several experimental animal studies, the relationship between
cigarette smoking and atherosclerotic peripheral vascular disease
has been investigated. Birnstingl et al. (9) evaluated the effect of
short-term exposure to carbon monoxide on platelet adhesion in
rabbits. In rabbits exposed on several occasions to an atmosphere
containing 400 parts per million carbon monoxide for 6 to 14 hours,
there was a highly significant increase in platelet stickiness immedi-
ately after exposure to carbon monoxide, followed the next day by a
significant fall to levels below the preexposure value.

Richardson (62) evaluated the effects of nicotine and tobacco
smoke on capillary blood flow in the rat. Red blood cell velocity in
single capillaries within the mesenteric tissue of anesthetized rats
was evaluated immediately before and after either intravenous
injection of nicotine or inhalation of tobacco smoke. Blood velocity
changes associated with tobacco exposure were considered to be
passive consequences of changes in systemic arterial blood pressure.
This study did not evaluate differential effects on various vascular
beds of cigarette smoke or nicotine.

Fisher et al. (27) evaluated the effect of exposure of cholesterol-fed
rabbits to the smoke of one cigarette daily over an ll- to 19month

189


period. The study failed to demonstrate quantitative or qualitative
differences in atherosclerosis in the aorta or coronary or visceral
arteries or significant changes in serum lipids. Rooyse et al. (II)
administered nicotine in the drinking water of New Zealand white
rabbits during a 25-week period. Fasting serum levels of glucose,
triglyceride, total cholesterol, and LDL cholesterol were elevated in
the nicotine-treated rabbits compared with the controls. However,
there was no significant difference between nicotine-treated and
control animals in leukocyte, erythrocyte, and platelet counts or in
hematocrit or hemoglobin. Endothelial cells from the aortic arch of
nicotine-treated animals showed extensive changes, including in-
creased cytoplasmic silver deposition, increased formation of micro-
villi, and numerous focal areas of "ruffled" endothelium (projections
from the cell surfaces).

Marshall et al. (55) evaluated the effects in minipigs of exposure to
cigarette smoke or varying concentrations of carbon monoxide for l-
to X-hour periods. Cigarette smoke and short carbon monoxide
exposure resulted in adherence of platelets to the endothelium. After
longer exposures, microscopic thrombi were found in the vessel
walls. Underlying degeneration in the endothelial cells developed
upon exposure to carbon monoxide.

Recent investigations have involved the training of subhuman
primates to smoke cigarettes in order to assess the effect on the
peripheral circulation and hematologic factors. Schwartz et al. (70)
have summarized data on experiments in baboons taught to smoke
cigarettes. Rogers et al. (63) reported on 36 young adult male
baboons who were fed an atherogenic diet. Twenty-eight baboons
were randomly assigned to smoke 43 cigarettes daily, and 18 baboons
were taught to puff air under equivalent experimental conditions.
The cigarette-smoking baboons demonstrated significantly higher
carbon monoxide and thiocyanate concentrations in blood and
cotinine concentrations in the urine than did the nonsmoking
baboons. There were no significant differences found in serum total
cholesterol, VLDL, and LDL cholesterol or triglyceride concentra-
tions in the smokers compared with the controls. Smoking baboons
had significantly higher fasting glucose concentrations and lympho-
cyte counts. Platelet counts, platelet aggregation, food and water
intake, and body weight were not significantly different in the two
groups. Such experimental models may provide a valuable method to
assess the long-term effects of smoking on the peripheral vascular
system of primates.

Intervention Studies

There is considerable indirect evidence that cessation of smoking
may significantly influence the effect of medical or surgical therapy
on peripheral arterial occlusive disease. Unfortunately, the tendency

190


of some patients with peripheral arteral occlusive disease to con-
tinue smoking often defeats the purpose of medical intervention.
Thiruvengadam et al. (76) evaluated the effect of diseases at different
organ sites upon the smoking habit of chronic smokers. A significant
reduction or cessation of smoking was observed in subjects with
cardiovascular, pulmonary, neoplastic, or gastointestinal disease,
diabetes mellitus, or cirrhosis of the liver. Medical advice played a
role in the reduction for only 19 percent of the subjects. Other
reasons for reduction or cessation of smoking were socioeconomic
factors, aggravation of disease, or belief in a possible relationship
between smoking and the disease. Only subjects with psychiatric
illnesses and peripheral vascular diseases showed no significant
reduction in the smoking habit in comparison with the controls. Of
89 subjects with peripheral vascular disease, 12 increased their
smoking with the advent of disease. Feinleib and Williams (26)
emphasized that peripheral vascular disease risk is elevated only in
cigarette smokers and not in cigar or pipe smokers. Smokers who
quit gradually approach the lower risk of nonsmokers. Birkenstock
et al. (8) reported on the role of cessation of smoking on the medical
therapy of 390 patients with peripheral vascular disease who were
either ineligible or unfit to undergo operative treatment. Conserva-
tive management included foot hygiene, walking exercise, cessation
of smoking, a low cholesterol diet, and vitamin E therapy. Of 277
patients who smoked, 164 were able to stop smoking. Eighty-five
percent of patients who stopped smoking showed improvement in
symptoms of peripheral vascular disease on the medical regimen, in
comparison with only 20 percent who improved among those who
continued to smoke. The degree of improvement was greater in ex-
smokers than in nonsmokers. No patient with diabetes mellitus who
continued to smoke improved under medical management.
Cessation of smoking appears to play an important role in the
long-term success of reconstructive arterial surgery. Wray et al. (901
recorded a significantly higher rate of late arterial occlusion in
patients who had undergone aortofemoral bypass and who persisted
in smoking when compared with patients who stopped smoking
postoperatively. In 30 patients who continued to smoke, 9 late
occlusions occurred, but no occlusions developed in 16 patients who
ceased smoking postoperatively. Myers et al. (5s) reported a retro-
spective study of 217 patients undergoing aortofemoral (135) or
femoropopliteal (107) vascular reconstruction. Patients who stopped
smoking or smoked no more than five cigarettes daily after their
operation had late patency rates of approximately 90 percent for
aortofemoral reconstruction and 80 percent for femoropopliteal vein
grafts. Patients who continued to smoke more than five cigarettes
daily had a late complication rate approximately three times greater
after aortofemoral reconstruction and four times greater after


femoropopliteal vein grafting, compared with examokers. The late
patency rate was approximately inversely proportional to the
number of cigarettes smoked per day after the operation. The
incidence of late complications was not correlated with the number
of cigarettes smoked prior to operation. Burgess et al. (13) noted that
among patients whose below-knee amputation failed to heal, six of
seven (85 percent) were cigarette smokers, whereas among those
whose distal amputations healed, only half were smokers.

Aortic Aneurysm
Nature of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm refers to the dilatation or expansion
of the aortic wall due to degenerative or inflammatory destruction of
the components of the wall. The vast majority of abdominal aortic
aneurysms are due to atherosclerosis, although other conditions,
including infection, trauma, dissection, or inherited metabolic dis-
ease (Ehlers-Danlos syndrome) may be causes. The dilatation may
involve only a portion of the arterial wall (saccular aneurysm), but
most often involves generalized fusiform enlargement of the artery.
Most abdominal aortic aneurysms are located distal to the renal
arteries and proximal to the aortic bifurcation. Abdominal aortic
aneurysms may coexist with aneurysmal changes in the iliac,
femoral, or popliteal arteries. Less commonly, an aneurysm may
involve the entire aorta, including the suprarenal and descending
thoracic aorta (thoracoabdominal aneurysm).

Most abdominal aortic aneurysms are asymptomatic and are
discovered incidentally during a physical examination or on X-ray
examination of the spine or abdominal organs. Symptoms, such as
back pain or shock, are usually associated with the complication of
rupture and constitute the main threat of abdominal aneurysm. Less
commonly, distal embolization may lead to acute or chronic periph-
eral arterial occlusive disease. Although palpation of aortic enlarge-
ment is the best clinical indicator of abdominal aneurysm, abdomi-
nal B-mode ultrasonography is the most accurate noninvasive
method to estimate the exact size of the aneurysm. Arteriography is
seldom used before an operation unless there is associated occlusive
peripheral vascular disease or a suspicion of renovascular hyperten-
sion; this is because the arteriogram may often not depict the true
size of the aneurysm owing to the mural thrombus contained within
the aneurysm. Surgical repair with a prosthetic graft is recommend-
ed for all abdominal aortic aneurysms more than 5 cm in diameter
unless associated diseases make the operative risk greater than that
of the prognosis of the aneurysm. The risk of rupture increases
exponentially with the diameter of the aneurysm.

192


TABLE S.-Mortality ratios and deaths (n in parentheses)' from nonsyphilitic aortic aneurysm related
     to smoking, prospective studies, United States

Author
and year

Number and
type of
population

Data     Followup     Number
collection     years     of deaths

Cigarettes per day        pipes      Cigars     Comments

Hammond
and Horn
1958
(32, 33)


Kahn
1966
(45)

187,783 white     Questionnaire
males in 9      and followup
states, !50-69      of death
years of age       certiticate



U.S. male       Questionnaire
veterans,       and followup
2,265,674        of death
person-years       certificate

1.5






8.5

68






491

NS' 1.00 (25) (expected)
SM' 2.72 (66) (p<O.o05)


>39 . . . . . 7.26  (17)
NS ._................ 1.00 (58)
Current cigarettes 5.24 (234)
l-9 cigarettes/day. 2.12 (13)
10-20 . . . . . 5.53 (124)
2139 ..t.. 5.95  (76)

NS-1.00 (58)   NS-1.00 (56)
SM-1.13 (8)   SM-2.06 (24)

Hammond &   358,534 males,     Questionnaire     6         337      NS .................. 1.00                     Data apply
Garfinkel    445,875 females,    and followup                      I-9.. ................ 2.62                       only to males,
1969      40-79 years of     of death                        lo-19 ............... 3.85                      M-69 years
(31)       age at entry       certificate                       20-39 ............... 4.54                      of age
                                                >40.. ............... 8.00

Weir and     68,153        Questionnaire     5-8         51      NS .................. 1.00                         SM includes
Dunn       California       and followup                     All .................. 2.64                       ex+mokers;
1970       male workers,      of death                        f10.. ............... 2.44                           NS includes
(85)       35-64 years of     certificate                        220 ................ 2.88                      pipe and
        age at entry                               230.. ............... 2.54                      cigar smokers

' Unless otherwise specified, disparities between the total number of deal he and the individual categories are due to the exclusion of occasional, miscellaneous, or former smokenr.
`NS = nonsmokers; SM = smokers.


Summary of Epidemiologic Data

Several large epidemiologic studies have suggested an elevated
incidence of death from ruptured abdominal aneurysm in smokers
compared with nonsmokers (31,32,33,45,85) (Table 2). Anderson et
al. (I) analyzed 344 autopsies for causes of death and relationship to
smoking history. The male to female ratio was 1.9:l.Q with a
smoking incidence of more than double that of the general popula-
tion. The overall longevity of men was less than that of women.
There was an inverse relationship between smoking and longevity.
Five diseases that accounted for 39 percent of the deaths of smokers
were bronchogenic carcinoma, peptic ulcer, aortic aneurysm, acute
myocardial infarction, and centrilobular emphysema. The 15 rup
tured abdominal aortic aneurysms were in 13 male and 2 female
smoking patients.

Auerbach and Garfinkel (4) evaluated atherosclerosis and aneu-
rysm of the aorta relative to smoking habits and age. In 1,412 aortas
collected at autopsy from 1965 to 1970 from male patients, there was
a direct relationship between the extent of atherosclerotic lesions
and both smoking habit and age. The aortic lesions were graded for
formation of plaques, ulceration, and calcification. The complexity of
the plaques increased with the number of cigarettes smoked and was
greater in ex-cigarette smokers and pipe or cigar smokers than in
nonsmokers. More extensive alterations were found in the abdomi-
nal aorta than in the thoracic aorta. Aneurysms were found eight
times more frequently among those smoking one to two packs of
cigarettes per day than among nonsmokers. Black subjects showed
about one-half the number of aneurysms and fewer extensive
atherosclerotic lesions than did white subjects. At ages over 65 years,
abdominal aortic aneurysms were found in 11 percent of all men and
in 16 percent of the heavy smokers.

Rogot and Murray (f%) evaluated the smoking relationship to
causes of death among U.S. veterans. Over a X-year period, there
was a significant reduction in mortality rate with the number of
years of smoking cessation. Aortic aneurysm, along with bronchitis
and emphysema and lung cancer, were among the diseases in which
substantial excess risk remained even after 20 years' cessation of
cigarette smoking.

Conclusions

1. Cigarette smoking is the most powerful risk factor predisposing
to atherosclerotic peripheral arterial disease.
2. Smoking cessation plays an important role in the medical and
surgical management of atherosclerotic peripheral vascular
disease.

194


3. Death from rupture of an atherosclerotic abdominal aneurysm
is more common in cigarette smokers than in nonsmokers.

195


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SECTION 6. PHARMACOLOGICAL
        AND TOXICOLOGICAL
         IMPLICATIONS OF
        SMOKE CONSTITUENTS
        ON CARDIOVASCULAR
         DISEASE

203


Introduction
Cardiovascular diseases are the leading causes of death in most of
the technologically advanced countries of the Western Hemisphere,
accounting for approximately half of all deaths annually in the
United States (see Appendix A). The most common among these
diseases are atherosclerosis and coronary heart disease; their
ischemic complications result in increased morbidity and mortality.
Coronary heart disease is the leading cause of death in the United
States, accounting for two-thirds of all cardiovascular deaths (9s).
It is generally acknowledged that coronary heart disease is a
multifactorial process; that is, a variety of factors are involved in the
development and clinical manifestations of this disease. Therefore, it
is not a simple task to determine the etiology and time course of
atherogenic development. In addition, the study of atherosclerosis is
singularly difficult because no model in the experimental animal
exactly replicates the human disease in physiological, morphological,
and clinical detail. Investigations in human subjects are further
limited by the inability to diagnose the disease in preischemic phases
(44). Most studies of the pathology of cardiovascular diseases (CVD)
have been based on autopsies by coroners or on hospital populations
in which only a limited fraction of decedents have been examined.
Individuals may show considerable variance in the degree of
atherosclerosis identified at autopsy, limiting the value of retrospec-
tive analysis (137).
In 1971, the U.S. Government established the Task Force on
Arteriosclerosis to assess research needs and to make recommenda-
tions on priorities for future program plans in this area. Most of the
recommendations of this task force have been implemented during
the past decade, and important advances have been made in basic
and clinical research (96'). Most important, major epidemiological
associations of cardiovascular disease risk not only have been
established, but also have been supported by examinations of the
arterial wall itself, enabling an increased understanding of the basic
mechanisms of disease processes.
Research in cell and molecular biology has provided new informa-
tion about the interaction of blood-borne components, such as
cholesterol, with the arterial wall. Basic research regarding this risk
will help to increase our understanding of the effects of other
circulating components, such as inhaled cigarette smoke constitu-
ents, and will elucidate the susceptibility of arterial cells to these
effects.
The most firmly established modifiable risk factors for atheroscle-
rotic CVD are hypercholesterolemia, hypertension, and cigarette
smoking. In addition to these, diabetes mellitus, lack of exercise,
obesity, and type A behavior have all been suggested as contributors
to the multifactorial process known as atherogenesis (82). The


assessment of any risk factor, such as cigarette smoking, must be
made within the constellation of other risks, i.e., susceptibility to
disease that is predicted by multifactorial analysis (53, 82).

In the case of cigarette smoking, we are faced with an extremely
difficult effort in determining direct cause and effect phenomena
that are attributable to single factors. Over 4,000 different com-
pounds have been identified in tobacco smoke (45), and the determi-
nation of the direct or indirect actions of each upon the arterial wall
seems an impossible task.

We will attempt, however, to examine the major components
believed to be associated with increased risk for CVD and to
remember the multiple risk factors that might be associated with the
development of cardiovascular dysfunctions in cigarette smokers.
The variety of possible pharmacological and toxicological implica-
tions of smoke and its constituents-and the absence of firm proof of
what mechanisms are precisely involved in the unequivocal cause
and effect relationship between smoking and cardiovascular dis-
ease--should not detract from our confidence in the epidemiological-
ly and clinically irrefutable evidence of the cause and effect role of
cigarette smoking in contributing importantly toward heart disease.

Tobacco Smoke: Physical Nature and Chemical Composition

Inside the burning cone of a cigarette, a variety of physical and
chemical processes occur in an oxygendeficient, hydrogen-rich
environment at temperatures up to 900oC. Two major regions for the
smoke formation are primarily observed-the heat-producing com-
bustion zone and the pyrolysisdistillation zone (II). The mainstream
smoke (MS) is formed during puff drawing; the sidestream smoke
(SS) is generated largely by the smoldering of the cigarette between
puffs. Throughout this review, data are discussed relating to
cigarette smoke generated by smoking machines, unless otherwise
noted. The standard machine smoking parameters for cigarettes
were primarily developed for comparing smoke yields obtained
under identical conditions. Today, these smoking parameters do not
reflect the smoking behavior of many of the cigarette smokers and
especially not that of smokers of low-yield cigarettes who tend to
draw puffs of greater volume more frequently (64, 68,145).

The mainstream smoke of tobacco products represents a very
dense aerosol. In the case of a cigarette without a filter tip, it
contains about 5 x 10' spherical particles per milliliter. The size of
the particles varies between 0.1 and 1.0 pm, with an average
diameter of 0.4 pm (12). Three to eight percent of the weight of the
total mainstream smoke of a cigarette without a filter tip is
attributable to the particulate matter. The remainder consists of
vapor phase components with nitrogen (So to 70 percent), oxygen (10


TABLE l.-Approximate number of smoke compounds
     identified in some major compound classes

Compound class           Number identified

          Amiden, imidea, lactonea
         Carboxylic acids
            LWtOneS
            Ektem
          Aldehydea
            KetOIlCS
            Alcohols
            Phenols
            Aminm
         N-Hetemcyclics
         Hydrocarbons
            Nit&n
         Anhydridee
         Carbohydridea
           Ethers

               Total


SOURCE: Dube and Groeo W'J.

237
227
150
414
108
521
379
292
196
921
755
106
11
42
311

4,720

to 15 percent), carbon dioxide (10 to 15 percent), and carbon
monoxide (3 to 6 percent) as major constituents (27,106). Of the more
than 4,060 components identified in cigarette smoke, 400 to 500 are
present in the vapor phase (27, 45). Table 1 lists some major classes
of smoke components as recently recorded by Dube and Green (45).
The total number of 4,720 in the table exceeds by far the total
number of identified compounds because of repeated listing of the
compounds that contain multifunctional groups. The acute toxicity
of tobacco smoke is influenced not only by the chemical composition,
aerosol concentrations, and particle sizes of the smoke, but also by
the smoke pH. With a pH greater than 6.2, the smoke contains
increasing amounts of unprotonated nicotine, which is the most toxic
form of this habituating agent (Figure 1) (26). The unprotonated
nicotine is at least partially present in the vapor phase and thus is
likely to be more rapidly absorbed by the smoker (5).

The U.S. cigarette is filled with a blend of tobaccos consisting of
Bright, Burley, and Turkish types. Its mainstream smoke pH lies
between 5.5 and 6.1. The smoke of cigarettes and cigars made up
entirely of Burley or dark tobacco varieties has pH values of about
6.5 for the first puffs and up to 8.0 for the last puffs (2s).

Sidestream smoke, which is formed between puff drawings, is
freely emitted into the air from the smoldering tobacco products. The
peak temperature in the burning cone of a cigarette during puff
drawing is about 900oC and between puffs it is about 600oC (162).
This is an important factor for the divergence of specific toxic agents
generated in mainstream and sidestream smoke. Another major

207


FIGURE l.-Protonation of nicotine
SNJRCJC Srunnemann and Hofimann LX9.

difference is that the side&ream smoke leaving the site of formation
is subjected to greater air dilution and faster temperature decline
than is the mainstream smoke, which travels through the tobacco
column and is then inhaled as a concentrated aerosol. These
conditions for sidestream smoke generation favor formation of
aerosol particles of smaller size (0.01 to 0.1 pm) than those occurring
in the mainstream smoke (0.1 to 1.0 urn) (12). The pH of sidestream
smoke of a U.S. blended cigarette varies between 6.7 and 7.5,
compared with pH values of less than 6.2 for the mainstream smoke
of the same cigarette (26). This sidestream smoke thus contains free
nicotine, which is essentially absent in mainstream smoke. Further-
more, during smoldering, sidestream smoke is generated in a zone
that is even more oxygen deficient than the zones involved in
mainstream smoke generation during puff drawing. Consequently,
components that are primarily formed in a reducing atmosphere are
released into the environment to a greater extent than those formed
in mainstream smoke that is inhaled by the smoker. Table 2 lists the
amounts of some selected toxic compounds in mainstream smoke and
the ratios of undiluted sidestream smoke components to mainstream
smoke components (691.
The air dilution of sidestream smoke emitted into the atmosphere
is, of course, a determining factor for any assessment of human
exposure. Nonetheless, in risk assessment, consideration must also


TABLE t.-Distribution of selected toxic compounds in
      cigarette mainstream smoke (MS) and
     sidestream smoke (SS) of nonfilter cigarettea

Compound                   MS           ss/Ms

Gas phase

Carbon monoxide
Carbon dioxide
Formaldehyde
Acmlein
Acetone
Pyridine
SVinylpyridine
Hydrogen cyanide
Nitrogen oxidea (NW
Ammonia
N-NitrcsdimethyLemine
N-Nitroeopyrrolidine
Particulate phase

lo-23 mg         2.M.l
=mg         a11
70-100 jig         0.1150
-100 )lg         a15
lo&250 pg         2-5
20-4ow          lo-20
1-w          20-40
-I@        0.1-0.25
l~lG3         4-10
50-130 pg         4U-130
10-4oW          20-100
ma3          6-30

Particulate matter
Nicotine
Phenol
Catechol
Aniline
2-Toluidine
2Naphthylamine
EZen$aJanthracene
B-Mw=ne
Quinoline
N'-Nitmeonomicotine
N-Nitmecdiethanolamine
Nickel
Polonium-210

1mmg         1.3-1.9
l-2.3 mg          2.63.3
ML120 pg         2.&3Jl
100-280 pg        0.M.9
3@Jng           30
l@J w           19
1.7 ng           30
2.0-7.0 ng         2-t
mng          2.5-3.5
5f3w@30 ng       8-11
2@J-w@J w       0.53
2&70 ng          1.2
-ng          13-30
0.0345 pci        ?

SOURCE Hoffmann et al. ( 70).

be given to the fact that nitrogen oxide (NO), emitted into the
environment as a sidestream smoke component, is rapidly oxidized
to the more toxic nitrogen dioxide (NOz) (27).

Nicotine

Chemistry

A number of observations have supported the concept that
nicotine is the major habituating agent in tobacco and tobacco smoke
(90). In addition to nicotine, tobacco contains a large variety of other
alkaloids, most of which are 3-pyridyl derivatives (Figure 2). In the
blended U.S. cigarette, nicotine constitutes 85 to 95 percent of the
total alkaloids. Its concentration in the leaf depends primarily on the
tobacco type and variety, stalk position, and cultivating practices
(140). A study on the fate of Wlabeled nicotine, added in the form of

209


a salt solution to the tobacco rod of a filter cigarette, revealed that
14.9 percent of labeled nicotine emerged in the mainstream smoke
and 37 percent appeared in the sidestream smoke; 18.5 percent of
Wnicotine was deposited in the butt, and the remainder (= 30
percent) was broken down into pyrolysis products (Table 3) (73). The
major pyrolysis products of nicotine in MS and SS of cigarettes are
carbon dioxide, carbon monoxide, 3-vinylpyridine, 3-methylpyridine,
pyridine, myosmine, and 2,3'dipyridyl(130).

In most countries, cigarettes have shown a gradual and significant
reduction over the last three decades in the sales-weighted average
delivery of nicotine. In the United States the sales-weighted average
nicotine yields decreased from 2.7 mg in 1955 to 2 1.0 mg in 1982
(146). These nicotine reductions have been achieved primarily by
technological modifications and perhaps some agricultural changes.
The technological methods encompass extraction, oxidation or
transformation of nicotine into less toxic compounds (91), formula-
tion, and whole leaf curing. Reduction of nicotine delivery may be
achieved by lowering the transfer of the alkaloid from tobacco into
the smoke. This is accomplished by use of expanded tobacco laminae,
adding leaf mid-veins and stems in the form of tobacco sheets
(reconstituted tobacco), and by modifications of cigarette paper and
by filtration (air dilution). From an agricultural standpoint, breeding
lines have been developed with low levels of nicotine; however, these
are not being used in commercial varieties at present (35).

In 1982, about 90 percent of the U.S. cigarettes sold had filter tips
made of cellulose or cellulose acetate or combinations of these with
charcoal. Twenty-five percent of these filter cigarettes were perforat-
ed to allow greater air dilution of the drawn smoke puffs. More
recent filter construction utilizes longitudinal air channels in
addition to perforation for maximal smoke dilution by air (70, 146).

From the machine smoking of cigarettes, using standardized
parameters of taking one puff per minute of 2 seconds' duration with
a volume of 35 ml, the U.S. Federal Trade Commission reported in
March 1983 that the nicotine values of 208 commercial brands
ranged from ~0.05 to 2.0 mg per cigarette (146). However, many
people who smoke these cigarettes derive very different levels of
smoke components from them, primarily because nicotine delivery
in the mainstream smoke influences human smoking behavior and
causes many smokers of low-yield products to draw puffs more
frequently, take larger puff volumes, and inhale more deeply. This
phenomenon has been observed by determining the smoking profiles
of individuals or by assaying nicotine and cotinine in the sera of
smokers (64,65,127). Cigarette filter construction that allows partial
occlusion of the perforations or air channels of the filter tip may also
lead to delivery of higher concentrations of mainstream smoke (89).
Nicotine in mainstream and sidestream smoke of tobacco products is

210


Nrcotine
(loo-3,000 "g)l

?a' -Formylnornicotine
  (40-200 uq)

Nornicotine
(20-100 ug)

CP
0  I

  N

Anabasine
(3-20 ug)

Cotinine          Nicotine-Xl-Oxide
(9-57 ug)        (n.d.)'

N'-Acetylnornicotine
     (n-d.1

Nrcotyrine
(<SO ug)

Hyosmine
(S-23 ug)

Nornicotyrin
  (n.d.1

O-9 QP
  N

Anatabine
(3-40 2'1)

2,3'-Diayridyl
  (7-20 ug)

FIGURE 2.-Major alkaloids in tobacco and tobacco smoke
' Numbersri~parrntheseedenoteIrgint~wokeofoaecigarette.
' n.d.:Nc&determined.

today primarily quantitated by gas chromatography (151). In physio-
logic fluids such as saliva, serum, or urine, smokers' exposure to
nicotine is assessed by measuring the alkaloid itself or its major
metabolite, either by gas chromatography with a special detector (63)

211


TABLE t.-Distribution of nicotine and its pyrolysis
      products in cigarette smoke

Smoke products

Nicotine     Nicotine pyrolyaia
kmcent)      producta (percent)

     Maid- particulstea
     - phase
              vapor
     Sidestream particulatea
     Side&ream phase
             vapor
     Butt (deposition)
      Ash

       Total


SOURCE: Hourman (73).

14.9             0.6
0.0             4.1
37.0            4.1
0.0            16.3
16.5             1.7
0.0             0.0

70.4       26.8

or, for large volumes of analyses, preferably by radioimmunoassay
(RW (92).

Metabolism

The quantity of nicotine absorbed by the smoker depends on a
number of factors, such as its concentration in the smoke, the
individual's smoking pattern, and the smoke pH. As discussed
earlier, pH values greater than 6.2 increase the amount of unproton-
ated nicotine in the smoke (Figure 1) (26). In the oral cavity, nicotine
absorption varies between 4 and 45 percent (5). In the case of cigar
smoke, the presence of free nicotine in the vapor phase, which is
readily absorbed, and the harsh nature of alkaline smoke appear to
be the major reasons for the cigar smoker's tendency to avoid
inhalation of this smoke (144). That levels of cotinine in the serum of
cigar smokers approximate those of cigarette smokers supports the
concept that nicotine from cigar smoke is absorbed through the
mucous membranes of the oral cavity. Smokers of blended cigarettes
and of British types of cigarettes (pH < 6.2) tend to inhale the smoke.
In general, between 15 and 25 percent of the nicotine in tobacco
appears in cigarette mainstream smoke, from which up to 90 percent
is absorbed (162). The extraction of nicotine from the lungs occurs
quite efficiently (143). Nicotine enters the pulmonary capillary blood
and reaches the brain via the arterial systems (4).

The metabolism of nicotine occurs principally in the liver. Its main
metabolite, cotinine, appears in the blood within a few minutes after
inhalation, and significant amounts of other metabolites appear in
the tissues after about 5 minutes. The kidneys and lungs may, to a
minor extent, also be involved in the metabolism of nicotine (24,143).

Figure 3 illustrates the pathways of the metabolism of nicotine
(54). Cotinine is the major metabolite of nicotine. It appears within a
few minutes in the blood of smokers and has a half-life time of
between 20 and 30 hours (92). Cotinine has been detected in

212


concentrations up to 10 pg per milliliter in the urine of smokers and
up to 40 ng in the urine of nonsmokers who remained in a heavily
polluted indoor environment for a minimum of 1 hour (65, 69).
Nicotine-N'oxide has been detected in the urine of smokers (55). In
the oral cavity of man, nicotine-N'oxide is reduced to nicotine (78). It
has also been found that ingested nicotine-N'-oxide is reduced to
nicotine by the gut flora or by intestinal enzymes (54). Nornicotine
has been observed to be formed by Ndemethylation of nicotine (54).
y-(3-Pyridyl)-y-methylamino butyric acid has been identified in
human urine as 3-pyridylacetic acid, the major end product of
nicotine metabolism (54).

Association With Cardiovascular Diseases

The pharmacological effects of nicotine absorbed by inhalers
might be considered small and transient, but they are repeated
many times each day and act directly on the sympathetic and
parasympathetic cells of the central nervous system (CNS). Nicotine
exerts a direct effect on ganglion cells, producing transient excita-
tion followed by depression or transmission blockade. At the level of
the central nervous system, nicotine causes CNS stimulation fol-
lowed by CNS depression (133).

Nicotine, like acetylcholine, discharges adrenaline from the adre-
nal glands and other chromaffin tissue, and releases noradrenaline
from the hypothalamus. It also releases antidiuretic hormone from
the pituitary (331, and by excitation of chemoreceptors in the carotid
body, augments various reflexes (36).

The cardiovascular responses to nicotine, in general, parallel those
that follow stimulation of the sympathicoadrenal system. Because
nicotine has both stimulant and depressant effects, the responses of
the cardiovascular system represent the sum of several different
modes of action of this compound.

Recently, progress has been made in identifying nicotine receptor
sites in the brains of animals (81). When microinjected into the third
cerebral ventricle, nicotine increased cardiac and respiratory rates,
but it did not alter these parameters when microinjected into the
periaqueductal gray.

Most studies have shown that in people with known coronary
heart disease, cigarette smoking increases the incidence of angina
pectoris, although angina directly precipitated by smoking is rare.
With additive risk factors such as hypertension, the threshold for
attacks of angina can be significantly lowered by daily cigarette
smoking. A long-term followup study of part of the Framingham
cohort demonstrated a lack of association between smoking at
diagnosis and subsequent cardiovascular events, however (74). This
appeared to be related to changes in habits following diagnosis,
implying that improved prognosis could be achieved by withdrawal

213


FIGURE 3.-Pathways of nicotine metabolism
SOURCE: US. Department of Health. Education. and Welfare (144~.

214


TABLE 4.-Effects of nicotine on the cardiovascular system

Increases in blood pressure
Increases in heart rate
Electorcardicgraphic changes
  Nonapecifk ST and T-wave changes
  Increased conduction velocity, propensity toward arrhythmias
Exacerbation of angina in coronary patients
Diminished left ventricular performance in coronary patients

SOURCE: Stimmel(136).

of daily cigarette smoking. The relationship here cannot be attrib-
uted solely to removal of nicotine; it can also be related to
improvements in cardiovascular status such as increased oxygen
saturation.

The exact mechanism whereby nicotine could trigger a cardiovas-
cular event is unknown. However, a common initial feature of
several suggested mechanisms is a sympathetic discharge (Table 4)
(14). This stimulation of sympathetic nerves, with consequent release
of the neurotransmitter norepinephrine within the myocardium, has
been shown to lower the ventricular fibrillation threshold in animals
(38). Responses to sympathetic activity such as hemodynamic
parameters of heart rate and systolic blood pressure generally reflect
plasma nicotine concentrations (88, 112, 135). Increase in pulse rate
and systolic pressure, decrease of pressure pulse transit time, and
digital blood flow are well correlated with nicotine levels of the
cigarettes smoked (88); the same effects can be noted with intrave-
nous injection of varying doses of Gnicotine (150).

In a recent study on the cardiovascular effects of infused nicotine,
Benowitz and colleagues (18) showed that nicotine infusions could
achieve plasma concentrations and cardiovascular effects similar to
those induced by cigarette smoking. Heart rate increased after low
concentrations of nicotine were administered and reached a plateau,
beyond which increasing blood concentrations of nicotine had no
effect. In these studies, as in those of Cryer et al. (38), elevations in
pulse rate and blood pressure occurred promptly after the start of
nicotine exposure and preceded the investigators' measurement of
increased increments of plasma epinephrine and norepinephrine
concentrations. These hemodynamic effects of nicotine are probably
not mediated by circulating catecholamine levels, but are due to
local release of the sympathetic neurotransmitter norepinephrine
from adrenergic axon terminals.

The increase in circulating catecholamines has been demonstrated
to be nicotine dose dependent by Hill and Wynder (66), who found an
increase in epinephrine levels in plasma to be proportional to the
nicotine content of the cigarette smoked. Although elevated with
smoking, norepinephrine levels were not correlated with plasma

215


NICOTINE

SYMPATHETIC NERVE GANGLION,
ADRENAL MEDULLA, NERVE ENDINGS
I

RELEASE OF EPINEPHRINE AND NOREPINEPHRINE

PHYSIOLOGICAL HEART CHANGES
    PERIPHERAL VESSELS
CARBOHYDRATE METABOLISM
      FAT METABOLISM
        PLATELETS
       COAGULATION

FIGURE I.-Net results of catecholamine elevations as
      mediated through nicotine stimulation
SOURCE:Schievelb& andE%erhardtWZ?J.

nicotine. The release of epinephrine is probably mediated through
the adrenal medulla and chromaffm tissue. A more recent study
showed that when the pH of the smoke is altered to favor more
effective absorption of the alkaloid, smokers compensate to adjust
nicotine intake, resulting in modulation of the epinephrine response
(5%

The net results of catecholamine elevations as mediated through
nicotine stimulation are summarized in Figure 4. In general, the
cardiovascular responses of increased heart rate and augmented
contractility create a variable oxygen need; nicotine also dilates the
coronary arteries, which exerts a measurable effect only in healthy
individuals without coronary heart disease (129).

216


Available evidence suggests that the release of adrenergic trans-
mitters by nicotine and other cholinergic agonists is mediated by
nicotine receptors (159). Norepinephrine outflow from adrenergically
innervated tissues is evoked by nicotine and the nicotinic agonist
dimethylphenylpiperainium, but not by the muscarinic agonists
methacholine and oxytremorine (20). Studies using a variety of
inhibitors of nicotinic receptors have resulted in a number of
possible and related mechanisms of action of nicotine on the central
nervous system and the cardiovascular system: (a) prevention of
inactivation of the adrenergic transmitter after its release, (b)
facilitation of adrenergic transmitter release, Cc) involvement of
histamine (311, (d) mediation of nicotine by neuronal uptake, (e)
induction of nerve action potentials, (f) depolarization of nerve
terminals, and (e;) exocytotic release of adrenergic transmitter. These
mechanisms are not necessarily mutually exclusive.

Through these mechanisms, nicotine might exert powerful effects
on the sympathicoadrenal control of cardiovascular function. Many
issues remain to be elucidated and understood, however, such as the
effects of drug interactions with nicotine (421, the inter-individual
variability in metabolism of this alkaloid (18), and tolerance (1321, as
well as the habituating mechanisms of the cigarette smoking habit
itself (77).

In addition to hemodynamic perturbations, nicotine intake has
been implicated in atherosclerotic changes in the arterial wall itself.
Nicotine has been associated with acceleration of atherosclerotic
disease, the initiation of which is becoming more clearly understood.
Experimental evidence is emerging that links atherogenesis to
tobacco smoke inhalation, possibly through mechanically induced
intimal damage as well as through hypoxia. The pathogenesis of
vascular injury might occur via two mechanisms. The first mecha-
nism is accelerated by high levels of blood fat, particularly cholester-
ol in the low density lipoprotein fraction, and it is the abnormal
accumulation of this lipid in the lining of large arteries that leads to
changes in cells of the arterial wall, causing a thickened intima rich
in fat and smooth muscle cells.

The other mechanism of atherogenesis resides in vessel injury and
thrombosis, with the thrombus persisting and becoming organized,
leading to vessel wall thickening (103). Plaque development may
therefore involve damage to the intima and a complex interaction
between intima and the circulating blood, resulting in (a) platelet
release of mitogenic factors, (b) increased uptake of serum lipopro-
teins, and (c) intracellular deposition of lipid (123). It has been shown
that platelets and cells, such as macrophages, can make available at
sites of injury a protein that will cause smooth muscle cells to
proliferate and another that will make them migrate into the
arterial intima (122).

217


Unfortunately, we have relatively little evidence about how the
endothelium can be injured. Blood flow, particularly at a high shear
rate, can damage the endothelium, and high serum lipid `levels can
be associated with vessel injury (125). Immune reactions have been
shown to damage vessels, and products from cigarette smoke
components are suspected of causing injury to the cellular lining of
vessels (87).

Nicotine can be implicated in the processes of atherogenesis
through several of its known actions on the cardiovascular system
(47). Via catecholamine release and the subsequent increase in free
fatty acids, nicotine affects different steps in blood coagulation
pathways, including platelet aggregation (48, 129) and increased
fibrinolytic activity, with possible injurious effects to the cells lining
the arterial wall. Blood pressure and heart rate can influence the
blood shear rate, and transitory increases in blood sugar can
influence basic metabolic rates (42).

A desquamating effect of nicotine on the vascular endothelium has
been demonstrated in rabbits when nicotine was given in relatively
low doses, as compared with those received by cigarette smoking (23).
In a clinical assay, smoking two cigarettes increased the number of
circulating endothelial cells by 50 percent. The interaction of
nicotine and other cigarette smoke constituents could influence this
increase in endothelial cells released into the bloodstream (137).

