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THE NEW ENGLAND JOURNAL OF MEDICINE

June 29, 1995

REVIEW ARTICLES

MEDICAL PROGRESS

THE PRIMARY PREVENTION OF CORONARY


HEART DISEASE IN WOMEN
JANET W. RICH-EDWARDS, SC.D.,
JOANN E. MANSON, M.D., DR.P.H.,
CHARLES H. HENNEKENS, M.D., DR.P.H.,
AND J ULIE E. B URING , S C .D.

ORONARY heart disease has long been recognized as the leading cause of death among middle-aged men, but it is an equally important cause of
death and disability among older women. By the age of
60 years, only 1 in 17 women in the United States has
had a coronary event, as compared with 1 in 5 men. After the age of 60, however, coronary heart disease is the
primary cause of death among women. In this age
group, one in four women, as well as one in four men,
die of coronary heart disease.1 The annual numbers of
American women and men who have myocardial infarctions are shown in Figure 1.2 Although the rates of
mortality from coronary heart disease have been falling
since the 1960s, the rate of decline has been slower
among women than among men since 1979.3
Most of the risk factors for coronary heart disease
and the strategies for preventing disease among men
are also important for women.4 However, the magnitude of their effects may be different. In addition, there
are risk factors and preventive strategies that are
unique to women. In this article, we review the main
risk factors and preventive strategies for coronary
heart disease among women (Table 1).
RISK FACTORS

PREVENTIVE STRATEGIES
WOMEN AND MEN

AND

FOR

Cigarette Smoking

Cigarette smoking is the leading preventable cause


of death among men and women in the United States.
A large body of evidence has consistently indicated that
the risk of coronary heart disease is two to four times
higher among women who are heavy smokers (usually
From the Division of Preventive Medicine (J.W.R.-E., J.E.M., C.H.H., J.E.B.)
and the Channing Laboratory (J.E.M.), Department of Medicine, Brigham and
Womens Hospital and Harvard Medical School; and the Department of Epidemiology, Harvard School of Public Health (J.W.R.-E., C.H.H.) all in Boston.
Address reprint requests to Dr. Rich-Edwards at 900 Commonwealth Ave. East,
Boston, MA 02215.
Supported by grants (HL-34595 and DK-36798) from the National Institutes of
Health. Dr. Rich-Edwards is the recipient of an Institutional National Research
Service Award (HL-07575) from the National Heart, Lung, and Blood Institute. Dr.
Manson is the recipient of a MerckSociety for Epidemiologic Research award.

defined as those who smoke 20 or more cigarettes per


day) than among women who do not smoke.34 Moreover, there is a clear doseresponse relation: as compared with nonsmokers, even light smokers (women
who smoke one to four cigarettes per day) have more
than twice the risk of coronary disease.6
Fortunately, after the cessation of smoking, the risk
of coronary heart disease in both women and men begins to decline within a matter of months and falls to
the level of the risk among nonsmokers within three to
five years after cessation, regardless of the amount
smoked, the duration of the habit, or the age at cessation.6,8,34 Although the prevalence of smoking among
U.S. women declined from 34 percent in 1965 to 24
percent in 1991, the rate of cessation of smoking is lower among women than among men.35 In lieu of quitting
or cutting back, women may switch to low-yield cigarettes with reduced tar, nicotine, and carbon monoxide.
The epidemiologic evidence, however, indicates that
smokers of low-yield cigarettes are at no lower risk for
coronary heart disease than those who smoke higheryield brands.36
Cholesterol

Most of the research on cholesterol and coronary


heart disease has involved middle-aged men, among
whom a 2 to 3 percent decline in the risk of coronary
heart disease has been associated with every 1 percent reduction in the serum cholesterol level.37 Extrapolation of these findings to women has been questioned,38,39 because estrogens affect the lipid profile.40
However, 9 of 10 prospective observational studies have
reported a positive association between total cholesterol levels and coronary heart disease in women.41-50 An
increased level of high-density lipoprotein (HDL) cholesterol is a particularly strong predictor of a decreased
risk of coronary heart disease in women.41,43,44 HDL
cholesterol was second only to age as a predictor of
death from cardiovascular causes among women in the
Lipid Research Clinics Follow-up Study.43
Whereas more than 10,000 men with preexisting coronary heart disease have been enrolled in trials of cholesterol reduction,51-54 just over 400 women have been
included in such secondary-prevention trials.55-59 Even
in these small trials, however, lowering low-density lipoprotein (LDL) cholesterol levels and raising HDL cholesterol levels were shown to impede the progression of
atherosclerosis in women as well as in men.55,56 Trials
have suggested that reduction of lipid levels reduces the
risk of subsequent myocardial infarction in women with
preexisting coronary heart disease, although these studies have included too few women to be definitive.57-59
The data on primary prevention of coronary heart
disease by modification of the lipid profile in apparently healthy women are equally limited.60 Only 5800 of

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lower LDL cholesterol levels and raise HDL cholesterol levels would benefit women as well as men.

Estimated Number of Persons


(thousands)

500
400

Men
Women

424,000

440,000
374,000

Hypertension

As in men, the strong association between elevated


blood pressure and coronary heart disease in women
has been demonstrated by a number of prospective
studies.62-65 Although the benefits of medication in the
treatment of severe hypertension are great and obvious
for both men and women, the benefit of treating mildto-moderate hypertension (i.e., diastolic blood pressure
between 90 and 114 mm Hg) has been debated. A
meta-analysis of randomized drug-treatment trials involving a total of 37,000 subjects, 47 percent of whom
were women, evaluated therapy of three to six years
duration for mild-to-moderate hypertension. A mean
decrease of 6 mm Hg in diastolic pressure significantly
reduced overall mortality from vascular disease by 21
percent, fatal and nonfatal stroke by 42 percent, and
fatal and nonfatal coronary heart disease by 14 percent.66 Inclusion of three subsequently published trials,
each with a sample in which approximately 60 percent
of the subjects were women, demonstrated an even
greater reduction in coronary heart disease (about 16
percent).9
The four randomized trials of drug treatment for
mild-to-moderate hypertension in which women were
separately assigned to treatment67-70 have reported a
9 to 30 percent reduction in the incidence of all cardiovascular events among women, yet only one trial has
reported a decrease in the incidence of coronary heart

300
200
136,000

123,000

100
3000

29 44

45 64

1759

65

Age (yr)
Figure 1. Annual Incidence of Myocardial Infarction in Women
and Men in the United States.
The data, which are from the Framingham Heart Study, are
adapted from the American Heart Association,2 with the permission of the publisher.

the more than 30,000 participants enrolled in primary-prevention trials of cholesterol reduction have
been women.9,60,61 None of these studies have had adequate statistical power to estimate the effect of altered
cholesterol profiles on the risk of coronary heart disease in healthy women. Although the data from randomized trials have yet to provide definitive evidence
that lowering cholesterol levels reduces the risk of coronary heart disease in healthy women, the consistency
of observational data suggests that interventions to

Table 1. Reductions in the Risk of Coronary Heart Disease among Women, According to the Type of Intervention.