The possible role of prostaglandins in the promotion of atherogene
sis is tied in with the nicotine induction of altered prostaglandin
activity (155, 157). EXdence suggests that smoking causes a throm-
boxane (TxAz):prostacyclin (PG12) imbalance. Nicotine increases
platelet activity in vitro, and cigarette smoking in general has been
shown to increase this activity in humans (95) as well as to
potentiate platelet aggregability in the presence of hyperlipidemia
(67). Nicotine inhibits the ability of coronary arteries to synthesize
prostacyclin-like substances in vitro, an effect that is more pro-
nounced in vascular cultures derived from patients who smoke than
from nonsmoking control subjects (156). This phenomenon and
alterations in endothelial barrier functions have also been investi-
gated in umbilical arteries derived from smoking and nonsmoking
mothers (7). Pronounced changes were seen in the endothelium of
the vessels derived from smoking mothers. These consisted of
swelling of the cells with numerous blebs on the luminal membrane.
In addition, extensive edema of the subendothelial spaces was a
regular feature,  as was an increase in basement membrane
thickness. These changes are consistent with an increase in endothe
lial permeability (7).

Cigarette smoking and nicotine in particular may therefore alter
platelet function and prostaglandin production in potentially delete-
rious ways, suggesting that smoking may interfere with vascular

218


defense against platelet deposition, a factor in atherogenesis (124).
Specifically, nicotine might alter the occupancy of endothelial
receptors for &adrenergic catecholamines, increasing the intracellu-
lar concentration of cyclic AMP and inhibiting the release of
arachidonic acid from endothelial cell phospholipids, and thereby
reducing prostacyclin synthesis (I).

Nicotine has been implicated at other levels of arterial cell
function. This alkaloid has been found to produce an exposure-time-
and concentrationdependent effect on the lysosomes of endothelial
cells through increases in lysosome fragility and formation of large
acid phosphatase positive vacuoles, presumably lysosomes, in rat
endothelial cells (158). These findings suggested that the lysosomal
vacuolar system should be examined as a possible target for cellular
dysfunction following chronic exposure to nicotine.

Alterations in the levels of lysosomal enzymes in atherosclerotic
tissue have been demonstrated in the presence of single risk factors
including hypercholesterolemia (601, hypertension, and diabetes
mellitus (160) in animals, as well as in diseased areas of human
vessels (49). Inhalation experiments have shown that aortic tissue
from animals chronically exposed to cigarette smoke exhibited
increased levels of several lysosomal enzymes as well as cholesterol
and cholesteryl esters (57). Studies are currently being carried out to
determine the specific cigarette smoke constituents responsible for
these changes.

Cigarette smoking has been implicated in elevation of serum lipids
and changes in lipoprotein distribution (127). Reports in the litera-
ture run from no alteration (118) to significant changes in the
direction of those levels promoting atherogenesis (25, 71). By
stimulating sympathetic nervous activity and catecholamine release,
nicotine can cause an elevation in plasma free fatty acids and
increased secretion of very low density lipoprotein triglycerides (21).
Kirchbaum and colleagues (84) found that the rise of free fatty acids
in plasma produced by smoking was twice as high in patients who
had suffered a myocardial infarction as in controls. This rise in free
fatty acids is probably a result of catecholamine-mediated lipolysis
and may be an important mediator in the production of endothelial
cell injury (161). In addition, cigarette smoking in general is
associated with a reduction in high density lipoprotein apoprotein
components (19) and may attenuate this lipoprotein's antiatherogen-
ic properties by altering surface phospholipid constituents (62).

Carbon Monoxide
Chemistry

The formation of carbon monoxide (CO) occurs in and close to the
burning cone of a cigarette by thermal decomposition, by reaction of

219


tobacco with atmospheric oxygen, and by secondary reactions of
tobacco with carbon dioxide, water, and other primary pyrolysis
products (13, 69). Studies with labeled precursors have shown that
CO is formed at temperatures above 460oC and that about 30 percent
of it derives from thermal decomposition of tobacco, 36 percent from
combustion of tobacco, and 23 percent from reduction of carbon
dioxide (13). The yield of CO in the mainstream smoke of a cigarette
depends on the amount of tobacco and the type of paper burned
during puff drawing, the concentration of pyrolytic precursors, the
temperature profile of the tobacco during puff drawing, and the
permeability of the wrapper for the outward diffusion of CO (111).
The CO concentration in the inhaled smoke is also a function of the
permeability of the cigarette paper and of the physical and chemical
properties of the filter (86,153).

The importance of the air velocity created during puff drawing is
demonstrated by the significant increase in the smoke with increas-
ing puff volume (Figure 5) (69). The somewhat higher CO yields in
the smoke of cigarettes with conventional filter tips compared with
those from nonfilter cigarettes have been attributed to the loss of air
dilution and to the increased smoke velocity that occurs when the
last 15 to 25 mm of the tobacco column are replaced by a filter tip
with a nonporous wrapper (69, 153). This concept is also reflected in
the higher CO yield for a filter cigarette smoked with puffs of
different volumes (Figure 5).

In recent years, cigarettes with perforated filter tips have gained
in market share. The air entering through the perforations in these
filter tips dilutes the mainstream smoke and thus reduces the
concentration of CO in the smoke (Figure 5). In addition, carbon
monoxide is selectively reduced, most likely because of the reduced
velocity of air entering the burning cone (86). Finally, the newly
introduced filter cigarettes with longitudinal air channels reduce CO
in the smoke even further (68). However, as discussed before, because
of the compensatory changes in smoking behavior that smokers
make in order to satisfy their need for a certain amount of nicotine
and because of the possible obstruction of perforated filter tips or
their air channels during puff drawing, the smokers may not fully
benefit from the intended air dilution of the smoke (64, 65, 68, 89,
127).

Association With Cardiovascular Diseases

The health effects of exposure to carbon monoxide are not fully
known. However, research findings in selected population groups
indicate that carbon monoxide acts as an added stress factor to
precipitate cardiac symptomatology or ischemic episodes in individu-
als already compromised by coronary disease (3). Additionally,
excessive levels of carbon monoxide in the blood have been found by

220


A
30-

25-

20-

5-

TAR

  30 35 40 45 50
PUFF VOLUME - ML

FIGURE 5.-Carbon monoxide, tar, and nicotine in the
      smoke of cigarettes
NOTE: NF = Nonfilter; F = Filter; PF = Perforated Filter.
SOURCE: Hoffmann et al. (69).

221


some investigators to impair certain perceptual and motor functions
(104).

Carbon monoxide is a common industrial pollutant generated by
any burning process, It is odorless and tasteless and gives no warning
of its presence in most circumstances, thus allowing for chronic
exposure over extended periods of time. The early symptoms of
carbon monoxide poisoning often resemble those of a variety of
diseases; thus, tissue hypoxia might occur in healthy people without
forewarning (163).
Carbon monoxide combines with hemoglobin in large quantities.
Its chemical affinity for hemoglobin is over 200 times greater than
that of oxygen. The ability of carbon monoxide to cause tissue
hypoxia stems from two effects on circulating processes: (a) a
reduction in the total amount of oxygen carried by red cells in blood,
which reduces delivery of oxygen to tissues, and (b) a shift to the left
of the oxyhemoglobin dissociation curve of the blood that contains
both oxyhemoglobin and carboxyhemoglobin. The leftward shift of
the oxyhemoglobin dissociation curve decreases the tension at which
oxygen molecules are dissociated from hemoglobin, and therefore
decreases the driving pressure for diffusion of oxygen into tissues
and cells (142). The concentration of carboxyhemoglobin reached in
blood will depend upon the concentration of carbon monoxide in the
inhaled gas mixture as well as on the alveolar concentration, and on
arterial oxygen tension, duration of exposure, and ventilation
volume (142).

It is noteworthy that carbon monoxide binds to muscle myoglobin
as well as to hemoglobin and may exert tissue hypoxia by interfering
with oxygen transport to muscle mitochondria. It can also have an
effect on other hemoproteins such as those present in the cyto-
chrome oxidase system (35). Cytochrome P-450, a mixed-function
oxidase, probably does not bind sufficient carbon monoxide to cause
inhibition of drug hydroxylation, even at a carboxyhemoglobin
saturation of 15 to 20 percent (126). However, smokers and nonsmok-
ers differ in their clinical reactivity to drugs such as phenacetin and
diazapam through acceleration of biotransformation processes. This
increased drug metabolism is believed to result from an induction of
microsomal drug-metabolizing enzymes after chronic exposure to
tobacco smoke (148). Although smoking in general results in
accelerated enzyme induction, carbon monoxide has been implicated
in decreased hepatic protein synthesis, a phenomenon that can be
duplicated by chronic cigarette smoke exposure (52). This effect
could be due to a deleterious reaction of hepatic tissue because of
binding of carbon monoxide to intracellular hemoproteins.

It is possible that carbon monoxide may bind to hemoproteins
other than cytochrome oxidase, hemoglobin, or myoglobin in suffi-
cient amounts to inhibit their function. Tryptophan dioxygenase and

222


cat&se have high affinities for carbon monoxide, which in the first
case, could result in increased serotonin levels in several tissues, and
through the latter enzyme, could cause the cellular accumulation of
hydrogen peroxide, a toxic oxidant (126).

Cigarette smoking causes increased carboxyhemoglobin levels,
thereby reducing the oxygencarrying capacity of the blood and
subsequent tissue oxygenation and, possibly, cellular metabolism.
Interpretation of the effects of carbon monoxide absorption by
healthy people is a subject of much controversy because effective
threshold levels have not been established. Environmental exposure
to carbon monoxide may be without chronic consequences in healthy
people who appear able to compensate for any acute effects at levels
of industrial exposure. However, in patients with angina pectoris,
exposure to carbon monoxide has reduced exercise time until the
onset of chest pain (3).

Atherosclerosis is a multifactorial disorder in which cigarette
smoking and carboxyhemoglobin levels may exert varying effects,
depending upon the other risk factors present. Carbon monoxide is
believed to be a contributing factor to the acceleration of the disease
process. Wald and associates (152, 153) have suggested that carboxy-
hemoglobin levels in tobacco smokers correlate better than a
smoking history with the development of myocardial infarction,
angina pectoris, and intermittent claudication. However, it should be
pointed out that in such studies, elevation in carboxyhemoglobin also
reflects the absorption of other constituents of tobacco smoke.

In his earlier studies, Astrup (8) found that carbon monoxide or
decreased oxygen tension enhanced coronary atherosclerosis in
cholesterol-fed rabbits and suggested that high carboxyhemoglobin
levels resulting from tobacco smoking were associated with the
development of occlusive arterial vascular disease. More recent
experiments, conducted in a blind fashion, confirmed the presence of
myocardial lesions, but failed to produce aortic atherosclerosis (91,
although other researchers had noted morphological alterations in
coronary arteries similar to those seen in the earlier experiments (8,
40).

Animal experiments on accelerated atherogenesis with carbon
monoxide must be considered to be unsatisfactory, and although
clinical trials have linked elevated carboxyhemoglobin levels with
cardiovascular symptomatology, a cause and effect phenomenon for
carbon monoxide and disease of the arterial wall has not been
elucidated.

Carbon monoxide exposure has been related to increases in
circulating blood lipids. This was first demonstrated in rabbits in
which carboxyhemoglobin levels were 15 to 25 percent, resulting in
elevations of serum cholesterol for a transient 2 to 3 weeks following
exposure (10). In an epidemiological study by Van Houte and

223


Kesteloot (147) involving 42,000 subjects, significantly higher serum
cholesterol levels were demonstrated in male smokers than in
nonsmokers, particularly in the 30- to 39-year age group. The early
Framingham results also reported slightly higher serum cholesterol
levels among smokers (41), whereas Blackbum et al. (22) report
nonsignificant differences between smokers and nonsmokers. Many
other epidemiological investigations have analyzed the correlation
between smoking status, serum cholesterol levels, and lipoprotein
distributions, but the majority of results suggest a trend rather than
significance in support of a connection between smoking and
elevated cholesterol (100). This relationship does not offer an
explanation for an effect of cigarette smoking on serum lipid levels,
but experimental evidence suggests that carbon monoxide might
exert an effect on the metabolism of chylomicron remnants (51).
Ascorbic acid levels could limit the conversion of cholesterol to bile
acids (85), or carbon monoxide could diminish hepatic degradation of
lipoprotein constituents (40).

Carbon monoxide has also been implicated in the noted decrease in
patency following vascular surgery and arterial reconstruction
among continuing cigarette smokers (138). Cigarette smoking as
measured by extrapolation from carboxyhemoglobin values had a
definite adverse effect on the healing process and success rate of
vascular surgery (20,56).

Additional Contributors

Hydrogen Cyanide

Nitrates in tobacco serve as precursors for hydrogen cyanide
(HCN) in the smoke (61, 79). This concept has been supported by
studies in which `5N-labeled nitrates of potassium, sodium, or
calcium, respectively, had been added to cigarette tobacco and in
which the isolated HCN from the smoke was found to contain l5N-
HCN (79). However, tobacco proteins appear to be the major group of
precursors for HCN in the smoke (27, 80). This was demonstrated in
pyrolysis studies with tobacco protein and amino acids and by
recovery in the smoke of 15N-HCN from cigarettes spiked with l5N-
glycine (27, 80). It has been shown that HCN is formed via N-
heterocyclic intermediates and from pyrolidine, the decarboxylation
product of proline (80). From these intermediates, hydrogen cyanide
is split off in the pyrolysis-distillation zone of the burning cigarette
under the opening of the N-containing ring (27, 80).
Several methods have been explored for the selective reduction of
hydrogen cyanide in cigarette smoke. Charcoal-containing filter tips
can remove 70 to 80 percent of the HCN from cigarette mainstream
smoke (139). With increasing smoke dilution through filter perfora-
tion, HCN can be selectively reduced up to 80 percent, with a 70

224


percent ventilation rate (105). The extraction of protein fractions
from cigarette tobacco leads also to a selective reduction of HCN
(141). The smoke of one cigarette contains from 20 to 480 pg of HCN,
the lowest values being measured in the smoke of cigarettes with
charcoalcontaining filter tips (120).

Although only nicotine and carbon monoxide have been incrimi-
nated as contributors to the increased risk of cigarette smokers for
cardiovascular disease, other gas phase constituents might also play
roles in the pathogenic processes. Hydrogen cyanide is an inhibitor
of several respiratory enzymes and as such can influence cellular
metabolism in the myocardium and arterial wall. It is also a
powerful ciliatoxic agent allowing for decreased efficiency in remov-
al of tar constitutents from the respiratory system (16).

The arterial effects of hydrogen cyanide, nitric oxide, and carbonyl
sulfide were investigated by Hugod and Astrup (76) in experiments
in which rabbits were exposed to these compounds alone or in
combination with carbon monoxide. The duration of exposure was
from 5 days to 12 weeks, and aortas were assessed morphologically
for intimal damage suggestive of early atherosclerotic changes. No
hi&toxic effect on intimal or subintimal morphology was noted, and
a parallel experiment demonstrated no effect on the coronary
arteries (75). The duration of exposure to these compounds must be
considered short, however, with the possibility that prolonged
exposure might result in morphological or enzymatic alterations.

Nitrogen Oxides

A number of studies have shown that nitrate is a major precursor
for nitric oxide (NO) and traces of nitrous oxide (NzO) and nitrogen
dioxide (NO2) found in cigarette mainstream and sidestream smoke
(79, 134). The mainstream smoke of a cigarette contains from 6 to
600 pg of NO per cigarette, depending primarily on the nitrate
content of the tobacco blend and the nature of the filter tip (105). The
correlation of nitrate content of tobacco with nitric oxide yield in the
mainstream smoke appears to be linear (27). The smoke of cigarettes
made with Burley tobacco and particularly those made with Burley
stems, which are rich in nitrate, is especially high in nitric oxide (29,
107). Tobacco proteins appear also to contribute to the NO yield in
cigarette smoke (79).

The concentration of nitrogen dioxide and that of methyl nitrite in
freshly generated cigarette smoke is very minute ( < 5 w/cigarette);
however, these agents increase rapidly as a function of the aging of
mainstream and sidestream smoke. Within about 3 minutes, 50
percent of NO is oxidized to NO2 (149). The best approaches toward
reducing NO in cigarette smoke are by reduction of nitrate in
tobacco and by dilution of smoke by air entering through the holes of
perforated filter tips (27,105).



Changes in cardiac function of rats acutely exposed to nitrogen
dioxide were examined by electrocardiographic records. Bradycardia
and arrhythmias were observed following exposure to 20 ppm for 3
hours (76). These alterations were attributed to changes in parasym-
pathetic nervous activity following exposure. The levels used were
high relative to those obtained from unaged tobacco smoke. In
addition, it has been suggested that enzyme-inhibiting effects
associated with cigarette smoking are due to nicotine N-oxide and
nitrogen dioxide. Because thiols are readily oxidized to disulfides by
either nitric oxide or nitrogen dioxide, they are potent inhibitors of
thioldependent enzymes (126). In the presence of cigarette smoke,
scavenger cells such as macrophages may not be readily activated. In
the respiratory system, the major histological sites of damage by
nitrogen dioxide are the terminal and respiratory bronchioles and
the proximal portions of the alveolar ducts. Nitrogen oxides are also
suspected of contributing to the development of pulmonary emphyse-
ma (43) and the acceleration of platelet aggregation (191).

Carbon Disulfide

Epidemiological studies have incriminated carbon disulfide (C&)
as a factor for the increased risk of arteriosclerotic diseases in
workers in the -rayon industry (39). The reported acute dose
levels of CSZ during workers' exposure were 20 ppm and higher (39).
In cigarette mainstream smoke, carbon disulfide can amount to as
much as 4 pg per cigarette (72, 114). It appears that the sulfur-
containing amino acids and proteins and certain pesticides serve as
major precursors for CSZ in tobacco smoke (15, 72).

Cadmium

The soil supplies tobacco with traces of cadmium (Cd), which are
selectively retained by the plant. Depending on the soil, the Cd in the
leaf can amount to a few parts per million (SO). The mainstream
smoke of a blended U.S. cigarette may contain up to 0.2 pg Cd (97,
102). In the blood of cigarette smokers, Manthey et al. (99) found 2.47
_+ 1.72 cog per liter; Cd levels in the blood of nonsmokers were only
0.43 +_ 0.22 pg per liter. Cd appears to accumulate in the kidney, and
has been found in higher concentrations in the kidneys of cigarette
smokers than of nonsmokers (115).
The potential consequences of increased lifetime exposure to low
levels of cadmium are not known. However, autopsy studies have
revealed increased cadmium levels in persons with emphysema and
hypertension (131). Cigarette smoke is known to contain traces of
cadmium (0.1 to 0.2 cog per cigarette) (97, 102). It is chiefly
accumulated in the liver and kidneys, and has been found in levels
about twice as high in the kidneys of hypertensive cigarette smokers
compared with nonsmokers in the normotensive range (113). It is


possible that an increased body burden of cadmium may be related
more directly to blood pressure (108), although animal studies have
implicated genetic differences in susceptibility to cadmium-induced
hypertension (109, 110). Furthermore, epidemiological studies may
be confounded by failure to separate cigarette smokers from drinkers
of soft water in determining risk of elevated blood pressure from
cadmium intake (I 7).
Cadmium has also been implicated in accelerated atherogenesis
and altered lipoprotein patterns in White Carneau pigeons, a species
often used to investigate risk factors for arterial disease (119). The
results of these studies showed that the number and size of
atherosclerotic plaques were increased in pigeons given drinking
water containing cadmium or lead and that the lipoprotein profile
was altered in an independent fashion. The possible mode of action of
cadmium on atherogenesis is unknown, but endothelial damage is
suggested by the work of Rohrer and colleagues (121). In their
studies, pregnant rats received a single administration of cadmium
(0.5 to 2.0 mg/kg), and vacuoles were observed in the endothelial
cells of fetal brains. These vacuoles distorted the shape and
orientation of the endothelial cells in the caudate nucleus.

Data on the relation between cigarette smoking and cadmium
intake remain inconclusive. Drinking water and genetic factors may
overwhelm the effects of cadmium as a cigarette smoke constituent
on cardiovascular disease, and more work in this area is necessary
before a cause and effect assignment can be made.

zinc

The average zinc (Zn) content in commercial cigarettes varies
between 50 and 80 ppm (140) and in the mainstream smoke of U.S.
cigarettes between 0.05 and 0.4 pg (102). So far, Zn has been
determined only in the urine of cigarette smokers, where it occurs in
significantly higher concentration than it does in the urine of
nonsmokers (46). Zinc is a metal component of many important
enzyme systems; its availability controls the rate of synthesis of
nucleic acids and protein (!83). In fact, zinc deficiency has been
associated with poor growth (30), and depressed plasma zinc levels
have been used as indicators of myocardial infarction (94). In
general, low zinc levels have been found to be associated with
depressed health status, and supplemental zinc has not been
correlated with increased risk of disease development.

Tar

The total particulate matter (TF'M) of a cigarette, often referred to
as tar, is defined as that portion of the smoke that is retained by a
glass fiber filter. This definition is widely accepted and can be
regarded as a quantitative approach, since the Cambridge glass fiber

227


filter retains 99.9 percent of particles of the mainstream smoke that
have diameters of 20.2 u (154). Different methods of smoking
cigarettes and of determining tar in the smoke have been applied
throughout the world; this needs to be considered when comparing
data on cigarette smoke yields in various countries (28).
According to the U.S. Federal Trade Commission report of March
1983, the tar yields of commercial U.S. cigarettes vary from ~0.5 to
30 mg (146). All cigarettes with >20 mg tar yield are nonfilter
cigarettes, and practically all cigarettes with tar yields < 12 mg are
cigarettes with perforated filter tips (146). As discussed before, it has
to be realized that the standard machine smoking method developed
for a comparison of the smoke yields of commercial cigarettes does
not reflect the average smoking habits of cigarette smokers, especial-
ly of those who smoke low-nicotine cigarettes (64, 65, 89, 127). A
person's smoking habit is largely dependent on the smoker's need for
nicotine. Consumers of low-nicotine cigarettes take larger puff
volumes and inhale more frequently than do the smokers of
cigarettes with high nicotine yields (> 1.0 mg cigarettes) (64). At
present, the most reliable assay for determining the uptake of
particulate matter by an individual smoker is seen in the analysis of
nicotine and cotinine in his or her serum (58).
In theory, reduction of the toxic components in cigarette smoke
should reduce the risk for neoplasms and cardiovascular diseases.
Therefore, the introduction of filter cigarettes, which should pre
elude the inhalation of some of the tobacco tar constituents, would be
expected to reduce the incidence of respiratory and cardiovascular
dysfunctions. End point analysis of the long-term followup of the
Framingham cohort made it possible to test the hypothesis that
those who smoke filter cigarettes would be less likely to manifest
clinical symptoms of cardivascular disease than would those who
smoke nonftiter cigarettes. Despite what seemed a more favorable
smoking history, the filter cigarette smokers did not have lower
incidence rates of cardiovascular d&eases than the nonfilter smok-
ers. This finding was unchanged after multivariate logistic regres-
sion analysis to adjust for age, systolic blood pressure, and serum
cholesterol (32). The relationship of this seemingly negative finding
to the tar component of tobacco smoke must remain imprecise
because other smoke constituents covary with the tar fraction.
Respiratory complications and immune hypersensitivity have
been correlated with intake of particulate phase components of
tobacco smoke. Cigarette smokers exhibit greatly increased risks for
pulmonary diseases, including emphysema and chronic obstructive
lung disease (144). Such diseases can also place increased stress on
the cardiovascular system. Cigarette smokers demonstrate more
frequent macroscopic and microscopic lung abnormalities than do


nonsmokers, with a dose-response relationship being apparent in
regard to these changes and the self-reported intensity of smoking.

Research Needs and Priorities

The evidence linking cigarette smoking to cardiovascular diseases
is strong. Understanding of the mechanisms whereby cigarette
smoking initiates or accelerates disease processes remains imprecise
because a variety of smoke constituents exert multiple effects upon
body systems.

Epidemiologic studies have correlated increases in atherosclerotic
CVD death rates with increased use of cigarettes and also have
shown that those persons who stop smoking do in fact exhibit lower
death rates than those who continue to smoke. Despite the demon-
strated association of smoking with enhanced atherogenesis, risk of
coronary death in persons who stop smoking appears to revert to
lower levels in a relatively short period following cessation. It is
quite likely that the precipitating events leading to thrombus
formation and occlusion are decreased, although fibrous plaques will
not regress so rapidly (82).

Methods for cessation of cigarette smoking, especially among high
risk populations, must be a priority in the research endeavor to
reduce cardiovascular disease morbidity and mortality. Although
termination of the habit is the ideal goal, it must be recognized that
this is a difficult task for a number of smokers.

Reduction of the harmful components delivered to the smoker has
been another priority objective, aimed at those smokers who will not
give up the habit. This task has resulted in the introduction of a
variety of low- and ultra-low-yield cigarettes. Whether risks for
cardiovascular diseases are truly reduced when these products are
used remains to be demonstrated. Several recent studies have shown
that smokers alter their smoking behavior when they switch to low-
yield cigarettes and can receive increased smoke constituents as they
attempt to satisfy a nicotine demand (64, 65). This compensatory
behavior may lead to accelerated atherogenesis through increased
uptake of smoke constituents such as carbon monoxide, hydrogen
cyanide, and nitrous oxides. Recently it was reported that the risk of
a nonfatal first myocardial infarction in young men was not related
to the nicotine or carbon monoxide levels of the cigarette. This could
be due to compensatory behavior (83).

One should not ignore the proportion of the population that
continues to smoke, nor should one accept unchallenged the concept
of a "safe" cigarette. The main objective is to reduce the harmful
constituents present in tobacco smoke. It is probable that promotion
of ultra-low-yield products will not suffice, since compensatory

229


mechanisms may be triggered by sensory needs for taste as well as
for nicotine.

A cigarette considered less harmful for cancer etiology might not
reduce the risk for coronary disease. It appears to be a formidable
task to develop a product that satisfies the smoker and does not
increase disease risk through exposure to carbon monoxide, hydro-
gen cyanide, nitrous oxide, or still unknown agents.

Of the major cardiovascular risk factors, cigarette smoking is a
powerful, prevalent, and potentially correctable contributor that
deserves the highest priority among preventive measures to control
cardiovascular disease (82).

Conclusions

1. Over 4,000 different compounds have been identified in tobacco
smoke.

2. Nicotine exerts an effect on ganglionic cells, producing transient
excitation. The pharmacological effects are small, but are
reinforced several times daily in habitual smokers. The exact
mechanisms whereby nicotine might influence cardiovascular
events are unknown, but a lowering of the ventricular fibrilla-
tion threshold is dose related to nicotine levels.

3. Carbon monoxide may act to precipitate cardiac symptomatolo-
gy or ischemic episodes in individuals already compromised by
coronary disease. In addition, carbon monoxide binds to hemo-
proteins, potentially inhibiting their functions.
4. Several studies have shown that smokers may alter their
smoking behavior when they switch to low-yield cigarettes. This
compensatory behavior may lead to the increased uptake of gas
phase constituents including carbon monoxide, hydrogen cya-
nide, and nitrous oxides.

5. It is unlikely that a "safe cigarette" can be developed that will
reduce cardiovascular risk.

230


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SECTION 7. CHANGES IN
        CIGARETTE SMOKING
        BEHAVIOR IN
        CLINICAL AND
        COMMUNITY TRIALS

241


Introduction

This section examines the changes in cigarette smoking behavior
resulting from intervention strategies. The next section presents
detailed data on CHD outcome resulting from these trials compared
with those prospective epidemiologic studies for which cessation
outcome information is available.

Large-scale primary preventive trials have used both single and
multifactorial intervention in high risk populations in an attempt to
test the effect of the modification of major risk factors, either alone
or in combination, on coronary heart disease (CHD) or respiratory
disease. Several of these trials have been developed and implement-
ed since the early 19708, and provide a valuable opportunity for
assessing the efficacy and outcomes of smoking intervention tech-
niques in particular high risk populations and the impact of smoking
behavior change on disease. The objective of this section is to present
and critically appraise the smoking intervention programs and the
smoking cessation outcomes in the large-scale controlled preventive
trials.

At present there are two types of preventive trials in cardiovascu-
lar or respiratory disease that either have been completed or are
currently in progress. One type includes clinical investigations in
which individuals are randomized either to an intervention group
for a risk factor reduction program or to their usual source of
medical care. These randomized trials are either single factor trials
that intervene on one variable such as cigarette smoking, as in the
London Civil Servants smoking trial (55, 60, 611, or multifactorial
trials that generally attempt to change the alterable risk factors of
cigarette smoking, hypercholesterolemia, and hypertension, or some
combination of these risk factors. In this group are the Goteborg
(Sweden) trial (78, 79, 801, the Oslo (Norway) study (16, 17), and the
Multiple Risk Factor Intervention Trial (MRFIT) (19,43).
The randomization of entire populations to an intervention or a no-
intervention group comprises the second type of trial. In this group
of community investigations are trials based on random allocation of
factories to intervention or regular care, as in the WHO study (621,
which involves four centers-London, Brussels/Ghent, Rome, and
Warsaw-using a common protocol, and trials in which entire
geographic areas are randomized, as in the North Karelia project
(52, 53, 54, 63, 64, 65). Although the Stanford study has been
described by its investigators as a community-based investigation
(13, 14, 36, al>, it did not involve random allocation of communities
and thus does not belong in this group as defined here. Although the
Stanford group studied three different communities, individuals
within one community were randomized to intensive or to communi-
ty intervention only. Therefore, for the purposes of this review, the

243


Stanford study will be included with the first group of trials,
although it somewhat overlaps both groups.

Smoking intervention methods and smoking behavior change
outcomes for each of these trials will be presented and critically
evaluated. These prospective studies use experimental design meth-
odology that maximizes comparability of treated and untreated
groups by maintaining a high degree of quality control on all aspects
of randomization, data collection, and evaluation; by utilizing
unbiased statistical treatment of the data; and by detailing a priori
specification of the intervention (38).

A major problem in assessing outcomes of smoking intervention
studies has been research that has often been poor in methodology,
quality control, and design. Although preventive trials have general-
ly conformed to the desired methodology as noted above, they too, as
with other smoking intervention studies, have been deficient in some
of the methods used or in the reporting of the data. The deficiencies
of smoking intervention studies have been well reviewed in past
investigations (5,34,45,67) and will be only briefly summarized here
to provide a basis on which to critically review the research and
smoking intervention designs in preventive trials.

Problems in Smoklng lnterventlon Studies

Lack of Objective Data to Verify Self-Reported Outcomes

A major deficiency in smoking cessation evaluation research has
been the use of self-reported smoking data that have not been
validated with objective measures. These data depend on the
subjects' honest and accurate reporting and often lead to an
overestimation of success, especially among participants who feel the
pressure to stop smoking, as in an intervention program. Neaton et
al. (46) found that when the reported quit-rate of the intervention
group in MRFIT was adjusted using serum thiocyanate (SCN) levels,
the overreporting ranged from 5 to 9 percent, while a much smaller
overreporting rate was found in the usual care group not treated in
the program. The demand characteristics of the intervention pr+
gram may prompt some individuals to falsely comply with the
expectations of the interventionist (2).

One approach to validation of self-reported data involves the use of
serum thiocyanate (SCN) determinations as objective measures of
smoking status, with a critical cutoff point used to differentiate
smokers from nonsmokers (3). SCN is the metabolite of hydrogen
cyanide, a pyrrolic product in tobacco smoke. In addition to cigarette
smoking, SCN may be elevated by the use of pipes, cigars, or
cigarillos. However, the interpretation of SCN concentration is
potentially confounded by at least two factors. Certain foods,
particularly those of the Brassica genus (cabbage, cauliflower, kale,

244


kohlrabi, broccoli, brussels sprouts, turnips, and rutabagas), as well
as fruit pits and almonds, may elevate levels. Also, diuretics tend to
raise SCN levels by an average of 8 pmol/liter (51). With such
limitations in mind, the biologic half-life of SCN, approximately 14
days (511, still makes it a measure well suited for corroboration of
self-reports. Determinations of SCN in saliva and urine have also
been used and are more adaptable to some settings (II, 42).
Measurement of carbon monoxide (CO) concentrations in serum or
expired air also can be used as a validation tool (29, 57, 76). The
major drawback of this measure is CO's short half-life of several
hours (56, 72); it may also be affected by various environmental
factors (72, 77).

The most specific objective indicator of tobacco use is nicotine
itself or its major metabolite cotinine, both of which can be measured
in blood, saliva, or urine (21, 31). The extremely short half-life of
nicotine, on the order of 30 minutes, makes it unsuitable for
verification of cessation or for quantifying estimates of tobacco
intake, but the 20- to 30-hour half-life of cotinine is much more
useful for these purposes (4. 82). Unfortunately, cotinine analyses
are rarely used in clinical trials because of the expense and the
relative unavailability of the complex analytic technique compared
with SCN determination.

Lack of Comparison Groups

Only recently have clinical assessments of smoking in intervention
programs been more consistent in their use of an experimental
design that includes random allocation to the experimental smoking
cessation condition or to an appropriate comparison group. Investi-
gators using a minimal treatment or attention-placebo comparison
group have demonstrated that these groups produce smoking
cessation results beyond those that no intervention would be
expected to produce (28, 32, 37). These outcomes have been partially
accounted for by certain "nonspecific factors" common to all
treatment settings and cannot be attributed to a specific interven-
tion technique. These nonspecific factors include the use of self-
monitoring, a structured program that promotes the expectation of
success, and a therapist's attention (1, 5, 40). Determination of the
effect of a proposed treatment on outcome results is not possible
without rigorous designs that include appropriate experimental
controls, preferably a minimal-treatment control group (37).

Classification Differences

Smoking control studies use variable criteria for grouping individ-
uals; this makes it difficult to compare outcomes. For example,
Straits' (73) successes achieved at least an 85 percent reduction in
smoking, whereas Keutzer's (25) successes achieved at least a 50

245


percent reduction. Kanzler et al's (23) "continuing successes" (3 l/2
to 4 years after treatment) were subjects who had not recidivated at
any time for "longer than a week," while Ockene et al.`s (50)
"continuing successes'* were at zero cigarettes for at least 2 years,
and self-reports were validated with SCN measurements.

Similarly, in some studies a smoker is someone who smokes pipes,
cigars, or cigarettes (e.g., Oslo study), while in other studies a subject
is classified as a smoker on the basis of whether or not he or she
smokes cigarettes only (e.g., MRFIT). Because of the lack of
consistency in groups compared and criteria used, outcomes of
studies are difficult to evaluate, and cross-validation can provide
onflicting outcomes. In order to avoid these problems, standard
classification categories have been suggested (69).

Followup Differences and Deficiencies

Experimental studies of smoking have used different followup
points to assess outcomes and to determine predictor variables.
These followup points have included immediately post-treatment
(25), 2 weeks' post-treatment (11, 3-month followup (221, 6-month
followup (@, l-year followup (701, and 3- to 4year followup (23, 30,
50). In most studies, cessation rates at followup points refer to
%onsmoking prevalence" at that point in time, rather than to
continued abstinence from immediately post-treatment onward.
Such studies give no indication of the dynamics of cessation and
relapse that determine the nonsmoking prevalence rate, nor do they
indicate what is happening long term with a cohort of smokers.
Ockene et al. (48, 49), in their analyses of the smoking data from the
Multiple Risk Factor Intervention Trial (MRFIT), demonstrate the
importance of following cohorts of smokers from baseline to followup
points in addition to determining cessation rates at a single point in
time. Careful definition of cessation rates should be given in all
research reports so that the reader can distinguish whether a given
rate refers to a single probe measure or to a quit status of some
known duration. Shipley et al. (71) have discussed this problem in
depth and offered potential standards for reporting in the smoking
cessation literature.

Because of the high recidivism rate in the first year of abstinence
(20), the comparison of a study that measures cessation at immediate
post-treatment to one that assesses cessation at l-year post-treat-
ment will demonstrate very different outcomes. As explained above,
the smoker reporting cessation at immediate post-treatment could
become either a continuing success or a recidivist at l-year post-
treatment. In effect, comparing stoppers at different points is similar
to comparing different groups (47). The smoker's continuing suscepti-
bility to relapse, even after being cigarette free for more than 2
years, needs to be reflected in smoking research and intervention by

246


the inclusion of followup and maintenance programs beyond the
usual 6 to 12 months (49).

Most studies also fail to note whether a followup point (e.g., 1 year)
indicates a period of time since the entire study began or since the
smoker entered the program. If it indicates the former, it is possible
that there is a different length of followup for participants in the
same study, depending on when they entered the program. Outcomes
for these participants should not be compared unless appropriate
analytic techniques such as life tables (7) or person-years (7) are used
to adjust for the differing lengths of followup.

Methods of Data Reporting

The continuing susceptibility of the smoker to relapse, as well as
the fact that it is long-term rather than short-term cessation that has
an impact on disease outcomes (48, 49), needs to be reflected in the
way data are reported in smoking cessation research, although this
rarely occurs. Cross-sectional cessation data are generally measured
and reported giving little indication of the dynamics of cessation and
relapse that determine the cessation rate at any one point in time
(49). Thus, a cessation rate of 36 percent at 2-year followup does not
mean that 30 percent of the smokers in a study remained cigarette
free for 2 years. Perhaps only 10 percent were nonsmokers for the
entire 2-year period. Studies of smokers quitting both with and
without formalized aid show that people often pass through several
cycles of cessation and relapse before permanent cessation is
achieved (20, G6.l. Analysis of data from cohorts of baseline smokers
followed longitudinally provides a more complete understanding of
smoking behavior change and "true" long-term cessation. It also
provides relevant data for evaluating the effect of cessation on
disease outcome. Cohort analyses are missing in all but a very few
studies.

The primary evaluation of treatment results should be based on
abstinence data for several reasons, as summarized by Pechacek (75),
including the following: abstinence is the primary goal of most
smokers enrolled in programs; smoking behavior change followup
data have indicated that most smokers who reduce their smoking
without totally stopping return to baseline smoking levels; a
clinically insignificant proportion of smokers at followup can be
abstinent and yet analyses of rate data can show statistically
significant treatment effects; and reports of abstinence rather than
reduction are less susceptible to exaggeration and the demands of
the program placed on the smoker. In spite of the importance of
cessation data and of true long-term data, these are often missing in
outcome reports.

247


The Use of Various Methods for the Determination of
Treatment Outcomes

Methods for determining treatment outcomes include telephone
calls (231, in-person interviews (19, 70), and mailed questionnaires
(12). The variability of the groups of smokers reached by these
different methods and their effects changes the criterion groups and
can be responsible for an extraneous source of variance leading to
distortion of the comparisons. Those subjects who respond immedi-
ately to smoking behavior assessment or followup are more often ex-
smokers, but those reached only after repeated tries are often smokers
(68). Therefore, the success and failure groups in a study in which
there is a high followup response (19, 47, 70) may be quite different
from these same groups in a study with a followup response of less
than 50 percent (23). It would be valuable to pursue a random sample
of nonresponders in order to be able to study and compare
responders with nonresponders in terms of generalizability of
outcomes.