INTERVENTION

SOURCE

Smoking cessation
Reduction in serum cholesterol level

Treatment of hypertension

Treatment of isolated systolic hypertension


Maintenance of normoglycemia in diabetic
patients
Avoidance of obesity
Physical activity
Small-to-moderate daily alcohol intake
Prophylactic low-dose aspirin
Antioxidant-vitamin supplementation
Postmenopausal hormone-replacement
therapy

OF

DATA

ON

WOMEN

Prospective observational studies in women6-8


Two randomized trials of drug and dietary
intervention (each with 52% women, some
with prior coronary heart disease)9,10
Trials in men4
Meta-analysis of randomized drug trials (50%
women)11
Unblinded randomized trials of nonpharmacologic interventions (30 to 60% women)
One randomized trial (57% women)12
Randomized trials in progress
Prospective observational studies in women13-15
Small prospective and retrospective
observational16-20 studies in women
Prospective and retrospective observational
studies in women20-25
Prospective and retrospective observational
studies in women26-29
Prospective observational studies in women30,31
Meta-analysis of observational studies in
women32
One randomized prospective study33

ESTIMATED MEAN REDUCTION IN RISK


HEART DISEASE*

OF

CORONARY

50 to 80% within 3 to 5 years


Insufficient data to provide estimates for
women
2 to 3% for every 1% reduction in serum cholesterol
16% after 3 to 6 years of treatment
Unknown
25%
Insufficient data to provide estimates for
women or men
35 to 60% for women at ideal weight, as compared with obese women
50 to 60% for physically active women, as
compared with sedentary women
Approximately 50% for women and men, as
compared with nondrinkers
Inconsistent data on women
Insufficient data
44% with estrogen alone
Data also suggest a reduction in risk factors
with estrogenprogestin therapy

*Estimated risk reductions refer to the independent contribution of each factor to the risk of myocardial infarction and do not account for the many known and hypothesized
interactions among factors. As Rothman has noted, because of the manifold causal pathways that lead to chronic disease, the total of the proportion of disease attributable
to various causes is not 100 percent but infinity.5

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disease.71 Although the reduction in blood pressure


achieved in these short-term trials led to the expected
reduction in the incidence of stroke, it may be necessary to maintain reduced blood pressure for many
years to realize the 20 to 25 percent reduction in coronary heart disease hypothesized on the basis of observational studies.72 There are few data that indicate
whether the side effects of antihypertensive drugs are
the same in women and men.73
The control of blood pressure through dietary intervention and weight loss has been moderately successful
in groups in which 30 to 60 percent of the patients were
women.74-76 None of these trials of nonpharmacologic
treatment of hypertension, however, have reported results separately for women.
There is evidence suggesting that preeclampsia,
which occurs in 5 to 10 percent of pregnancies, may
predict subsequent coronary heart disease. Without
information on blood pressure before and after pregnancy, it is difficult to distinguish preeclampsia and
pregnancy-induced hypertension (unaccompanied by
proteinuria) from chronic hypertension. Studies have
thus far relied on a physicians diagnosis of preeclampsia rather than the strict definition adopted by the
American College of Obstetrics and Gynecology.77 Some
casecontrol studies have reported an association between physician-diagnosed preeclampsia and subsequent coronary heart disease that appears to be independent of hypertension.78-80 It is not known whether
pregnancy-induced hypertension is associated with coronary heart disease. Because of the possible diagnostic
confusion among preeclampsia, pregnancy-induced hypertension, and chronic hypertension, studies with
clear case definitions are needed.
Of particular concern in older women is isolated systolic hypertension, an indication of the loss of arterial
elasticity. More prevalent among women than men, isolated systolic hypertension is estimated to affect approximately 30 percent of women over 65 years old.81
Several studies have linked isolated systolic hypertension with an elevated risk of death from stroke82 or coronary heart disease.83,84 In the Systolic Hypertension in
the Elderly Program, in which women accounted for 57
percent of the study population, antihypertensive treatment resulted in a 36 percent reduction in the incidence of stroke and a 25 percent reduction in that of
coronary heart disease.12
Diabetes Mellitus

Diabetes is an even stronger risk factor for coronary


heart disease in women than in men. Mortality rates for
coronary heart disease are three to seven times higher
among diabetic women than among nondiabetic women, as compared with rates that are two to four times
higher among diabetic men than among those without
diabetes.85-88 Diabetes exacerbates the effects of known
coronary risk factors and may impair estrogen binding,
negating the protection against coronary heart disease

June 29, 1995

that endogenous estrogens confer on premenopausal


women.89 Although it is not yet clear whether strict
glycemic control reduces the risk of coronary heart disease, there is promising evidence that intensive treatment of insulin-dependent diabetes slows the development of other diabetic complications.90 At present,
however, recommendations for diabetic patients rely
on the modification of other risk factors. Because cigarette smoking, hypertension, and obesity act in synergy
with diabetes,86 control of these risk factors yields
greater reductions in the risk of myocardial infarction
in patients with diabetes than in the nondiabetic population.
Gestational diabetes, which develops in 3 percent of
pregnant women in the United States, may be a marker
for an increased risk of coronary heart disease. In longterm follow-up studies, more than a third of women
with gestational diabetes subsequently had non-insulindependent diabetes,91-93 as compared with the approximate 5 percent incidence of non-insulin-dependent
diabetes among women with normal pregnancies. Longterm follow-up has demonstrated a higher incidence of
insulin resistance,94 hypertension,93 adverse lipid profiles,91 and abnormal electrocardiograms91 in women
with gestational diabetes than in those with normal
pregnancies. Although there is little evidence to suggest that gestational diabetes is associated with a risk
of coronary heart disease that is independent of the
risk associated with overt diabetes mellitus, young women with gestational diabetes may be suitable targets for
early preventive efforts.
Obesity

Direct positive associations between obesity and the


risk of coronary heart disease have been demonstrated
in a number of large, prospective cohort studies of
women.13-15 In the Nurses Health Study, involving over
120,000 middle-aged women, the risk of coronary heart
disease was over three times higher among the women
with a body-mass index (expressed as the weight in kilograms divided by the square of the height in meters)
of 29 or higher than among the lean women (bodymass index, 21).15 Even the women who were mildly
to moderately overweight (body-mass index, 25 to 28.9)
had nearly twice as high a risk of coronary heart disease as the lean women.15 Although a large portion
of the excess risk is attributable to the influence of adiposity on blood pressure, glucose tolerance, and lipid
levels, after adjustment for these variables a moderate
residual effect persists that may be due to other mechanisms.15
Unfortunately, direct evidence that weight loss reduces the risk of coronary heart disease is not yet available because of the small numbers of subjects able to
maintain a reduced level of weight. Weight loss in
women achieved by dieting either alone or in combination with exercise does reduce blood pressure and LDL
cholesterol levels.95 Because weight loss is difficult to

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achieve and maintain, prevention of obesity is critical.


Women who maintain their ideal body weight have a 35
to 60 percent lower risk of myocardial infarction than
women who become obese.13-15
Several studies have suggested that excess abdominal and upper-body fat may confer a particularly high
risk of coronary heart disease.96 Cross-sectional and
prospective studies have linked cardiovascular disease
and its precursors to upper-body obesity an association that is independent of the degree of overall obesity.97-101 The risk of coronary heart disease rises steeply
among women whose waist-to-hip ratio is higher than
0.8.96 The increased lipolytic activity of intraabdominal
fat has been associated with insulin resistance, reduced
HDL cholesterol levels, hypertriglyceridemia, hypertension, and decreased sex hormonebinding globulin
levels.102,103 Cross-sectional studies of women have
shown that abdominal adiposity is positively associated
with cigarette smoking,104,105 parity,105,106 and weight
cycling106 and negatively related to physical activity.105
Data are sparse, however, on the efficacy of approaches
to reducing upper-body obesity or the potential cardiovascular benefits of such weight reduction.
Physical Activity

Of the 43 epidemiologic studies that have been conducted since 1950 to assess the relation of exercise to
coronary heart disease, only 7 have included women.107
Four prospective studies16-18,108 and two casecontrol
studies19,20 have analyzed and presented data on women separately. The results of these analyses generally
indicate that physically active women have a 60 to 75
percent lower risk of coronary heart disease than inactive women. These studies have been small, however,
and the best estimate may be the 50 percent reduction
in risk derived from a meta-analysis of studies based
largely on men.109
A cross-sectional analysis of data from the Healthy
Women Study has shown associations between physical
activity and reduced weight, lower blood pressure, and
favorable lipid and insulin profiles in perimenopausal
women.110 After three years of follow-up, the women
who exercised more had gained less weight and had a
smaller drop in HDL cholesterol levels than the more
sedentary women. Physical activity, however, was not
linked to blood pressure or triglyceride, LDL cholesterol, or insulin levels, as it had been in the cross-sectional analysis.111 An eight-year prospective study of
3120 healthy women demonstrated associations between
physical fitness (assessed by treadmill testing) and reduced rates of mortality from cardiovascular disease
and from all causes. The age-adjusted rate of mortality
from cardiovascular disease among the most fit women
was 0.8 per 10,000 person-years, as compared with 7.4
per 10,000 person-years among the least fit women.112
Thus, although there is scant direct evidence that physical activity reduces the incidence of coronary heart
disease in women, the association between physical ac-

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tivity and coronary risk factors suggests that such benefits would be apparent in large, long-term studies of
women.
Alcohol Consumption

Although heavy alcohol use increases the risk of


death from cardiovascular causes, there is a large body
of evidence from both casecontrol studies20,21 and cohort studies22-25 that low-to-moderate daily consumption of alcohol provides protection against coronary
heart disease in women as well as in men.113 As compared with nondrinkers, women in the Nurses Health
Study who consumed 10 to 15 g of alcohol per day (the
equivalent of one 12-oz [355-ml] beer, one glass of
wine, or one drink of hard liquor daily) had a 40 percent reduction in the risk of coronary disease.25 Other
investigators examining this association in women have
reported estimated risk reductions of 30 to 70 percent
among moderate drinkers as compared with nondrinkers.20-23 Similar relative-risk estimates have been reported for men.20,22,24,114 This apparent protective effect
does not appear to depend on the type of alcoholic beverage consumed.
Several possible mechanisms for the protective role
of alcohol have been hypothesized, including increased
levels of HDL cholesterol,115 an increased ratio of prostacyclin to thromboxane,116 increased levels of tissuetype plasminogen activator,117 and reduced platelet
aggregation.118 Such antithrombotic effects of alcohol
may increase the risk of hemorrhagic stroke,25 however,
and even moderate alcohol consumption has been
linked to hypertension.119 Furthermore, alcohol consumption may increase the risk of breast cancer,120 and
heavy consumption is the second leading preventable
cause of all deaths in the United States.113 A recommendation that women drink moderate amounts of alcohol
in order to prevent heart disease is therefore unwarranted. A better understanding of the mechanisms of
alcohols cardioprotective effect may suggest other interventions that mimic the benefits of alcohol without
its deleterious consequences.
Low-Dose Aspirin

Meta-analyses of randomized trials involving people


with a history of occlusive vascular disease have demonstrated that aspirin reduces the incidence of subsequent myocardial infarction, stroke, and death from
cardiovascular causes by about 25 percent in both men
and women.121 Similarly, aspirin has a clear benefit in
men and women with acute evolving myocardial infarction.122 In primary-prevention trials, the incidence
of a first myocardial infarction has been reduced by 33
percent in men taking low doses of aspirin.121 The U.S.
Preventive Services Task Force recommends aspirin
for the primary prevention of myocardial infarction in
men 40 years of age and older in whom the risk of myocardial infarction is sufficiently high to warrant risking the possible adverse effects of the drug.123 No sim-

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ilar recommendation has been made for women, since


no completed primary-prevention trials have included
women.
The current data on aspirin for the primary prevention of coronary heart disease in women are limited to
four observational studies with inconsistent findings.
Two studies demonstrated a reduced incidence of myocardial infarction among women who took aspirin,26,27
one a possible adverse effect on ischemic heart disease,28 and one no effect.29 To distinguish smallto-moderate effects of aspirin from other, unidentified
differences between the treatment and control groups,
the only reliable design is a randomized trial of adequate size.124
The need for a randomized trial of aspirin in apparently healthy women is critical because the riskbenefit
ratio for aspirin may be different in women and in men.
This issue is being addressed in the ongoing Womens
Health Study, a randomized trial of low-dose aspirin
(100 mg on alternate days) among over 40,000 apparently healthy female health professionals 45 years of
age or older.125 Although aspirin may reduce the risk of
a first myocardial infarction, it may increase the risk
of hemorrhagic stroke; the ratio of the incidence of
stroke to that of myocardial infarction is higher in
women than in men.
Antioxidant Vitamins