Lack of Information and Precautions Needed to
Adequately Interpret Outcomes

A smoking cessation program or trial cannot be adequately
evaluated or interpreted without sufficient information about the
methods used in the design and implementation of the study, the
data included for determination of outcomes, and the methods used
for the analysis of the outcomes (9). DerSimonian et al. (9) surveyed
67 clinical trials reported in 4 well-respected medical journals, and
found that only 56 percent were clearly reported with respect to 11
important variables. The 11 variables were selected with regard to
their importance in determining the confidence that a reader could
place in the author's conclusions, their ability to be discerned by the
scientifically literate general medical reader, and their applicability
across a variety of medical specialties.

A related point specifically aimed at the clinical trials reviewed in
this section is the need to specify all treatments other than smoking
cessation (e.g., modification of other risk factors) that participants
received. What precautions should be taken comparing smoking
cessation results from a trial modifying only smoking behavior to a
trial simultaneously modifying several risk factors? Specific as well
as nonspecific treatment differences are probably operative on
outcomes.

In summary, a critical evaluation of any smoking intervention
program needs to consider the deficiencies inherent in the study and
data analysis design as well as the deficiencies manifested in the
study report by the lack of adequate information. Precautions
regarding comparison with other studies and generalizations should
also be considered. In the following section, the eight major large-

248


scale preventive trials implemented since 1970 that include a
smoking intervention component and have reported smoking cessa-
tion outcomes will be reviewed. (Three-year followup data are
available for most of the trials; therefore, whenever possible these
data will be presented in addition to whatever other data are
available and relevant for comparisons.)

Individual Allocation Trials

Single Factor Controlled Clinical Trials
The London Civil Servants Smoking Trial

The participants in the London Civil Servants smoking trial were
drawn from the 16,016 men, aged 40 to 59, who had undergone a
cardiorespiratory screening examination in the Whitehall study of
London Civil Servants carried out between 1968 and 1970 (55,60,61).
The results of the screening were used to select smokers for the trial
who had the highest risk of CHD or chronic bronchitis or both, based
on a risk score calculated from the multivariate combination of risk
factors (60, 61). Men were excluded if they had heart disease, severe
hypertension (DBP> 115 mm Hg), diabetes mellitus, or major
concomitant disease; were taking psychotropic drugs; or had a
history of previous inpatient psychiatric treatment. The selected
men were randomly allocated to an intervention group (IG) or to a
"normal care" (NC) group. The results were first sent to the
participants' general practitioners, who had the opportunity to
withdraw their patients from the study. Random allocation resulted
in an intervention group of 714 men and a control group of 731 men
(Table 1). The two groups were well balanced on all characteristics
measured, with a mean age of approximately 53 years and a mean
number of cigarettes smoked of 19 in the two comparison groups.

The smokers randomized to the intervention group were sent a
letter inviting them to come and discuss "one or two points
personally with a physician" (58). This session took about 15
minutes, and the smokers were advised of the health gains of
cessation rather than the dangers of continuation and then asked to
decide if they wanted further help and support (58, 59, 60). Booklets
prepared for the study were handed out at this visit. Most men
indicated that they would like help and were seen on an average of
three more visits in the first 10 weeks, and then at 6 months, with
each visit taking about 15 minutes. The only other health advice
given was on calorie restriction for those who gained weight. Close
contact was maintained over several months, and help was available
for those smokers who continued to need it. A special substudy was
implemented in which a group of intervention participants were
randomly allocated either to the usual procedure of further contact

249


TABLE l.-Population, randomization, and baseline smoking data for five major controlled clinical
       trials

Clinical trial
(duration)

Population

Randomization methods/              Baseline age and
  study groups                   smoking data

London Civil Servants
Smoking Trial
(60 61)
(10 years)

1,445 healthy males

Aged 40-59
High risk for CHD and/or
chronic bronchitis based on
risk score

Randomized to smoking
intervention or normal care

Intervention (IG) = 714 males
Normal care (NC) = 714 males

x age = 53
X cigs = 19

Gdteborg (Sweden)
Study
(78, 79, 801
(4 years)
(Screening 1970-1974)
&examination:
1974-1977)

30,000 males

Aged 47-54
Living in GMeborg

Randomized to intervention
for smoking, hypertension,
hypercholesterolemia, and
low physical activity; or to
control group

Intervention group (IQ = 10,000 males
Two control groups (CG) = 20,CWl males

X age = 51
X cigs = ?

65% of 7,455 screened
in IG were smokers


16% of IG smoked
2 15 &s/day

Oslo (Norway) Study
(16, 17. 181
(5 years)

1,232 healthy normotensive
males

Agad 4&59

Upper quartile CHD risk
based on risk scare

Randomized to intervention
for smoking and cholesterol;
or to control group

Intervention group (1) = 604 males

Control group (Cl = 628 males

X age = 45
X cigs (I) = 12.5
X cigs (C) = 13.0

60% were smokers



TABLE l.-Continued.

Clinical trial
(duration)

Population

Randomization methods/             Baseline age and
  study groups                  smoking data

Multiple Risk Factor
Intervention Trial
(MRFIT)
(19. 43)
(1974-1982)

12.666 healthy males

Aged 35-37

Top lo-E% risk for CHD
baaed on risk wore

Randomized to intervention
for smoking, cholesterol,
and/or blood pressure; or
to control group

Special intervention (SI) = 6,428 males
Usual care WC) = 6,428 males

x age = 46
X cigs = 21

64% were smokers
X cigs (smokers) = 34

Stanford Three
Community Study
(36' 41, 4x
(1972-1975)

Residents of Wataonville,
Gilroy, and Tracy, in
California

Random sample of 590
residents asweed in each
community (ages Z&59)

Upper quartile of CHD risk
selected from random samples

Communities matched, not
randomized

Wataonville high risk
sample randomized:
media only (W-R0 = 56 ppts.
media and intensive instruction
(W-II) = 113 ppts
Gilroy: media only (GM01 = 136 ppts.
Tracy: control (0 = 136 ppts

X age (3549
sample) = approx. 47
X cigs (high risk
sample) = approx. 14


by personal consultations or to further contact by mailed personal
responses from the physician (58, 59).

In the initial stage of the trial no contact was made with the
control subjects, who were at no time made aware of their high risk
status or participation in the trial (58, 60). Intervention and control
groups were invited in for a physical examination at 1, 3, and 9
years. They were also sent a self-administered questionnaire on
current smoking habits, symptoms, and recent illnesses at years 1,3,
and 9. When the control group smokers were invited for the l-year
examinations, they were told that their names were included in a
"statistically chosen sample" (58). At l-year followup, 19 percent of
the smokers in both groups did not attend, and a similar loss to
followup rate was true for the intervention group at 9 years (59, 61).

No objective measures were used in this trial to validate self-
reported cigarette smoking behavior. On the basis of the self-reports,
there was a cigarette smoking cessation rate of 51 percent for
intervention group smokers at l-year followup (nonattendee baseline
smokers were included as smokers) (Table 2). Only 31 percent
reported cessation of all tobacco, as many had switched to pipes and
cigars (58). Of all of the men who stopped smoking cigarettes by the
end of year 1, 80 percent reported doing so immediately after the
first interview (60). At 3 years the reported cessation rate went down
to 36 percent, perhaps partly owing to the drop in attendance at
examinations and in return of questionnaires (i.e., only 64 percent
returned for assessment and nonattendees are included at baseline
levels).

A comparison of the intervention subgroups who were contacted
by mail with those who had a personal consultation indicates that
outcome was significantly poorer when the personal contact was
omitted, with a 59 percent cessation rate at 10 weeks for the personal
contact group and a 46 percent cessation rate for the postal contact
group (62).

In the normal care group, 10 percent of the total smokers reported
cessation at year 1 and 14 percent at year 3. Only 70 percent of the
normal care group returned for the third-year examination. At 1
year and 3 years, respectively, there is a 41 and 22 percent net
difference in intervention versus control group reported cigarette
smoking cessation rates. At 9 years, the return rate for intervention
men was 83 percent, with 55 percent reporting cessation, producing
a 46 percent reported cessation rate for all baseline smokers (62).
About one-third of the cigarette abstainers continued to smoke pipes
and cigars. The final g-year smoking cessation rates have not been
reported for the normal care group, but cessation rates reported in a
postal survey to which 60 percent of the survivors responded
indicated that 41 percent of the normal care respondents reported
that they were no longer smoking. As these figures have been

252


TABLE 2,-Intervention, followup, and cessation results for five major controlled clinical trials

Clinical trial

Intervention

Control group contact           Foliowup

Reported cessation rates/
(objective measures)

London Civil
Servants Smoking
Trial
b% 59, 60)

Letter inviting ppt. to meet
with MD


Initial 15 min session

Three more 15 min visits (with
MD) in 10 weeks

6 mo visit

Additional help if needed

Not told of high risk
status or trial participation

Physical exams &
smoking & medical
Hx questionnaire at 1. 3.
& 9 yrs for both groups


Missed visit rates

Treated    Control   Time


51%' (cige) 10% (cigs)  1 Yr
31% call
smokmg)
36% (cigsl 14% (cigs) 3 yrs

IG NC   Year       46% (cigs) -    9 YB

19%   19% 1         (no objective meaeures used)
30%   30% 3
17% - 9

Goteborg (Swedenl
Study
( 78)

Smokers 2 15 g tobacco/day
invited to antismoking clinic

Five biweekly small group
sessions

2d session: ppts given
nicotine chewing gum

Baseline smoking &
medical Hx questionnaxe
sent to all ppts. in one
CG

2% random sample of one
CG screened

Physical ,exams &
smoking & medical
Hx questionnaire at
4 yrs for all IG males
&`all males in one CC


No missed visit rates
noted

31% '     26%   4 yrs



(no objective meashres usedi

Followup letters at 3, 5, 12 mo


!E   TABLE 2.-Continued.

Extended interwntmn
protocol 11 still smoklny

SI UC'   Year

4.x   5.Yi    1
II)`>   loci 6


TABLE 2.-Continued.

Clinical trial

Intervention

control group contact

Followup

Reportd cessation rates/
(objective measures)

Stanford Three
Community Study
(36, 41)

Media: TV, radio, posters,
mail, phone, newspapers


Face-t+face intervention:
group sessions 10 wks, then
biweekly, yr 1

Continued intervention for
yrs2&3

Baseline survey (physical       Surveys (physical +
+ interview)            interviews) yrs 1. 2. & 3

lst, 2d. & 3d yr surveys       High nonattendance rate
repeated: 40 min contact       each yr


Medical results sent to        Highest rate for WI1
MD                    group

       Year 3


WII: 32% cessation1


W-RC: 0% cessation


GMO: 11.3% cessation
(nonattenders excluded)


TC 14.9% cessation
(nonattenders excluded)

WN measured, but not used
to adjust cessation rates)

I P < 0.05.
' Not significant.
SP so.01.
IG: Intervention Group; CG: Control Group; SI: Special Intervention group; UC Usual Care group; WII: Watsonv~lle Intensive Intervention group; W-RC: Watsonville m&ia+,nly group; GMO.
Gilroy medisady group; `I"2 Tracy Control group.


obtained with different means at g-year followup, they cannot be
compared.

During the first year of the trial, the reported number of cigarettes
smoked fell dramatically for the intervention group from 19
cigarettes per day to about 4 cigarettes per day, which was about
one-quarter of the consumption of the control group. There was a
steady decrease over the next 9 years in the number of cigarettes
smoked by the control group, but there was a steady increase for the
intervention group. The net apparent reduction in number of
cigarettes smoked at 9 years was 7.6 cigarettes for the intervention
group(62).

Multifactor Clinical Trials
The Giteborg CSweo!en) Primary Prevention Trial

The GGteborg study (78, 79, 80), a Cyear multifactor clinical trial,
began in 1970 and was designed to determine whether alteration of
the risk factors of smoking, hypertension, hypercholesterolemia, and
to some degree, low physical activity in men aged 47 to 54 would
lower the incidence of CHD and stroke in a random sample (78, 79,
80). At the time that the study began, 30,000 men aged 47 to 54 were
living in GGteborg. One-third of them, 10,000 men, were randomized
into an intervention group, and the other 20,000 were placed into
two control groups (Table 1). Screening took place between 1970 and
1973, and reexamination took place between 1974 and 1977. All men
in the intervention group and in one control group were sent a
questionnaire that included an assessment of smoking and symp
toms of CHD and family history. All men in the intervention group
were invited to a baseline health checkup; a 2 percent random
sample of men in one control group was also screened to assure
comparability to the intervention group. At the 4year followup, all
intervention men and men in one control group returned for a
physical examination and questionnaire assessment (78, 79, 80). The
whole population will be followed for 10 years.

Of the 10,000 men randomized to the intervention group, 7,455 (or
75 percent) took part in the entry examination; approximately 65
percent were smokers (78). There are no indications in the scientific
reports that investigations were implemented to determine whether
there were any differences in individuals who participated when
compared with those who did not come for screening. All men who
smoked 15 or more g of tobacco per day (equivalent to 15 cigarettes
or 3 cigars) were invited to an antismoking clinic (78, 79). Only 2.7
percent of the men screened smoked 25 or more cigarettes per day
(79). Hypertension and hypercholesterolemia were given interven-
tion priority so that men with elevated blood pressure or cholesterol
would be referred for treatment to the relevant clinic and the clinic
physician would also provide antismoking advice. The smokers of

256


more than 15 cigarettes per day were eventually sent to the special
smoking clinic. The smoking clinic included about five small group
sessions run by a physician and a psychologist (79). Very occasional-
ly, men had an individualized session. All smokers, regardless of
number of cigarettes smoked, were sent information about smoking
and cessation and followup letters at 3,5, and 12 months.

Objective measures of smoking were not used in this trial. The
immediate rate of smoking cessation among the smokers referred to
the antismoking clinic was 35 percent. mere is no indication
whether this is for all smokers or just for those who attended.) After
3 months this rate fell to 23 percent. At the 4-year rescreening visit,
it was reported that there was no significant difference in reported
smoking cessation between the intervention and the control groups
(78) (Table 2). A table presented in a paper reporting the trial results
shows cessation rates of 31 and 26 percent at 4 years for the
intervention and control groups, respectively (781, but upon which
smokers these results are based is not indicated; thus, interpretation
is difficult.

The Oslo (Norway) Study

The Oslo study (16, 17, 181, a 5year randomized clinical trial, was
designed to determine whether the lowering of serum lipids and
cessation of cigarette smoking in middle-aged men would lower the
incidence of CHD. Of the 16,202 volunteers screened, 40 to 49 years
old, 1,232 healthy men free of overt cardiac and other chronic
diseases but at high risk for CHD were randomized to an interven-
tion (I) group (n. =604) or to a control (C) group (n =628) (Table 1).
All of the men at entry were normotensive with systolic blood
pressures less than 150 mm Hg; had serum cholesterol levels of 290
to 380 mg/dl; and were in the upper quartile of CHD risk based on
smoking and elevated serum cholesterol. Eighty percent were
smokers. The two groups were very comparable on all risk factors,
with a mean age of approximately 45 and the mean number of
cigarettes smoked daily at 12.5 and 13 for intervention group and
control group men, respectively (16, 17).

The smoking intervention program for the intervention group
started immediately after randomization when each of the smokers
met with Hjermann for 10 to 15 minutes and were informed about
the risk factors and strongly advised to stop smoking all forms of
tobacco. Special emphasis was placed on the synergistic effect of
smoking and hyperlipidemia. Participants and their wives then
attended a group session of 30 to 40 persons, where intervention
included motivating the wives to aid their husbands in changing
their smoking and eating habits. Half way through the trial, those
men who continued to smoke were invited to attend in one group a
%-day smoking cessation program" (16).

257


The intervention group had followup examinations at the center
every 6 months. These examinations took 20 to 30 minutes and
included a physical examination aimed at cardiovascular symptoms,
a resting ECG, and questions about smoking and dietary habits (16,
17). The control group returned for a similar examination annually.
At the 5-year examination, followup was excellent, with only 1
percent of the men who were alive refusing to attend.
Self-reported smoking behavior at 3 years produced a cessation
rate of 29 percent in the intervention group and 13 percent in the
control group (16), a difference of 16 percent. Objective measures
were not made at this point. Pipe smokers were included as smokers,
one pack of pipe tobacco per week equaling seven cigarettes per day.
Self-reported smoking behavior at 5 years indicated a 31 percent
cessation rate in the intervention group and 18 percent cessation in
the control group, producing a difference of 13 percent. Cessation of
all tobacco smoking was 25 percent by self-report at year 5 in the
intervention group and 1 percent in the control group (16). Although
serum thiocyanate (SCN) was determined at the end of the trial as a
validation of self-reported smoking, the corrected rates have not
been reported. The investigators have noted that when serum SCN is
used, the difference in cessation between the intervention group and
the control group becomes smaller and there is a greater discrepancy
between reported and corrected rates in the intervention group (16).
When smoking behavior is strati&d, it can be noted that about 10
percent of the men at baseline both in the intervention group and in
the control group were light smokers (one to nine cigarettes per day).
This increased to about 30 percent in the intervention group by the
end of trial. An increase in this group of light smokers was
accompanied by a decrease in the group with heavier levels of
smoking. This reported reduction in smoking did not occur in the
control group. Most of the cessation in the control group occurred in
the 10 to 19 cigarettes per day group and not in the lighter or heavier
smokers (16,17X
The percentage of nonsmokers continued to increase steadily in
the control group over the duration of the trial, but the greatest
increase in the intervention group occurred in the first year, with
slight increases through year 4 and a slight decline in year 5; thus, a
decrease occurred in the differences between the intervention and
control groups during the ftih year (16). The number of cigarettes
smoked per day decreased from 13 in both groups to about 7 in the
intervention group and 11 in the control group, resulting in an
almost 50 percent reported decrease in smoking in the intervention
group (17).


The Multiple Risk Factor Intervention Dial (MRFIT)

The Multiple Risk Factor Intervention Trial was a randomized
clinical prevention trial followed for an average of 7 years, designed
to test the effect of a multifactor intervention program on coronary
heart disease (CHD) mortality and morbidity (19, 43). There were
12,866 high-risk men, 35 to 57 years of age distributed among 22
clinical centers. They were randomly assigned either to a special
intervention @I) group that received treatment for hypertension,
cigarette smoking, and elevated blood cholesterol levels or to a usual
care (UC) group that received their usual health care in the
community (Table 1). Persons were designated "at increased risk" if
their levels of the three risk factors were sufficiently high at a first
screening visit to place them in the upper 10 to 15 percent' of a risk
score distribution based on data from the Framingham heart study.

Eligibility was determined at three successive screening visits.
Men were excluded from the trial on the basis of low risk, history of
certain diseases, among which were CHD and diabetes mellitus
requiring medication, expected geographic mobility, a serum choles-
terol level of 350 mg/dl or higher, or a diastolic blood pressure of 115
mm Hg or higher. Randomization resulted in an SI group with 6,428
participants and a UC group with 6,438 participants. There was
excellent agreement in prerandomixation levels of numerous risk
factors and risk-factor-related variables (19, 43, 491, with a mean age
of approximately 46 years and a mean number of 21 cigarettes
smoked per day. The 64 percent of the participants who were
smokers smoked an average of 34 cigarettes per day (19, 49). The
proportion of men who were smokers decreased markedly as the age
of the participants increased (19).

Since smokers were defined by their cigarette smoking habits, an
individual who smoked only pipes and/or cigars or cigarillos at
baseline but not cigarettes was not included in this group. Approxi-
mately 9 percent of the MRFIT participants smoked only pipes
and/or cigars or cigarillos at baseline. Classification of this group as
nonsmokers was in accord with the lack of substantial evidence
linking this type of smoking with coronary artery disease.

Intervention for smoking cessation began after randomization at
the third screening visit, when the smoker met with a physician who
noted the effects of smoking on the cardiovascular and respiratory
systems and strongly advised him to stop smoking. At this time the
smoker also met with a "smoking specialist" who discussed the
smoking intervention program with him and invited him to attend
the intensive intervention group (19). Ninety-four percent agreed to
join the group program, and 6 percent of the men elected to be seen
individually. Each group included about 10 men and met for 10

259


sessions. The men were encouraged to bring their spouses or friends
to the series of weekly group discussions, which were intensive
efforts to intervene in the three risk factors (19, 48). The smoking
intervention program included a broad spectrum of educational,
cognitive, and behavioral approaches for cigarette smoking cessa-
tion; no special effort was made to alter the smoking habits of
persons smoking only pipes or cigars. Uniformity of content and
structure was sought by the use of common protocols and education-
al material (19,48,49).
After the initial intensive intervention phase, individual counsel-
ing planned and executed by an intervention team became the
general approach. Behavioral scientists often headed the interven-
tion team, which also included nutritionists, nurses, physicians, and
health counselors (19, 49). The smoking cessation program following
the termination of the integrated intervention group was either a
"maintenance program," directed at participants who had success-
fully quit cigarette smoking, or an "extended intervention program,"
directed at those who continued to smoke cigarettes or had stopped
and recidivated. The key item in both the maintenance and the
extended intervention components was a specified minimum con-
tacts schedule. The maintenance program was based on a series of
scheduled contacts between staff and participant, with the frequency
of contacts decreasing over time as the participant continued to
remain a nonsmoker. Participants who maintained their nonciga-
ret&smoking status were eventually seen by the smoking specialist
at regular Cmonth followup visits only.
Although similar methods, materials and protocols for schedules
of contact and suggested sequencing of methods were used for
smokers in the extended intervention phase, an individualized
approach took into account individual needs and differences. Thus,
although uniformity of content and structure was sought by the use
of common protocols, methods, and educational materials, a single
stepby-step procedure could not be used for smokers in this phase of
intervention. It was not the goal of this study to treat all smokers
alike; rather it was intended to produce the optimal treatment effect.
On or about each anniversary of randomization, participants in
both the SI and the UC groups returned for assessment of risk factor
levels, status on physical examination, laboratory studies, and
morbidity status (19, 43, 48, 49). UC participants visited the clinical
center once a year, and the results of the examinations were sent to
their usual source of medical care. The missed-visit rates (the
number of men alive at the time of the specified annual visit who did
not attend, divided by the number of men randomized) were 4.5
percent for SI and 5.2 percent for UC men at 12 months; these
increased only slightly each year and, although somewhat higher for


the UC group at each visit, remained below 10 percent through 6
years for both groups (43).

Serum thiocyanate (SCN) and carbon monoxide (CO) levels provid-
ed objective measures and a check on the validity of self-reported
smoking. MRFIT used a multiple regression model, which takes
factors affecting SCN (e.g., use of diuretics, pipes, or cigars) into
account in order to "adjust" the reported data on cessation (46').
Cessation rates that have been reported from MRFIT (19, 48, 49)
therefore include both self-report and SCN-adjusted rates. At year 6,
43 percent of the SI smokers were reporting cessation, and 25
percent of the UC noted that they were not smoking (Table 2) (48).
These rates include all baseline cigarette smokers so that individuals
who did not attend the sixth annual visit were included at their
baseline levels of smoking. When these rates are adjusted for SCN
levels, they are 42 percent and 24 percent for SI and UC smokers,
respectively, producing a statistically significant difference (p < 0.01)
between SI and UC of 17 percent. Significantly more cessation
occurred among lighter smokers in both treatment groups than
among heavier smokers.

The reported cessation rate for SI smokers was relatively stable
from year 1 to year 4-about 40 percentand then increased in
years 5 and 6 to 41 percent and 43 percent, respectively; cessation
rates for UC smokers increased in a linear fashion from year 1 (about
13 percent) to year 6 (25 percent). Thus the SI-UC difference in
reported and adjusted rates decreased each year, although always
remaining significant. Similar to the Oslo study findings (IQ, there
were greater discrepancies between reported and adjusted rates for
SI smokers than for UC smokers early in the trial, although by the
sixth year there was little discrepancy in either group. In year 3, the
reported cessation rates were 40 and 16 percent for SI and UC
smokers, respectively, and the adjusted rates were 35 and 15 percent
(48).

Cohort analyses revealed that 26 percent of all SI smokers and 6
percent of all UC smokers stopped at year 1 and continued to report
cessation through year 6 (48). That is, the 43 percent of the baseline
SI smokers who reported cessation at year 6 included the 26 percent
of the baseline smokers (or 60 percent of those smokers who initially
stopped) who continued to report cessation each year and the 17
percent who had stopped later in the trial at years 2 through 5 or
had recidivated and then stopped again. At year 2, 6.9 percent of
baseline smokers were new stoppers. The rate of new reported
cessation ranged from 3.3 to 4.7 percent at years 3 through 6.
Similarly, the 25 percent reported cessation rate at 6 years for the
baseline UC smokers include the almost 7 percent of the baseline
smokers who continued to report cessation each year to year 6 and
the 19 percent of the baseline UC smokers who had stopped later in

261


the trial at years 2 to 6 or had stopped earlier, then recidivated and
stopped again. At year 2, 7.5 percent of baseline UC smokers
reported new cessation. The rate of new cessation reported at years 3
through 6 was 4.2 to 4.8 percent.

Among smokers who stopped early in the trial (i.e., the early
abstainers), the SI smokers had significantly less recidivism than did
the UC, but among the late abstainers, the UC participants
maintained their nonsmoking status somewhat better than did the
SI cohort. The latter finding may reflect the differences in the
remaining pool of smokers at the end of the first year of the program,
with the smaller group of remaining SI smokers being those who
were more recalcitrant and who would recidivate more readily. The
data indicate that regardless of the conditions surrounding cessation
(i.e., amount smoked, time from entry into the study at which
cessation occurred, assignment to either the SI or UC group), the
recidivism rates for the second and third year after cessation are
much lower than for the first year (49).

Although the primary objective of the MRFIT smoking interven-
tion program was total cessation, a program for dosage reduction
was extended to smokers who had not been successful in their
cessation attempts (19). It provided the trial an opportunity to
continue working with participants who stated that they did not
want to stop smoking completely. Reduction data that were reported
through 4 years of the trial indicate that participants in the SI group
who did not quit smoking reported reducing their cigarette smoking
by approximately 10 cigarettes per day at year 1, smoking about
three-quarters of their baseline rate (19, 49). This reduction contin-
ued to be reported through 4 years, but was not accompanied by a
marked decrease in SCN levels. Since SCN levels can be utilized as a
correlate of cigarette smoke exposure, there are at least two possible
explanations of this finding. First, underreporting of cigarette
consumption was occurring among continuing smokers. Second,
smokers compensated for reductions in the number of cigarettes
smoked, increasing the intensity of smoking by modifying the
topography of puffing (15).

The Stanford Three-Community Study

From 1972 to 1975, the Stanford Heart Disease Prevention
Program (SHDPP) conducted the Stanford Three-Community study,
a field study in three comparable Northern California communities
(13, 14, 36, 41). The noted objective of this communitywide health
education project was to develop successful methods for reducing
cardiovascular risk for the adult population at large that would be
generally applicable within communities, hoping to demonstrate
that it was indeed possible to reduce risk in this way (36,411. In order
to demonstrate that a community-based health education program


can decrease the risk of CHD, the program compared changes in risk
behaviors and in risk factors (smoking, increased serum cholesterol,
and hypertension) for subjects in two communities, using two
different approaches to intervention, and in a third community, used
as a no-intervention control.

To assess the effects of interventions on risk factor knowledge and
behavior change, baseline and three annual followup surveys
(medical examination and interview) were conducted for a random
sample of approximately 500 men and women, aged 35 to 59, in each
of three intervention groups (one community had two intervention
groups) and in the control group (36,41,44). These exams took about
40 minutes each. High risk samples of individuals who were in the
top quartile of risk at baseline were selected from these groups for
further study (41). The male to female ratios in these high risk
samples of individuals ranged from 0.97 to 1.36 (41).

One community, Gilroy, received a mass media program only; in a
second community, Watsonville, a media approach was used, and in
addition, intensive face-to-face intervention was provided for a
randomized two-thirds of the participants who were in the top
quartile of risk for CHD. A third community, Tracy, was selected as a
no-treatment control community because it is geographically remote
from the other two and does not have the media systems they share
(36, 41) (Table 1). Followup at all three annual examinations was
between 58 and 68 percent for each of the four groups, with the
highest nonattendance occurring in the media plus face-to-face
intervention groups (14, 36, 41). Of the high risk subjects, 59 to 66
percent of those subjects seen at baseline in three communities
attended all three annual surveys, with the greatest nonattendance
again in the face-to-face intervention group (41).

The media campaign consisted of spots on radio and television,
newspaper columns, and mailings of different materials (44). The
intensive instruction, or face-to-face counseling, took the form of
group meetings or at-home instruction, whichever the participant
preferred. The group, usually 12 to 15 participants, met in local
church rooms for 10 weekly sessions and then twice a month for the
first year. In many respects the intensive face-to-face intervention
for the Stanford study is very similar to the MRFIT intensive
intervention. Of the 169 subjects identified as being at high risk in
Watsonville, 113 were randomized to treatment. Of these, 107
started treatment, and a cohort of 77 continued until the second
annual examination. During the third year, little intervention took
place.

Plasma thiocyanate (SCN) concentrations were determined at each
annual survey to help distinguish smokers from nonsmokers. A
concentration of greater than 100 ~mol/liter was chosen to indicate
possible inaccurate reporting (41). The investigators reported that

263


SCN measurement indicated that about 4 percent of those reporting
abstinence "may have given false reports" (14), but SCN data were
not integrated with the reported cessation rates (24). Therefore, the
reported smoking behavior change results that follow have not been
adjusted with SCN findings. The reported findings (36, 41) are also
based only on those individuals attending followup surveys; dropouts
and refusals are not an integral part of the analyses. Cessation
results have been reported for high risk participants only.
For those individuals who attended all followup visits in the
Watsonville intensive instruction group, a 50 percent cessation rate
was reported (41) (Table 21. This rate becomes 32 percent when the
13 dropouts are included. Significantly fewer subjects stopped
smoking in the Watsonville media-only group than did in the Tracy
control community. In fact, no smokers who attended the 3-year
followup visit in the Watsonville media-only group reported cessa-
tion, while 14.9 percent of the control group who attended the visit
reported cessation. In the Gilroy mediaonly group, 11.3 percent
reported cessation (41). For the cohort of individuals who attended
all survey visits there was a steady increase in the number of
smokers reporting cessation each year in the Watsonville face-to-face
intervention group. This appeared to be true also for the control
group. No cessation in the Watsonville media-only group was noted
during any survey.

With regard tc reduction in number of cigarettes smoked, there
was a reported reduction of 51.6 percent for the smokers in the
intensive instruction group who attended all three surveys (41). Data
are not provided for the group of nonattendees. More reduction was
reported in the control group (21 percent) than in the two media-only
groups (10 and 11.8 percent, respectively).

Deficiencies in the Clinical Trials

In this review, the objectives, smoking control methods, and
smoking behavior change findings of the major large-scale preven-
tive trials have been presented. As noted in the beginning of this
section, because of their emphasis on experimental design, preven-
tive trials provide a valuable opportunity for scientifically assessing
the efficacy and outcomes of smoking intervention techniques with
special populations. Although they have greatly added to the quality
of the available smoking-behavior-change data and the methodology
used to assess intervention techniques and outcomes, they too are
beset with deficiencies in some important areas. The major deficien-
cies noted in the reviewed trials are the lack of objective data to
verify self-reported outcomes, the use of cross-sectional analyses to
the almost complete exclusion of cohort analyses, failure to provide
sufficient information in scientific reports to allow adequate inter-

264


pretation of outcomes, and lack of evaluation of components of the
intervention packages.
The use of objective data to verify self-reported data was missing
in two of the trials: the London Civil Servants smoking trial and the
Goteborg study. Although SCN was reported to have been measured
in the Stanford study and in the Oslo study, the findings were not
used tc correct the reported data. Only one trial-MRFIT-mea-
sured and used objective data to adjust reported cessation rates. As
observed in the discrepancies between reported and objectively
measured cessation data for intervention group smokers in studies
that have used objective data for verification (e.g., MRFIT and the
Oslo study), self-reports that have not been verified need to be
interpreted with caution: often pressures tc stop smoking, perceived
and real, are felt by participants in an intervention program, which
may cause misreporting and inflated cessation rates. The same
pressures may lead to underreporting of consumption levels among
continuing smokers, a possible interpretation of the MRFIT data
showing reduced reported smoking among nonstoppers but main-
tained high SCN levels, Because of differences in the samples studied
and in the intervention methods used, it is difficult to extrapolate
from a study that has used objective data to a study that has not used
these data. The very use of biochemical verification techniques of
which subjects are aware has been shown to lower deception rates
(II, 35). Thus, although MRFIT found a discrepancy of about 6 to 9
percent between reported and SCN-adjustment cessation rates,
depending at which point of followup the measurements were made
(as), the possibility of a similar discrepancy in another study using a
different intervention approach and making different demands on
different populations of smokers cannot safely be suggested.

None of the trials, with the exception of MRFIT, reported
cessation outcomes for cohorts of smokers; they used cross-sectional
data almost exclusively. Therefore there is very little understanding
of the actual degree of recidivism occurring each year in either the
intervention groups or the control groups in these trials or of the
rate of new cessation taking place in either of the groups. A program
that obtains an outcome of 30 percent cessation at year 2 and
includes a large proportion of individuals who have been cigarette
free for the 2 years is perhaps fulfilling the needs of smoking control
programs more successfully than a program that yields a 40 percent
cessation rate at 3 years and includes a large group of smokers who
have gone back and forth with regard to smoking cessation. As has
been consistently noted in the smoking literature, stopping is not the
major problem, it is stopping and staying stopped (5,20,34). Even the
commonly cited relapse curves (20) use cross-sectional data and do
not give the true picture of relapse. In order to judge the effective-
ness of a program, in addition to knowing cessation rates it is

265


important to know whether any new cessation occurs as the program
progresses or whether all of the smokers available for cessation
made changes early in the program. Is there a group of recalcitrant
smokers whom the program never reaches? For example, Ockene et
al. (48) noted with their use of cohort data that although there were
new stoppers in the SI group each year, approximately 27 percent of
baseline cigarette smokers never reported cessation during the next
6 years of the trial. Thus the program never reached slightly more
than one quarter of the smokers, a fact that would not be brought
out by cr ass-sectional data. None of this information can be provided
with cross-sectional data.
The 51 percent reported cessation in the London Civil Servants
trial (58) is impressive on first look, especially given the seemingly
less expensive intervention approach, when compared with studies
such as the Stanford study and the MRFIT. A major difference for
this trial when compared with the other trials in this section is that
the London Civil Servants trial was a one-factor trial, that is,
smoking, and the others were multifactorial trials. This difference is
an important one when considering intervention outcomes. In year
3, the rate fell considerably, to 36 percent. How many of the 36
percent of the smokers who reported cessation at year 3 in the Civil
Servants trial also reported not smoking cigarettes at year l? It is
possible for this rate to be made up of individuals who were, in fact,
not part of the original 51 percent at year 1. This lack of cohort data
coupled with a lack of objective data makes it difficult to adequately
interpret the outcomes. The Coleborg study investigators noted that
there was no significant difference at 4 years for the intervention
group relative to the control group. Although the cessation rates
may not be significantly different, there may be significant differ-
ences in the percentage of smokers who met with long-term success
in each group; thus, there is a possibility that the program had an
effect on long-term outcome without differentially affecting the
prevalence of smokers.
The nonuse of cohort data is also part of a third deficiency in the
preventive trial literature: a lack of adequate information in the
scientific reports to permit proper interpretation of outcomes. Also
included here is a lack of adequate definitions of terms or criteria.
Investigators in the London Civil Servants study (55, 60, 61) noted
that additional smoking intervention help was provided "if needed."
Likewise, the Oslo study provided a "&day smoking cessation
program" halfway through the trial for those who "continued to
smoke" (26). There are no indications in either case of specifically
how smokers who received additional help were defined, what
percentage in fact needed it, what types of intervention were
included in these programs, or what the outcomes of these specific
programs were.


The lack of important data in the reports of some of the trials is
yet another concern. In the Stanford study, 3-year cessation rates for
each study group are provided for individuals who attended the visit,
but rates that include nonattendees are not given for each communi-
ty. A rate of 11.8 percent for the control community of Tracy does
not give the full story. Likewise, the investigators in the Gijteborg
study provided a control group in which only 2 percent were initially
screened, but all were assessed at 4 years (78, 79, 80). Comparison of
4-year data for the control group participants who were screened at
baseline with those not screened would also have been useful, as a
major problem noted for some of the trials is the possible interven-
tion effect of screening. The Giiteborg study could provide a valuable
opportunity to investigate this possible intervention effect.

Another deficiency noted in the trials is the lack of evaluation of
parts of the intervention packages. Most of the trials used ap
proaches that combined many different behavioral, educational, and
medical interventions, but were not able to note which components
were most effective among all of the approaches. The data available
at present tell us only the effects of the total intervention. The total
package may have many components that can be delivered in
different intensities or sequences to different subgroups of the target
population (24). It is not possible to estimate the outcome of some
changes in the total package, as there are too many confounding
variables that prevent procurement of secure inferences with regard
to the additive or interactive effectiveness of the individual compo
nents (24). Sorting out the effectiveness of single stages or elements
in treatment packages has been a particularly complex area of
research, with results indicating that simpler models can be superior
(30). Also lacking are adequate studies designed to determine which
subgroups of smokers benefit from certain interventions and which
smokers respond poorly to these interventions (4750). Some persons
may not need as intensive and expensive an intervention as used in
the Stanford study and MRFIT and may do well with approaches
similar to the less expensive and intensive approaches of the London
Civil Servants study or the Oslo study or with less intervention.
Trials testing differential intervention effects for subgroups of
smokers would be able to provide valuable information.

Comparison of Clinical Trial Outcomes

Although deficiencies are present in the clinical trials, there are
also many advances that these trials have made in smoking
intervention studies. Each trial provided randomized control and
intervention groups, long-term followup of at least 3 years, and
standardized points of followup. The long-term followup of control
and intervention groups provides some valuable data with regard to
the process of smoking behavior change, although interpretation of

267


these data remains difficult because of the deficiencies as well as
some of the differences inherent in the trials. In spite of these
deticiencies and differences there remains much that we can learn
from the trials reviewed above. The major points will be summarized
in this section.

As noted in Table 2, the 3-year reported outcomes for all of these
trials (except for the Goteborg study) showed a significant difference
between the intervention groups and the control groups. The
Gijteborg study did not have 3year data available, and the 4year
data showed no significant difference in cessation between the
control and the intervention groups. The control groups in the trials
where sufficient data are available (i.e., London Civil Servants study,
the MRFIT, and the Oslo study) generally showed a steady increase
in cessation as the trial progressed. In each of these studies there was
a yearly examination for the control group smokers, raising the
possibility of an intervention effect. In spite of the steady yearly
increase of control group cessation rates in the trials, the MRFIT
cohort data demonstrated that a significantly smaller percent of the
control group smokers reporting cessation each year were long-term
stoppers compared with the intervention group participants (48).
Although cessation occurred among nonintervention smokers, it was
probably not as well maintained as among the intervention group
smokers. Because of the lack of cohort data, this issue cannot be
reasonably addressed for the trials presented.
The range of cessation rates among the control groups at 3 years is
13 to 16 percent (except for the Goteborg study, which will be
discussed below), with the highest rate recorded for the MRFIT. The
London Civil Servants study provided an annual examination for the
control group, but did not inform the participants of their high risk
status. This latter point does not seem to have lessened the effect on
cessation in the comparison group. On the contrary, the nonatten-
dance rate for the control group in the London study was high-19
percent at year 3-which may in fact have decreased the cessation
rate, since nonattendees were included as smokers.
The Goteborg study control group is unusual, with a possible
cessation rate of 26 percent at 4 years. As noted, it is difficult to
discern the rate from the investigators' scientific report. (Three-year
rates were not reported.) Although the rate is slightly higher than
what might possibly be expected at 4 years from the other control
groups, it might be anticipated that with the steady yearly increases
observed in the other trials, they would also have higher 4year
rates. A cessation rate of 21 percent was reported for the MRFIT UC
group at 4 years, and at the 6-year visit this rate was 26 percent (48).

Where yearly data are available (i.e., London Civil Servants,
MRFIT, Stanford study), control groups increased their cessation
rates about 2 or 3 percent each year, and during the first year,

268


reported rates were about 10 percent. The 2 or 3 percent cessation
rate each year is not unlike what might be expected from smoking
cessation in the general population of smokers who stop smoking on
their own each year without intervention (75). The greater cessation
rate for the control group relative to the general population of
middle-aged men at year 1 suggests that factors related to the
trials-identification as being at high risk, the screening process,
and the yearly examinations that include questions about smoking
and cardiovascular fitness-may have had an intervention effect (49).
Also, illness in this high risk group may have led to cessation.
With regard to the possibility of the effect of being at high risk, the
Giiteborg population is the only non-high-risk population in the
noted trials, and they exhibited a high control group cessation rate.
Likewise, although the London Civil Servant smokers were at high
risk, the control group smokers were not informed of this status.
Therefore, the increased awareness of one's smoking behavior
through examination and questionnaires may be enough to motivate
some persons to stop smoking. The onset of disease is certainly
another possible factor. More analyses of the data for the control
group smokers, including their reasons for cessation, must be
accomplished before the variables affecting cessation in these groups
can be better understooci.
The reported cessation rates for the intervention groups (Table 2)
in the trials at 3 years range from 29 percent for the Oslo study to 40
percent for the MRFTI'. (For the Stanford study, only the results for
the WII group are used here for comparison, i.e., 32 percent reported
cessation.) In many respects, the five trials reviewed are remarkably
similar with regard to the samples studied. The smoking cessation
results reported were for healthy middle-aged men at high risk for
CHD, except for the Giiteborg study, which involved all middle-aged
men, and for the Stanford study, which included an almost equal
number of men and women in the intensive intervention group. The
mean ages were similar in three studies (45 to 47), and in the
Giiteborg study and the London Civil Servants study the mean ages
were 51 and 53, respectively. The greatest number of cigarettes
smoked was by the men in the MRFIT study who smoked an average
of 21 cigarettes per day. (The data for the Gijteborg study are not
clear with regard to the average number of cigarettes smoked per
day by the smokers.) The least intensive intervention for smoking
and the least expensive approach seemed to occur in the London
Civil Servants smoking trial and the Oslo study, both of which used
short initial visits with physicians and then one to three followup
visits either individually (London study) or in a group (Oslo study).
The fewest intervention visits were noted for the Oslo group. Both of
these studies noted the use of additional intervention when neces-
sary, but what this means or how much additional intervention was


provided is not specified. The Stanford study and the MRFIT seemed
to provide the most intensive intervention, with at least 10 weekly
group sessions and more if necessary. The smoking intervention
program in the Giiteborg study-small group sessions-falls between
the two levels of intervention. In addition to the group sessions, the
Goteborg study provided nicotine chewing gum at session two.

Each of the trials provided some continued contact, at least every 6
months and generally more often, for the intervention group
smokers during the first 2 years of the trials. It appears as though
the least maintenance contact may have been provided in the
London Civil Servants study, although this is not entirely clear from
the reports. Hypothetically, the more continued maintenance and
intervention contacts provided, the greater the likelihood of new
cessation and maintenance of cessation occurring. This possibility
has been tested only for the MRFIT, since as noted previously, only
cross-sectional data were available for the other studies. New
cessation continued to occur in MRFIT each year at the rate of about
3 to 6 percent, and by the sixth year about two-thirds of the smokers
who stopped initially continued to maintain cessation. Relative to
past reports, this maintenance rate is indeed very promising, and it
would be useful to know the maintenance rates of trials that used a
lesser frequency of contact. Because of the continued contact, it is
difficult to assess whether the followup data are good indicators of
the level at which intervention effects stabilize (24).
The outcomes in the Stanford study are puzzling. At the third
annual examination, the control community of Tracy showed the
same rate of smoking cessation as the media-only town of Gilroy and
significantly more cessation than the media-only intervention group
in Watsonville:Zero percent of the Watsonville media-only group
reported cessation, but there was a steady increase in the control
group each year to about 15 percent. These data provide no support
for the possibility that an intensive media blitz has an impact on
smoking cessation that is greater than the impact of "usual"
community intervention. Perhaps there is a "saturation point" with
regard to the effectiveness of increased awareness, which when
reached requires intervention to be at an intensive individual level
before the next level of smokers can be affected. Albeit, a demon-
strated intervention effect that is less than what is observed
spontaneously in the general population merits investigation.

The Oslo study has the lowest 3-year reported cessation rate for
the intervention groups, 24 percent, and seemed to deliver the least
intensive intervention among the trials; the MRFIT had the highest
cessation rate at 3 years, 40 percent, and perhaps provided the most
intensive intervention among the trials. The best outcome was
attained with the most intensive and perhaps the most expensive
approach of the MRFIT, which demonstrated the possibility of long-

270


term cigarette smoking cessation with large numbers of people.
Whether the intensive approach is cost effective must be evaluated.
Similarly, as noted previously, it is important to determine whether
there are certain groups of smokers who may not need intensive
intervention and others who may require even more intensive work.
Even with the use of intensive intervention (Stanford study and
MRFIT), a cross-sectional cessation rate of less than 50 percent was
obtained. Is even more intensive intervention (or a different treat-
ment package) desirable, or is this rate all that can be hoped for?
Perhaps such intense interventions are not cost effective in terms of
the outcome achieved, and much more attention should be devoted to
self-help approaches.

Community Prevention Trials

The Heart Disease Prevention Project: World Health
Organiza tion European Collaborative Trials
The World Health Organization (WHO) European Collaborative

Trials (81) were set up to evaluate the ability of a multifactoral
intervention program to alter risk factors for CHD in industrial
workers, aged 40 to 59, and the effect of such changes on CHD
incidence and mortality. The allocation units were factories or other
large occupational sites, thus permitting community health educa-
tion as well as an individual approach. In most cases the program
operated at the participants' workplace. The Collaborative Group
included four centers: the United Kingdom, Belgium, Italy, and
Poland. Although there was organizational diversity and each trial
was essentially autonomous and self-sufficient, the experimental
design was the same in each center with standardization of screening
methods, intervention objectives, and end-point criteria (81). It was
planned that each trial would run for about 5 years.

In each trial, factories or other occupational facilities were
arranged in pairs and matched according to size, location, and type
of industry, and then randomly allocated to an intervention or a
control group. A central team visited each factory for screening. All
men in the intervention factories between the ages of 40 and 59 and
a random 10 percent of the men in the control factories were invited
for a screening examination. The rest of the control men were not
told of their participation in the trial, thus preventing a possible
influence on risk factor change. The 10 percent of the controls who
were initially screened were reexamined after 2 years. Random 5
percent samples of men in the intervention factories were reexa-
mined annually in order to monitor risk factor changes. All
survivors were examined at the termination of the trials (81).

Intervention was provided for hypercholesterolemia, cigarette
smoking, sedentary activity, weight control, and hypertension. All of

271


the men in the intervention factories were exposed to mass
intervention approaches such as posters, groups, films, and demon-
strations and received a report of their results along with printed
advice for change. Their personal physicians also received copies of
the reports. Individualized intervention consultations were provided
for the 10 to 20 percent of the men who, as a result of screening, were
asses.& to be at the "highest risk for CHD." The intervention
approach used in this trial was similar in some respects to that of the
Stanford study insofar as both used a combination of facetiface and
mass media techniques.

Information specific for the United Kingdom and Belgium trials
and their results is presented below. The Rome and Warsaw trials
have not yet reported their results.

United Kingdom Heart Disease Prevention Project

Recruitment for the heart disease prevention project in the United
Kingdom occurred between 1971 and 1973. Twenty-four large
industrial groups, generally factories, employing a total of 18,210
men, were recruited and paired (62). One of each pair was allocated
to the intervention group (9,734 subjects) and to the control group
(8,476 subjects). Intervention began with the acceptance of screening
by 86 percent of the men aged 40 to 59. A cutoff risk factor score was
determined within each intervention factory, such that it was
exceeded by 12 to 15 percent of the examined men who were at "high
risk" for CHD. Differences between factories in the mean levels of
risk factors were slight (62,811, with a mean age of approximately 50
for both groups and a mean number of cigarettes smoked of
approximately 8 cigarettes per day for alI men and 14.3 cigarettes
per day for the high risk men (62,811 (Table 3).

Intervention for all of the smokers in the intervention factories
was initiated at the screening examination, when they were asked if
they would like to stop smoking (62). The 40 percent who were
interested were sent a letter of encouragement, smoking record cards
that they were asked to return after 3 weeks, and a booklet with
smoking cessation advice. All screened participants were sent
general information on risk factors, and the mass health education
intervention included posters, evening meetings to which spouses
were invited, films, talks, and question and answer sessions. Because
of the generally poor response to the community intervention in the
first 2 years, more personal contact was added for men whose risk
scores came close to the high risk scores. Annual examinations were
also used to give personal advice on smoking and diet. In the third
year, antismoking clinics for all smokers were held by a nurse. The
high risk men were recalled after screening by the company
physician, who advised and treated them individually. There was an

272


TABLE 3.-Population, randomization, and baseline smoking data for three major community
      prevention trials

Community trial
(duration)

Population

Randomization methods/
  study groups

Baseline smoking data

WHO European
Collaborative Trial:
United Kingdom
(62, 81)
(5 years)
bcreening 1971-1972)

18,210 factory workers

Aged 40-59

24 large industrial groups
(paired)

Factories paired for similarities

Random allocation of one in each pair
to intervention or to no intervention

Intervention group (IG) = 9,734 males
Control group (CG) = 8,476 males

x CigB for all
participants = 8

x cigs for high risk
males = 14.3

WHO European
Collaborative Trial:
Belgium (8, 26, 27)
(5 years)
(screening 1972-1974)

16,222 factory workers

Aged 40-69
30 industrial groups (paired)

Same randomization as above

Intervention group (IG) = 7,398 males

Control group (CC) = 8,240 males

I( cigs not noted

Y
w


!j TABLE 3.-Continued.

Community trial
(duration)

Population

Randomization methods/
  study groups

Baseline smoking dara

North Karelia
(Finland) Project
63 54. 6.x 64. 65l
(5 years)
(screening 1972-1977)

Residents of North Karelia
M.ervention community = 10

Residents of Kuopio
(Control community = CC)

Surveyed residents aged 2L59
at start of study

No randomization

North Karelia had a high CVD rate
and intervention was indicated

Community similar to North Karelia
was matched as a control

IC: 50.2% males smoked
11.7% females smoked

CC: 50.9% males smoked
13.1% females smoked

X cigs (CC) = 6.9 for
all males

Random 6.6% sample of population aged        X cigs UC) = 9.9 for
25-59 in each community surveyed in 1972         all males
                         X cigs UC) = 19 for
                                  all smokers

Random 6.6% sample (independent of 1st
sample) surveyed at study end in 1977

Over 10,COO subjects studied each time


average of about four E-minute visits per high risk smoker during
the first year (62).

Changes in risk factors for intervention were assessed each year
for a new 5 percent random sample of all entrants. At year 5, half of
all the men who had not been previously assessed were called, and at
year 6, assessment was accomplished for the other half still
employed. Followup of high risk men occurred at either the second
or fourth year. A random 10 percent of the men in the control group
were invited to an examination at entry and again at 2 years and at
4 years. The results for the intervention group were corrected for
corresponding changes in the control group (62). Followup visits in
all groups ranged from 86 to 94 percent of those invited.
Objective measures were not used to validate self-reported smok-
ing behavior. High risk men reported the best changes in smoking
levels, with a decrease in number of cigarettes per day from
approximately 13 at entry to about 9 at the final examination, a 29
percent decrease. No decrease was noted for the control group; thus,
the corrected estimate for the effect of intervention at the final
examination was also minus 29 percent (62). There was a net
reduction in number of cigarettes smoked of 19 percent for all
smokers and of 16 percent when high risk smokers were removed.

At the end of the trial, a 12 percent cessation rate for the high risk
men in the intervention group was reported, but no change was
reported in the control group (Table 4). About 9 percent of all of the
intervention smokers reported cessation by the end of the trial,
which is about 7 percent if high risk smokers are excluded (62).
These differences are statistically significant (p <O.OOl). A compari-
son of risk factor levels at the final examination between the 90
percent of the control group men who had no contact with the trial
before the examination and the remaining 10 percent who had been
examined showed almost identical results for smoking (62).

The Belgium Heart Disease Prevention Project

After a preliminary feasibility study in 1971-1972 for the Belgium
trial, initial examination for the main trial began in 1972 and
terminated in April 1974 (81). The trial paired 30 Belgian industries,
with 1 member of each pair randomized to the intervention and 1 to
the control group (8, 26, 27). Out of 19,390 male workers in the age
group of 40 to 59, 83.7 percent agreed to be screened, yielding 7,398
men in the intervention group and 8,821 men in the control group.
There are no indications that investigations were implemented to
determine whether there were differences between persons who
were screened and a random sample of those who were not screened.
Ten percent of the subjects in each occupational unit were randomly
selected for an examination similar to that of the intervention group;
the other 90 percent had a resting electrocardiogram (8, 26, 27). The



Y  TABLE I.--Intervention, followup, and cessation results for three major community prevention trials

Community trial

Intervention

Control group contact

Followup

Reported cessation rates/
(objective measures)

WHO European
Collaborative Trial:
United Kingdom
(62)

Mass media intervention for
all factory workers

Antismoking clinics for all  (
smokers

High risk smokers (top IO-15%
risk) offered individual
treatment (four 15 min sessions
in year 1 with company
physician)

Random 10% sample invited    Random 5% IG examined
for screening           yearly

The rest of control males
not told of their
participation in the trial

All survivors examined
at end of trial

Same random 10% CG
screened, reexamined at
2 yea*

Treated

Control

Time

12% '
(high risk
smokers)

ho   5 yrs
change)

9% (all
smokers)

7% (non-
high-risk
smokers)
(no objective measures used)

WHO European
Collaborative Trial:
Belgium
(62)

Mass media intervention for
all factory workers

High risk smokers (top 21%
risk) offered counseling and
examination by project
physicians twice per year

Random 10% invited for
screening

Other 90% had resting
ECG only

Random 5% IG examined
yearly

All survivors examined
at end of trial

18.7% *    12.2%   2 Ym
(high risk (high risk
smokers)   smokers)

12.5% (all 12.6% (all
smokers)  smokers)

(no objective measures used)


TABLE 4.-Continued.

Community trial

Intervention

Control group contact            Followup

Reported cessation rates/
(objective measures)

North Karelia
(Finland) Project
(52, 53, 63)

Comprehensive "community action"
program against risk factors


All forms of media used

Special groups set up aa needed

6.6% random sample examined
at baseline and 5 years

Random 6.6% of each
community surveyed and
examined in 1977

Results compared to
assess RF change

1763     15%     5 Yn
(male     (male
smokers)   smokers)


(SCN drawn for random
    subsamples)
Gxrelations reported. but
adjustments not made)

1P <O.Ol.
'P <0.05.
*Not significant


intervention subjects in the top 21 percent of the risk score
distribution were placed in the high risk group (n= 1,601).

All smokers in the intervention factories received the mass media
approach previously noted for the WHO trials, and all family and
factory physicians received regular information about the partici-
pants' risk factors and took part in intervention (8, 26, 27). Twice a
year, high risk subjects were individually counseled and examined
by two project physicians (8, 26,27) (Table 3).

Reports of the smoking results for this trial have included
comparisons of the results for the 5 percent random sample in the
intervention group with the results for the 10 percent random
sample of the control group at 2-year followup and comparisons of
the results of the high risk subjects in the intervention group with
the results of the high risk subjects selected from the 10 percent
random sample of the control group screened at baseline (9, 26, 27).

Reported smoking rates have not been validated with objective
measures. Among the high risk smokers, 18.7 percent in the
intervention group and 12.2 percent in the control group reported
cessation at 2 years, producing a statistically significant difference
(p ~0.05). For the random samples there was no difference in
reported cessation, with approximately 12.5 percent of the smokers
reporting cessation in both groups (26, 27). Smoking cessation rates
for the intervention group at 1 year was 12 percent and 8 percent for
the high risk subjects and the random sample, respectively (27),
indicating that cessation occurred gradually over the 2-year period.

The North Karelia (Finland) Project

The North Karelia project was carried out in Finland during 1972-
1977 as a comprehensive community program to study the control of
cardiovascular disease (CVD), with special emphasis on CHD, by
reduction of the major alterable CHD risk factors (smoking, in-
creased serum cholesterol, and hypertension (52, 53, 54, 63, 64, 65).
The intervention area was the county of North Karelia in eastern
Finland, which had the highest rates of CVD in that country. The
county of Kuopio, also in eastern Finland, was selected as the control
area because of its similarity to North Karelia.

Both in 1972 and in 1977 a representative random 6.6 percent
sample of the population born between 1913 and 1947 (aged 25 to 59
in 1972 and 30 to 74 in 1977) was drawn from the two counties by
using the national population register (53, 54). The samples in 1972
and in 1977 were independent of each other. Those persons surveyed
were sent a letter explaining the study, a questionnaire assessing
medical history, health behavior and attitudes, attempts to change
health behavior, and stress and an invitation and date for a physical
examination. Over 10,000 subjects were studied each time, with a
participation rate of about 90 percent (52,53,54,63,64,65).


The comprehensive "community action" program against risk
factors was integrated into the health and social services of the
county and was aimed at primary and secondary prevention,
although primary prevention was emphasized. Public information
was provided through newspapers, radio, leaflets, posters, health
education meeetings, and campaigns at schools and places of work
(53); new services were set up if needed, personnel were trained, and
environmental changes (e.g., smoking restrictions) were implement-
ed. The project team planned the activities, prepared the educational
material, helped train personnel, and got the community into action
(54). Smoking cessation group activities were available to those
smokers who wanted them, on the basis of a 3-week model developed
by the project (63). Approximately 55 percent of the smokers were
willing to join the groups, and 71 percent of those who started
completed the groups (63). Approximately 27 percent of those who
started the group reported smoking cessation at 6 months.
The outcomes concerning changes in smoking are based on the
comparison of data obtained in the baseline survey and in the s-year
terminal survey from the study community and the matched control
community. The validity of. the self-reports of smoking behavior was
tested on a random subsample of subjects who were given a second
interview about smoking by trained nurses unaware of the answers
to the survey questionnaire (53). When classified by an interval of 5
or 10 cigarettes, the agreement between the two results was 93 and
97 percent, respectively. The agreement was 99 percent when
classification was smoker or nonsmoker (53). Serum thiocyanate
(SCN) determinations made during the termination interview pro-
vided further validation. Since it is not otherwise noted in the
scientific reports, it is assumed that the results are based on self-
report and are not corrected, Individuals who reported ever having
smoked regularly or having smoked during the preceding month on
an average of more than once a day were classified as smokers. The
reported number of cigarettes, cigars, and pipes smoked per day was
calculated as the amount smoked (53).

The prevalence of smoking in the study and in the control area for
men was 50.2 and 59.9 percent, respectively, and for women 11.7 and
13.1 percent at the start of the study. At year 5, 17 percent of the
baseline male smokers in North Karelia reported smoking cessation
and 15 percent of the baseline male smokers in Kuopio reported
cessation of smoking (52, 53) (Table 4). Thus, smoking had decreased
considerably in both the control and the study groups, yielding a
nonsignificant net reduction in North Karelia of 2.5 percent for the
men and 6.1 percent for the women. With regard to amount smoked,
North Karelian men smoked more than did the men in the control
area in 1972 (9.9 versus 8.9 cigarettes per day), and both groups were
smoking 8.1 cigarettes per day by the end of the study (531, producing

279


a significant net reduction among North Karelian men of 9.8
percent. The mean number of cigarettes smoked by smokers in
North Karelia was 19 cigarettes per day, which remained stable
during the study (63).

A small net reduction occurred in the prevalence of smoking
because, even though considerable cessation was reported in North
Karelia, smoking also decreased at a similar rate in Kuopio, the
control area. The investigators noted several possible explanations
for this decrease (53). There was an increase in interest in antismok-
ing activities toward the end of the study period: the Finnish
Parliament passed new antismoking legislation in 1976, and a new
medical school opened in Kuopio in 1972. They also indicated on the
basis of internal followup surveys that most of the reduction in
smoking occurred at the beginning of intervention in North Karelia,
after the first intensive public antismoking campaign, and that this
lower level of smoking was maintained during the rest of the period
(39. 63).

Deficiencies in the Community Preventive Trials

The major deficiencies in these community preventive trials are
the same as those noted for the clinical trials; i.e., lack of objective
data to verify self-reported outcomes, use of cross-sectional analyses
to the almost complete exclusion of cohort analyses, failure to
provide sufficient information in scientific reports to allow adequate
interpretation of outcomes, and lack of evaluation of components of
the intervention packages.

Objective data to verify self-reports were not used in the United
Kingdom and the Belgium heart disease prevention projects, and
although SCN was measured in the North Karelia study, it was not
used to adjust the self-reported cessation data. Data for strata of
smokers by age were presented for the North Karelia study (74), but
not for cohorts of smokers by smoking-behavior-change categories.
Longitudinal data for cohorts of smokers in the other two trials were
not presented. The value of cohort data is illustrated by a statement
made by the North Karelia investigators in which they noted that
even though the smoking cessation rates were similar in North
Karelia and Kuopio, most of the cessation in North Karelia occurred
at the beginning of the project and was maintained (63, 74). This
information was obtained by the use of followup surveys of samples
of residents. It was hypothesized that most of the cessation for the
comparison community may have occurred near the termination of
the project when antismoking legislation and other changes had
occurred there (39, 63). Cohort data for the comparison community
or for subgroups are not available; thus, the hypothesis cannot be
tested.


Use of the same subjects for baseline and termination surveys are
likely to influence outcomes; therefore, the change may look better
than it actually is (53, 54, 63). The use of a cohort design might
therefore produce a net effect that is not totally a consequence of the
intervention alone, but may also include the effect of the first survey
as well as its interaction with the intervention (63). Thus, there is a
possible need to examine independent cross-sectional population
samples in the two areas under study at the start and termination of
the project. This hypothesis is not supported by data from the North
Karelia study, where cessation rates for 6.6 percent of the random
sample of smokers in the baseline survey of the control community
who were also included in the termination survey were similar to the
rates for the rest of the smokers who were surveyed only at
termination (63). Data from the United Kingdom heart disease
prevention project (62) also failed to support the hypothesis of a
possible intervention effect from screening.

Different components of intervention were not differentially
evaluated within any of the community trials because of the
community orientation of the projects. Thus, conclusions about the
relative contributions of different programs, subprograms, or chan-
nels of action cannot be drawn (39).

Comparison of Community Trials Outcomes

As is noted in Table 4, the 2-year cessation data for both the
Belgium and the United Kingdom WHO trials demonstrate that
there were significant differences in reported cessation rates for the
intensively intervened-with high risk smokers as compared with the
smokers in the control factories, but there were no significant
differences between the non-high-risk smokers in the intervention
factories who received a media-only approach as compared with the
non-high-risk smokers in the control factories. This outcome is
similar to the previously noted finding in the Stanford study; i.e.,
media only had no more intervention impact than had no interven-
tion. This lack of demonstrated impact for a media approach to
smoking cessation in the Belgium study was in part due to the 12.5
percent cessation rate achieved by the control group. This occur-
rence of cessation in a control group is similar to that demonstrated
in each of the clinical trials. Again, a saturation point may have been
reached in groups in which there is already an increased level of
awareness, and intensive intervention may be necessary if additional
cessation is to be realized in the next level of smokers. It may also be,
as previously noted, that although cessation occurred among the
nonintervention smokers, the long-term maintenance rate among
those in this group who stop smoking may be significantly different
from the long-term maintenance rate for the intervention group


smokers. Because of the lack of cohort data, this issue cannot be
addressed.

The range of cessation rates among the comparison groups for the
three trials is large, 0 to 15 percent, with the lowest rate recorded for
the United Kingdom group of the WHO collaborative study and the
highest for the Belgium group of the same study. The 0 percent
cessation rate for the control group in the United Kingdom trial is
puzzling, as this is less than the spontaneous cessation rate observed
in the general population. More in-depth analysis of the data for the
10 percent random sample of the control group who were screened at
baseline and reexamined at 2 years is indicated. Different protocols
for contact with the control group were used for the United Kingdom
from those used for the Belgium groups. The most notable difference
was that 90 percent of the United Kingdom control group were not
told of their participation in the trial, but 90 percent of the Belgium
group were told of their participation and had a resting ECG. An
additional 10 percent were told of their participation and had
complete physical examinations. It can be hypothesized that the use
of an ECG may have had an intervention effect for the Belgium
control group. The 15 percent rate for the North Karelia study was
determined at 5 years. One might hypothesixe that this rate would
be lower at 2 years, the point at which the other two studies
conducted followup.

The 5year cessation rate for the United Kingdom collaborative
trial is also low when compared with the 2-year rate for the Belgium
collaborative trial, which utilized a similar protocol. A major
difference for these two groups was that high risk smokers in the
Belgium study received two examinations per year while those in the
United Kingdom were given one. There was also a difference in the
number of physician-intervention visits during year 1; two were used
in the Belgium study and four were used in the United Kingdom
trial. Perhaps the feedback provided by an examination has a
greater intervention effect than a session with a physician intended
for counseling only. It can also be hypothesized that cultural
differences may have affected the differences in outcome between
the two groups in the same trial.

In general, the use of community programs that used only a media
approach did not produce a greater intervention effect than was
observed in the comparison community. The incorporation of more
intensive intervention in groups in addition to the media approach
was necessary before significant differences could be realized. The
same outcomes were observed in the Stanford study.

282


Conclusions
1. Smokers involved in intervention programs demonstrate higher
  smoking cessation rates than those in control groups.
2. In general, the success of smoking intervention programs is
  related to the amount of intervention provided.


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289


SECTION 8. THE EFFECT OF
        CIGARETTE SMOKING
         CESSATION ON
         CORONARY HEART
         DISEASE

291


Epidemiologic Evidence Regarding Smoking Cessation and
Coronary Heart Disease

The epidemiologic data on smoking and coronary heart disease
(CHD) were reviewed in detail in a preceding section, as well as in
the Reports of the Surgeon General for 1964,1971, and 1979 (60, 61,
62). Coronary heart disease (ICD/G and ICD/7 No. 420) before 1968
and ischemic heart disease (ICD/8 and ICD/9 Nos. 410414) since
1968 are considered synonymous with one another for all practical
purposes and are abbreviated as CHD. Terminology and data on
CHD are discussed in detail elsewhere (33, 34, 44). This discussion is
limited to epidemiologic data on smoking cessation and CHD.
Several prospective studies involving self-selected questionnaire
respondents include extensive epidemiologic data on smoking cessa-
tion and CHD mortality. The results, summar@ed in Table 1, show
CHD death rates for former smokers relative to never smokers as a
function of the number of years stopped smoking cigarettes, general-
ly determined as of the time the questionnaire was completed. Data
in this form are available only for men, generally white men. The
studies are as follows: the British physicians study, including 10-year
followup (10, II) and 20-year followup (12); the American Cancer
Society S-State study (22, 23) and the American Cancer Society 25
State cancer prevention study (20, 21); the U.S. veterans study with
&&year followup (32) and X-year followup (49); and the Swedish
representative sample study with l@year followup (4). Excluded
were numerous studies that present data only on former smokers as
a whole or have data on a few special categories of former smokers,
such as Shapiro et al. (58) and Hirayama and Hamano (25). Much of
these other epidemiologic data on former smokers is summarized in
the 1979 Report of the Surgeon General on Smoking and Health (60)
and in the preceding section of this Report on coronary heart disease.

Numerous epidemiologic studies (10, II, 12, 14, 20, 21, 32) have
shown a decrease in CHD mortality for ex-smokers compared with
continuing smokers, and it has been suggested that smoking
cessation accounts for this salutary effect. Another view (57) has
been that continuing smokers and quitters are somehow constitu-
tionally different and that their health experiences might also be
different, independent of smoking status. Two prospective studies of
current smokers, some of whom became persistent quitters during
the course of the study, show that persistent quitters have lower
CHD and total death rates than do continuing smokers (17, 18).
Friedman et al. (17) examined this question in some detail in the
Kaiser-Permanente study of over 25,000 persons. They compared 18
baseline characteristics related to coronary disease in quitters and
continuing smokers at a time when all were smoking. They found
that the beneficial effects of quitting on CHD mortality could not be
explained by differences in their baseline characteristics (Table 2).

293


F  TABLE l.-Male coronary heart disease and total mortality ratios for current and former cigarette
       smokers relative to never smokers, as a function of years stopped smoking

Overall cohort        Smoking selection
description                criteria

Years
stopped '

Coronary heart disease
mortality ratbE

All causes
mortality ratio2

British physicians'









British physicians'









American Cancer Society
S&ate study S

Cigarettes only         0                1.41 (464)                        1.37 (1566)
                l-4                1.05 (28)                         0.96 (71)
                5-9                1.25 (61)                         1.18 (204)
               10-14               1.16 (59)                          1.12 G?O4)
               15+               1.12 (40)                         1.11 (153)
                NS               1.00 (113)                        1.00 (436)

                          Attained age                     Attained age

                         3c-54        55-64       65+         30-64        65+        30+

Cigarettes only,        0        3.5         1.7         1.3          2.0         1.6          1.8
at least 5 years        l-4        1.9 (71       1.9 (19)      1.0 (24)       1.7 (67)      1.4 (99)      1.5 (1661
                5-9        1.3 (10)       1.4 (34)      1.3 (76)       1.6 (141)      1.4 (242)      1.5 (383,
               lo-14       1.4 (101      1.7 081      1.2 (62)       1.4 (104)      1.2 (206)      1.3 (310)
              15+       1.3 (7)       1.3 (45)      1.1 (148)      1.1 w6)      1.1 wEa      1.1 (590)
               NS       1.0 (32)      1.0 (75)      1.0 w?2)      1.0 (326)      1.0 (611)      1.0 (9371

                       Cigarettes smoked per day             Cigarettes smoked per day

                             l-19           2t+                 1-19           20+

Cigarettes only         0           1.75 @J4)        2.20 (6041             1.61 (2303)        2.02 (1326)
               <l           2.10 (23)         3.00 (18)              2.04 (51)         2.69 05)
                l-9           1.54 (80)         2.06 (64)              1.30 (159)        1.82 (135)
              lO+           1.09 (401         1.60 (40)              1.08 (141)        1.50 (87)
               NS           1.00 (709)        1.00 (709)              1.00 (1644)        1.00 wx4)


TABLE I.-Continued.

Overall cohort         Smoking selection
description                criteria

Coronary heart disease
mortality ratio'

All causes
mortality ratio'

American Cancer Society
25State study'

Cigarettes only

Cigarettes smoked per day

for initial ages 40-79

              1-19           20+

0           1.90 (1063)        2.55 (2822)
*. 1           1.62 (29)        1.61 (62)
l-4           1.22 (57)         1.51 (154)
5-9          1.26 (55)         1.16 (135)
10-19          0.96 (52)         1.25 (133)


201           1.08 (70)         1.05 (80)

Cigarettes smoked per day
   for initial ages 54S74

1-19           20+

1.72 I20151        1.94 (3741)
1.61 (641         2.18 (213)
1.44 (1441        1.98 (499)
1.34 (1261        1.49 (416)

1.02 (2551        1.32 (5461

NS           1.00 (1841)       1.00 (1841)             1.00 (3512)        1.00 (3512)

Attained age. 55-64

Attained age. 55-64

U.S. veterans'        Cigarettes with or       0                  1.66 (3064)                          1.72 (6928)
              without cigars/pipes,     l-l                 1.34 (155)                           1.56 (379)
             stopped for other       5-9                 1.47 (279)                           1.42 (5961
                than doctor's orders     lo-14                 1.13 (161)                           1.28 0651
                               15+                 0.97 (342)                           107 (7791
                                NS                1.00 (1218)                          1.M) (2617)

                                                 Attained age, 31-99                     Attained age, 31-99

U.S. veterans'        Cigarettes with or       0                  1.56 (13,645)                          1.73 (36,143)
              wthout cigars/pipes,     14                 1.35 uO1                          -1.5  (384)
              stopped for other       5-9                 1.36 (599)                          -1.4  (1441)
               than doctor's orders     lo-14                 1.29 (997)                          - 1.3  (2445)
                                E-19                 1.21 (1101)                         - 1.2  (2767)
                                20+                 1.05 (2418)                         -1.05 (6049)

E
01                                     NS                1.M) (-6500)                      1.00 (16,224)


TABLE L-Continued.

Overall cohort
description

Smoking selection
   criteria

Years
stopped I

Coronary heart disease
mortality ratio*

All causes
mortality ratio '

Swedish representative
samples

0
l-9 '
10+
NS

Years smoked cigarettes, initial age, 40-69      Years smoked cigarettes, initial age, 40-69

<20         >20        Total         <20         >20
         L                                      Total
                                         A
                   1.7 (212)                            1.4 (557)
0.9 (71       1.6 (84J       1.5 (97)       1.0 (26)       1.4 (212)      1.3 (253)
0.9 (40)      1.1 (46)      1.0 (86)       1.0 (1231      1.0 (117)      1.0 (241)
1.0 (219)      1.0 (219)      1.0 (219)      1.0 (671)      1.0 (671)      1.0 (671)

' Years stopped smoking was measured as of beginning of followup. except for the U.S. veterans study. where the number of years stopped was increased by 1 with the passage of each calendar year
unless death occurred 0 years stopped denotes current smoker; NS denotes never smoker.
`Mortality ratio is former emoker death rate relatrve to never smoker death rate, properly adjusti for age; ratio for never smokers is delined to be 1.0. Number of deaths are in parentheses.
"Study of 34,445 men aged 201. at lOyear followup. 1951-1961. Doll end Hill (10. 11).
.Study of 34,440 men aged 20+. et Myear followup. 1951-1971. Doll and Peta (12).
`Study of 187,783 men aged 5O-fj9. et 44.month followup, 1952-1955. Hammond and Horn (22,23).
`Study of 440,558 men aged 301, approximately at 4-yeer followup. 1959-1963. for total mortality, end 358,534 diseasefree men at Gyear followup. 1959-1965, for CHD mortality Hammond (20),
Hammond and Carfinkel(21).

`Study of 248,046 men a& 31-&1. at 5.5.year or 8Syear followup. 1954-1962. Kahn (32).
a Study of 248.045 men aged 3184. at E-year or E-year followup. 1954-1969. Royot and Murray (49).
`Study of 51.911 men aged 18-69. at l&year followup. 1963-1972. Cederlof et al. (4).


People who persisted in cigarette smoking had more than twice the
risk of dying from CHD than those who quit even after taking into
account the other baseline differences. These studies provide stron-
ger evidence regarding the benefits of quitting than do the studies in
which all of the ex-smokers had stopped smoking before the
beginning of the followup.

Data from two "natural experiments" of smoking cessation among
physicians in Britain (12) and in California (14) are presented in
Table 3. Because these physicians have stopped smoking to a much
greater extent than has the general male population, the subsequent
CHD mortality trend in physicians as a whole relative to the general
population constitutes a crude estimate of the overall mortality
benefits of smoking cessation, This assumes that there have been no
other major risk factor changes in the compared populations, but
unfortunately, other risk factors were not measured in these two
studies. Both studies support the earlier prospective studies with
regard to the benefits of smoking cessation on CHD mortality. In
addition, they show the benefit of smoking cessation among a cohort
as a whole, including the continuing smokers with the quitters.
The most straightforward interpretation of ex-smoker data indi-
cating that CHD mortality rates of persons who stopped smoking are
substantially lower than those of persons who continued smoking, is
that smoking cessation directly results in the reduction of risk of
heart disease mortality. Underlying this presumed CHD benefit is
the assumption that ex-smokers are a representative sample of
smokers, except that they have stopped smoking. If the assumption
of representativeness is not valid and significant baseline differences
in relevant factors exist between ex-smokers and smokers, then the
mortality comparison of ex-smokers and continuing smokers may
not properly describe the benefits of smoking cessation for the
typical smoker. In the Kaiser-Permanente study (17), there were
small differences in risk profiles and other factors between those
who continued to smoke and those who quit, but these differences
were not large enough to account for the differences in CHD death
rates.