It has been hypothesized that antioxidants such as


beta carotene, vitamin E, and vitamin C may reduce
the risk of cardiovascular disease.126 This belief is supported by basic research, which has demonstrated that
these vitamins inhibit either the oxidation of LDL cholesterol126 or its uptake into the coronary-artery endothelium.127 Epidemiologic data, although sparse, are
consistent with this hypothesis. Some but not all prospective observational studies in women,30,31 men,128
and both sexes129,130 have indicated an inverse association between a high intake of antioxidant vitamins, either through diet or supplements, and the risk of coronary heart disease. In particular, the women with the
highest intakes of beta carotene30 and vitamin E31 were
reported to have approximately a 25 percent lower risk
of coronary heart disease than the women with the lowest intakes. Data on the possible protective role of vitamin C are inconsistent.31,130
The only completed randomized trials of antioxidant-vitamin supplementation in well-nourished people
have involved men, and the results are contradictory.
In the Physicians Health Study, a subgroup of 333
men with a history of chronic stable angina or coronary
revascularization who were assigned to take 50 mg of
beta carotene on alternate days had half as many major coronary events as similar men assigned to placebo.131 In contrast, the Finnish Alpha-Tocopherol, Beta
Carotene Cancer Prevention Study reported no reduction in the incidence of coronary heart disease among
middle-aged male smokers randomly assigned to a regimen of daily supplements of beta carotene, vitamin E,

June 29, 1995

or both.132 In this trial, the very low dose of vitamin E


(50 mg daily) may have been insufficient to yield the
hypothesized cardiovascular benefits.133 Of concern
was an apparent increase in the risk of hemorrhagic
stroke among the men taking vitamin E supplements.
These results, though neither disproving the value of
antioxidant vitamins nor proving their harmful effects,
do raise the possibility that the potential cardiovascular benefits of antioxidant vitamins have been overestimated, and their potential adverse effects underestimated.
RISK FACTORS AND PREVENTIVE STRATEGIES
UNIQUE TO WOMEN
Menopause

The incidence of coronary heart disease in women


increases dramatically in middle age, which has led to
the speculation that menopause marks the end of a
protective effect of ovarian hormones on cardiovascular disease. Indeed, women who had an early and
abrupt menopause as a result of bilateral oophorectomy
and who did not receive estrogen-replacement therapy
had a risk of coronary heart disease 2.2 times higher
than that of premenopausal women of the same age.134
The women who received estrogen-replacement therapy had no higher risk of coronary heart disease, and
they may even have had a lower risk than the premenopausal women.
No such sudden increase in the risk of coronary
heart disease accompanies the natural cessation of menstruation. This is not surprising, since menopause
marks only one moment in the gradual waning of ovarian function that spans more than a decade. The widely
held belief that natural menopause signals an abrupt
increase in cardiovascular risk is based on analyses
with a number of methodologic flaws.135 In fact, the
narrowing gap between rates of cardiovascular disease
in older men and those in older women is due in large
part to a decelerated increase in the rate of mortality
from coronary heart disease among men,136 as well as
to earlier mortality among men than among women.
Postmenopausal Hormone-Replacement Therapy

Although the effect of postmenopausal hormonereplacement therapy on the overall health of women remains unclear, there is compelling evidence that such
therapy reduces the risk of coronary heart disease. A
review of 31 observational studies estimated a statistically significant 44 percent reduction in the risk of coronary heart disease among postmenopausal women receiving estrogen-replacement therapy.32 This apparent
protective effect is biologically plausible, since estrogen
has been shown to reduce LDL cholesterol levels and
increase HDL cholesterol levels by 10 to 15 percent137
and since it may have beneficial effects on the vasculature and endothelial function.138 Whereas estrogen may
decrease the risk of coronary heart disease, osteoporosis, and menopausal symptoms, however, it is a wellrecognized cause of endometrial cancer and increases

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MEDICAL PROGRESS

the risk of gallbladder disease. Furthermore, the possible influence of estrogen-replacement therapy on the
development of breast cancer is not yet clear, although
any increase in risk is likely to be small.139 Conclusive
answers to these questions are forthcoming from the
Womens Health Initiative, a large-scale, multicenter,
randomized trial.
The addition of a progestational agent to estrogenreplacement therapy may well decrease the risk of endometrial cancer, but whether the combined treatment
will still provide protection against coronary heart disease is unclear. Some observational studies have indicated that such combinations may be as beneficial as
unopposed estrogen in reducing the risk of cardiovascular disease.140,141 The best evidence comparing estrogen-replacement therapy with combined regimens
comes from the recently reported Postmenopausal Estrogen/Progestin Interventions Trial.33 This randomized, double-blind, placebo-controlled trial followed 875
healthy postmenopausal women for three years to test
the effect of unopposed estrogen therapy and three
combined estrogenprogestin regimens on systolic blood
pressure and levels of HDL cholesterol, insulin, and
fibrinogen. The combined regimens, as well as unopposed estrogen therapy, increased HDL levels, decreased LDL levels, and lowered fibrinogen levels, with
little effect on insulin levels or blood pressure. Although
estrogen alone raised HDL levels more than did the estrogenprogestin regimens, the women taking unopposed estrogen had an increased rate of endometrial
hyperplasia. Each of three estrogenprogestin regimens raised HDL levels significantly higher than did
placebo. Cyclic micronized progesterone had a more favorable effect on HDL levels than did medroxyprogesterone acetate. These findings strongly suggest a cardioprotective benefit from estrogen alone or combined
with progestin, particularly among women at high risk
for coronary heart disease, those who have preexisting
coronary heart disease, and those who have had a hysterectomy.138
Oral Contraceptives

The use of the older high-dose oral contraceptives increased the risk of cardiovascular disease by raising
LDL cholesterol levels and lowering HDL cholesterol
levels, reducing glucose tolerance, raising blood pressure, and promoting clotting mechanisms.142 The relative risk of myocardial infarction was elevated among
women who used these oral contraceptives. However,
the absolute risk of coronary heart disease, which is
rare in premenopausal women, was increased by only
1 percent among oral-contraceptive users under the
age of 40 years who did not smoke.143,144 Although few
data have been accumulated on the safety of new lowdose formulations, the results of some recent casecontrol studies suggest that oral contraceptives containing
lower doses of steroids may carry less risk of coronary
heart disease.145
There was a clear and alarming synergy between the