In summary, each of the several major prospective studies of
smoking cessation demonstrates that ex-cigarette smokers have a
decreased risk of subsequent mortality relative to continuing smok-
ers. The decreased risk occurs fairly quickly after cessation of
smoking, suggesting that the effects of cigarette smoking are
reversible. The quitters were self-selected in these observational
studies, however, and may include cigarette smokers at lower risk of
disease. However, the steadily decreasing risk over time after
quitting suggests that more is going on than the simple selection of a
lower risk group. Conversely, some smokers may quit in response to
symptoms or diagnosis of smoking-related illness, thus possibly

297


TABLE 2.-Age-, sex-, and race-adjusted death rates according to smoking category and selected major
          causes

Adjusted death rate per thousand person-years'

Category

No. of
subjects

No. of
person-
years

Ail causes

All causes
except mjuries
and poisoning

  All       Lung
neophms       cmm?r

  All
circulatory
diseasea

Persistent smokers

9,394      70,348       9.2 (557)        8.1 (465)        3.2 (191)      0.9 (58)       4.0 (240)      2.6 (166)

Tcamporary quitters        970       6,666       7.1  (46)         6.7  (43)        2.2  (14)       0.9  (6)       3.8  (24)       2.3  (16)

Persistent quitters       2,856      16,798       5.3 (107)         5.0 (102)        1.9  (39)       0.3  (6)       2.2  (46)       1.4  (31)

Never smokers        12,697      9%~       5.1 (569)         4.8 (540)        1.8 WW       0.02 (2)       2.4 (275)       1.6 W36)

' Figures m parentheses denote number of deaths.
Source: Fredmen et al. (17).


TABLE 3.-Relative trends in cigarette smoking and
     coronary heart disease mortality among male
      physicians in Britain and California in two
      natural experiments of smoking cessation,
       where status of other risk factors is unknown

British male physicians, 1951-71'

Percentage of physician current
smokers at start of time period
Ratio of smokers
(physicians/British males)

         Time period
1951-55    195660    1961-65    19671
-   -   -   -


  41        3.3        27        21


  88        68        al       51

Standardimd mortality ratio (physiciane/Britiah males)

CHD and myocard. degen., attained age
  Y20-54
  55-64
  65-74
  7&84
All causes, attained age
  2c-64
  65a4

107        85        62
120   -    103        a6
109       100        91
88        94       100


82        76        70
75        77        78

California male physicians, 1950-79'

Time period

                       KM-54 1955-59 1960-64 196.5-69 1970-74 1975-79
                       ------
Percentage of physician current
smokers at start of time period       53 48 39 28 20 14
Ratio of smokers
(phy&iaw/U.S. males)           100 a3 66 55 44 35

                    Standardized mortality ratio (phyeiciane/U.S. males)

Cl-ID                       115     97     86     80     74     69
Allcauaea                     a9     80     79     78     67     67

`Studyof31,CIOmenagsd20+.folfor~- DollandPeto (12)
`Study of 10,310 mea aged 26+, followed for 30 years. En&mm (14).

underestimating the benefits of quitting that would he expected in
an otherwise healthy population. Other variables that may contrib
ute to mortality may not have heen included in the analysis.

Randomized Controlled Trials of CHD Prevention Not Involving
Smoking Cessation

The most rigorous way to determine the value of smoking
cessation is the randomized controlled trial. A series of important
experimental or clinical trials have been conducted in the United
States and other countries over the past 25 years in order to

299


establish the effectiveness of primary prevention of CHD through
modification of risk factors. These randomized controlled trials
involve both primary and secondary prevention (2). The primary
prevention trials select subjects who are free of CHD or stroke at
entry to the study. The secondary prevention trials attempt to
modify risk factors after a heart attack or stroke in order to reduce
the risk of a second heart attack or death (6, 7, 8, 38, 40). Secondary
prevention trials and nonrandomized trials are not discussed further
here.

Most previous primary prevention trials of CHD have been limited
to a single risk factor such as serum cholesterol reduction. Many
single risk factor intervention trials include a pharmacologic agent
that lowers either serum cholesterol or blood pressure and is
compared with a placebo. Most of these studies are further limited to
higher risk subjects, such as subjects with serum cholesterol levels in
the highest 10 to 15 percent of the population, or to relatively small
sample sizes. They did not monitor or control for changes in cigarette
smoking habits.

The most extensive primary prevention trials involve dietary
reduction of cholesterol; they are described in more detail elsewhere
(2, 39). The major randomized trials are the Los Angeles veterans
domiciliary study (9), the Helsinki, Finland, mental hospital study
(42, 59), and a feasibility study of free-living and institutionalized
Americans (45). Each of these studies involved about 200 to 400 men
in the dietary intervention group and a similar number in the
control group.

Another set of randomized trials has involved reduction of high
blood pressure using antihypertensive medication-the U.S. Veter-
ans Administration cooperative study (631, the U.S. hypertension
detection and followup program (30, 31), the Australian therapeutic
trial (I), and the Oslo drug trial (24). These large studies followed
three small studies-Hamilton et al. (191, Wolff and Lindeman (67),
and the Cooperative Randomized Control Trial (CRCT) (5). These
studies generally show that lowered blood pressure results in some
reduction in CHD among the treated groups relative to the control
#FouP~

Intervention Trials of CHD Prevention Involving Smoking
Cessation

The observational epidemiological studies strongly suggest that
cigarette smoking cessation decreases the risk of heart attack and
CHD mortality compared with the risk for continuing smokers (60,
61, 62). All of the observational studies, however, have the limitation
that the individuals were not experimentally assigned to smoking
and nonsmoking status. Experimental studies such as randomized



controlled trials offer a solution to this problem, because they test a
smoking cessation intervention in the most rigorous way .possible
using human subjects (2, 37, 70). However, even in such trials, those
assigned to the no-intervention group modify their smoking habits,
and those assigned to the intervention group have incomplete
success in quitting.

Ideally, each risk factor should be treated independently, but
modification of one risk factor often results in changes in other risk
factors. For instance, some studies have noted that cigarette smoking
cessation can lead to a modest weight gain (3, 26, 47). In a good
primary prevention program there would be an effort to reduce or to
eliminate the weight gain that sometimes accompanies cessation.
Although the multifactorial approach is less precise, it has been
considered to be a more practical approach to the problem. There has
been only one trial of smoking cessation per se (50, 51).
Two types of primary prevention trials involving smoking cessa-
tion are underway. The first type of study, exemplified by the
Multiple Risk Factor Intervention Trial (MRFIT), selected subjects
at high risk of CHD based on a combination of cigarette smoking
history, elevated blood pressure, and high serum cholesterol level
(43). Subjects were then randomized into either a special treatment
group or a comparison group. The Whitehall study (50, 51) and the
Oslo study (27) are also of this type.

In the second type of study, communities or groups rather than
individuals are randomized into a treatment or a control group. The
WHO heart disease study randomized men according to the factory
where they work and followed the individual factory workers (70).
The North Karelia study randomized two separate communities in
Finland (48). Whereas the factory workers were individually fol-
lowed, the communities were monitored only in a cross-sectional
manner and individuals were not followed longitudinally.

The primary hypothesis in these studies is that reduction of the
risk factors will reduce the incidence of and mortality from CHD.
The first step in testing this hypothesis requires that the subjects or
groups be successfully recruited and categorized at entry to the study
and that a very high percentage be successfully followed for the
duration of the study.

The second step in testing the hypothesis requires the successful
reduction of the major risk factors-smoking, high blood pressure,
and high serum cholesterol. Often a selected subsample of high risk
subjects receives more intensive individual intervention, but the rest
of the treatment group receives only community health education. It
is not known how large a reduction in risk factors is necessary to
observe a decrease in CHD, except that the larger the reduction in
risk factor the greater the chance for a decrease in CHD. Specific
goals for reduction of risk factors can be based on the presumption

301


that such reduction would result in a statistically significant
decrease in the incidence of and mortality from CHD according to
the observational epidemiologic studies. The relationship between
the reduction of this risk score and actual reduction in the frequency
of disease is, of course, the hypothesis being tested.

The third and most critical step depends on the first two: that is,
the measurement of outcome-changes in the incidence of or death
from CHD. The ability to measure the incidence requires careful and
unbiased monitoring of the sample. The determination of total and
cardiovascular mortality is much simpler, since it depends only on
minimizing the number of participants lost to followup. The commu-
nity studies attempt to compare the death rates between two or more
communities, and the power of such a statistical test is obviously
very weak.

Roth the community studies and the individualized studies are
also confounded by the uncertainty of the interval between risk
factor change and reduction in risk of disease. Those subjects most
likely to die or to have a heart attack in the first few years of the
study are those with the most extensive disease at baseline. Unless
the population is followed long enough to include both the lag period
and the effects of the initial selection of those with advanced
subclinical disease, a spurious interpretation of the study results is
possible.

Generally, studies of experimental communitywide interventions
are unlikely to determine the efficacy of smoking cessation on
reducing the incidence of and mortality from CHD because of the
difficulty in determining the effects of smoking cessation on specific
individuals in the community and in separating out the effect of
smoking cessation from other changes in the community. In many of
these studies the percentage of men who reported quitting smoking
is relatively small, which reduces the power of the study at least in
terms of smoking cessation.

This review focuses on all intervention studies involving smoking
cessation for which CHD mortality outcome data have been pub
lished. In another section of this Report a detailed review on
smoking cessation in clinical and community trials is presented.
Discussed in detail here are data from the U.S. Multiple Risk Factor
Intervention Trial (43), the Whitehall study in London, England (511,
the Oslo study in Norway (27), the WHO European Collaborative
study (691, and the North Karelia project in Finland (48). Omitted
from this section are smoking intervention studies without published
mortality outcome data, such as the Stanford, California, three-
community study (16), the Stanford five-community study (15), the
Goteborg, Sweden, study (64, 65, 66), and the Helsinki, Finland,
study (46).

302


Essential details from each trial are described in the following
pages and tables. The initial population characteristics and risk
factor changes are summarized in Table 4. The mortality outcomes
in the intervention and control groups are summarized in Table 5 for
coronary heart disease and total mortality. Available results are also
given for other circulatory diseases, lung cancer, and other cancer.
The results for the four trials involving cohort mortality followup
are combined in Table 6. Coronary heart disease incidence rates
from the Oslo and WHO studies are presented in Table 7. A
comparison of death rates in the MRFIT intervention and control
groups as a function of initial smoking status and status at l-year
followup is summarized in Table 8. Observed deaths in the MRFIT
and Whitehall studies are compared with expected deaths based on
general population rates in Table 9. Comparisons of reductions in
CHD and total mortality from the observational studies and from the
MRFIT and Whitehall studies are made in Table 10.

Randomized Controlled Trials of Individuala
Multiple Risk Factor Intervention Trial

The Multiple Risk Factor Intervention Trial (MRFIT) was a
randomized controlled trial to investigate the effect of reducing
cardiovascular risk factors in a group of asymptomatic men at high
risk of cardiovascular disease (43). Out of 361,662 men initially
screened, 12,866 men aged 35 to 57 were selected for the trial
because they were at increased risk of death from CHD, but without
clinical evidence of CHD, and agreed to be randomized and reexa-
mined. A series of three complex screening procedures were used to
select the final 12,866 men, who constituted only 3.6 percent of those
screened. Men were designated as at increased risk because their
levels of three risk factors-cigarette smoking, serum cholesterol,
and blood pressure (BPtwere sufficiently high at a screening visit.
All of these men were in the upper 15 percent of a risk score
distribution based on data from the Framingham heart study; about
twothirds were in the upper 10 percent of risk. For example, a man
whose diastolic BP was 90 mm Hg and who reported smoking 30
cigarettes per day was risk eligible at the 10 percent level if his
serum cholesterol level was at least 295 mg/dl. The study was
restricted to men, since including women, with their substantially
lower risk of CHD, would have necessitated a larger study popula-
tion.

The men were randomized into two groups of equal size and
identical baseline characteristics from December 1973 through
February 1976. A special intervention (SD group of 6,428 men
received an intensive counseling program, aimed at cessation of
cigarette smoking, weight loss, and a change of diet for a reduction of
elevated serum cholesterol and BP levels. A usual care (UC) group of


TABLE 4.-Basic description of smoking cessation
      intervention studies of males, including
      demographic characteristics and risk factor
      changes

Variable

                 FhrY    Community
  Imiividual intervention      intervention   intervention

MRFlT whitehdl onlo      WHO    North Karelia

Number in intervention (I) group   6423
Number in control (0 group      6438

46.2
36-57

90

Followup period: Start date     1211973
          End date      211982
   Average leagth Gym)       7

Riskfactor(RFlat&ut
Cigarette smokers (%)
  Relative change `/end
  Belative change/whole period

Average no./day cigarettes
Belative change/end
Relative change/whole period

serum cholesterol (mg/dl)
Relative change/end
Relative change/whole period

Blocd pressure6 (mm H@
Relative change/end
Relative change/whole peri@

Combined change in CHD r&k

59
-29%
-31%

20
-3o%c'
30%

251
-2%
-2%

91
-4%
4%

-22.2%

714     604      24,615
731     626      25,169

52.9     45.2       46.5
40-5940-49      4049

-100    -100      -100

1968-70   1972-73     1971-76
1979     1978       1982
10      5        6

100     79.4
-24%    -12%
-54%    -16%

19.3     12.7
-33% 37%
-63% 45%

60        51.5
-3.4%'       -2.5%
-1.9%        -3

11.2
-10.1%
-8.9%

213'     329
-     -12%
-     -13%

-4      -*
-      -
-      -

-      -

217
a.596
-1.2%

138
-2.0%
-2.0%

-11.1%

1972   1977
--
1834   1785
2665 2616

-42   -47
25-59 30-64

  -100

   1972
   1977
    5

9.4
-9.8%
-

263
-4.1%
-

91.5
-2.6%
-

-17.4%

`Relative change = (RF, - RFcMtFc. except for North Karelia. where relative difference in determined from
(I4 1977 and tIJ2:, 1972.
' Estimated fmm avaiL3ble data.
*Not meamumd or not reported.
o Riskfactorienot partofinteneotiml.
`Diastolic. except for systolic in WHO study.

6,438 men received annual checkups including medical history,
physical examination, and laboratory studies at the MRFIT clinics,
but were referred to their personal physicians or other community
medical facilities for such treatment of their risk factors as was
considered individually appropriate. Thus, no intervention program
was offered to them. The results of their screening and annual
examinations were provided to their respective physicians who were
also informed as to the scientific objectives of the study.

The smoking intervention urged those SI participants who smoked
cigarettes to quit, but no effort was made to alter the smoking habits
of those who smoked only pipes and cigars (29). Dosage reduction-

304


Reported                        Thlocyanale-adjusted
agarene smokmg                     agarene smokmg

70 r

60

50

40


30

10 12 3 4 56

St

     S,                                 Sl
         YEARS OF FOLLOWUP                     YEARS OF FOLLOWUP

FIGURE l.-Mean risk factor levels for cigarette smoking
     by year of followup for Mulcple Risk Factor
      Intervention Trial Research Group participants
NOTE2 SI idicntea special intervention
     UC indicates UsuaI care
    6,illdicat4aftirraning~t

SOUFtCI3 Multiple Rid Fwtc.r Intervention Trial Research Group (13).

switching to cigarettes low in tar and nicotine-was recommended
only as an intermediate step to cessation. Conventional behavior
modification techniques were used throughout the trial; aversive
techniques and hypnosis were used in selected instances. Ten-week
group sessions at the beginning of the trial and 5day quit clinics
during the final years were found to be particularly successful
intervention approaches. Further details on the smoking interven-
tion are provided in an earlier section of this Report, and the serum
cholesterol and BP interventions are described elsewhere (43).

Statistically significant CHD risk factor reductions between the SI
and UC groups were obtained at each annual visit. Of particular
interest was the reduction in number of cigarette smokers, as shown
in Figure 1. At the beginning of followup, 59 percent of all men had
reported themselves as current cigarette smokers. At the E&month
followup, the stated quit rates were 43 percent for SI men and 14
percent for UC men; at 72 months, the rates were 50 percent and 29
percent, respectively. Serum thiocyanate-adjusted quit rates at 12
months were 31 percent for SI men and 12 percent for UC men; at 72
months they were 46 percent and 29 percent, respectively. This
means that the SI group reduced its level of smokers 30 percent more
than the UC group. The risk factor changes are summarized in Table
4.

As of February 23, 1982, after an average period of followup of 7
years, there were 260 deaths among the UC men, of which 124 were
ascribed to CHD and 21 to other cardiovascular causes, as summa-


rixed in Table 5. There were 265 deaths among the SI men, of which
115 were ascribed to CHD and 23 to other cardiovascular causes. The
key mortality endpoint of CHD was 7.1 percent less in the SI group
than in the UC group, while the death rate for all causes was 2.1
percent higher for the SI men. The approximate 90 percent
confidence interval (CI) for the percentage change in CHD mortality
attributable to MRFIT intervention ranges from a 25 percent
decrease to a 15 percent increase. There were 34 lung cancer deaths
in the SI group and 28 in the UC group and 47 other cancer deaths in
the SI group and 41 in the UC group.
The number of deaths in the UC group was substantially short of
expectation for the 6 complete years of followup as well as for the
average followup period of 7 years, as shown in Table 9. These
mortality patterns appear to be similar to those seen in healthy
persons selected for life insurance policies (22, 41). On the basis of
the design risk factor change assumptions and the Framingham risk
functions, 442 deaths (including 187 from CHD) were expected
among the 6,438 UC men by the end of 6 years of followup, but only
219 (including 104 from CHD) occurred (50 percent of expected);
about 515 deaths (including 220 from CHD) were expected after 7
years, but only 260 deaths (including 124 from CHD) occurred.
At least three possible explanations for these results must be
considered: (1) such an intervention program is without benefit in
terms of substantial decreases in mortality; (2) the intervention
program does affect CHD mortality, but the benefit was not observed
in this study, an effect of chance; or (3) one or more constituents in
the intervention program may have had an unfavorable effect on
survival in some subgroups, offsetting the beneficial effects of others.
Of these possible interpretations, a combination of favorable and
unfavorable effects of the intervention program seems most plausi-
ble to the MRFIT investigators. Even with the unexpected sizable
risk factor reduction among the UC men, the lower-thanexpected
UC mortality, and the duration of intervention averaging only 7
years, the likelihood that these factors resulted in missing an overall
positive effect is relatively low. The data suggest that except for
some groups of hypertensive persons, particularly those with resting
ECG abnormalities, the MRFIT intervention is apparently associ-
ated with a lower CHD mortality in the SI group.
The MRFIT data also warrant analysis as an observational study
(Table 8). Of those who had been cigarette smokers at entry, 1,365
reported quitting at year 1 interview (and had confirmatory blood
SCN levels) and 6,298 did not quit. Over an average 6 years of
further followup, those who quit smoking at year 1 had a 1.10
percent CHD mortality rate, while those who continued smoking had
a CHD mortality rate of 2.03 percent. This corresponds to a relative
risk of 0.54 (1.10/2.03) or a 46 percent lower risk of CHD death for


TABLE Ei.-Comparison of deaths (d) and death rates (r) in
     the intervention. and control groups of four
       randomized controlled trials

Cause of death

Intervention group     Control group

n'     dl'       rc'    dc'

MRFlTr `I-year deaths
Coronary heart dieaee
Other circulatory diaeaae
Lung cancer
other cancer
All other causea
All cauaea

Whitehall: l&year de&ha
colvnaly heart dhaae
other circulatory dieeaae
Lung cancer
Other -r
All other cawen
All canam

oalo: &year death8
Cmonary heart dinease
(Fatal Ml and
sudden cwvnary death)
Other cimtlatory diaeaw
All can0e.r
All other cawes
Allcauaea

WHO: 6year deaths
coroMryheartdisurse
All other causes
All CauNH

.0179
.00.36

.0053
.a073
.@I72
.a412

.0666
.0162
.0252
St392
0210
.17!23

.0099
II033
.0033
.mio
.om6



.OMO

115       .0193    124       -7.1
23       .m3     21      +9.El
34       a043     28     + 21.6
47       a064     41      +14.8
46       .0071     46      +0.1
265      .oQoll-   260      +2.1

49       .0348
13       .0164
19       .0326
26       .0164
15       a246
123       .I761

6       .0222     14      -55.4
2       .0016     1     + 106.3
5       .0127     6      -34.6
3       .0016     1     +212.5
16       a362     24      -30.6

367       .0162
630       a253
997       a415

62      -19.1
12     +11.0
24      -23.2
12    + 139.0(p=.Olf
16      -14.6
128       -1.6

355

-7.4
+o.a
-2.7

' Death mte (r) equala deatha (d) divided by initial number in group.
' unloa idk?d?d with a p value. diffemm are not ti-y rigni6mt (p>O.ow. based 00 * tw&ailad teat
for a Poiron variable.

those who quit smoking compared with those who continued. For all-
cause mortality, the relative risk was 0.73 or a 27 percent lower risk
for those who quit compared with those who continued to smoke.
As demonstrated in subsequent portions of Table 8, when these
subjects are analyzed according to level of smoking at entry or by
status in the SI or the UC group, those who quit smoking always
enjoyed a substantially more favorable survival rate than those who
didn't quit.

Thus, MRFIT data are entirely consistent with the numerous
previous studies showing that those who quit cigarette smoking
enjoy a substantially improved survival.
In conclusion, the MRFIT study has shown that it is possible to
apply an intensive long-term intervention program against three


coronary risk factors with considerable success in risk factor
changes. These results are accompanied by an apparent heterogenei-
ty of effects among sizable subgroups, and there must be caution in
reaching conclusions from such subgroup data. It may be relevant
that multifactor intervention received a less than optimal test,
owing in part to unexpected declines in risk factor levels and in part
to lower-thanexpected mortality in the UC group. In regard to the
former, the UC men thus constituted to a considerable extent a
"treated" group.

Whitehall Civil Servant8 Study

A randomized controlled trial was set up to provide an unbiased
estimate of the consequences of smoking cessation in middle-aged
men (SO, 51). A total of 1,445 male cigarette smokers with an
especially high cardiorespiratory risk were selected from 16,016 men
aged 40 to 59 who had undergone a cardiorespiratory screening
examination in the Whitehall study of male civil servants in London.
Using a modification of the multivariate linear discriminant func-
tion coefficients that were calculated for predicting coronary heart
disease (CHD) among the Framingham men aged 30 to 62, a risk
score was similarly calculated for each man who smoked five or more
cigarettes a day. This score ranked the smokers according to their
estimated risk of major illness or death from cardiorespiratory
disease. The distribution of the score was tested early in the study,
and a cutoff point was determined such that the scores of 10 percent
of all men and 32 percent of smokers were eligible and exceeded this
value, which was thereafter used to define eligibility for the trial.

Men receiving medical care for heart disease or elevated blood
pressure, those found to have either severe hypertension or diabetes
mellitus, and those with major concomitant disease were excluded
from the trial. Additionally, all men taking psychotropic drugs or
with a record of previous psychiatric inpatient treatment were
eliminated. If during the l-year interval between initial screening
and trial interview they had died, moved away, or stopped smoking,
they were then not eligible for the study. The remaining 1,445 high
risk eligible cigarette smokers were randomly allocated to study
groups; 714 men composed the intervention group, and 731 men were
in the normal care group.

Men in the intervention group were recalled for a series of
personal interviews with the physician. First, each received a letter
inviting him to an appointment to discuss the results of his previous
examination. At that visit the reason for recall was presented:
evidence in his particular case that smoking represented more than
the average risk to his future health, not the discovery of disease.
The scientific evidence that stopping smoking was likely to bring
benefits was explained and illustrated by charts, with the emphasis


' ' * ' ' ' ' 1
0                  5

          YEARS OF FOLLOWUP

1
10

FIGURE 2.-Mean daily cigarette consumption by year of
      followup for the Whitehall intervention study
SOURCE: Rae et al. (51).

throughout on the evidence for the positive benefits and practicali-
ties of stopping rather than on the hazards of continuing to smoke.

A full report of the screening examination results and information
that further action was in his hands was sent to the practitioners of
men in the normal care groups. The men were not made aware that
they were involved in a trial. At the l-year and 3-year points in the
study, they were asked to return for an examination to help
research. Examinations were popular because most men saw them as
beneficial checkups. The questionnaire response rates among survi-
vors were 84 percent at 1 year and 83 percent at 9 years. Dropouts
were mainly retirees. The proportion of responders in the interven-
tion group who were not smoking any cigarettes was 63 percent at 1
year, decreasing to 55 percent at 9 years; initially, all of those in the
study were smokers. Figure 2 shows the trends in stated numbers of
cigarettes smoked in the intervention group. After 1 year, consump
tion in the intervention group was one-quarter of the normal care
group level. By 9 years, the estimate of cigarette consumption for
intervention men was 70 percent of that for the normal care
controls. Over the 10 years, the net apparent reduction in the
intervention group averaged 7.6 cigarettes/day (-53 percent), com-
pared with the control level, as shown in Figure 2 and Table 4.

During the 10 years of followup, there were 128 deaths in the
control group compared with about 130 deaths expected from the
age-specific rates for England and Wales in 1974, as shown in Table
9. The fact that all men entering the trial were high risk smokers
should have increased the observed deaths, but this may have been
offset by the "healthy worker" effect in an occupational study group
or by the selection process that excluded very sick men. Deaths were
also close to national levels for coronary heart disease (111 observed,
94 expected), lung cancer (42 observed, 35 expected), and other

309


TABLE 6.-Summary of deaths and intervention/control
      differences from coronary heart disease, all
      other causes, and all causes in four randomized
       controlled tri&

Percentage

Diaeaae

Olmxved deaths in    Expect4 deaths bawd   difkren~ '
intervention group      on control group       (O-EVE

Cmonary heart disease

  Whitehall
  Old0
  WHO
Unweighted total


All other canaea


  Whitehall
  OElO
  WHO
Unweighed total

115               123.6          -7.1
49               60.6         -19.1
6               13.3         -55.4
367               396.4          -7.4
537               594.1        -9.6(p=.O2)



150               135.8        t10.5
74               64.4         f14.9
10                9.1         +3.1
630               627.7         +0.4
864               837.6         +3.2

All cauea
                      265              259.6         +2.1
  whitehau               123               125.0          -1.6
  CM0                   16               23.0         -30.6
  WHO                  997              1024.1          -2.7
Unweighted total            1401              1431.7          -2.1


' Unlsss indicated with a p value. difYerenoes are not statistically aignifiamt (p > 0.06). bawd on a twotailed tent
for a Poiemn variable.

cancers (40 observed, 41 expected). Seventy-two percent of deaths
occurred in a hospital, and in 45 percent there was an autopsy.
Additional data were obtained from the National Cancer Register of
cases histologically confirmed either by biopsy or at autopsy for
deaths from other causes.

Table 5 shows that the USyear CHD death rate was 8.5 percent (62
deaths) for the normal care group and 6.9 percent (49 deaths) for the
intervention group, a proportionate change of -19 percent (95
percent confidence limit of -43 to + 18 percent). Among the 369 men
who entered the trial with evidence of myocardial ischemia (angina
pectoris, history of possible myocardial infarction, or positive electro-
cardiogram) the reduction was -23 percent compared with -11
percent in those without such evidence. The number of deaths from
cardiovascular causes other than CHD was 12 in the normal care
group and 13 in the intervention group.

Mortality from all causes was initially higher (though not signifi-
cantly so) in the intervention group, but during the last 6 years of
the trial, the rates were higher in the normal care group. During the
whole 10 years, 123 intervention men (17.2 percent) died, compared

310


with 128 (17.5 percent) of the normal care group-a proportionate
change of -2 percent (95 percent confidence limits of -22 percent to
+23 percent). Causes of death were also grouped according to
whether or not they were smoking related. The smoking-related
causes included coronary heart disease, chronic bronchitis, and
cancers of the respiratory tract, esophagus, urinary tract, and
pancreas. There were 92 such deaths in the normal care group and
81 in the intervention group, a proportionate change of -9 percent
(95 percent confidence levels of -31 percent to +20 percent).
The trial was designed to test whether the total reduction in
cardiorespiratory disease among middle-aged men was as large as
that indicated by the observational studies of ex-smokers. Its size was
planned in the expectation that incidence as well as mortality data
would be available; when this proved unattainable, the resultant loss
of power was partly offset by extending the mortality followup to 10
years.

At l-year followup, almost twothirds of the intervention subjects
had given up cigarettes altogether, while others claimed to be
smoking less than before. Unlike the MRFIT study, objective tests of
smoking behavior were not made here. However, the authors felt
that those who reported complete cessation were generally truthful,
while those claiming to have cut down may have been exaggerating.
The reports were based on questionnaires completed at home, with
little external pressure; they were largely consistent over the
ensuing years. The progressively narrowing gap between the two
groups was due mainly to a gradual reduction in smoking by the
normal care men. Although the size of the gap may have been
overestimated, there is no doubt that throughout the earlier years of
the trial it was large.

Over the trial as a whole, the intervention group's level of total
smoking exposure was estimated as about half that of the normal
care group, implying that the effects of complete cessation might be
substantially more than those observed in the trial. The results for
total mortality represented the approximate balance of a favorable
trend for smoking-related diseases and an adverse trend for non-lung
cancers. After an exhaustive analysis of the data, the Whitehall
investigators think the difference in non-lung-cancer mortality in
this trial was more likely due to chance than to an effect of
intervention. Such evidence as there is for the latter view should be
considered as a hypothesis for further study, not as the basis for
conclusions or for any recommendation to smokers.

Oslo Study

The purpose of the Oslo study was to find out whether the
cessation of smoking and the lowering of high levels of blood lipids by
dietary changes, if maintained for many years, would lead to

311


reduction in the incidence of first attacks of CHD in men aged 40 to
49 (26, 27, 28). All Oslo men aged 40 to 49 were invited for screening
of coronary risk factors during 1972-73, and 65 percent (16,202 men)
attended. From this cohort, healthy normotensive men were selected
for a controlled trial if they had serum cholesterol levels (mean of
two measurements) of 290 to 380 mg/dl, coronary risk scores (based
on cholesterol levels, smoking habits, and blood pressure) in the
upper quartile of the distribution, and systolic blood pressures (mean
of two measurements) below 150 mm Hg. Those selected had normal
ECGs at rest and were free of any cardiovascular disease, chest pain
on exercise, clinical diabetes mellitus, fasting blood sugar levels
above 135 mg/dl, cancer, disabling disease, psychopathological
disease, and alcoholism.

Men who met the selection criteria were sent a letter explaining
the experimental design of the trial; 97 percent were found willing to
participate. There were no significant differences between the
intervention and control groups for subject factors such as age,
history of CHD symptoms, cigarette consumption and smoking
status, serum cholesterol and triglyceride, systolic blood pressure,
and diet. After the screening examination, two reexaminations were
made before randomization, the first of these when the subjects were
fasting.

Each of the men in the intervention group was individually talked
with for 10 to 15 minutes by the investigator and introduced to the
risk factor concept and the purpose of the study. Anti-smoking
advice was given individually to all smokers in the intervention
group. They were informed that cessation of smoking might be of
special importance for those with high blood lipid levels. In addition,
the dietitian established a diet record for each man and gave
extensive dietary advice based on this record. Other risk factors were
not subjected to intervention. Followup exams were made every 6
months for intervention subjects and every 12 months for controls.

The intervention of advice on smoking and eating habits resulted
in changes in risk variables. Tobacco consumption, expressed as the
number of cigarettes smoked per man per day, fell about 45 percent
more in the intervention group than in the controls, as seen in Table
4. Pipe smoking was included, taking one pack of pipe tobacco
weekly to equal seven cigarettes daily. The percentage of cigarette
smokers fell by only 16 percent more. The data were assessed by a
questionnaire and by the thiocyanate method. The mean difference
in serum cholesterol between the two groups during the 5 years was
13 percent.

As the design of the study was based on CHD evidence, events of
myocardial infarction (MI) plus sudden death were most important.
CHD mortality (fatal MI plus sudden coronary deaths) was 55
percent lower in the intervention group as compared with the

312


TABLE 7.-Comparison of coronary heart disease incidence
      rates 69 and cases (n) in two randomized
       controlled trials

Intervention group

  n      nl

control group      PerCentage

rc     nc        difference '

Oslo: 6-year rem&
Fatal Ml and
sudden deaths
      coronary
Nonfatal MI

Total CHD incidence

WHO: 6year results
Fatal MI and
sudden deaths
      cmonmy
Nonfatal MI

Total CHD incidence

.0099     6        a222     14       55.4
0215     13        .0350     22       -36.6

.0314     19        .Il573     36     -452(p=.O3)





.0150    367        .0162    355       -7.4
.0195    406        .0203    401       3.9

.0316    773        II331    756       -3.9

`Unlem indicatsd with a p value. ditkeness are not statistically significmt (p>O.OS). bawd on a twckGhl test
for a Poimon variable.

control group, but the difference was not statistically significant
(p>O.O5), as shown in Tables 5 and 7. Total CHD incidence, which
included fatal and nonfatal MI and sudden death, was 45 percent
lower in the intervention group than in the control group, and this
difference was significant (p < 0.051, as shown in Table 7. This is the
only trial to date to show a significant reduction in CHD incidence.
All cases of sudden death satisfied the diagnostic criteria for
coronary death except one unexplained sudden death. The total
coronary deaths, which included fatal MI and sudden death, were
lower, but not significantly lower in the intervention group than in
the control group.

An estimate was made of the proportion of the difference in total
CHD incidence between the two groups (36 versus 19 cases) due to
the reduction in cigarette consumption and of the proportion due to
the reduction in serum cholesterol using logistical regression tech-
niques (28). The percentage of the decline in incidence that was due
to reduction in cigarette consumption was estimated to be 26 percent
among smokers only, predicting a difference between groups of 3.9
cases, out of a total difference of 17 CHD cases. Similar procedures
indicated that the percentage due to cholesterol changes was 60
percent for all men, predicting a difference in CHD incidence of 10.1
cases. It seems, therefore, that the change in cigarette consumption
caused about 25 percent of the difference in CHD incidence between
the two groups and that the difference was due mainly to the
reduction in serum cholesterol. The difference between the groups
was 17 cases: 14 can be explained by this analysis, and the other 3
cases may be due to unexplained intervention effects or to chance.

313


Community-Based Intervention Trials
WHO European Collabomtive Trial

As set out in the recent WHO report on the prevention of coronary
heart disease (701, effective prevention must involve the population
as a whole: A high incidence in the population reflects a mass
elevation of risk factors, and most cases of the disease occur in the
large number of people with moderate elevations rather than in the
high risk minority. The first issue of public health policy, therefore,
is to know the effect of population-based prevention, using resources
that could reasonably be afforded. Thus, a trial of CHD prevention
has been undertaken by collaborators in Belgium, Italy, Poland,
Spain, and the United Kingdom (68, 69). It involved the random
allocation of 44 factory pairs, employing 63,732 men aged 40 to 59,
either to a cardiovascular screening and health education interven-
tion program or to a control group. Separate analyses have been
prepared for Belgium factories (35,36) and United Kingdom factories
(52,531, but these subgroups are not discussed in detail here.

Randomization of individuals in a trial of community health
education is not feasible, so a somewhat unusual design was used
that randomized entire communities, which in this trial were
factories or other large industrial groups. They were arranged in
matched pairs and randomized, one to intervention and the other to
serve as a control. All men aged 40 to 59 in the intervention factories
were invited to complete a questionnaire and take part in a simple
cardiovascular screening examination during working hours; 87
percent responded. On the basis of a multifactorial scoring system
for risk factor levels (age, job activity, cigarettes smoked per day,
systolic blood pressure, and serum cholesterol), 15 percent or more of
the men in each factory were designated as high risk. A general
campaign of risk factor modification was undertaken with posters,
brochures, personal letters, progress charts, and group discussions
and included advice on reducing or stopping cigarette smoking,
losing weight, lowering serum cholesterol, and increasing leisure
physical activity. The high risk men received more individual
attention, in addition to the general educational program, including
a series of personal sessions with the factory or project physician. All
men with mild hypertension were treated with diuretics or other
drugs in the factory or were referred to a personal physician. Drugs
were not employed to lower serum cholesterol. Annually, a random
sample of men was rescreened. All high risk men were seen at every
anniversary in some centers, or in other centers, at particular
anniversaries. All men remaining in employment at the end of the 5-
or 6-year intervention period were offered a final examination.

In the control factories, a 10 percent random sample of men was
screened initially, and the same 10 percent were asked to return
after 2 years, again at 4 years, and then at the final screening at 5 or

314


6 years, when all remaining men in the original cohort, aged 40 to 59
at the start, were offered screening. It was therefore possible to
compare risk factor levels at the start between all screened
intervention men and 10 percent of controls, between a 5 percent
random sample or more of the intervention men and the same 10
percent of the controls at 2 years and 4 years, and between all
remaining men in both sets of factories at the final screening.
Numbers were reduced by death, by leaving employment, and by
nonresponse to the invitation on the screening day. The risk factor
score used in each intervention factory to designate high risk men
was applied to the 10 percent of the screened men in the paired
control factory in order to identify those who would act as high risk
controls for purposes of measuring risk factor change. Incidence and
mortality results are now available (69) from this controlled trial,
involving randomization of 66 factories (49,781 men) in the United
Kingdom, Belgium, Italy, and Poland (Cracow). Results for Poland
(Warsaw) are not yet complete, and the results have been separately
presented for the United Kingdom (53) and Belgium (35). Net
average reductions in risk factors (all subjects) were 8.9 percent for
daily cigarettes, 1.2 percent for serum cholesterol, 0.4 percent for
weight, 2.0 percent for systolic blood pressure, and 11.1 percent for a
combined CHD risk estimate. Greater reductions occurred in high
risk subjects (19.4 percent for the combined CHD risk estimate).
Tables 5 and 7 show that the net overall changes in CHD rates
were -7.4 percent (95 percent confidence interval from -29 to +15
percent) for deaths (722 deaths) and -3.9 percent (95 percent
confidence interval from -10 to +2 percent) for fatal CHD plus
nonfatal myocardial infarction (1,502 cases). Among men aged 40 to
49 the reduction for this end-point was 15 percent; at ages 50 to 59
there was a small net increase. Deaths from all causes after an early
adverse trend showed a -2.7 percent change overall. There were
large differences between centers, ranging from a 5 percent net
increase in CHD for the United Kingdom to a decrease of 24 percent
in Belgium. In Belgium the decrease both in CHD incidence and in
all deaths was significant at the 5 percent level (35). The effect on
CHD in the different centers correlated broadly with their changes
in risk factors. The authors concluded that a reduction in major
coronary risk factors in industrial populations is possible, but it
depends on adequate resources. The results support the hypotheses
that CHD risk in middle-aged men is reversible and that community
intervention can be beneficial; however, additional followup is
necessary to determine if there are statistically significant reduc-
tions in CHD and total mortality commensurate with the risk factor
changes in the entire factory population.

315


North Karelia Study
The purpose of the North Karelia, Finland, project was to provide
a systematic comprehensive community program to reduce the
currently high mortality and morbidity from CHD, primarily by
reducing the known cardiovascular risk factors of smoking, serum
cholesterol, and blood pressure, while promoting early detection,
treatment, and rehabilitation in people with severe CHD (48, 54,Ss).
The focus was on middle-aged males; women were included, but are
not discussed here. A further test was made of the feasibility and the
effect of this approach in the control of CHD and other health
problems on a nationwide level.
Baseline data concerning cardiovascular diseases and their main
risk factors in the target community of North Karelia and in the
control area of Kuopio were studied in detail. To do this, a
representative random 6.6 percent sample was drawn for the 1972
population of the two communities by using the national population
register. The sample comprised men and women born during 1913 to
1947 (then aged 25 to 59). About 52 percent of the men in the study
were current smokers, and each smoker consumed an average of 18
cigarettes per day. Their mean levels of serum cholesterol and blood
pressure were above normal, as seen in Table 4.
Owing to the high general level of the known CHD risk factors in
this population, a comprehensive program was integrated into the
health and social services of the community. The program consisted
of (1) information given to the public, especially about the practical
activities directed toward the risk factors in the community, by
means of media (newspapers, radio, leaflets, posters, and stickers)
and at health information education meetings and public campaigns,
schools, and places of work; (2) organization of services by systemati-
cally integrating the program into existing services and creating new
services when necessary, such as special supporting services for
stopping smoking; (3) training personnel for the special practical
tasks of the program; (4) environmental services to support the
desired lifestyle, for example, with regard to smoking restrictions;
and (5) internal information services to support registers for
hypertension, myocardial infarction, and stroke and to help with
followup surveys.
No differences were found in the prevalence of smoking between
the target area and the control area at the beginning of the study in
1972. By 1977, there was a nonsignificant net reduction of 2.5
percent in the prevalence of smoking among North Karelia men
relative to the control men. But when the reported amount of
smoking was taken into account, a net 9.8 percent reduction was
significant. This was a result of the finding that in 1972 North
Karelian men smoked more than did those in the control area. There
was a highly significant 4.1 percent net reduction of mean serum


TABLE 8.-Death rates and relative risk of death in those
     MRFIT subjects who quit at 1 year and those
     who continued smoking (average further
      followup, 6 years)

Smoking status
at entry

Smoking status
  at year 1

No.     No.
quit   continued

CHD death rates      Total death rates

Percent    Percent     Percent   Percent
quit    continued     quit   continued

By level of smoking
l-29 cigs/day        613    1,627
230 cigdday        752   4,471

By group status
Special intervention     991    2,642
usual care          374   3,456

Total            I.365   6,298

Relative risk of death (quit/continued)

1.47      2.30       3.43      4.27
0.80      1.92       3.06     4.47



1.11      2.04       2.93      4.68
1.07      2.03       4.01      4.20

1.10      2.03       3.22      4.41

By level of smoking
l-29 &s/day
230 cigslday
By group status
Special intervention
usual care

Total

0.64              0.80
0.42              0.68



0.54              0.63
0.53              0.95

0.64              0.73

cholesterol concentrations in the North Karelia men. At the start of
the study, the mean serum cholesterol concentrations were higher in
people in North Karelia than in the control area. There was a highly
significant net reduction in systolic blood pressure from baseline for
the North Karelia men. The prevalence of raised values in 1972 was
similar among men in the two areas, and the net reduction in the
prevalence of raised values in North Karelia was substantial and
highly significant.
The estimates of CHD risk showed that in 1972 the North
Karelians had a higher mean risk score than did the population in
the control area. During the followup period, this difference was
reversed among the men and there was a highly significant net
reduction in the estimated CHD risk in North Karelia of 17.4 percent
among the men. However, there were no significant relative
reductions in CHD or total mortality among the North Karelia men
compared with the control men as of 1977. However, a more recent
analysis of mortality trends in Finland suggests that a longer period
of followup may yield some significant relative reductions (55).
Because of the different methodology used, the mortality results

317


TABLE 9.-Observed deaths in MRFIT and Whitehall
     studies and expected deaths based on general
      population and Framingham death rates

Study

   Coronary heart disense              All causes

observed Expected          ObeeNd   Expected
in UC group (U.S. males) SMR   in UC group (U.S. males)   SMR
         (1979)                  (1979)

MRFIT study
UC group (n=643a)
Yl?M
1
2
M
7
l-7

9        -19
20        -20
75        -a7
20        -24
124       -150

l-7

UC smokers (n=4091)

Yema l-7

124       -220

     (U.S. males)
      (lgw

a9        -95

47       17        -48     35
100       31        -50     62
a6      171       -223     77
a3       41        -63     65
a3      260       -384     68

          fl+WiWh)

56      260       -516     50

(U.S. male43~
(1979)

94      190       -244     78

Whitehall study           (English males)             (English males)
NC group (n=731)             (1974)                  (1974)

Years l-10           62        -48     129      128       -130     98

from this study have not been summarized in Tables 5 and 6, but the
risk factor changes are shown in Table 4.

Comparison of Resutts From Intervention Trials and
Epidemiologic Studies

Table 10 summarizes the expected reduction in CHD and total
mortality for former smokers who stopped for 1 to 4 years or for 5 to
9 years, based on the three major observational studies in Table 1
(10, II, 20, 49). This shows that, relative to current smokers, former
smokers who have stopped for 1 to 9 years have a CHD mortality
rate that is 25 percent less and a total mortality rate that is 18
percent less, in approximate terms. The cigarette smokers in the
MRFIT and Whitehall studies have been subjected to smoking
cessation intervention as the sole, or as a major, risk factor change.
As seen in Table 4, smoking reduction in the intervention group
relative to the control group was 31 percent in MRFIT and 54
percent in the Whitehall study, for an average reduction of about 40
percent in proportion of current smokers. This means that the
expected reduction in mortality should be about 40 percent of that
associated with total cessation; in other words, 10 percent for CHD
mortality and 7 percent for total mortality. Combining the observed

318


TABLE lO.-Comparison of reductions in CHD and total mortality from observational studies of former
       smokers and from MRFIT and Whitehall intervention studies

     Coronary heart disease                   Total mortality

British     ACS      U.S.                British     ACS      U.S.
physicians   25-State    veterans   Average     physicians   25-state    veterans   Average

Current smokers
Former smokers. 14 yrs
Former smokers, 5-9 yrs
Average former smokers, l-9 ym
Percentage reduction. former smokers, l-9 yrs
Percentage reduction, -40% former smokers



MRFIT smokers at SI (Table 7)
Whitehall smokers (Table 5)

Unweighted total
95% confidence interval

1.00      1.00
,744      ,613
,667      ,544






01       Et

a6       89.4
49       60.6

135       150.0

l.Kl      1.00
,854      ,737
.a73      ,766
       ,753
     -24.7%
     -9.9%

  %difllO-EVE

     -3.7%
     -19 1%

     -10.0%
-2490-+790

1.00      1.00
.701      ,934
,661      ,773






01       P

201      190.4
123     125.0

324     315.4

1.00      1.00
,667      .a34
.a09      .a14
       .a24
     -17.6%
     -7.0%

  %difffO-EYE

     +5.6%
     -1.6%

     +2.7%
4%-+ 15%


deaths from these two intervention groups shows a change in CHD
mortality of -10 percent (95 percent CI from -26 percent to +6
percent) and a change in total mortality of +2.7 percent (95 percent
CI from -9 percent to +14 percent). Thus, these two trials have
yielded a result after 5 to 10 years of followup that is in good
agreement with the observational studies for CHD deaths, but is not
particularly close for total mortality. Because of the fairly large 95
percent confidence interval, the intervention results are consistent
both with the observational studies and with no change at all. It
must be noted that in MRFIT, other risk factor interventions took
place on blood pressure and cholesterol, and interpretation of the
results has raised the real possibility that an adverse effect on
survival was associated with anti-hypertensive efforts in a specific
subgroup of hypertensive patients, a finding which, if true, might
mask a larger beneficial effect of smoking cessation.
As previously noted and as shown in Table 8, an analysis of
survival in MRFIT participants who had been smokers at entry,
demonstrates that those who quit at year 1 of followup had a 46
percent lower CHD mortality and a 27 percent lower allcause
mortality than those smokers who did not quit at year 1. This is
further powerful evidence consistent with substantial improvement
of survival associated with the cessation of cigarette smoking.

Conclusions

1. In the four intervention trials involving mortality followup of
individual men for 5 to 10 years, the intervention groups had a
combined total of 10 percent fewer CHD deaths than did the
comparable control groups. Differences for other causes of death
or for total deaths were not significant.
2. In these trials, the amount of cigarette smoking has been
reduced 10 to 50 percent more in the intervention group than in
the control group, demonstrating that intervention can alter
smoking behavior.

3. In the two trials involving morbidity followup, the intervention
groups had 4 and 45 percent lower total CHD incidence than did
the respective control groups.

4. The relative reductions in CHD mortality in each of the four
intervention studies involving individual followup are reason-
ably consistent with the reduction in CHD risk factors, and for a
combination of all four studies, the reduction is statistically
significant.

5. Numerous studies have shown that those who quit cigarette
smoking experience a substantial decrease in CHD mortality
and an improvement in life expectancy.

320


6. A number of prospective epidemiological studies indicate that
former cigarette smokers substantially reduce their CHD and
total death rates from that of current smokers.

321


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(59) TURPEINEN, O., KARVONEN, M.J., PEKKARINEN, M., MIE'ITINEN, M.,
   ELOSUO, R., PAAVILAINEN, E. Dietary prevention of coronary heart
   disease--The Finnish mental hospital study. International Journal of
   Epidemiology 8: 99-118,1979.
(60) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking
   and Health: A Report of the Surgeon General. U.S. Department of Health,
   Education, and Welfare, Public Health Service, Office of the Assistant
   Secretary for Health, Office on Smoking and Health, DHEW Publication No.
   (PHS)79-!%066,1979,1136 pp.

(61) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the
   Advisory Committee to the Surgeon General of the Public Health Service.
   U.S. Department of Health, Education, and Welfare, Public Health Service,
   Center for Disease Control, PHS Publication No. 1103,1964,387 pp.
(62) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
   Report of the Surgeon Geneml: 1971. U.S. Department of Health, Education,
   and Welfare, Public Health Service, Health Services and Mental Health
   Administration. DHEW Publication No. (HSM)71-7513,1971,458 pp.

325



(63) VETERANS ADMINISTRATION COOPERATIVE STUDY GROUP ON
  ANTIHYPERTENSIVE AGENTS. Effecta of treatment on morbidity in
  hypertension. II. Results in patients with diaetolic blood pressure averaging
  90 through 114 mm Hg. Journal of the American Medical Asmciation 213(7):
   1143-1152, August 17,197O.

(64) WERKO, L. Prevention of heart attacks. A multifactorial preventive trial in
  Gothenburg, Sweden. Annals of Clinical Research ll(2): 71-79, April 1979.
(65) WILHELMSEN, L. Risk factors for disease according to population studies in
  Gothenburg, Sweden. Paper presented at Skandia International Symposia,
  September 23-25, 1980. In: Boetrom, H., Ljungstedt, H. (Editors). Medical
  Aspects of Mortality Statistics. Stockholm, Almquist and W&sell Intema-
   tional, 1981, pp. 73-88.
(66) WILHELMSEN, L., TIBBLIN, G., WERKO, L. A primary preventive study in
   Gothenburg, Sweden. Preventive Medicine 1: 153-180, March 1972.
(67) WOLFF, F.W., LINDEMAN, R.D. Effecta of treatment in hypertension.
  Results of a controlled study. Journal of Chmnic Diseases 19: 227-240,
   March 1988.

(68) WORLD HEALTH ORGANIZATION EUROPEAN COLLABORATIVE
  GROUP. Multifactorial trial in the prevention of coronary heart disease: 2.
  Risk factor changes at two and four years. European Heart Journnl3(2):
   184-190, April 1982.

(69) WORLD HEALTH ORGANIZATION EUROPEAN COLLABORATIVE
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   Number 678, Geneva 1982,53 pp.

326


APPENDIX A: TRENDS IN
          CARDIOVASCULAR
          DISEASES

32-i'


Introduction and Overview

Mortality Trends

The cardiovascular dise -primarily heart, cerebrovascular,
hypertensive, and peripheral vascular diseases-are widely preva-
lent in our society and cause substantial illness and death. With the
increasing control of infectious and parasitic diseases, especially
during the first half of the 20th century, life expectancy has
improved and the major cardiovascular diseases as a group have
become the underlying cause of approximately 50 percent of all
deaths in the United States. They are responsible for more than
950,000 deaths each year (Table 1) (16, 27). The economic cost of
heart disease alone was estimated in 1977 to be at least $40 billion
annually (34), and heart disease is ranked first among causes for
utilization of acute care hospitals (31). About 21 percent of these
cardiovascular deaths occur prior to age 65; 45 percent occur prior to
age 75. Until recently, as the Nation's population became proportion-
ately older, the crude death rate for the cardiovascular diseases had
increased to a plateau. In contrast, the age-adjusted death rate,
stable until 1940, has since declined (2, 17, 19, 27, 40, 41). During the
196Os, the downward trend in the age-adjusted rate steepened
markedly. Almost twothirds of the decline between 1950 and 1978
occurred after 1968, a 27 percent decline (Figure 1; Table 2) (I, 18,22,
23, 24, 27, 30). Death rates for most cardiovascular diseases declined
over the entire period from 1950 to 1978, except for the major
subgroup of coronary heart disease (CHD), for which there was a
consistent rise in mortality in the 1950s and 196Os, followed by a
dramatic decline (Figure 2) (2, 25, 27). The age-adjusted death rate
for all cardiovascular diseases combined was lower by 63 deaths per
100,000 population in 1967 than in 1950. This decrease reflected
declines for cerebrovascular and hypertensive diseases that counter-
acted the increase of 27 deaths per 100,000 population for coronary
heart disease. In the more recent period, 1998 to 1978, the death rate
for all cardiovascular diseases declined by 100 deaths per 100,000
population, with declines for CHD and cerebrovascular diseases
accounting for almost all of the decline. The reversal in mortality
from CHD during 1968-1978 was real, although partly attributable
to the shift in classification of deaths that brought more hyperten-
sive disease deaths into the CHD classification (see the Technical
Notes at the end of this appendix). It was accompanied by an
acceleration in the rate of decline for mortality from the cerebrovas-
cular diseases and a continuation of the percentage declines for other
subgroups of cardiovascular diseases.
The decline in deaths from cardiovascular diseases since 1968 was
striking in comparison with the trends for other causes of death. As
Figure 1 and Table 2 show, the decline since 1968 for all noncardio

329


ii!  TABLE l.-Number of deaths from all causes and from the major cardiovascular diseases by age,
         United States, 1979

Causes of death1
(terminology used
in this report)

Total

Under
25

25-34

m4

45-54

55-64

65-74

75-M

85 and
O"er

Age
not
Stated

All causes             1.913,641     113,636     47,941     57,723     135,265     2@066    449,266     493,676    328,725 652

Major cardiovascular
diseases (39bV?8)
Coronary heart
disease (410-414)
   Acute myocardial
   infarction (410)
   Other coronary
   heart disease (411414)
Cerebrovaecular
diseases (430-M)
Hypertensive
diseases (401-405)
Diseases of arterioles,
capillaries (440-448
   Atherosclerosis (440)
   Aortic aneurysm (441)
   Other (442-448)
Ml other cardio
vascular (residual)
All other causes
of death (residual)

958,282      3.214   ' 4,209     14,108     49.830    126,410

300.520

229.510

173

551.365        191      1.289      3.568      31.211      81.722

142,119

88,526

53,593

169.062

118,112

42,102

76.010

91

300,462        115       677

250,903

76

412

5,310

2.256

21,694

9,517

55,524

26,198

86,262

82,800

42

49

169.48E       679       947     2.277      6.061     14.610

34,807


7,849

9,888
3,736
4,701
l,r151

60.324

49.760

23

9,567     W3     16

31,916

47

210

679

48,264        146       173      302
28.801         4        5       37
14,031        43       70       127
5,452        99       98      138

2,102


1,028
208
464
356

4,643

3&34
1,023
1.m
893

15,671     17,166
9,625     14,260
4,713      1,937
1,433       989

157.229      2.151      1.590     3.282      9.428

21,551

160,566

35,645

218,917

45.896

37.649

37

110,424     43,732    43,615     85,435

193.156

99.215

479

' Coded to the Infwna~ronal Classr/icafio~ of L&a-es. Ninth Reuision. World Health Organization (45).
SOURCE: National Center for Health Statistics (273.


400






350






300

1950      1955      1960      1985      1970      IQ75      1960

YEAR

FIGURE l.-Age-adjusted* death rates for cardiovascular
             .

dreams and all other causes of death, United

states, 1950-1978

' Bated are age-adjuted to tba 1940 U.S. population distribution.
souRcE: Natiod Center for Health Statiatiw G?5,27). Bureau of the Census (2~.

vascular causes of death combined was only 13 percent. The decline
in all cardiovascular disease deaths since 1963 translates into
239,090 fewer deaths in 1980 than would have occurred had the
death rate remained at its 1970 level. The large decline for CHD
alone translates into 237,000 fewer deaths in 1980 than would have
occurred if the rate had remained at its peak (1963) level (see the
Technical Notes at the end of this appendix). The decline in
cardiovascular disease mortality, therefore, represents a major
contribution to reduced total mortality and improved average life
expectancy flable 2; Figure 3) (19, 29).

Percentage declines were particularly steep for younger adults, for
women, and for the nonwhite population, but were substantial for all
demographic groups, including the elderly (Table 3). There are some
geographic differences in U.S. cardiovascular mortality trends, but
all areas have experienced substantial declines (13). Moreover, the
United States differs from other countries in this decline, for in most
countries the death rate continues to increase, especially for CHD
among middle-aged men (Figure 4) (46).

331


TABLE 2.-Changes in the age-adjusted death rate for all causes, cardiovascular diseases, and all
      other causes of death, United States, 1950-1967 and 1968-1978


                                           I Y50-I!%"
                                            I ,                                     196X-1%X


                              t`hanye ,n                                 (`hanyr in
                                  rate pet                 I'rlwnt                 I'il,? pw             Pewcm
(`ause 01 death                     100.01n~ pop              rh;m&y              lfUO~3~1 pop           ct1mlLy


All (`:i"hCs                             -1 15.9                  -1:ix                  -14x.x              L'o.0

T&II cardiovamtlat                        -63 0                   -14 H                  -l(N 4              -`27 3

(`omnary hcwt dlseasr                     * 26.6                  ,144                   44 I              -")1, .'

(`twbrowscular dlseaaes                    -lY 1                   -21 .,5                   -26 Y              -37.7

tl~pertenswr dtseasrs                      -33 x                   40 1                   -;1 1              -5-i 3

Other- artermcleros~s                       -5. I                   -53 6                   4 ;              -3X.5

Hheumat IC heart dtsease                     -7 5                   -31.5                   -2x              -3x.9

Othrr cardiovascular dwases                 -24.1                   -36 H                   * p `2               -75

AlI other c:\uses or death                                          -12.;
                                   -52 9                                       -48.4              -12.Y


1950      1955      1960      1965      1970      1975      1980


                        YEAR

FIGURE 2.-Ag~adjusted* death rates for coronary heart
       disease, United States, 195B-1978
o Ratea are ageadjwted to the 1940 U.S. population dietribution.
SMRCE2 Natiad Center far Haalth StdstidpS. 27h Bureau of the Census CR.

Methodological Considerationa

Measurement of trends in death rates from 1950 to 1979 has been
affected by (1) revisions of the International Classification of Disease
in 1953, 1963, and 1979, (2) revisions of population estimates
following census counts in 1960, 1970, and 1980, and (3) the major
influenza epidemics in 1957, 1963, and 1963, which were years of
unusually high mortality. The Technical Notes that appear at the
end of this appendix discuss the International Classification of
Diseases codes and explains certain adjustments, limitations, and
other points of methodology of these statistics.

Cardiovascular and Noncardiovascular Mortality

The recent decline in cardiovascular mortality has not been
unique. Between 1968 and 1978, the period during which the eighth
revision of the International Classification of Diseases was in use,
the age-adjusted death rate in the United States declined for all
major causes of death except lung cancer and chronic obstructive
pulmonary disease (COPD), i.e., emphysema and chronic bronchitis

333


So r

l-----J
1040                   1960                  lse0

                 YEAR OF BIRTH

FIGURE 3.-Life expectancy at birth, United States, lB4B-
        1980

SOURCE: National Center for Health Statistics (J9,29).

(Table 4). Excluding these two causes, mortality from the other
causes of death declined a total of 160 deaths per 100,000 population.
The percentage declines in mortality apply to both middle-aged
persons and those 65 years of age or older. Although the percentage
declines in mortality from diabetes mellitus and influenza or
pneumonia exceed those for the cardiovascular diseases, mortality
declines for the cardiovascular diseases contributed greatly to the
declining overall mortality, accounting for 63 percent overall and 81
percent of the decline in mortality at age 65 and older.
Figure 5 shows that mortality rates from influenza, pneumonia,
and diabetes mellitus have declined since the late 1960s. After a
long-term increase, mortality from cirrhosis of the liver has declined
since about 1975. Thus, the decline in cardiovascular disease
mortality is not unique, but is notable for the magnitude of the
decline in terms of reduced numbers of deaths and the acceleration
in the declining mortality from stroke. The percentage decline in the
death rates from coronary heart disease between 1969 and 1978 were

334


TABLE 3.-Percent changes in death rates' for selected
      causes of death by sex, color, and selected age
      groups, united states, l!wS1978

cerdiova9cular dieeaew (390-458)

color, sex, age

          cmonaty    Cm-ebm
             heart     vascular    Other cardie   All other
All           diseasea disaeea      vaecular     callees of
caueea    Total   (410-413)   wo-438)     dieeaea      death

Both sexes'       -20.0    -27.3     -26.5
2.534        -16.2    -30.8     -37.5
3544        -25.4    -35.7     -36.9
4h54        -18.8    -27.2     -26.7
5564        -18.6    -n.a     -27.0
674        -19.0    -28.1     -27.8
75-64        -19.1    -25.9     -24.4
85+         -21.0    -24.7     -21.1

-37.7       -16.9       -12.9
46.9       35.2       -12.9
a.6       -29.6       -21.0
-38.6       -20.0       -12.6
a.3       -15.1        -9.3
-40.7       -11.6       -5.9
-35.5       -16.3       -4.0
-33.4 -     -24.5       -10.1

white melee'      -17.7    -24.7     -24.5      -37.5       -11.1       -10.3
2534         -7.5    -34.5     -31.7      44.4       -24.2       11.6
35-44        -22.9    -33.9     -36.4      -37.5       -19.4       -17.2
45-54        -19.4    -26.5     -21.0      Al.2       -13.4       -12.7
55-64        -19.9    -26.4     -27.0      41.0       -10.4       -12.4
674        -17.1    -245.0     -24.9      40.0        -6.3       -5.8
7&%34        -13.4    -21.8     -20.0      -34.8        -9.9       +2.5
85+         -16.9    -22.9     -18.7      -34.7       -21.8       -1.9

white females'     -20.4    -26.3     -27.3      -36.2       -20.7       -12.7
25-34        -18.5 -30.5     40.9      41.7       -35.6       -15.2
35-44        -25.8    -34.1     -35.6      -34.4       32.2       -23.4
45-54        -16.5    -27.2     -25.1      -32.9       -26.4       -12.0
5544        -13.5    -27.3     -27.4      35.0       -18.9       -2.9
6674        -20.0    -30.7     -31.1      110.3       -14.0       11.4
75-84        -22.1    -27.7     -26.0      -35.9       -29.2       4.9
86+         -23.2    -25.9     -22.2      -33.6       -26.9       -14.2

Nonwhite malen '    -21.1    -n.i     -24.1      -40.0       -20.8       -16.7
2534        -30.3    -43.1     -40.6      -52.1       -39.1       -28.5
3544        -28.9    -38.2     37.3      44.0       -35.4       -25.0
46-54        -20.4    -27.2     -24.4      -41.6       -21.5       -15.6
5564        -18.3    -28.0     -24.4      44.8       -20.1       -8.5
6&74        -18.4    -28.4     -25.2      40.8       -20.7       -5.1
75-84        -13.2    -21.7     -18.6      -33.5       -11.5       -0.1
85+          -7.4    -15.7     -14.5      -26.6        -3.8       +a.0

Nonwhite females'   -29.7 436.0     33.7      45.9       -28.3       -23.8
2534        41.9    -68.1     -65.7      -68.4       -55.0       -37.4
3!%4        42.5    43.9     -53.5      -60.9       -48.1       -36.8
4554        -31.5    42.3     -38.1      -52.4       -39.7       -23.1
5544        -29.6    -40.0     -39.1      -51.4       -25.3       -17.7
65-74        -27.2    -36.1     -33.9      47.7       -23.4       -11.6
75-64        -19.7    -26.6     -25.4      34.4       -16.4       -3.9
85+         -13.3    -17.0     -13.9      -25.9       -12.6       -3.9

SOURCEI National Center for Health Statics (Zn; Bureau of the Census (8.

335


PERCENT CHANGE

FIGURE 4.-Percent of change in the death rate for
      coronary heart disease in males, ages 35-74, by
       country, 196!3-1978*
' Age-averaged rates.
*- 1969-1977.
*** 1969-1976.
SOURCE: World Health Organization (46).

similar for the United States, Australia, Japan, and Israel (Figure 4).
These percentage declines in coronary heart disease mortality
among middle-aged men were at least twice the percentage decline
for the noncardiovascular causes of death. The same was true for
women. Elsewhere in the world, cardiovascular mortality did not
decline; its percentage change was not much different from changes
for the noncardiovascular causes of death as a group (46).

Smoking-Related Diseases

The substantial declines in cardiovascular mortality trends are a
long-term pattern that can be correlated to trends in cigarette
smoking in men. Before the 195Os, total mortality in the United

336


TABLE I.-Change in age-adjusted death rates for all ages and two age groups by cause of death,
      United States, 1968-1978

Cause of death

       All ages                    Ages 2S64                   Ages 65+

Rate/100,lMO            Percent     R&/100,000            Percent      Rate/1O@lOO            Percent
1968    1978   Change    change     1968    1978   Change    change      1966     1978    Change   change

All causes            743.8    595.0    -148.6    -20.0      591.4    476.3    -115.1      -19.5    5.519.6    4.453.0    -10666    -19.3

Coronary heart disease
Cerebrovascular diseases
Other cardiovascular
Lung cancer
Other cancer
COPD
Influenza and pneumonia
Diabetes mellitus
Cirrhosis of the liver
Accidents. poisonings,
and violence

241.6    177.5     X4.1    -26.5      168.5    120.6     47.9      -28.4    2.297.4    1.711.6    4858    -25.5
71.3     44.4     -26.9    -37.7       36.3     21.7     -14.6      -40.2     760.4     483.3    -285.1    -37.1
55.5     46.1      -9.4    -16.9       41.0     32.8     -8.2      -20.0     493.4     414.7     -7R.7    -16.0
24.9     33.2     +a.3    + 33.3       29.0     37.0     +a.0     +27.6     152.3     214.4    162 1    t40.a
104.3     98.4     -5.9     -5.6      103.3     94.4      -8.9       -8.6     723.4     716.4      -7.0     -1.0
11.6     14.5     +2.9    + 25.0       8.8      9.1     +0.3      13.4     103.2     143.6    +404    +39.1
26.9     15.1     -11.8    43.9       15.3      8.0     -7.3      -47.7     205.7     143.8     -61.9    -30.1
14.6     10.2     -4.4    -30.1       11.6      8.1      -3.5      -30.2     126.0      88.7     -37.3    -29.6
13.9     12.4      -1.5    -10.8      22.5     19.6      -2.9      -12.9      36.9      37.3     +0.4     fl.1

76.5     66.7      -9.8    -12.8       84.7     73.6     -11.1      -13.1      158.6     ,111.2     47.4    -29.9

121 other causes         102.7     76.5     -26.2    -25.5


SOURCE: National Center for Health Statistic+ f271. Bureau of the Census (2).

70.4     51.4     -19.0      -27.0     454.3     386.0     -66.3    -14.6


1  Influenza and Pneumonia     cungcancea (
                            . ..dC

  ..i' - 1 Bronchitis. Emphysema,

.P..,'     and Asthma

YEAR

FIGURE 5.-Age-adjusted* death rates for the leading
      causes of death, United States, 1950-1978
' Rateaare age-adjusted to the 1940 U.S. population distribution.
** This break in trend is due to a revision of the International Classification of Diseases. It aiT& the
cardiovascular diseases more than other cnwea of death.
"' Pnmarily hypertensive. peripheral, and rheumatic heart disease.
SOURCE. National Center for Health Statistics (16'. 22, 23.27.30). Bureau of the Cenaue II, 2).

States declined rapidly, as the decreased mortality from infectious
and parasitic diseases masked an increasing mortality rate from
diseases associated with smoking-especially CHD, lung cancer, and
COPD. Between 1955 and 1965, the total mortality decline stopped
for men and slowed for women, partly because the numbers of deaths

338


from the smoking-related diseases of lung cancer, chronic obstructive
lung disease, and cardiovascular disease were increasing quite
substantially (especially among men), cancelling the gains made in
other causes of death. Percentage increases were greater for lung
cancer and COPD than for CHD, but compared with rates for CHD,
death rates for these two diseases were lower in absolute terms.
Since the mid-1960s. the remarkable decline in the coronary death
rate has resulted in a new decline in total mortality. Although death
rates for lung cancer and COPD are still increasing, the rate of
increase is slowing, and in recent years, there is a suggestion of a
reversal in lung cancer mortality among the younger cohorts (39).

Coronary Heart Disease Mortality

The age-adjusted death rate for CHD increased 19 percent. from
1950 to 1963, peaked in 1963, and then declined 30 percent from 1963
to 1979 (Figure 2). (This assumes good comparability of cause-of-
death assignment and classification to CHD for 1963 and 1979. See
the Technical Notes at the end of this appendix.) The reversal of the
trend was gradual; however, the inflection point was the mid-1960s.
During the period between 1968 and 1978, when CHD mortality was
classified according to the eighth revision of the International
Classification of Diseases, the age-adjusted death rate declined 26.5
percent (Table 3). The decline was greatest at younger ages, ranging
from 38 percent for ages 25 to 34 to 21 percent for age 85 and older.
Nonwhite females experienced the largest decline of any sex/color
group-34 percent, with declines exceeding 50 percent in persons 45
years of age or younger. The mortality trends for CHD displayed in
Figure 6 show a striking change from the differential trends among
the four sex/color groups prior to 1968 and remarkably similar
downward slopes since then. Rates for white and nonwhite females
appear to have begun their current decline in about 1964. The
earliest that the rates for white and nonwhite males began their
current decline was 1967, following a brief plateau. Further, age-
specific CHD mortality trends prior to the current decline showed
greater differences than during the current decline (Figure 7). As
stated above, however, declines continue to be steeper for younger
than for older persons. The decline in CHD mortality is substantial
in every State in the country, but is less marked in Appalachia, an
area of relatively high CHD mortality. There is also some evidence
that for life insurance policyholders, constituting a higher socioeco-
nomic group than the general population, declines are steeper than
for the general population (15).
A breakdown of CHD deaths into deaths from acute myocardial
infarction and deaths from other types of CHD is possible, but it is
not known to which group most sudden or out-of-hospital CHD

339


loo0 ,                                                1

         _-e-e----
-d@-- L-        Non-WhileMale   `*
                              -- . . . . . . . . .

-.3--- -~~--"-"--'  ---- -0.. - . ..I 1-_.
                   WhiteFemales        --a-
- -Non-White Females

----I

10 f                 I         I         I        1     J

1950      1955      1960      1965      1970      1975      1990

                         YEAFI

FIGURE 6.-Age-adjusted* death rates for coronary heart
      disease by sex and color, all ages, United
       States, 1956-1978

* Batea are ageadjuated to the 1940 U.S. population distribution.
SOURCE: National Center for Health St.&Me L25,271. Bureau of the Censw (2).

deaths are classified (Table 1). A much steeper decline in the death
rate for acute myocardial infarction than for other CHD occurred
during the 1968-1978 period (Figure 8). More information is needed
before it can be determined what significance to ascribe to this
difference.

Other Cardiovascular Disease Mortality

The leading cause of death after heart disease and cancer is stroke,
a cerebrovascular disease and a major component of cardiovascular
diseases. The underlying process for about 80 percent of all strokes is
arteriosclerosis, and hypertension is a major contributing factor (38).
However, the age-adjusted death rate for stroke has been declining
since before 1930, and has shown an accelerated downward trend in
recent years (Figure 9). In the time period 1950-1967, the age-
adjusted death rate for cerebrovascular disease declined almost 22
percent; this rate of decline accelerated during the time period 1968-
1978 to 38 percent (Table 2). The death rate declined 1.0 percent per
year in the 1950s and 1.8 percent per year in the 1960s. As is the case
for CHD, the trend for stroke mortality since 1968 has been

340


10,000

I----=-- -==-I
                             w-
    -#--

05+


75-34

          ---                                       65-74


2
E       -..--.---.-..*e...- -.-..-I--_.----. a...*_       ----_   '45-54
8

1950      1955      1960      1965      1970      1975      1980

                        YEAR

FIGURE 7.-Age-adjusted* death rates for coronary heart
       disease by age, white males, United States,
         1950-1978

' Rates me agegdjusted to the 1940 U.S. population dintribution.
SOURCE: National Center for Health Statistics L25,27), Bureau of the Census (2).

uniformly downward for the sex/color groups, with declines being
especially steep for nonwhites and younger adults (2, 21, 23, 27).

The age-adjusted death rate for hypertensive disease declined an
average of 4.9 percent per year in the 195Os, 5.0 percent between
1960 and 1967, and 7.2 percent between 1970 and 1978. Similar to
the trend for stroke, there is a steepening of the long-term decline in
mortality from hypertensive disease, with recent declines being
steeper among nonwhites than among whites. Large declines for the
general arteriosclerosis category and for all other cardiovascular
diseases combined occurred throughout the 1950-1978 period, in-
cluding a decline in mortality rates for aortic aneurysm from 1968 to
1978.

Incidence and Case-Fatality

A decline in mortality rates may reflect changes in either the
number of new and recurrent coronary attacks (incidence) or the
survivorship from such attacks (case-fatality). Reliable national
statistics of either incidence or case-fatality are not available.
National prevalence and hospital discharge statistics are limited as

341


   200-

p 150-
s
2
; lot)-------II-c
E
r
d    50-                                        - ActIteM
                                           "olt-mrcm

u I          1          I          I          I         1
1966       1970        1972        1974        1976       1976

                        YEAR

FIGURE 8.-Age-adjusted* death rates for acute myocardial
      infarction and other CHD, United States, 1968-
        1978

' F&ten are age&Wed (0 1940 US. population distribution.
SOURCE: National Center for Health Statistica (27), Bureau of the Ceruus (2).

measures of these trends. Reliance therefore must be placed primari-
ly on available community- or hospital-based studies.

In a study of male employees of the DuPont company in Delaware,
the incidence rate of acute myocardial infarction was 18 percent
lower in the 1973-1979 period than in the 1957-1964 period (33).
Overall 3O-day case-fatality rates and the proportion of sudden
deaths did not change significantly. However, beginning about 1969,
the 3O-day mortality among persons who survived 24 hours after the
attack declined significantly.

In the Kaiser-Permanente Medical Care Program in the San
Francisco area, the proportion of persons hospitalized each year
(rate/l,000 subscribers) for acute myocardial infarction declined 27
percent between 1971 and 1977 (5). The proportion of persons
hospitalized for any coronary heart disease event declined 18
percent. The decline was seen in both first and recurrent events and
did not result from shifting to noncoronary diagnoses. No clear trend
could be ascertained in the proportion of persons who died from
acute myocardial infarction of all persons hospitalized for this
disease each year.

In a study of the population of Rochester, Minnesota, there was no
change in the incidence of initial manifestations of coronary heart

342


1950      1955      1960      1965      1970      1975      1980

YEAR

FIGURE 9.-Age-adjusted* death rates for cerebrovascular
             .
        dxeases 9 alI ages, United States, 1950-1978
' Rates are age-adjusted to the 1940 U.S. population distribution.
SOURCE: National Center for Health Statistics W, 21.27). Bureau of the Census G'J.

disease between 1950 and 1969 (3). However, the case-fatality rate,
based on sudden, unexpected deaths and myocardial infarction
deaths under 30 days, was 34 percent in the 1970-1975 period,
whereas it had been 47 percent in the 1950-1955 period. In contrast,
during 1971-1978, males under 65 years of age enrolled in the
Health Insurance Plan of Greater New York who had recovered
from a first myocardial infarction showed no better survival over 4.5
years than did a comparable group during 1961-1970 (43).

One study provides secular trends on the severity of coronary
atherosclerosis between 1960-1964 and 1968-1972 (36). Autopsy
findings in this New Orleans study reveal that the extent of intimal
surface covered by raised lesions decreased significantly between

343
-


1960-1964 and 1968-1972 among white males 25 to 44 years of age,
and also decreased slightly among black males.

In the Kaiser-Permanente study, the proportion of persons hospi-
talized for cerebral thrombosis dropped 64 percent between 1971 and
1977, most of the drop occurring after 1973. The decline for all
cerebrovascular diseases combined was 15 percent. In the Rochester,
Minnesota, population there was a 45 percent decline in the
incidence of stroke between 1945 and 1974, with reductions more
pronounced in the elderly (6). The Framingham study observed a
lower incidence rate for stroke among women (but not among men)
followed since 1962, as compared with women followed since 1950
(10).

Trends in national hospital discharge statistics from the National
Center for Health Statistics are available, but difficult to interpret.
Discharge rates for both acute myocardial infarction and stroke
between 1970 and 1978 show no increase in incidence of acute events
(Figure 10) (26, 37). These data, however, are not inconsistent with a
decline in CHD incidence, because patients are increasingly being
admitted for cardiac pacemaker insertion and replacement, for
catheterizations, and for other diagnostic and therapeutic proce-
dures (Table 5). Figure 11 shows annual data on hospital case-fatality
rates. Despite annual fluctuations, the trend in case-fatality rates
from 1970 to 1978 is clearly downward for acute myocardial
infarction. This could result from an increased tendency to admit
milder cases not previously hospitalized, from a real improvement in
therapeutic efficacy, or from a mixture of both.

Risk Factors and Treatment
Risk Factor Reduction

As is discussed elsewhere in this Report, three major modifiable
risk factors-cigarette smoking, hypertension, and hypercholesterol-
emia-are statistically significant contributors to cardiovascular
risk for both men and women (Table 10) (14). Cigarette smoking,
hypertension, and a high serum cholesterol each have been found to
increase coronary heart disease risk. The nationwide efforts to
reduce cigarette smoking, to control high blood pressure, and to
avoid foods high in saturated fats (4) have reduced the levels of these
risk factors during the past 15 years (Tables 6,7,8, and 9) (24,28,32).
The reduction in each of the risk factors coincides with the observed
decline in CHD mortality.