1763

previously used high-dose oral contraceptives and cigarette smoking, leading to a dramatically elevated risk
of myocardial infarction.143,146 Whether the risk is also
elevated among smokers who use low-dose oral contraceptives and if so, to what degree is unclear.
Concern has been expressed that the atherogenic effect of oral contraceptives may lead to an increased risk
of coronary heart disease among older women who
used such contraceptives in the past. A meta-analysis of
13 studies, however, concluded that there was no increased risk of coronary heart disease among past users of oral contraceptives.147 There is a rapid return to
the base-line risk of cardiovascular disease among
women who have stopped using oral contraceptives,
and the duration of their use does not affect the risk
among current users.142 These findings suggest that a
short-term mechanism, such as an increased risk of
thrombosis, explains most, if not all, of the increase
in the risk of myocardial infarction among current
users.147
CONCLUSIONS
It is clear that advising women to quit cigarette
smoking, avoid obesity, and increase their physical activity, as well as preventing and treating hypertension
(including isolated systolic hypertension), will result in
substantial reductions in the risk of coronary disease.
Furthermore, a reduction in the ratio of total cholesterol to HDL cholesterol is likely to reduce the incidence
of coronary heart disease in women. More evidence is
needed to evaluate the overall balance between the
risks and the prophylactic benefits of aspirin, small daily amounts of alcohol, and antioxidant vitamins, as well
as low-dose oral contraceptives and postmenopausal
hormone-replacement therapy. The results of studies
now in progress will help establish more effective programs for the primary prevention of coronary heart disease in women. The clinical and public health challenge remains to help women avoid or change harmful
elements of their lifestyles as a way of decreasing mortality from coronary heart disease, which remains the
leading killer of women as well as men in the United
States.
REFERENCES
1. National Center for Health Statistics. Vital statistics of the United States,
1989. Vol. II. Mortality. Part A. Washington, D.C.: Government Printing
Office, 1993. (DHHS publication no. (PHS) 93-1101.)
2. 1993 Heart and stroke facts statistics. Dallas: American Heart Association,
1992.
3. Higgins M, Thom T. Trends in CHD in the United States. Int J Epidemiol
1989;19:Suppl 1:S58-S66.
4. Manson JE, Tosteson H, Ridker PM, et al. The primary prevention of myocardial infarction. N Engl J Med 1992;326:1406-16.
5. Causal inference in epidemiology. In: Rothman KJ. Modern epidemiology.
Boston: Little, Brown, 1986:14.
6. Willett WC, Green A, Stampfer MJ, et al. Relative and absolute excess
risks of coronary heart disease among women who smoke cigarettes.
N Engl J Med 1987;317:1303-9.
7. LaCroix AZ, Lang J, Scherr P, et al. Smoking and mortality among older
men and women in three communities. N Engl J Med 1991;324:161925.
8. Rosenberg L, Palmer JR, Shapiro S. Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med 1990;322:213-7.

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9. Dorr AE, Gundersen K, Schneider JC Jr, Spencer TW, Martin WB. Colestipol hydrochloride in hypercholesterolemic patients effect on serum
cholesterol and mortality. J Chronic Dis 1978;31:5-14.
10. Frantz ID Jr, Dawson EA, Ashman PL, et al. Test of effect of lipid lowering
by diet on cardiovascular risk: the Minnesota Coronary Survey. Arteriosclerosis 1989;9:129-35.
11. Hebert PR, Moser M, Mayer J, Glynn RJ, Hennekens CH. Recent evidence
on drug therapy of mild to moderate hypertension and decreased risk of
coronary heart disease. Arch Intern Med 1993;153:578-81.
12. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP).
JAMA 1991;265:3255-64.
13. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000
men and women. J Chronic Dis 1979;32:563-76.
14. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-77.
15. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity
and risk of coronary heart disease in women. N Engl J Med 1990;322:8829.
16. Brunner D, Manelis G, Modan M, Levin S. Physical activity at work and
the incidence of myocardial infarction, angina pectoris and death due to ischemic heart disease: an epidemiological study in Israeli collective settlements (kibbutzim). J Chronic Dis 1974;27:217-33.
17. Salonen JT, Puska P, Tuomilehto J. Physical activity and risk of myocardial
infarction, cerebral stroke and death: a longitudinal study in eastern Finland. Am J Epidemiol 1982;115:526-37.
18. Lapidus L, Bengtsson C. Socioeconomic factors and physical activity in relation to cardiovascular disease and death: a 12 year follow up of participants in a population study of women in Gothenberg, Sweden. Br Heart J
1986;55:295-301.
19. Magnus K, Matroos A, Strackee J. Walking, cycling, or gardening, with or
without seasonal interruption, in relation to acute coronary events. Am J
Epidemiol 1979;110:724-33.
20. Scragg R, Stewart A, Jackson R, Beaglehole R. Alcohol and exercise in
myocardial infarction and sudden coronary death in men and women. Am
J Epidemiol 1987;126:77-85.
21. Rosenberg L, Slone D, Shapiro S, Kaufman DW, Miettinen OS, Stolley
PD. Alcoholic beverages and myocardial infarction in young women. Am
J Public Health 1981;71:82-5.
22. Klatsky AL, Friedman GD, Siegelaub AB. Alcohol consumption before
myocardial infarction: results from the Kaiser-Permanente epidemiologic
study of myocardial infarction. Ann Intern Med 1974;81:294-301.
23. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S. Risk of vascular disease
in women: smoking, oral contraceptives, noncontraceptive estrogens, and
other factors. JAMA 1979;242:1150-4.
24. Gordon T, Kannel WB. Drinking habits and cardiovascular disease: the
Framingham Study. Am Heart J 1983;105:667-73.
25. Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary
disease and stroke in women. N Engl J Med 1988;319:267-73.
26. Boston Collaborative Drug Surveillance Group. Regular aspirin intake and
acute myocardial infarction. BMJ 1974;1:440-3.
27. Manson JE, Stampfer MJ, Colditz GA, et al. A prospective study of aspirin
use and primary prevention of cardiovascular disease in women. JAMA
1991;266:521-7.
28. Paganini-Hill A, Chao A, Ross RK, Henderson BE. Aspirin use and chronic
diseases: a cohort study of the elderly. BMJ 1989;299:1247-50.
29. Hammond EC, Garfinkel L. Aspirin and coronary heart disease: findings of
a prospective study. BMJ 1975;2:269-71.
30. Manson JE, Stampfer MJ, Willett WC, et al. A prospective study of antioxidant vitamins and incidence of coronary heart disease in women. Circulation 1991;84:Suppl II:II-546. abstract.
31. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett
WC. Vitamin E consumption and the risk of coronary disease in women.
N Engl J Med 1993;328:1444-9.
32. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary
heart disease: quantitative assessment of the epidemiologic evidence. Prev
Med 1991;20:47-63.
33. The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/
progestin regimens on heart disease risk factors in postmenopausal women:
the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA
1995;273:199-208.
34. Reducing the health consequences of smoking: 25 years of progress: a report of the Surgeon General, 1989. Rockville, Md.: Department of Health
and Human Services, 1989. (DHHS publication no. (CDC) 89-8411.)
35. Surveillance for selected tobacco-use behaviors United States, 1900
1994. MMWR Morb Mortal Wkly Rep 1994;43(SS-3):1-43.
36. Palmer JR, Rosenberg L, Shapiro S. Low yield cigarettes and the risk of
nonfatal myocardial infarction in women. N Engl J Med 1989;320:156973.