Attempts have been made to estimate how much of the reduction
in cardiovascular disease mortality can be ascribed to observed
reductions in risk factor levels (II, 12, 35). Findings have not been
definitive because of data limitations. It has not been possible to
quantify or to rank the separate contributions of a reduction in any

344


??     ?      ?      ?      ?      I     I      I

1970          1972

1974

YEAR

1076          1978

FIGURE lo.-Rate of hospital discharges for major
      components of cardiovascular disease, ages
       45-65, United States, 1970-1978
SOUBCB: National Center for Health Statktica C2@. Thorn et al. GVJ.

345


TABLE S-Number of selected cardiovascular surgical
      procedw, united states, 1970, 1975, 1989

`lcD/6 coda 2ss; ICDKJ coda 38.1-38.3.
=wD/a mda 292-29.4 ICDIS ada 36.1.26.2.35.99.
*IcDIB cnda 30% IcD/9 coda 37214723.
o ICLV8 cocka 30.4; ICD/Q co&w 37.7.
`ED/8 coda 24-3Q ICD/D coda 36.140.6.
`JIxchdmrn~~

SOURCE: Netiwal Center for Hdtb Statistica C2@, Them (37).

one risk factor to the mortality decline, but one analysis concluded
that "elimination of smoking would have the greatest impact on
CHD death rates" (II). The extent to which changes in these risk
factors may have contributed to the decline in mortality depends, in
part, on their prevalence in the U.S. population, and thus, on the
reduction in prevalence that has taken place in recent years.

An estimated 38.3 percent of adult men and 29.2 percent. of adult
women smoke cigarettes, that is, 50 to 55 million persons as of 1980
(Table 6). These percentages represent large declines from the 52.4
percent and 34.1 percent, respectively, in 1965 (28). Table 6 gives the
age-adjusted and age-specific rates that correspond to these crude
rates of smoking. In a 1976 to 1980 survey, an estimated 22 percent
of persons 25 to 74 years of age, about 25 million persons, had
hypertension, i.e., a sy&lic blood pressure of 160 mm Hg or greater,
a diastolic blood pressure of 95 mm Hg or greater, or were on
a&hypertensive medication (Table 8) (32). Although the prevalence
rate in 1960-1962 was about the same (20 percent), a much larger
proportion of persons with hypertension in the more recent period
were aware of it (73 vs. 49 percent), were on treatment for it (56 vs.
31 percent), and had it controlled (34 vs. 16 percent). In a survey in
1971-1974, an estimated 21.9 percent of persons 18 to 74 years of age,
28 million persons, had serum cholesterol levels of 260 mg/lOO ml or
greater (24). After adjusting these crude rates to make them
comparable by age to estimates in the 1960-1962 survey, the
percentage of persons at that level or greater was less than in the
MB-1962 survey, although the decline was not statistically signifi-
cant for all age/sex groups (Table 9). As of 1979, there were about 5
million adults with diabetes mellitus, 3 percent of the adult
population (28). There apparently has been no reduction in preva-
lence in recent years.

346


40









30









20









10









0

1970    1971     1972    IQ73     1974    1975     1976    1977

                         YEAR

1878

FIGURE ll.-Hospital case-fatality rate for acute
       myocardial infarction and chronic CHD,
       United States, 1970-1978

NOTE Fir&listed diegnads on disharge: ED/8 cc& 410 for acute Ml, and 412 for chronic CHD.
SOURCE: National Center for Health Statistica (26). Thorn et al. (37).

The correlation of independent risk factors to cardiovascular
disease risk is shown in Table 10. The documented changes in risk
factors in Tables 6-9 suggest that the decline in the prevalence of
cigarette smoking, which affected the greatest number of people,
may have contributed more to the decline than did changes in the
other risk factors. This assertion depends on the quality of data on

347


the prevalence of smoking, the changes in prevalence of smoking,
and the relative strength of the association between smoking and
CHD risk, as well as evidence that cessation of smoking lowers the
risk of acute and recurrent myocardial infarction mortality.

Impact of Improved Treatment

Improvements have been made in recent years in the medical care
of the coronary patient prior to, during, and after hospitalization.
Treatment is now more aggressive and sophisticated, and the
improved management techniques are more generally available
throughout the country. Today's coronary patient has a much better
chance of arriving alive at a hospital and at an earlier stage of the
episode than was the case a decade or two ago (7). Once hospitalized,
the patient is monitored for arrhythmias and changes in cardiac
function, usually in a coronary care unit. Catheterizations and
coronary artery bypass surgery have been performed with greatly
increased frequency in recent years (Table 5). It is likely that
improved treatment in a hospital has reduced the case-fatality rate
of these patients (Figure 11). The post-discharge treatment is better
managed today. The coronary patient with angina pectoris or
hypertension receives more aggressive and effective treatment;
antiarrhythmic drug therapies are widely used; and many patients
are advised to stop smoking, modify their diet, and lose weight.
Although documentation of the occurrence in time of many of these
treatment improvements is incomplete, most were made in the 1960s
and 1970s.

Trends and Associafed Factors

The reversal of the death rate for CHD and the acceleration of the
decline for stroke have coincided over time with increased efforts in
primary and secondary prevention. These efforts include the anti-
smoking campaigns since 1964, the nationwide campaign against
hypertension since 1972, a trend away from saturated fats in the
diet, and changes in treatment, such as expanded utilization of
coronary care units, cardiac surgery, cardiac catheterization, and
pacemakers (8). The public is now more aware of cardiovascular risk
factors, especially cigarette smoking, hypertension, and elevated
serum cholesterol. Also, when a heart attack or stroke occurs,
today's patient generally receives more aggressive medical manage-
ment (7, 9).

Trends and Smoking

The proportion of both cigarette smokers and CHD mortality
increased until the mid-1960s and then declined markedly. Tempo-

348


TABLE &-Percentage distribution of adult current and
      former cigarette smokers, according to sex,
      race, and age, in 1965, 1976, and 1980

Sex, race, and age

current Bmoker' @wcent)
1965    1976 19K1'

Former smoker (percent)
196.5     1976    1960'

52.1     41.6     37.9          20.3     29.6     30.5
59.2     45.9     39.7           9.0     12.2     12.1
60.7     46.5     43.1          14.7     16.3     20.6
56.2     47.6     42.6          20.6     27.3     27.6
51.9     41.3     40.8          24.1     37.1     36.9
28.5     23.0     17.9          2.8.1     44.4     47.4

51.3     41.0     37.1          21.2     30.7     31.9
58.1     46.3     39.0           9.6     13.3     12.2
60.1     47.7     42.0          15.5     18.9     21.9
57.3     46.8     42.4          21.5     28.9     28.8
51.3     40.6     40.0          25.1     38.1     36.4
27.7     22.8     16.6          28.7     45.6     50.1

59.6     50.1     44.9          12.6     20.2     20.6
67.4     52.8     45.5           3.8     4.1     10.6
68.4     59.4     52.0           6.7     il.8     11.9
67.3     58.8     44.2          12.3     13.8    21.2
57.9     49.7     46.8          15.3     28.6     26.3
36.4     26.4     27.9          21.5     33.0    26.6

34.2     32.5     29.8           6.2     13.9     15.7
41.9     34.2     32.7           7.3     10.4     11.0
43.7     37.5     31.6           9.9     12.9     14.4
43.7     38.2     34.9           9.6     15.8     18.9
32.0     34.8     30.8           8.6     15.9     17.1
9.6     12.8     16.6           4.5     11.7     14.2

34.5     32.4
41.9     34.4
43.4     37.1
::t  3:
9.8   13:2

30.0           8.5     14.6     16.3
33.3           8.0     11.4     12.5
31.6          10.3     13.7     14.7
35.6           9.9     17.0     20.2
30.6           8.8     16.4     17.4
17.4           4.5     11.5     14.3

32.7     34.7     30.6           5.9     10.2     11.6
44.2     34.9     32.3           2.5     5.0     2.2
47.8     42.5     34.2           6.7     8.9     11.6
42.8     41.3     36.5           7.0     9.6     12.5
25.7     38.1     34.3           6.6     11.9     14.1
7.1     9.2     9.4           4.5     13.3     14.1

' A current mnoker hiw smoked et least 100 cigarettes and now smokes; includes occasional smokers.
`Find estimatea. Based on data for the last 6 months of 1960.
aBaBe ofpemtsge excludea p.3laona with unknown making ste"LIm
`Includes all other racea not shown separately.
`Age adjusted by the direct method to the 1970 civilian rnCnatitutionalii population usin 5 age groups.
NOTE: Percentages do not add up to 100 because of %ever smokers" in the survey population.
SOURCE: Data from the Nationd Health Interview Survey, National Center for Health Statistics, 1965.1976,
and 1960, based on howehold interviewa with a sample of the civilian noninstitutional&d population.

rally, the beginning of the decline in CHD mortality closely followed
the decline in prevalence of smoking after the issuance of the first

349


TABLE ?.-Change in percentage of current cigarette
       smokers and of those who smoke 25 or more
     cigarettes per day, by color, sex, and age,
      united states, 1966 to 1980

Color, sex, and age

All
current
smokera

Smoke 25 or
more tz&ettm
per day

Whit.emen,age20+           -n.o                +0.7


   20-24                     -31.8                 -9.2
   25-34                       -30.6                 -12.1
   3u4                     -26.5                 -21
   4544                      -21.6               +18.2
   65 and older                  -37.5                + 14.3

Black mea. 20+
       age                    -35.8            -125

   20-2-4                      -39.4                 -11.1
   25-34                     -33.1                 -24.2
   3&u                     -37.6                 -32.1
   45-64                       -19.7               +22.2
   65 and older                 -20.6               +x6.7

whitewomell,age2o+               -13.7           +16.2

   20-24                      -21.2                +38.6
   25-34                       -27.2               +16.7
   35-44                       -18.9                +55.6
   45-64                       -7.6               +66.0
   65 and older                 +76.6               +257.1

Black women, age 20+                -14.0               +50.0


   20-24                       -28.7               unknown '
   25-34                      -31.2                +26.2
   35-44                      -19.6               + 15.4 '
   45-64                       31.1              +344.4'
   65 and older                +22.5               unknown'

' Fire does not meet standards of reliability or precision.
SOURCE: National Center for Health Statiica &?&I

Report of the Surgeon General on The Health Consequences of
Smoking. The same phenomenon has been reported in other
countries as well (37).

The decline for CHD mortality is occurring among adults of all
age, color, and sex groups, a pattern similar to that of the reduction
in the proportion of the population who are cigarette smokers. The
mortality decline is steeper among younger adult age groups, which
is consistent with not starting to smoke or early smoking cessation.
Since 1950 for males and 1960 for females, each succeeding sex
cohort has experienced a lower peak prevalence of smoking (42). The
evidence of more rapid declines in mortality for persons on a higher



TABLE &-Prevalence, awareness, and control rates of
      hypertension, persons 2&74 yeara of age,
      united states, 1964%1992,1974-1975, 1976-19801

YW

Percentage of
population
with hyperten-
  sion '

  Percentage of total with hypertension

      Aware,    Aware,   Aware,'
           medication, medication,
Unaware' u&Zion no control controlled

1960-1962              20.3            51.1     17.6      15.3      16.0

1974-1975              22.1            36.4     29.4      14.6      19.6

19761990              22.0            26.6     17.2      22.1     34.1


' Bate ageadjusted by the direct method to the population at the midpoint of the 19761990 National Health
and Nutrition Examination Survey.

' Systolic blood pressure 160 mm Hg or greater, or di&.olic blood pressure 95 mm Hg or greater. or on
antihypertensive medication.

' Reported never told by phynician of having hypertension.
' Three with hypertension taking antihypstensive medication whose blood p-we wan not hypertensive.
SOURCE: National Center for Health Statistica (32).

TABLE O.-Percentage of adults with serum cholesterol
      levels of 269 mg/199 ml and over, by sex and
      age, United States, Health Examination Survey
      (HES) 1990-1962 and Health and Nutrition
      Examination Survey (HANES) 1971-1974'

Age

HJB, M&1962


Men       Women

HANIB, 1971-1974


Men       Women

Percentage

Total. age 16-74               17.6        22.7        14.7        17.5

16-24                    3.9         4.6         2.8         3.0
2544                    10.4         7.4         8.2         5.6
35-44                    20.2        12.9        17.1         9.6
4a54                    25.7        28.0        24.1        24.6
5664                   23.5        49.7        20.2        35.3
65-74                   21.6        51.0        20.9        40.7

' Age adjusted by the direct method to 1971-1974 civilian noninstitutional&d population.
NOTE: All choleat.eml values have been a&ot.ed to approximate the values of Abel1 et al. (Abell, L.L.. Levy.
G.B., Bralie. B.B., Kendall, F.E. A simplified method for the estimation of total cholesterol in amum. and
demonstration of its epeciricity. Journal of Eiologiml Chemistry 196: 357-265, 19521, the common referenced
metlmd, by reducing the 1960-1962 data by 7.6 percent and the 1971-1974 data by 4.5 percent.
SOURCE: National Center for Health Statistics (24X

socioeconomic level and lesser declines in poorer areas of the country
are also consistent with a favorable impact of smoking prevention or
cessation efforts on CHD mortality, in view of the clearly demon-
strated inverse relationship of male income level and prevalence of
smoking.

351


TABLE 10.-Regression coefficients, risk ratios, and
      statistical significance for the risk of
      cardiovascular disease in 8 years, men and
      women, age 36-74 years, Framingham heart
      study

Risk ratice evaluated

MultiDle
regreiion
coefficient '

T'

at age 55'

Risk
ratio

Flisk factor
difference

Rick factor

c!igamw smoking
Serum cholesterol
Cholesteml/age interaction
Systolic blood p-re
Glucces intolerance

cigarette smoking
senlm eholenterol
Cbolesteml/age interaction
Systolic blood preeeure
Glucose intolerance

MEN

0.580
0.020
4mo1
0.017
0.410

WOMEN

0.233
0.019
-0.001
0.015
0.757

6.46       1.8
3.65       1.3
-2.61       -
9.12       1.4
2.92       1.5

2.37       1.3    Smoker/nonsmoker
2.66       1.2      46 mgldl
-2.77       -         -
6.59       1.4     M-&l
5.40       2.1     Preeentlatwnt

Smoker/nonsmoker
  42 m&ll

20 mm xig
Present/absent

' Unetandardisd meffcient of the multiple risk function for cardiovascular dineme within 8 years with the
independent variables being w-am cholasteml. &&stem1 timea age. syetolie blood premure. cigar&e smoking,
gluame intaleran~> left ventricular hypertrophy on ECG. age, and age sguared; estimati over the age range 3&
74 yean.

' Thme tik fectors are statistically significant for both men and women. The critical value of T ia
appmxbnately equal to 2.0 at a=OM.

' The hypothetical risk of development of cardiovsseular diwase asawiated with the 6,.&&d difference in risk
rector levels when other risk factors in the model are held constant. A ratio greater than 1 reprecenia pmitive
amociation with cardiovancular d&we. For serum cholesterol and systolic blood pressure, the difference chceen
wan one standard deviation of the measurement.
SOURCE: McGee and Abbott Ml.

Some questions remain unanswered regarding the contribution of
smoking cessation to the decline in CHD mortality. The percentage
of smokers who are heavy smokers appears to be increasing,
although it is not known whether this represents a greater cessation
rate among lighter smokers than among heavier smokers. The
percentage decline in CHD mortality for women has been as large as
for men, although proportionately fewer women than men have
given up smoking. Assertions that preventive measures have re-
sulted in smoking changes that caused the decline in CHD mortality
differences by age, socioeconomic status, and geographic area are
based on limited available data.

352


Conclusion

The evidence supports the conclusion that changes in smoking
habits have contributed to substantial improvement in mortality
rates from the cardiovascular diseases in the United States.

353


Technical Notes

International Classification of D&eases

Tables A and B contain the code numbers of the International
Classification of Diseases (ICD) applicable to the causes of death
described in this report (16,20,44, 45). Between each revision of the
ICD there are breaks in the continuity of these classifications,
affecting some diseases more than others. For cardiovascular dis-
ease, the most serious breaks in continuity are between the seventh
and eighth revisions and between the eighth and ninth revisions for
CHD and for hypertensive disease.

The cause of death commonly referred to as coronary heart disease
(CHD) was listed in both the sixth and seventh revisions of the ICD
(1949-1957, 195&1967) as "Arteriosclerotic heart disease, including
coronary heart disease," code 420; in the eighth revision (1968-1978)
as "Ischemic heart disease," codes 410-413; and in the ninth revision
(after 1978) as "Ischemic heart disease," codes 410-414.

Expected Minus Observed Deaths

Multiplying the 1970 age-specific death rates Wyear age groups)
for total cardiovascular diseases times the 1980 census gives an
estimate of the number of cardiovascular disease deaths expected in
1980: 1,294,564 deaths, based on the level of mortality in 1970. An
estimate of the number of cardiovascular disease deaths observed in
1980 is 1,005,692. This latter estimate is made by combining the
estimated 989,000 deaths from major cardiovascular d&eases in 1980
(ICD/S codes 390-448) and the 4,803 deaths from diseases of the
veins in 1980 (ED/S codes 451-459) (27, 29). The difference is
288,872 cardiovascujar disease deaths "averted" in 1980 because of a
decline in mortality from the level in 1970.

Multiplying the 1963 age-specific death rates W&year age groups)
for coronary heart disease (ICD/7 code 420) times the 1979 popula-
tion estimate gives the number of CHD deaths, 804,000, expected in
1980, on the basis of the level of mortality in 1963 (2, 25, 27). The
observed number of deaths from CHD in 1980 for ED/9 codes 410-
414 was 566,000, or 238,000 fewer than expected, based on the level
of mortality in 1963. This procedure assumes reasonably good
comparability of ICD classification of CHD in these 2 years.

Age-Adjusted Rates

Age adjustment for this Report is by the direct method. Age-
specific death rates in l@year age groups are multiplied by the
"standard million" for 1940-the U.S. population by age as enumer-
ated in that year.

354


TABLE A.-Codes of the 6th, 7th, 8th, and 9th revisions of the International Classification of Diseases
      for Selected Diagnoses

Diagnosis

   1949-1967                     1966-1978                     1979
6th and 7th revisions                 6th revision                 9th revision

Cardiovascular diseases                  330-334,400460
Coronary heart disease                   420
  Acute myocardial infarction            no code for this diagnosis
  Other coronary heart disease           no code for this diagnosis
Cerebrovascular diseases                  330-334
Hypertensive disease                    440-M7
Other diseases of arteries                 450-456
  Atherosclerosis                      450
  Aortic aneurysm                     451
  Other                           452456
All other cardiovascular disease            403-416. 421-434, 460-460
Lung cancer                       162, 163
Other cancers                     140-161, 164-205
Diabetes mellitus                       260
Influenza and pneumonia                   4so493
Chronic obstructive pulmonary disease         500, 501, 527.1
Cirrhosis of the liver                     561
Accidents, poisonings, and violence             FBOO-Em5

390-456
410-413
410
411413
430-436

44cM48
440
441
442-448
390-390. 420-429, 450-456
162
14Si61. X3-209
250
47&474, 400-46
493-492, 519.3
571
E9oa-E999'

390-459
410-414
410
411414
4zQ-436
401-405
440440
440
441
442-440
390-398, 415-429, 451-459
162
140-161, 163-205
2.54
480-487
490492, 494-496
571
EI4mo-E999

SOURCE: World Health Organization (44,45), National Center for Health Statistica (20).


TABLE B.-Iutmnational classification of diseases codes for
       cardiovascular-renal diseases1 and
      cardiovascular diseases*, 1900-1979

                   YearS
Revieion              inuse             codes

1St
2nd
3rd

4th

5th                193%1946
6th               194%1966
7th                1959-1967
8th               1966-1978
9th               197%

190&1909
1910-1920
1921-1929


I%?#-1936

47,64-a, 77-66,120, 142
47, 64-66, 77-66, 120, 142
51, 74, 75, 03. 87-90.
9lb, 91c, 9%96, 129, 151
56, 82.9&95.97-103,
131. 132

' Thmugb 6th revision.
' After 6th revision.

SOURCEz Moriyama et al. (16-h National Center for Health 6tatietia Cm). World Health Chgmizatior, (&)b).

Population Estimates

Death rates for census years and for years prior to 1961 are based
on the resident or census population estimates that were available at
the time the official U.S. vital statistics were prepared. Rates for
1961 to 1969, however, are based on estimates of the resident
population revised to reflect the 1970 census, and rates for 1971 to
1979 are based on estimates of the resident population revised to
reflect the 1980 census (I, 2).

356


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APPENDIX B: TRENDS IN U.S.
        CIGARETTE USE, 1965
          TO 1980


introduction

This discussion of national trends in adult cigarette smoking over
recent years in the United States includes data on prevalence,
consumption, and cessation. It focuses on adult cigarette smoking
patterns and cessation by age and sex cohorts. Data were drawn from
an analysis of three national surveys by the National Center for
Health Statistics (NCHS) and three other national surveys on adult
use of tobacco conducted by the former National Clearinghouse for
Smoking and Health over the period from 1965 through 1980 (6, 7,s).
A brief description of the data sources is presented, followed by a
discussion of the data.

Surveys of Tobacco Use
The 1999 Survey on the Use of Tobacco

Two separate national probability sample surveys on adult usage
of and attitudes toward tobacco conducted by the National Clearing-
house for Smoking and Health in 1966 have been combined and are
treated here as a single survey.

One study design imposed a two-way stratification on all house-
holds in the continental United States, classifying each household by
three types of population and nine geographic areas. The other
design divided the entire area of the United States into approximate-
ly 1,700 primary sampling units PSUs). Weighting procedures
resulted in the selection of 5,770 respondents.

Within each household, the first eligible respondent (age `21 or
older) was the person interviewed; all current and former smokers
were also interviewed, but only a subsample of those who had never
smoked was interviewed. Weighting procedures were used to bring
the three groups into balance.

The 1970 and 1975 Surveys on the Adult Use of Tobacco

The 1970 and 1975 surveys sponsored by the National Clearing-
house for Smoking and Health employed the same sampling and
interviewing methodologies. Where possible, questions were phrased
similarly. The questionnaires for current, former, and never smokers
differed slightly.

In both surveys, the sample design consisted of two parts: a
national probability sample of telephone households and a national
probability sample of nontelephone households.
The respondent selection procedure was designed to produce 75
percent of the interviews with "ever" smokers and 25 percent with
"never" smokers. Weighting procedures were used to compensate for
this oversampling of ever versus never smokers. Other weighting
factors were used to adjust for age, sex, and smoker mix of the


household. The weighted number of respondents (age 21 or older)
was 5,875 in 1970 and 12,079 in 1975.

Smoking Supplement to the National Health Interview
Survey

The National Health Interview Survey (NHIS), a continuous
nationwide sample personal household interview survey by the
National Center for Health Statistics, included questions on ciga-
rette smoking in 1965,1966, 1970, 1974,1976,1977, 1978, 1979, and
1980. Information is routinely obtained on personal and demograph-
ic characteristics. Questions focused primarily on such characteris-
tics as present smoking status, amount smoked daily, and in more
recent years, attempts to quit, and on tar and nicotine levels of
cigarettes smoked. Information was not obtained on opinions,
attitudes, or beliefs related to smoking.

The universe for the NHIS is the civilian noninstitutionalized
population of the United States. The survey is based on a multistage
probability sample of primary sampling units in about 42,000
households containing about 85,000 persons. A one-third subsample
of the adult respondents is interviewed for the smoking supplement
(during 1965 and 1966 smoking data were obtained for all adults).

Patterns of Smoking Prevalence and Cessation
Prevalence of Cigarette Smoking

The percentage of adults who report being current regular
smokers, defined as persons who have smoked at least 100 cigarettes
and who were smokers at the time of interview, has been declining
steadily over the last _15 years (Table 1). For the total white male
population, this decline has been from 51.3 percent in 1965 to 37.1
percent in 1980, and for white females, from 34.5 to 30.0 percent.
Among black adults a similar pattern was seen-for males a decline
from 59.6 to 44.9 percent, and for females, from 32.7 to 30.6 percent.
Conversely, the percentage of the white adult male population who
reported being former smokers increased between 1965 to 1980 from
21.2 to 31.9 percent, and of white females, from 8.5 to 16.3 percent by
1980. Again, a similar trend was observed among blacks, with the
percentage of former smokers increasing from 12.6 to 20.6 percent of
males, and from 5.9 to 11.8 percent of females. This increase in the
percentage of former smokers is more marked among males (20.3 to
30.5 percent) than among females (8.2 to 15.7 percent), although the
proportion among males increased by a factor of 1.5, while that
among females doubled.

In addition to this increase in percentage of former smokers over
the E-year period, among most of the sex, race, and age groups there
also appears to be an increase in the percentage of persons who

364


TABLE I.-Percentage distribution of adult current and
     former cigarette smokers, according to sex,
      race, and age, in 1965, 1976, and 1980

Current smoker' @wcent)         Former smoker (percent)
1965    1976 1960'          1965     1976    1980=

    MALE
Total 3.'
All agea>m
20-2-i
2534
3544
45-64
t=
White
All ages>20'
20-24
25-34
3544
45-64
265
Black
All agea>20"
20-24
2.534
3544
45-64
t=

52.1     41.6     37.9          20.3     29.6     30.5
59.2     45.9     36.7           9.0     12.2     12.1
60.7     46.5     43.1          14.7     18.3     20.6
58.2     47.6     42.6          20.6     27.3     27.6
51.9     41.3     40.8          24.1     37.1     36.9
28.5     23.0     17.9          28.1     44.4     47.4

51.3     41.0     37.1          21.2     30.7     31.9
56.1     46.3     39.0           9.6     13.3     12.2
60.1     47.7     42.0          15.5     18.9     21.9
57.3     46.8     42.4          21.5     28.9     28.8
51.3     46.6     40.0        25.1     36.1     38.4
27.7     22.8     16.6          26.7     45.6     50.1

59.6     50.1     44.9          12.6     20.2     20.6
67.4     52.8     45.5           3.8     4.1     10.6
68.4     59.4     52.0           6.7     11.8     11.9
67.3     59.8     44.2          12.3     13.8     21.2
57.9     49.7     46.8          15.3     26.6     26.3
36.4     26.4     27.9          21.5     33.0     26.6

34.2    32.5     29.8           a.2     13.9     15.7
41.9     34.2     32.7           7.3     10.4     11.0
43.7    37.5     31.6           9.9     12.9     14.4
43.7     38.2     34.9           9.6     15.6     18.9
32.0    34.8     30.8           8.6     15.9     17.1
9.6     12.8     16.6           4.5     11.7     14.2

34.5     32.4     Xl.0           8.5     14.6     16.3
41.9     34.4     33.3           8.0     11.4     12.5
43.4     37.1     31.6          10.3     13.7     14.7
43.9     38.1     35.6           9.9     17.0     20.2
32.7     34.7     30.6           8.B     16.4     17.4
9.8    13.2     17.4           4.5     11.5     14.3

32.7     34.7     30.6           5.9     10.2     11.6
44.2     34.9     32.3           2.5     5.0     2.2
47.6    42.5     34.2           6.7     8.9     11.6
42.0    41.3    36.5          7.0     9.6     12.5
26.7     36.1     34.3           6.6     11.9     14.1
7.1     9.2     9.4           4.5     13.3     14.1

' A current smoker haa amoked at kast 100 eieustta, rod now smokea; includes -ional smokers.
`Knalestimatas.Basedondarsforthe~Gmonthsofl~.
J Bane of percentage excludea peraau with unknown smoking status.
`lnCluded all other - not ohown rpuately.
o A@z odjuntad by the direct me&cd to the 1970 civilian noninstitutionalized population using 5 age gn~~p.
NOTE: Percentagea do not add up to 100 because of "never smoken" in the survey population.
SOURCE: Data from the National He&h Interview Swvey, National Center for Health Statistics. 1965.1976.
and 1960, baaed on household interviewa with a aample oftbe civilian noninstitutiioaalized population.

report never having smoked. In males, this is demonstrated by both
races and by the age groups younger than 45 years of age. In females,

365


TABLE 2.-Average number of cigarettes smoked per day
      by current and former smokers, by sex, age,
      and educational level, in 1970, 1975, and 1980

   1970 '             1975 '             1980'
Current Former     Current Former      Current Former
smoker  smoker      emoker  smoker      smoker  smoker

Total
Alla@ 221

Male
All agea 221
21-24
25-34
3544
45-54
5544
2%

Female
Au ages 221
21-24
25-34
35-44
45-54
5544
265

Educational level
o-8
9-11
12
13-15
216

20.0    22.6        21.2    24.5        21.7    25.0

21.8    25.0        22.8    n.2        23.4    28.1
20.8    16.2        18.9    20.8        19.4    18.7
21.0    23.4        22.1    24.0        22.1    24.0
23.0    27.7        23.4    28.0        25.6    28.7
24.2    25.4        W.l    29.5        27.2    31.6
21.6    n.7        25.0    28.1        23.3    31.3
17.2    25.3        20.3    28.0        20.9    n.1

17.7    17.3        19.1    18.8        19.7    19.8
16.1    13.8        18.6    14.7        17.8    17.6
18.1    16.7        18.5    17.7        19.4    20.3
18.6    18.2        20.1    19.5        22.5    19.8
18.4    19.0        20.3    20.8        20.7    22.4
17.0    15.4        19.0    20.8        20.0    20.4
14.0    14.6        16.1    17.1        15.6    17.2

18.1
20.3
20.2
20.3
20.8 d

21.7        21.7    25.9        20.5    26.2
22.2        21.6    25.0        22.3    n.a
22.8        20.8    24.2        21.9    24.4
22.5        21.3    25.1        22.1    24.3
23.2        20.6    22.1        21.1    24.0

' National Survey on Adult Use of Tobacco. PHS. 1970.
`National Health Interview Survey Smoking Supplement, PHS, 19&l.
NOTE: Data from 1966 National Survey were not compatible with other years

the increase in percentage of persons who report never having
smoked is limited to the age groups younger than 35 years.

Average Daily Consumption of Cigarettes

Table 2 shows data on the average number of cigarettes smoked
daily during three survey periods (1970, 1975, and 1980) for both
current and former smokers.

Overall, current smokers reported an increased consumption, from
a mean of 20.0 cigarettes per day in 1970 to 21.7 cigarettes per day in
1980. The 1970 to 1980 increase in mean number of cigarettes
smoked daily was slightly greater for females than for males (2.0
versus 1.2), a finding consistent with the increasingly similar
smoking behavior in females and males. Thus, although males
continue to smoke a greater average number of cigarettes per day


than do females, the difference in daily consumption between the
sexes for current smokers in 1980 was less than that observed a
decade earlier.

The heaviest daily consumption is observed in the middle-aged
groups (35 to 64 years). A greater mean increase from 1970 to 1980
was observed among women aged 35 to 64.

Male former smokers generally reported greater daily cigarette
consumption than did current smokers in each survey. This trend
was not found in females. This finding is contrary to the widely held
belief that those who smoke fewer cigarettes per day are more likely
to quit. It may be due in part to a tendency of former smokers to
overestimate their consumption and of current smokers to underesti-
mate their consumption or both.

Among former smokers of both sexes, average daily consumption
rates increased with age, peaking at the 45- to ELI-year-old age
~tegory.

No trend over time is discernible by educational level in the
overall mean daily consumption among current smokers. There was,
however, an increase in the daily cigarette consumption of former
smokers with 8 or fewer years of education, from 21.7 in 1970 to 26.2
in 1980. Within each survey year, there is also no discernible trend
between level of education and daily cigarette consumption. The
greater reported average daily consumption by educational status
for former smokers than for current smokers may reflect cognitive
dissonance, or changing social pressures that result in reporting bias.

Table 3 displays the percentage distribution of current smokers by
grouped number of cigarettes smoked daily, over the 1965,1976, and
1980 NHIS surveys. Cigarette smokers had a tendency to round off
their reported number of cigarettes smoked per day (3) (Table 4).
Approximately one-third of the smokers reported smoking exactly 20
cigarettes (one pack) a day in each of the survey years. The
proportion of current smokers reporting consumption levels of 21 to
29 or 31 to 39 cigarettes per day remained relatively constant
between 1970 and 1980.

Although the proportion of smokers who report consumption
levels of 20 to 39 cigarettes per day has remained fairly stable over
the last 10 years (46.6 vs. 49.31, a clear difference is observed at the
more extreme ends of the distribution, i.e., among those smoking
fewer than 20 cigarettes and those smoking 40 or more cigarettes per
hY-

In 1970, only 11.4 percent of the respondents reported smoking 40
or more cigarettes per day; by 1980, 16.8 percent reported smoking
40 or more cigarettes per day. During the same period, smokers
reporting consumption levels of less than 20 cigarettes per day
decreased from 39.8 percent in 1970 to 33.8 percent in 1980 (Table 4).

367


TABLE 3.-Percentage distribution of adult current
     smokers' by grouped number of cigarettes
     smoked per day by sex, race, and age, 1965,
      1976, and 1980

Ciittea smoked rer dav

                 <15             15-24           225
Sex, race, and age    1965   1976   1930'    1965   1976  1960'   1965   1976  1960'

    MALE
Total 3.'
All ages>20
2&a
25-34
35-M
4544
L-65
white
All ages>20
20-24
25-34
35-44
4564
>a
Black
All agee>
20-U
25-34
35-U
45-a
>a

    FEMAJ.5
Total 3.'
All ages>20
20-24
iE
45-64
>=J
white
All agee>
20-24
25-34
3544
45-64
t=
Black
All ages>20
2&24
2534
3544
4564
>a

28.3   24.2   23.1    46.3   44.8   42.7    25.4   31.0   34.1
34.9   31.6   32.0    49.1   49.9   47.8    15.4   18.5   20.2
25.1   25.5   23.6    50.0   45.8   46.5    24.3   28.7   29.9
23.7   19.6   15.8    44.8   41.2   42.3    31.5   39.2   41.9
26.7   18.5   21.6    45.3   44.1   36.4    28.0   37.4   42.0
47.1   39.1   29.2    39.0   42.7   46.1    13.8   16.2   24.7

25.9   21.4   19.1     46.8   44.9   43.6    27.4   33.7   37.4
32.3   27.5   27.1     50.8   62.8   50.4    16.9   19.7   22.4
22.8   22.1   19.5    51.1   46.5   41.4    26.1   31.4   33.1
21.3   17.2   12.8    44.6   40.4   42.1    33.9   42.5   45.1
24.6   16.2   17.3    45.4   43.3   37.4    30.0   40.4   45.3
44.6   37.5   26.1     40.3   42.2   46.2    15.1   20.4   27.7

48.1   43.8   46.7     42.6   44.0   40.3     9.3
52.7   56.9   66.6    41.9   34.2   36.7     5.3
47.8   46.0   44.4    41.7   43.5   46.2    10.5
42.5   38.5   45.6    45.5   44.8   41.1    12.0
46.9   35.9   51.1     43.7   50.8   35.0     9.4
64.9   53.0   41.1     31.9   47.0   47.2     3.2

11.5
8.9
10.5
16.7
13.3

10.9
6.8
9.6
13.2
14.1
11.1

43.6   36.5   34.2    42.2   43.8   42.0    14.2   19.6   23.7
48.4   43.1   42.0    41.9   42.4   41.1     9.7   14.5   16.1
41.4   34.3   33.5     43.1   45.2   41.9    15.5   20.5   24.6
39.1   33.8   27.8    43.7   44.4   39.3    17.1   21.8   33.0
44.4   34.3   29.8    42.0   44.2   45.9    13.6   21.5   24.2
62.6   4t3   48.9    31.0   38.9   37.7     6.4   11.8   13.4

41.0   33.2   30.6    43.9   45.2   4.8    15.1   21.6   25.6
45.3   39.3   37.4     44.4   44.3   44.1    10.4   16.4   18.5
37.9   30.6   28.6    45.4   46.8   44.9    16.7   22.6   26.5
36.2   29.5   24.6    45.3   45.4   39.9    16.4   25.1   35.5
42.4   32.0   26.4    43.2   45.1   47.0    14.5   23.0   25.9
61.5   45.7   46.1    31.8   41.7   37.7     6.8   12.6   14.2

67.7   60.0   61.1    26.4
73.4   65.7   78.0    22.1
66.2   58.8   61.9    25.1
63.4   60.4   555.6    30.4
69.4   53.2   53.8     26.9
63.2   loo.0   66.3    16.8

33.8
31.3
33.6
39.1
36.7

28.9
22.0
22.0
35.6
34.2
34.7

5.9   6.1
4.5   3.0
8.7    7.7
6.2    1.4
3.6   10.1

10.0

16.2
8.8
12.0

' A current smoker has smoked at least 100 cigarettes and now amokeq include occasional smokers.
' Based on data for the last 6 months of 1980.
*Base of percentage excludes unknown amount smoked.
`Includes all -not shown seperate$.
SOURCE: Data from the National Health Interview Survey. National Center for Health Statistics. 1965.1976,
and 1980, based on household interviewa with a aample of the civilian noninstitutionaIized population.


TABLE 4.-Percentage distribution of adult current
      smokers who reported smoking specific
      numbers of cigarettes per day, in 1970, 1975,
       and 1980

Percentage of current smokers

Number of cigarettes/day            1970 '         1975 '        1980'

l-9                    15.8         13.5         13.1
              39.81       37,O 1       33.81
l&19                   24.0         23.5         20.7
20                     34.9         32.0         34.8
21-29                    3.1          2.8          2.3
30                     9.6         12.1         11.5
31-39                    1.0          0.8          0.7
40                     8.8         10.7         11.1
              11.41       15.2 1       16.8 1
41+                     2.6          4.5          5.7

' National Survey on Adult Use of Tobecm. PHS, 1970 and 1975.
' Natiind Health Interview Survey Smoking Supplement, PHS W'reliminary). 1990.
NOTE: Data from 1966 National Survey are not compatible with other yean.

These findings may be due to several factors, including (1)
increased smoking (possibly among those who have switched to lower
tar cigarettes), (2) a higher cessation rate among persons smoking
fewer cigarettes, (3) the entry of new smokers of greater numbers of
cigarettes, or (4) some combination of these factors.

Number of Attempts to Quit Smoking

Survey data have shown that the majority of current smokers
have made at least one serious but unsuccessful attempt to quit (4).

Table 5 shows the percentage of current smokers who reported
having made three or more attempts to quit. Similar data are shown
for former smokers for two of the survey years. A modest downward
trend is observed in the percentage of current smokers who reported
making three or more attempts to quit (from 41.2 percent in 1966 to
38.7 percent in 1980), but the proportion of former smokers reporting
three or more attempts to quit increased from 36.0 percent to 53.2
percent over the period from 1966 to 1975; this increase is seen in
most of the sex, race, and age groups.

Comparing the proportion of current smokers who had made three
or more attempts to quit by years of education showed a general
downward trend over time for all education levels except in the less
than 8 years of education group, where the proportion increased
from 38.9 percent in 1966 to 47.0 percent in 1980. Among the most
educated current smokers, the decline was from 59.8 to 39.4 percent.


TABLE S-Percentage of current and former smokers who
     made three or more attempts to quit, by sex,
      age, and educational level, in 1996, 1975, and
       1980

   1966'             1975 '             1980'
Current Former'     Current Former'     Current Former'
smoker  emoker      smoker  smoker      smoker  smoker

All ages 221         41.2    36.0        40.5    53.2        30.7

Male
All e&et3 221
21-24
2&34
3544
4l5-54
56-64
>_=

40.7    36.9        36.4    55.1        38.8
35.4    21.6        39.0    50.0        31.5
37.4    50.0        38.2    43.7        38.7
41.8    36.6        37.1    43.8        35.0
42.9    36.8        44.1    58.4        39.8
44.1    34.1        45.6    63.3        42.0
46.9    30.1        31.0    61.9        52.6

Female
Allegw 221
21-24
2544
35-44
45-54
55-64
>a

41.5    34.0        42.0    49.1        38.7
28.6    35.3        32.3    52.9       31.3
34.5    36.1        39.5    47.2        31.0
43.5    33.3        45.1    42.7        42.5
56.7    23.9        44.0    57.0        37.1
36.6    43.6        44.7    50.9        49.2
43.5    28.6        46.9    46.4        46.1

Educational level
o-6
9-11
12
13-15
216

38.9    32.3        44.3
42.7    30.0        40.8
36.4    36.2        40.0
37.7  _  42.0        36.4
59.8    36.0        41.4

56.5        41.0
53.6        30.4
56.3        37.2
46.8        35.2
62.2        36.4

`National Survey on Adult Use 0fTobac.x~. PHS, 1966 and 1975.
`National Health Interview Survey Smoking Supplement. PIiS fl'reliminary), 19&J.
* Inclu&a the last s-ful attempt.
o 1980 former lunoker data not availblc.

Recent Attempt to Quit

Data in Table 6 show the percentage of current and former
smokers who reported an attempt to quit in the 12 months prior to
the interview. Although there was little change overall from 1966 to
1975 in the percentage of current smokers who reported making an
attempt to quit smoking in the previous year (1.5 percent), from 1975
to 1980 there was an increase of almost 10 percent. This increase is
shown consistently for all the sex, race, and age groups. Among those
who had attempted to quit, proportionately more young persons
(under 35 years) than older persons reported attempting to quit
during the previous 12 months.

370


TABLE 6.-Percentage of current and former smokers who
      attempted to quit during the last year, by sex,
      age, and educational level, in 1966, 1975, and
       1966

sex, age.
and education

   1966'             1975 '             1980'
Current Former     Current Former      Current Former'
smoker  smoker      smoker  smoker      smoker  smoker

Total
Allegea 221

Male
All ages 221
21-24
25-34
3644
u
5664
2-a

Female
Allages 221
21-24
26-34
3644
45-54
55-64
265

Edueationd level
o-8
9-11
12
13-15
> 16

26.0

23.3    12.1        25.5     8.2        33.4
44.0     6.7        44.0    29.2        52.5
23.8    20.4        20.7    15.8        37.3
19.4    11.2        19.1    6.3        26.9
19.1    14.8        20.0    7.0        27.3
12.2    13.1        25.3     1.9        29.9
15.6     1.8        19.3     3.1        29.2

29.4    17.2        30.0    12.7        40.6
40.0    33.3        50.8    27.5        55.1
35.7    24.2       33.0    aI.        47.1
25.0    12.5        29.1    11.7        39.5
25.2    13.0       19.8     9.3        30.0
17.9    11.4        23.6     6.4        31.8
27.8    17.9        26.2     4.2        37.0

26.4    12.1        27.6     4.2        36.7
25.9    15.5        28.0     9.9        38.8
268    15.1        26.1    10.0        37.7
25.0    10.2       29.1    13.4        31.3
26.1    15.5        27.5     9.3        38.4

13.8        27.5

9.8        36.7

' Nationni Survey on Adult Ua of Tobaax,, PEE?.. 19M aad 1976.
*National Health Interview Survey Smoking Supplement, PISS (Reliminnry), 1980.
* lseo former smoker da&i not ._vaileble.

Relationship of Tar Yields to Smoking Behavior

In 1972, the Public Health Service classified tar as one of the
"most likely" contributors to the health hazards posed by cigarettes,
and studies have confirmed its carcinogenicity (4). In response to this
finding, a major change occurred in the cigarette products manufac-
tured and actually used. Over the last two decades, the proportion of
domestically consumed cigarettes yielding 15 mg or less of tar has
increased from 15 percent in 1968 to 66.9 percent in 1981(7).

The cigarette industry has also increased its promotional activities
in marketing brands yielding 15 mg or less tar. The percentage of
dollars expended in the United States on advertising and promotion
of cigarettes yielding 15 mg or less tar has increased from 19.6
percent in 1975 to 48.1 percent in 1978. These factors may account,


TABLE 7.-Percentage distribution of current regular
      smokers by tar level of primary brand of
      cigarettes, by sex and age, in 1975 and 1989

Sex and age

       1975 '                    1980'
     Tar level                   Tar level


<5   5-9 lo-14 15-19 2fJ+    <5   5-9 lo-14 15-19 20+
mg w mg mg mg    w w me me mg

Total
All ages 221     0.8   0.6    9.5   67.9   20.2    6.3   13.1   26.4   44.0   10.4

Male
AllageE 221     0.5   0.6   9.5   63.6   25.8    4.1   10.6   22.6   49.6   13.3
21-24          -    -   a.4   79.0   12.6    2.6   8.1   22.2   66.0    1.0
25-34         0.5    0.8   10.3   70.6   17.9    3.9   10.2   23.7   50.4   3.7
3544         1.1    0.2   8.5   65.8   24.4    3.8   10.9   25.3   45.0   14.9
45-54          -   0.5   12.1   56.1   31.3    5.0   10.1   22.2   39.0   23.6
55-64         1.2    1.6   8.5   50.2   38.5    5.4   11.6   19.6   39.8   23.6
t=          0.4   0.8   6.7   49.3   42.1     3.7   15.6   16.2   38.3   26.3

Female
Au ages 221     1.1    0.6   11.7   73.2   13.4    8.9   15.9   28.7   39.4    7.1
21-24         1.2    0.3   11.7   80.4    6.4    5.5    8.5   32.5   51.9    1.7
25-34         0.6   0.4   10.9   78.4   9.7     6.7   18.9   28.9   44.5   0.9
35-44         1.2    0.9   13.0   74.6   10.3    13.6   15.2   29.1   37.1    5.1
4I5-54         1.5    0.3   10.8   65.6   21.9     8.1   17.8   29.9   32.5   11.7
55-64         0.8    -   12.6   70.3   16.3    9.7   13.7   24.2   37.6   14.9
$5          2.1    3.1   12.5   63.9   18.5    9.6   18.6   26.6   30.2   14.9

' National Survey on Adult Use of Tolmcco, PHS, 1975.
' National Health Interview Survey Smoking Supplement, PIiS (preliminary). 1980.

in part, for the ever-in&easing use by current smokers of lower tar
cigarettes.

The definition of cigarettes as "lower tar" at 15 mg is arbitrary.
Nonetheless, this breakpoint has gained general acceptance. Special
note should be taken, however, that tar yields vary continuously, and
groupings by relative yield measurements do not automatically
imply differences in either the type or the magnitude of their
biological effects.

The percentage distribution of current regular smokers by tar
level of their primary brand of cigarette is presented in Table 8. A
clear trend toward increased use of lower tar products is apparent.
The 1975 data on brands were coded to the 1975 Federal Trade
Commission (FTC) values for tar yield, and the 1980 data were coded
to the 1979 FTC values. As tar values have bean progressively
declining, the 1980 data probably represent slightly higher values of
tar yields than were actually being used at that time.


Conclusions

1. The proportion of current regular smokers declined steadily
  between 1965 and 1980. The decline was steeper among males
  (from 52.1 to 37.9 percent) than among females (from 34.2 to
  29.8 percent).
2. The proportion of never smokers increased steadily from 1965
  to 1980 among males (27.6 to 31.6 percent), except those 45
  years old and older. Among females, only 20- to 34-year-olds
  showed an increase in proportion of never smokers.
3. The mean number of cigarettes smoked per day by current
  smokers increased slightly from 1970 to 1980 (from 20 to 21.7
  cigarettes).
4. Males smoked a higher mean number of cigarettes throughout
  the 1970-1980 period, but the number for males and females
   increased about the same amount.
5. Heaviest daily consumption was in the middle-aged group (35-
  65 years). The greatest mean increase was observed among
  women aged 35 to 44.
6. The proportion of current smokers who smoked less than 20
  cigarettes per day decreased between 1970 and 1980 (39.8 to
  33.8 percent); the proportion smoking one pack exactly (20
  cigarettes) remained constant (34.9 to 34.8 percent); the propor-
  tion smoking from 21 to 39 cigarettes increased slightly (13.7 to
  14.5 percent); and the proportion smoking two or more packs
  per day increased (11.4 to 16.8 percent).
7. The proportion of current smokers who attempted to quit three
  or more times decreased slightly from 1966 to 1980 (41.2 to 38.7
  percent).
8. The proportion of former smokers having made three or more
  attempts to quit increased sharply (36 to 53.2 percent) from
   1966 to 1975.
9. The proportion of current smokers who had attempted to quit
  during the past year increased from 1966 to 1980 (26.0 to 36.7
  percent).
10. Among current smokers, younger persons and females were
  more likely than older persons and males to have attempted to
  quit during the previous 12 months.
11. The proportion of former smokers who had attempted to quit
  during the previous 12 months decreased from 1966 to 1975
  (13.8 to 9.8 percent).
12. Among former smokers, younger persons and females were
  more likely than older persons and males to have quit during
  the previous 12 months.


References

(I) MAXWELL, J.C., Jr. Maxwell estimates 1981 cigarette s&a up 2.6 percent.
    United Stutea Tolxxco JournuI209@3-24): 1,6,8,50, December 6-22, 1961.
(2) NATIONAL CENTER FOR HEALTH STATISTICS. He&h, United States,
    1981. U.S. Department of Health and Human Services, Public Health
    Service, National Center for Health Statistics, National Center for Health
    Services Research, DHHS Publication No. (PHS)&X?+1232, December 1981,
    337 PP.
  (3) U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Changing
    Cigarette: A Report of the Surgeon Gxeml. U.S. Department of Health and
    Human Services, Public Health Service, Ofke of the Aseietant Secretary for
    Health, Office on Smoking and Health, DHHS Publication No. @VIS)61-
    !50156,1981,262 pp.
  (4,I U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking
    and Health: A Report of the Surgeon General. U.S. Department of Health,
    Education, and Welfare. Public Health Service, Of&e of the Ae&tant
    Secretary for Health, Office on Smoking and Health, DHEW Publication No.
    @`HS)7940066,1979,1136 pp.
(5) U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. The
    Health C~nwquencea of Smoking for Worn... A Report of the Surgeon
    Ceneml. U.S. Department of Health, Education, and Welfare, Public Health
    Service, Office of the Assistant Secretary for Health, Oftice on Smoking and
    Health, 1960,359 pp.
(6) U.S. PUBLIC HEALTH SERVICE. Use of Tobacco, Pm&ices, Attitudes,
    KmwMge, wuf Beliefs, United States: Fall 1964 and Spring 1966. U.S.
    Department of Health, Education, and Welfare, National clearinghouse for
    Smoking and Health, July 1969,607 pp.
(7) U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1970. U.S. Depart-
    ment of Heakh, Education, and Welfare, Public Health Service, Center for
    Disease Control, National Clearinghouse for Smoking and Health, DHEW
    Publication No. (I-ISMj73-6727, June 1973,129 pp.
(8) U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1975. U.S. Depart-
    ment of Health, Education, and Welfare, Public Health Service, Center for
    Diseaee Control. National clearinghouse for Smoking and Health, June
      1976.



INDEX

ADVERTISING
low tar cigarettea, 371372
AGE FACTORS
arterial disease prevalence, 133-134
atheroecleroais and smoking rela-
  tionship, 32
atherosclerosis, aortic aneurysm,
  and smoking relationship, 194
cardiovascular disease mortality
  trends, 331
cerebrovascular d&ease risk, 5, 8
cessation attempts, 1611, 370, 373
CHD mortality, 7, 113, 128, 339,
   352, 354
CHD relationship, 75-76, 91, 92,
   101-102, 133-134
daily cigarette consumption, 10,
   367, 373
intermittent claudication preva-
  lence, 184
prevalence of smoking, 10, 259,
  365.366, 373
stroke incidence, 165-166, 171
stroke mortality trends, 341
ALCOHOL CONSUMPTION
CHD mortality relationship, lll-
   112
CHD relationship, 68, 91
coronary calcification relationship,
   32
lipoprotein level relationship, 96
stroke risk factor, 162
sudden cardiac death relationship,
   104-105
ALLERGY
tobacco allergy and cardiovascular
  effects, 55-56, 133-189
AMISH
mortality, 126127
AMPUTATION
healing failure and smoking, 192
ANGINA PECTGRIS
carbon monoxide exposure and ex-
  ercise tolerance, 136, 223

ANGINA PECI'ORIS-Contd.
carboxyhemoglobin level, 223
CHD manifestation, 67, 7&71
incidence in Belfast, 34
incidence in smokem with CHD,
   213

risk in female smokers, 102
smoking relationship, 70, 77, 36-37
AORTA

aneurysm diagnosis, 192
aneurysm prevalence in smokers
  and nonsmokers, 45
atherosclerosis and nicotine expo
   sure, 50
atherosclerosis and smoking, 22, 34,
  -,56
atherceclerosie as cause, 16
atherosclerosis development, 5, 18
epidemiologic data, 194-195
mortahty trends, 341
tobacco smoke effects in rata, 53
ARTERIOSCLEROSIS
See also ATHEROSCLEROSIS)
angina pectoris relationship, 70
carbon disulfide exposure relation-
  ship, 226
cardiovascular disease causation, 5
definition, 15
mortality trends, 341
percent attributable to smoking, 65
underlying process of stroke, 340
ATHEROMA
definition, 15
small arteries of myocardium, 34
ATHEROSCLEROSIS
L%? also ARTEIuosCLERosIs)
age and smoking relationship, 194
aortic aneurysm relationship, 192
atherogenesis, 19-21
cadmium exposure relationship, 227
carbon monoxide expoeure relation-
  ship, 223
cardiac arrest, 69
cardiovascular disease causation, 5


INDEX

ATHEROSCLEROSIS-Contd.
clinical significance, 16-17
definition, 15-16
dietary cholesterol effect, 196
epidemiologic studies, 21-48
incidence in smokers and nonsmok-
  ers, 67
literature reviews, 17
mortality and smoking, 229
natural history, 17-19
nicotine effects, 216
pathophysiologic mechanisms of to
  bacca smoke, 48, 56-5~
plasma triglyceride correlation, 181
risk factors, 205-206
severity trends, 343344
smoking cessation effects, 5
smoking effecta, 5-6
topographic distribution, 18

BLOOD FLOW
nicotine and tobacco smoke effects,
   189
nicotine effects, 215
smoking relationship, 187-188
BLOOD PRESSURE
c3ee cd90 HYPERTENSION)
CHD risk factor, 97-98, 108, 130,
   134
coronary atherosclerosis relation-
  ship, 33
intermittent claudication relation-
  ship, 184
intervention trial effects, 315, 317
intervention trial for single risk
  factor, 300
nicotine effects, 3, 215
race factors, 77
smoking cessation relationship, 96-
   97
smoking relationship, 55, 96-97,
   187-188
BODY FAT
CHD risk factors, 132
BODY WEIGHT
Bee also OBESITY)
smokers versus nonsmokers, 55
smoking effect in baboons, 196
stroke incidence relationship, 163
sudden cardiac death risk factor,
   104

CADMIUM
physiological effects, 226-227
tobacco smoke constituent, 226

Cancer See NEOPLASMS
CARBON DISULFIDE
arteriosclerotic diseases, as risk fat-
   tar, 226
CARBON MONOXIDE
atherogenic effects, 5, 51-52
blood levels in smoking baboons,
   196
cardiovascular disease relationship,
   220, 222-224
cardiovascular effects, 230
chemistry, 219-226
exercise tolerance relationship, 186
fibrinolysis relationship, 187
myocardmi infarction risk, 229
platelet adhesiveness relationship,
   189-190
steelworkers' exposure and CHD
  mortality, 111
toxicologic effects, 9
validation of self-reported smoking
  cessation, 245, 261
CARBONYL SULFIDE
atherosclerotic effecta, 225
Catecholaminea See EPINEPH-
RINIQ NOREPINEPHRINE
CENTRAL NERVOUS SYSTEM
nicotine effects, 213
CEREBROVASCULAR DISEASE
s?e also STROKE)
atherosclerosis of cerebral vascuia-
  ture, 48
cerebral thrombosis incidence, 344
cessation of smoking relationship,
   168
incidence trends, 344
morbidity and mortality, 159469
mortality trends, 329, 346
oral contraceptives relationship,
   168-171
prevention, 170
risk factors, l-162, X8-171
smoking as risk factor, 5, 8, 162-
   166
subarachnoid hemorrhage, 5, 8, 167
transient ischemic attacks, 166-167
CESSATION OF SMOKING
hsee aLso Ex-sMoK.EI& REDUG
  TION OF SMOKING; SMOK-
  ING INTERVENTION TRI-
  ALS)
attempts to quit, 16-11, 369370,
  373
blood pressure correlation, 96-97


INDEX

CESSATION OF SMOKING-ConM.
CHD epidemiology, 243-233, 3CG
   321

CHD mortality rates, 8-10, 122
126, 123, 29-21
definition in intervention trials,
246-247

following cardiovascular events,
213, 215

intervention trial effecta, 9, 252,
257-258, 261, 264-271, 275, 27%
279,28%283

peripheral vascular disease treat-
  ment, 5, 8, 179, 190, 192, 194
peripheral vascular effects, 187-188
stroke mortality risk, 168
stroke prevention, 176
sudden cardiac death risk, 7, 105
validation of self-reports, 244-246,
  258, 261, 265, 27C280, 305, 312
CHEROOT SMOKERS
myocardial infarction risk, 88
CHEWING TOBACCO
intermittent claudication relation-
  Ship, 186

CH0LIBTRR0L
(See a&o DIETi LIPIDS; LIPO-
  PROTRINS)

aortic tissue levels following smoke
exposure, 219
atherogenesis relationship, l%ZO,
50-54, 216-217
atherosclerosis and diet in rabbita,
189-191
carbon monoxide, diet, and athero-
sclercais, 223
cardiovascular disease risk and
blood levels, 265
CHD risk, 5, 7, 89, 91-93, 96-100,
127, 129130, 136. 344
coronary atherosclerosis and serum
levels, 53
hypercholesterolemia prevalence,
346
intermittent claudication and se
rum levels, 184
intervention trial effects, 312-313,
315, 317
intervention trials for single risk
factor, 309
myocardial infarction and serum
levels, 165
peripheral vascular disease rela-
tionship, 180-182, 184

CHOLESTRR0L-Cont.d.
smoking and blood levels, 188, 224
smoking and serum levels, 6, 56,
   182

stroke risk predictor, 161
sudden cardiac death and serum
  levels, 104
CHRONIC OBSTRUCTIVE PUL
MONARY DISEASE
(See .aIso EMPHYSEMA)
mortality trends, 333, 338-340
smoking correlation, 228
CIGAR SMOKERS
aortic lesions, 194
CI-ID mortality, 8, 122
CHD risk, 86, 123
coronary event risk, 76-77
former cig-arette smokers, 252
inhalation avoidance, 212
myocardA infarction risk, 88
peripheral vascular disease risk,
   191
stroke mortality, 163
thiocyanate elevation, 244
COFFEE CONSUMPTION
blood lipid effecta, 182
CHD risk factor, 91, 97
stroke risk factor, 162
CORONARY ARTERIES
atherosclerosis in, 18
atherosclerotic lesions after nico-
  tine exposure, 50
carbon monoxide effect on lipid
  metabolism in, 52
smoking and atherosclerosis in, 22-
  34, 56
CORONARY HEART DISEASE
(See also MYOCARDIAL IN-
  FARCTION)
age factors in smoking effect, 112
  113, 116117, 123
atherosclerosis aa underlying cause,
   16
cessation of smoking and epidemiol-
  ogy, 5-6, 10, 122-126, 128, 293
   321
clinical manifestations, 67-71
death certificate ascertainment, 69-
   70
incidence studies, 342343
intervention trial effects on inci-
  dence, 9
low risk populations, 126127
low yield cigarettes, 12%122, 128


                 INDEX

CORONARY HEART DISRASE-Contd. DIET-Contd.

mortality trends, 329, 334, 336,
336-346,34%362
pipe and cigar smokers, 122, 128
prevalence trenh, 3
prospective cohort studies, 106-113
risk assessment, 129-136
risk factor reduction and mortality
trends, 344, 346-346
risk factors, 91-93, 96-97
smoking relationship, 4-3, 65-67,
113-119. 127-126
synergism among risk factors, 97-
100
treatment improvementa, 346

cigar smokers serum, 212
nicotine metabolite, 212-213
serum levels and uptake of particu-
  lates, 223
urine concentration in smoking ba-
  bOOM, 190
validation of self-reported cessation,
   245
CROSS-CULTURAL STUDIES
atherosclerosie topographic d&tribu-
  tion, 18
CHD incidence and mortality, 79-
   91

Demographic Factor8 See-AGE
FACTORS; EDUCATIONAL AT-
TAINMRNT; RACE FACTORS;
SEX FACTORS; SOCIOECO-
NOMIC STATUS
DIARRTESMRLLITUS
atherogenesis relationship, 26
cardiovascular disease risk factor,
   205
CHD incidence relationship, 89
CHD risk factor, 91-92
mortality trends, 334
peripheral vascular disease rela-
  tionship, 179, 183, 165, 191
prevalence, 346
stroke risk factor, 162, 165
DIRT
(See also CHOLESTEROL; SATU-
  RATED FATS)
atherogenesis correlation, 19-20
CHD mortality relationship, 112
high cholesterol diet, nicotine, and
  arterial damage, 50

nutritional etatus and smoking role
  in atherosclerosis, 33
treatment of peripheral vascular
  disease, 179
Dose-ReapoMe RelfttioMhip see
SMOKING PATTERNS
DRUG INTRRACTIONS
atenolol physiologic effects in
  smokers, 136
diasepam reactivity in smokers,
   222
methacholine effects on norepineph-
  rine, 216
norepinephrine effects of dimethyl-
  phenylpiperaxinium, 216
oxytremorine effecta on norepineph-
  rine, 216
phenacetin reactivity in smokers,
   222
propranolol physiologic effecta in
  smokers, 166

EDUCATIONAL ATTAINMENT
cessation attempt frequency rela-
  tionship, 369

cigarette con8umption relationship,
367

ELRCTROCARDIOGRAM
abnormalities as stroke risk factor,
  162-163, 166

CHD risk prediction, 134
intervention effect, 232
nitrogen dioxide exposure and car-
  diac function, 226
EMPHYSEMA
Wee ah CHRONIC ORSTRUCTIVE
PULMONARY DISRASR)
cadmium exposure as risk factor,
226

nitrogen oxides exposure a8 rbrk
factor, 226

smoking relationship, 223
ENZYMES

carbon monoxide affinity, 222-223
RPINEPHRINE
nicotine effects, 213, 215-216
plasma level8 and smoking, 166
ERYTHROCYTES
(See ah HEMATOCRIT)
counts in smokers, 55
nicotine effects in rabbits, 196


INDEX

M-SMOKERS
(See a&o CESSATION OF SMOK-
  ING)
aortic lesions, 47, 194
atheroeclerceie mortality, 229
CI-ID incidence, 82
CHD mortality, 5-6, 8
death risk after my& infarc-
  tion or angina, 105
differences from smokers, 297
peripheral arterial disease in wom-
   en, 185
stroke mortality, 163, 166
FAMILY
wives' participation in intervention
  trials, 257,260
Fmus
(See also MATERNAL SMOKING)
maternal cadmium administration
  effects on fetal brain in rata,
   227
maternal smoking effecta, 189
FIBRINOGEN
smoking effectas, 55, 18`7
FIBRINoLYsIS
nicotine effects, 218
smoking effects, 55, 187
FILTER CIGARETTE3
(See also LOW YIELD CIGAR
  ETTES)
carbon monoxide yields, 220
cardiovascular d&ease incidence,
   228
CHD mortality effects, 8
CHD l-i& 120
hydrogen cyanide removal, 224-225
nicotine delivery, 210
nitrogen oxide reduction, 225
GLUCOSE
atherogenesis and blood levels, 218
intermittent claudication and blood
  levels, 184
intolerance and peripheral vascular
  disease, 182
smoking and blood levels in
  baboons, 55, 190
HEART RATE
atherogenesia correlation, 218
nicotine effecta, 3, 21%216
smoking effecta, 187
HEIGHT
CHD risk factor, 107
stroke risk factor, 163

HEMAm
(See a&o ERYTHRoCYTJC3)
nicotine effects in rabbits, 190
smoking effects, 55, 187
HEMOGLOBIN
carbon monoxide binding, 222
nicotine effecte in rabbits, 190
smoking effects, 55, 186-187
HEREDITY
cadmilim-induced hypertension, 227
CHD risk factor, 91-92, 108
coronary disease history and platel-
  et activation, 55
stroke risk factor, 166
HORMONES
estrogen and myocardial infarction,
   103 *
nicotine effecta on antidiuretic hor-
  mone secretion, 213
HYDROGEN CYANIDE
coronary arteries and aorta effects,
   52
serum thiocyanate a8 metabolite,
   244
tobacco smoke constituent, 22-4
HYPERTENSION
(See also BLOOD PRESSURE)
atherogenesis relationship, 20
cadmium level relationship, 226-
   227
cardiovascular disease risk factor,
   205
CHD risk factor, 5, 7, 89, 91-93,
  127. 344
educational campaign effects, 348
mortality trends, 329, 341
peripheral vascular disease rela-
  tionship, 179, 181
prevalence trends, 346
renal artery steno&, hypertension,
  and smoking relationship, 185
stroke risk factor, 161-163, 16!S-
  166, 170, 340
sudden cardiac death risk factor,
   104

IMMUNE SYSTEM
alterations in smokers, 55-56
hypersensitivity and tar exposure,
   228
INFLUENZA
mortality trends, 334


INDEX

INVOLUNTARY SMOJiJNG
atherosclerotic cardiovascular die-
  ease etiolcgy, 166
Cotinine in urine of nonsmokers,
  212213

KIDNEYS
cadmium localization, 226
nicotine metabolism, 212
renal artery stenosis, hy-pertension,
  and smoking interrelationship,
   135

atherosclerosie and lead in drink-
  ing water, 227
LEGISLATION
smoking restrictions in F'inland,
  279-280, 316

LEuKocYTm
elevation in smokers, 55-56
nicotine effects. 190
LINOLEN-IC ACID
CHD incidence and consumption,
   86
LIPIDS

(See also CHOLESTEROL)
atherogenesis relationship, 19-21,
52-54, 217-218
carbon monoxide and blood levels,
223-224

dietary cholesterol and serum level,
190

nicotine administration and serum
level, 190

race factor8 and plasma levels, 77
smoking and serum levels, 219
smoking Berum level8 in baboons,
190

LIPOPROTEINS
atherogenic role, 21
cadmium exposure relationship in
  pigeons, 227
CHD incidence, 92
hyperlipoproteinemia and athero
  genesis, 20
hyperlipoproteinemia and peripher-
  al vascular disease, 130-181
oral contraceptives and smoking ef-
  fects, 104
race factors, 77
smoking effects, 6, 53, 54, 56, 93,
  96, 136, 219
stroke relationship, 161-163

cadmium accumulation, 226
cirrhosis mortality trends, 334
lipoprotein metabolism impairment
  and peripheral vascular disease,
   182
nicotine metabolism, 212
prOtein SyntheSi8 and carbon mon-
  oxide exposure, 222
LOW YIELD CIGAIWITES
Hea also FILTER CIGAIEITES)
cardiova8cular disease relation8hip,
   229-230
CHD mortality effecta, 8, 120422,
   123
smoking pattern effects, 9, 210,
  218, 239, 272
stroke mortality relationship, 164-
   165
LUNG CANCER
Bee a&o NEOPLASMS)
death8 in smoking intervention tri-
  ale, 30% 309
excess death8 attributable to emok-
  ins, 65
mortality trenda, 333, 338-339
LUNGS
nicotine metabolism, 212
LYMPHOCYTES
smoking effects in baboons, 199
LYSOSOMES
nicotine effects, 219

MASS MEDIA
in smoking intervention trials, 263-
  264, 270, 272, 278-279, 231-233,
   316

MATERNAL SMOKING
See also FETUS)
fetal cardiovascular effects, 189
umbilical artery changes, 219
MENOPAUSE
CHD risk, 7, 101-104, 127
MORMONS
CHD mortality, 126
MORTALITY
calculations, 333, 356
cardiovascular disease mortality
  trend8, 329-344
cardiovascular disease risk factor
  reduction effects, 344-343
cessation of smoking effecta, S9,
  194, 293-321


INDEX

MORTALITY-Co&d.
CHD mortality and smoking rela-
  tionship, 4, 7, 65-66, 113-128,
   346-353

CHD mortality trends, 339-341
coronary care improvement effects,
343

prospective studies of CHD mortali.
ty, 105-113

MYOCARDIAL INFARCTION
(See also CORONARY HEART
  DISEASE)

carbon monoxide exposure correla-
tion, 51

carboxyhemoglobin level relation-
ship, 223

cardiac arrest etiology, 69
casefatality trends, 344
CHD manifestation, 67
clinical manifestations, 6746
discharge rate trends, 344
free fatty acid elevation in smokers
following myocardial infarction,
219

hyperlipoproteinemia in survivor8,
181

incidence, 342343
mortality trends, 33944.0
nicotine and carbon monoxide de-
livery relationship, 229
oral contraceptive use a8 risk fac-
tor, 7, 128

smoking a8 risk factor, 72-75, 77-
79, 64439, 91, 101-102, 105, 108,
121, 165

zinc deticiency correlation, 227
MYOCARDIUM
atherosclero8i8 of small arteries, 34
MYOGLOBIN

carbon monoxide binding, 222

NM)PLASMS

See also LUNG CANCER)
cancer death8 in smoking interven-
tion trial, 306, 310
cancer mortality in Seventh Day
Adventista, 126

cerebral neoplasm8 and stroke, 166
death rate8 and smoking patterns,
81

respiratory tract cancer mortality
and smoking, 81

NICOTINE
atherosclerosis pathogenesis, 5, 46,
   50-51
blood flow effects, 189
blood pressure and heart rate ef-
   fects, 3
cardiovascular effects, 213, 215-219,
   230
chemistry, 209-212
fibrinolysis relationship, 187
hematologic effects, 190
metabolism, 212-213
myocardial infarction risk, 229
particulate uptake and serum lev-
   els, 228
peripheral vascular effects, 187-138
serum lipid effects, 190
toxicologic effects, 9
validation of self-reported smoking
  cessation, 245
yield8 in U.S. cigarettes, 210
NICOTINE CHEWING GUM
smoking intervention, 270
NITROGEN OXIDES
coronary artery and aorta effecta
  of nitric oxide, 52
nitric oxide, carbon monoxide, and
  atherosclerotic change8, 225
tobacco smoke constituents, 22.5-
   226
NOREPINEPHRINE
nicotine effects, 213, 215-216
smoking and plasma levels, 136

OBESITY
(See also BODY WEIGHT)
atherosclerosis and smoking in-
  terrelationships, 31, 46
cardiovaecular disease risk factor,
   205
CHD risk factor, 91, 92
lipoprotein level relationship, 96
stroke risk factor, 162
OCCUPATIONS
farm laborers, 133-134
grade of employment and CHD
  mortality, 110-111
industrial workers, 275-278, 230-
  282, 303, 314-315
nur8e8, 102
physiciams, 65, 110, 112, 123-124,
  164,297
steelworkers, 111

381


INDEX

ORAL coNTRAcEpTTvE8
CHD risk factor with smoking,
  101-104, 126
myocardial infarction and smoking
  interrelationehips, 7
stroke risk factor with smoking,
   166-171
subarachnoid hemorrhage and
  smoking interrelationships, 5, 8

PERIPHERAL VASCULAR DIS
  EASE
anirnd StUdieS, 189-190
atheroeclerosis a8 underlying cawe,
   16
cea8ation of smoking effecta, 190-
   192, 194
clinical investigations, 166-189
diagnosis, 179
epidemiologic studies, 182-186
reactivity of patients to tobacco
  glycoprotein, 56
risk factors, 16&182, 194
smoking effecta, 8
treatment, 179-W
PERSONALITY
cardiovascular d&ease risk factor,
   205
CI-ID risk factor, 91-93
PHYSICAL ACTIVITY
cardiovascular disease risk, 205
CHD risk, 91-92, 132
exercise tolerance and carbon mon-
  oxide exposure. 166
stroke incidence, 162
treatment of peripheral vascular
  disease, 179
PIPE SMOKERS
aortic lesions, 47. 194
CHD mortality effects, 8, 122,
CHD risk, 66, 123
coronary event risk, 76-77
former cigarette smokers, 252
myccardial infarction risk, 66
peripheral vascular dieease risk,
   191
stroke mortality, 163
thiocyanate elevation, 244
PLATELETS
adhesiveness and carbon monoxide
  effects, 189-190
atherogenesis role, 217-219
nicotine effect in rabbits, 190
smoking effects, 6, 5556, 187

PLATELEB-&ntd.
smoking effecta in baboons, 190
thrombocytopenia a8 stroke risk
  factor, 166
PNEUMONIA
mortality trends, 334
PROSTAGLANDINS
nicotine effecta and athemgeneais,
   216-219

RACE FACTORS
aortic aneury&ms and atheroecler+
  Si8, 1%
atheroecleroeia in aorta, 46
atheroeclerceis in coronary arteries,
  22, 31
atheroeclemsis severity trends, 343-
   344
Cardiova8cular disease mortality
  trends, 331
cerebrovascular disease incidence,
   170
CHD incidence, 77-79, 132-134
CHD mortality, 339
hyperteneive diaea8e mortality
  trends, 341
lipoprotein levele, 93
prevalence of smoking, 364-365
8moking patterns, 77
stroke mortality, 159, 165, 341
RECIDIVISM
rate following intervention trials,
  261-263, 265
REDUCTION OF SMOKING
criteria for succes8ful intervention,
   245-247
intervention trial effecta, 9, 256,
  258, 262, 264, 275, 279-2.80, 309,
  311313, 315
peripheral vascular disease pa-
  tients, 191

nicotine effects, 213
REORGANIZED CHURCH OF
JESUS CHRIST OF LATTER
DAY SAINTS
mortality rates, 126

SATURATED FATS
(See also DIET)
consumption trends, 348
diet and atherogenesis, 19
lipoprotein composition relation-
  Ship. 53


                  INDEX

SEVENTH DAY ADVENTISTS
CHD and cancer mortality, 126
SEX FACTORS
Bea also WOMEN)
aortic aneurysm mortality, 194
brain infarction and mywardial in-
  farction, 159
cessation attempts, 11, 373
CHD mortality, 110-113. 339
CHD mortality and smoking ceasa-
  tion trenda, 348-352
CHD rates, 7
cigarette consumption trends, 10,
  36fx367, 373
lipoprotein levels, 93
peripheral vascular d&ease preva-
  lence, 184-185
8moking pattem8,7
smoking prevalence, 7, 364, 373
stroke incidence, 165, 344
stroke mortality, 164
sudden cardiac death incidence, 68
SMOKING HABIT
prevalence trende, 336,344, 346-
  350, 364-366, 373
Sweden, 111
SMOKING INTERVENTION TRI-
Au3
ceesation outcome, 9, 267-271, 281-
   283
wmmunity-ba8ed trial& 271-282,
   314-318
individual clinical investigations,
  249471. 303-313, 318. 320
methodological problems, 244-249,
  264-267,28W281,30&302
SMOKING PATTERNS
cefmation rate effect8,261
CHD incidence, 81433,128
CHD mortality rat+ 113, 115-119,
   127
wronary event tik, 75-76
daily consumption trends, 373
intervention trial effecta, 9
low yield cigarettes, 9
myocardial infarction incidence, 87-
   88
peripheral vascular disease rela-
  tionship, 185
raw factorm, 77
reduction of smoking effects, 262
stroke mortality rates, 163-164, 171
sudden cardiac death rick, 7. 104
trenda, 352                 CHD incidence, 92

SMOKING PATTRRNS - Contd.
women, 101-102, 104
SNUFF
intermittent claudication relation-
  Ship, 186
SOCIOECONOMIC STATUS
CHD mortality rates, 111-112, 339,
   350-352
CHD risk factor, 91
coronary atherosclerosis and smok-
  ing interrelationships, 33
STRESS
CHD risk factor, 91
STROKE
Gee also CEREBROVASCUIAR
  DI!3RASEI
atheroeclero+ as underlying cause,
   16
discharge rate trends, 344
incidence study, 344
mortality trends, 334, 340-341
SUDDEN CARDIAC DEATH
clinical manifestations, 68-69
risk factors, 104-105
smoking as risk factor in women,
   102
smoking pattern relationship, 7,
   128

TARS, TOBACCO
smoking behavior relationship, 371-
   372
tobacco smoke constituent, 227-228
yields in U.S. cigarettea, 228
THIOCYANATE
blood levels in smoking baboons,
   190
serum levels and lipoproteins, 182
validation of self-reported smoking
  cessation, 24&246,258,261-265,
  279-280,305,312
TOBACCO SMOKE
athemecleroek pathogeneais, 48,

constituents, 8-9
physical and chemical characteris
  tics, 206!m
TRIGLYCERIDES
atherosclerosis and plasma wncen-
  tration, 181
CHD development and plasma lev-
  els, 84


INDEX

TRIGLYCERIDEg-Contd.
elevation in peripheral vascular
  disease, 160
nicotine effects, 219
stroke risk factor, 161, 165

VITAMIND
arterial lesion8 in monkey8 caused
  by dietary excess, 50-51

WEIGHT GAIN
cessation of smoking correlation,
  96-97, 301

WOMEN
(See also MENOPAUSE; ORAL
  CONTRACEPTIVRS; SM
  FACTORS)
brain infarction and LDL cholester-
  ol, 162
cardiOva8dar disease mortality
  trend8, 331
CHD incidence, mortality, and
  smoking interrelation8hip8, lOl-
  104, 127-126
subarachnoid hemorrhage risk and
  smoking, 5, 167, 170

ZINC
t.obacco smoke constituent, 227

3234
.-.-