June 29, 1995

37. La Rosa JC, Hunninghake D, Bush D, et al. The cholesterol facts: a summary of the evidence relating dietary fats, serum cholesterol and coronary
heart disease: a joint statement by the American Heart Association and the
National Heart, Lung, and Blood Institute. Circulation 1990;81:1721-33.
38. Wenger NK. Exclusion of the elderly and women from coronary trials: is
their quality of care compromised? JAMA 1992;268:1460-1.
39. Froom J, Froom P. Prudence in disease prevention. J Clin Epidemiol
1991;44:1127-30.
40. Busch TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem 1988;34:B60-B70.
41. Castelli WP, Garrison RJ, Wilson PWF, Abbott RD, Kalousdian S, Kannel
WB. Incidence of coronary heart disease and lipoprotein cholesterol levels:
the Framingham Study. JAMA 1986;256:2835-8.
42. Isles CG, Hole DJ, Gillis CR, Hawthorne VM, Lever AF. Plasma cholesterol, coronary heart disease, and cancer in the Renfrew and Paisley survey.
BMJ 1989;298:920-4.
43. Jacobs DR Jr, Meban IL, Bangdiwala SI, Criqui MH, Tyroler HA. High
density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics
Prevalence Study. Am J Epidemiol 1990;131:32-47.
44. Livshits G, Weisbort J, Meshulam N, Brunner D. Multivariate analysis of
the twenty-year follow-up of the Donolo-Tel Aviv Prospective Coronary
Artery Disease Study and the usefulness of high density lipoprotein cholesterol percentage. Am J Cardiol 1989;63:676-81.
45. Barrett-Connor E, Khaw KT, Wingard DL. A ten-year prospective study of
coronary heart disease mortality among Rancho Bernardo women. In: Eaker E, Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary
heart disease in women. New York: Haymarket Doyma, 1987:117-21.
46. Higgins M, Keller JB, Ostrander LD. Risk factors for coronary heart disease in women: Tecumseh Community Health Study, 1959-80. In: Eaker E,
Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary heart disease in women. New York: Haymarket Doyma, 1987:83-9.
47. Keil JE, Gazes PC, Loadholt CB, et al. Coronary heart disease mortality
and its predictors among Charleston, South Carolina, women. In: Eaker E,
Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary heart disease in women. New York: Haymarket Doyma, 1987:90-8.
48. Tyroler HA, Heyen S, Bartel A, et al. Blood pressure and cholesterol as
coronary heart disease risk factors. Arch Intern Med 1971;128:907-14.
49. Stampfer MJ, Colditz GA, Willett WC, Rosner B, Speizer FE, Hennekens
CH. Coronary heart disease risk factors in women: the Nurses Health
Study experience. In: Eaker E, Packard B, Wenger NK, Clarkson TB, Tyroler HA, eds. Coronary heart disease in women. New York: Haymarket
Doyma, 1987:112-6.
50. Kannel WB. Metabolic risk factors for coronary heart disease in women:
perspective from the Framingham Study. Am Heart J 1987;114:413-9.
51. Leren P. The Oslo Diet-Heart Study: eleven-year report. Circulation 1970;
42:935-42.
52. Bierenbaum ML, Fleischman AI, Raichelson RI, Hayton T, Watson PB.
Ten-year experience of modified-fat diets on younger men with coronary
heart-disease. Lancet 1973;1:1404-7.
53. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986;8:1245-55.
54. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and
fibre intakes on death and myocardial reinfarction: Diet and Reinfarction
Trial (DART). Lancet 1989;2:757-61.
55. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA 1990;264:3007-12.
56. Levy RI, Brensike JF, Epstein SE, et al. The influence of changes in lipid
values induced by cholestyramine and diet on progression of coronary artery disease: results of the NHLBI Type II Coronary Intervention Study.
Circulation 1984;69:325-37.
57. The Scottish Society of Physicians. Ischaemic heart disease: a secondary
prevention trial using clofibrate. BMJ 1971;790:775-84.
58. Trial of clofibrate in the treatment of ischaemic heart disease: five-year
study by a group of physicians of the Newcastle upon Tyne region. BMJ
1971;790:767-75.
59. Rosenhamer G, Carlson LA. Effect of combined clofibratenicotinic acid
treatment in ischemic heart disease. Atherosclerosis 1980;37:129-42.
60. Moreno GT, Manson JE. Cholesterol and coronary heart disease in women:
an overview of primary and secondary prevention. Coron Artery Dis 1993;
4:580-7.
61. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ
1990;301:309-14.
62. Kannel WB, McGee D, Gordon T. A general cardiovascular risk profile: the
Framingham Study. Am J Cardiol 1976;38:46-51.
63. Johnson JL, Heineman EF, Heiss G, Hames CG, Tyroler HA. Cardiovascular disease risk factors and mortality among black women and white women aged 4064 years in Evans County, Georgia. Am J Epidemiol 1986;123:
209-20.

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MEDICAL PROGRESS

64. Sigurdsson JA, Bengtsson C, Lapidus L, Lindquist O, Rafnsson V. Morbidity and mortality in relation to blood pressure and antihypertensive treatment: a 12-year follow-up study of a population sample of Swedish women. Acta Med Scand 1984;215:313-22.
65. Fiebach NH, Hebert PR, Stampfer MJ, et al. A prospective study of high
blood pressure and cardiovascular disease in women. Am J Epidemiol
1989;130:646-54.
66. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary
heart disease. 2. Short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990;335:82738.
67. The Management Committee of the Australian National Blood Pressure
Study. Prognostic factors in the treatment of mild hypertension. Circulation
1984;69:668-76.
68. Medical Research Council Working Party. MRC trial of treatment of mild
hypertension: principal results. BMJ 1985;291:97-104.
69. MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992;304:405-12.
70. Amery A, Birkenhager W, Brixko R, et al. Efficacy of antihypertensive
drug treatment according to age, sex, blood pressure, and previous cardiovascular disease in patients over the age of 60. Lancet 1986;2:589-92.
71. Hypertension Detection and Follow-Up Program Cooperative Group. Effect of stepped care treatment on the incidence of myocardial infarction and
angina pectoris: 5-year findings of the Hypertension Detection and FollowUp Program. Hypertension 1984;6:Suppl I:I-198I-206.
72. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary
heart disease. I. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;
335:765-74.
73. Anastos K, Charney P, Charon RA, et al. Hypertension in women: what is
really known? The Womens Caucus, working group on womens health of
the Society of General Internal Medicine. Ann Intern Med 1991;115:28793.
74. Stamler R, Stamler J, Grimm R, et al. Nutritional therapy for high blood
pressure: final report of a four-year randomized controlled trial the Hypertension Control Program. JAMA 1987;257:1484-91.
75. Langford HG, Blaufox MD, Oberman A, et al. Dietary therapy slows the
return of hypertension after stopping prolonged medication. JAMA 1985;
253:657-64.
76. Trials of Hypertension Prevention Collaborative Research Group. The effects of nonpharmacologic interventions on blood pressure of persons with
high normal levels: results of the Trials of Hypertension Prevention, phase
I. JAMA 1992;267:1213-20. [Erratum, JAMA 1992;267:2330.]
77. Complications of pregnancy. In: Hughes EC, ed. Obstetric-gynecologic terminology. Philadelphia: F.A. Davis, 1972:422.
78. Mann JI, Doll R, Thorogood M, Vessey MP, Waters WE. Risk factors for
myocardial infarction in young women. Br J Prev Soc Med 1976;30:94100.
79. Croft P, Hannaford PC. Risk factors for acute myocardial infarction in
women: evidence from the Royal College of General Practitioners Oral
Contraception Study. BMJ 1989;298:165-8.
80. Rosenberg L, Miller DR, Kaufman DW, et al. Myocardial infarction in
women under 50 years of age. JAMA 1983;250:2801-6.
81. Saltzberg S, Stroh JA, Frishman WH. Isolated systolic hypertension in the
elderly: pathophysiology and treatment. Med Clin North Am 1988;72:52347.
82. Shekelle RB, Ostfeld AM, Klawans HL Jr. Hypertension and risk of stroke
in an elderly population. Stroke 1974;5:71-5.
83. Kannel WB. Implications of Framingham study data for treatment of hypertension: impact of other risk factors. In: Laragh JH, Bhler FR, Seldin
DW, eds. Frontiers in hypertension research. New York: Springer-Verlag,
1981:17-21.
84. Society of Actuaries, Association of Life Insurance Medical Directors of
America. Blood Pressure Study, 1979. Schaumburg, Ill.: Society of Actuaries, 1980.
85. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA 1979;241:2035-8.
86. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in
women. Arch Intern Med 1991;151:1141-7.
87. Barrett-Connor E, Wingard DL. Sex differential in ischemic heart disease
mortality in diabetics: a prospective population-based study. Am J Epidemiol 1983;118:489-96.
88. Pan WH, Cedres LB, Liu K, et al. Relationship of clinical diabetes and
asymptomatic hyperglycemia to risk of coronary heart disease mortality in
men and women. Am J Epidemiol 1986;123:504-16.
89. Ruderman NB, Haudenschild C. Diabetes as an atherogenic factor. Prog
Cardiovasc Dis 1984;26:373-412.
90. The Diabetes Control and Complications Trial Research Group. The effect
of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl J
Med 1993;329:977-86.

1765

91. OSullivan JB. Workshop 4: subsequent morbidity among gestational diabetic women. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism in pregnancy and the newborn. Edinburgh, Scotland: Churchill Livingstone, 1984:174-80.
92. Stowers JM. Workshop 5: follow-up of gestational diabetic mothers treated
thereafter. In: Sutherland HW, Stowers JM, eds. Carbohydrate metabolism
in pregnancy and the newborn. Edinburgh, Scotland: Churchill Livingstone, 1984:181-3.
93. Mestman JH. Follow-up studies in women with gestational diabetes mellitus: the experience at Los Angeles County/University of Southern California Medical Center. In: Weiss PAM, Coustan DR, eds. Gestational diabetes.
Vienna, Austria: Springer-Verlag, 1988:191-8.
94. Ward WK, Johnston CLW, Beard JC, Benedetti TJ, Halter JB, Porte D Jr.
Insulin resistance and impaired insulin secretion in subjects with histories
of gestational diabetes mellitus. Diabetes 1985;34:861-9.
95. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma
lipoproteins of a prudent weight-reducing diet, with or without exercise, in
overweight men and women. N Engl J Med 1991;325:461-6.
96. Bjorntorp P. Regional patterns of fat distribution. Ann Intern Med 1985;
103:994-5.
97. Harlan LC, Harlan WR, Landis JR, Goldstein NG. Factors associated with
glucose tolerance in adults in the United States. Am J Epidemiol 1987;126:
674-84.
98. Reichley KB, Mueller WH, Hanis DL, et al. Centralized obesity and cardiovascular disease risk in Mexican Americans. Am J Epidemiol 1987;125:
373-86.
99. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a
12 year follow up of participants in the population study of women in
Gothenburg, Sweden. BMJ 1984;289:1257-61.
100. Blair D, Habicht JP, Sims EAH, Sylwester D, Abraham S. Evidence for an
increased risk for hypertension with centrally located body fat and the effect of race and sex on this risk. Am J Epidemiol 1984;119:526-40.
101. Hartz AJ, Rupley DC Jr, Kalkhoff RD, Rimm AA. Relationship of obesity
to diabetes: influence of obesity level and body fat distribution. Prev Med
1983;12:351-7.
102. Kaplan NM. The deadly quartet: upper-body obesity, glucose intolerance,
hypertriglyceridemia, and hypertension. Arch Intern Med 1989;149:151420.
103. Haffner SM, Katz MS, Dunn JF. Increased upper body and overall adiposity is associated with decreased sex hormone binding globulin in postmenopausal women. Int J Obes 1991;15:471-8.
104. Barrett-Connor E, Khaw KT. Cigarette smoking and increased central adiposity. Ann Intern Med 1989;111:783-7.
105. Kaye SA, Folsom AR, Prineas RJ, Potter JD, Gapstur SM. The association
of body fat distribution with lifestyle and reproductive factors in a population study of postmenopausal women. Int J Obes 1990;14:583-91.
106. Rodin J, Radke-Sharpe N, Rebuffe-Scrive M, Greenwood MRC. Weight
cycling and fat distribution. Int J Obes 1990;14:303-10.
107. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activity
and the incidence of coronary heart disease. Annu Rev Public Health 1987;
8:253-87.
108. Kannel WB, Sorlie P. Some health benefits of physical activity: the Framingham study. Arch Intern Med 1979;139:857-61.
109. Berlin JA, Colditz GA. A meta-analysis of physical activity in the prevention of coronary heart disease. Am J Epidemiol 1990;132:612-28.
110. Owens JF, Matthews KA, Wing RR, Kuller LH. Physical activity and cardiovascular risk: a cross-sectional study of middle-aged premenopausal
women. Prev Med 1990;19:147-57.
111. Idem. Can physical activity mitigate the effects of aging in middle-aged
women? Circulation 1992;85:1265-70.
112. Blair SN, Kohl HW III, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality: a prospective study of
healthy men and women. JAMA 1989;262:2395-401.
113. Hennekens CH. Alcohol. In: Kaplan NM, Stamler J, eds. Prevention of coronary heart disease: practical management of the risk factors. Philadelphia:
W.B. Saunders, 1983:130-8.
114. Rimm ED, Giovannucci EL, Willett WC, et al. Prospective study of alcohol
consumption and risk of coronary disease in men. Lancet 1991;338:4648.
115. Thornton J, Symes C, Heaton K. Moderate alcohol intake reduces bile cholesterol saturation and raises HDL cholesterol. Lancet 1983;2:819-22.
116. Landolfi R, Steiner M. Ethanol raises prostacyclin in vivo and in vitro.
Blood 1984;64:679-82.
117. Ridker PM, Vaughan DE, Stampfer MJ, Glynn RJ, Hennekens CH. Association of moderate alcohol consumption and plasma concentration of endogenous tissue-type plasminogen activator. JAMA 1994;272:929-33.
118. Laug WE. Ethyl alcohol enhances plasminogen activator secretion by endothelial cells. JAMA 1983;250:772-6.
119. Klatsky AL, Friedman GD, Siegelaub AB, Grard MJ. Alcohol consumption and blood pressure: KaiserPermanente Multiphasic Health Examination data. N Engl J Med 1977;296:1194-200.

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Downloaded from nejm.org on November 2, 2012. For personal use only. No other uses without permission.
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1766

THE NEW ENGLAND JOURNAL OF MEDICINE

120. Longnecker MP. Alcoholic beverage consumption in relation to risk of


breast cancer: meta-analysis and review. Cancer Causes Control 1994;5:7382.
121. Antiplatelet Trialists Collaboration. Collaborative overview of randomised
trials of antiplatelet therapyI: prevention of death, myocardial infarction,
and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81-106.
122. ISIS-2 (Second International Study of Infarct Survival). Randomised trial
of intravenous streptokinase, oral aspirin, both, or neither among 17 187
cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:34960.
123. Aspirin prophylaxis. In: Guide to clinical preventive services: report of the
U.S. Preventive Services Task Force. Baltimore: Williams & Wilkins, 1989:
258-60.
124. Hennekens CH, Buring JE. Epidemiology in medicine. Boston: Little,
Brown, 1987.
125. Womens Health Study Research Group. The Womens Health Study: rationale and background. J Myocardial Ischemia 1992;4:30-40.
126. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond
cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-24.
127. Keaney JF Jr, Gaziano JM, Xu A, et al. Dietary antioxidants preserve endothelium-dependent vessel relaxation in cholesterol-fed rabbits. Proc Natl
Acad Sci U S A 1993;90:11880-4.
128. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett
WC. Vitamin E consumption and the risk of coronary heart disease in men.
N Engl J Med 1993;328:1450-6.
129. Gaziano JM, Manson JE, Branch LG, et al. Dietary beta carotene and decreased cardiovascular mortality in an elderly cohort. J Am Coll Cardiol
1992;19:Suppl A:377A. abstract.
130. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among
a sample of the United States population. Epidemiology 1992;3:194-202.
131. Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. Beta carotene therapy for chronic stable angina. Circulation 1990;82:Suppl III:III201. abstract.
132. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group.
The effect of vitamin E and beta carotene on the incidence of lung cancer
and other cancers in male smokers. N Engl J Med 1994;330:1029-35.

June 29, 1995

133. Hennekens CH, Buring JE, Peto R. Antioxidant vitamins benefits not
yet proved. N Engl J Med 1994;330:1080-1.
134. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens
CH. Menopause and the risk of coronary heart disease in women. N Engl
J Med 1987;316:1105-10.
135. Stampfer MJ, Colditz GA, Willett WC. Menopause and heart disease: a review. Ann N Y Acad Sci 1990;592:193-203.
136. Heller RF, Jacobs HS. Coronary heart disease in relation to age, sex, and
the menopause. BMJ 1978;1:472-4.
137. Bush TL, Miller VT. Effects of pharmacologic agents used during menopause: impact on lipids and lipoproteins. In: Mishell DR Jr, ed. Menopause:
physiology and pharmacology. Chicago: Year Book, 1987:187-208.
138. Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease
and prolong life in postmenopausal women. Ann Intern Med 1992;117:
1016-37.
139. Goldman L, Tosteson ANA. Uncertainty about postmenopausal estrogen
time for action, not debate. N Engl Med 1991;325:800-2.
140. Nabulsi AA, Folsom AR, White A, et al. Association of hormone-replacement therapy with various cardiovascular risk factors in postmenopausal
women. N Engl J Med 1993;328:1069-75.
141. Falkeborn M, Persson I, Adami HO, et al. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynecol 1992;99:821-8.
142. Stadel BV. Oral contraceptives and cardiovascular disease. N Engl J Med
1981;305:672-7.
143. Hennekens CH, Evans D, Peto R. Oral contraceptive use, cigarette smoking, and myocardial infarction. Br J Fam Plann 1979;5:66-7.
144. Mann JI, Vessey MP, Thorogood M, Doll SR. Myocardial infarction in
young women with special reference to oral contraceptive practice. BMJ
1975;2:241-5.
145. Thorogood M. Oral contraceptives and cardiovascular disease: an epidemiologic overview. Pharmacoepidemiol Drug Saf 1993;2:3-16.
146. Stolley PD. Epidemiologic studies of coronary heart disease: two approaches. Am J Epidemiol 1980;112:217-24.
147. Stampfer MJ, Willett WC, Colditz GA, Speizer FE, Hennekens CH. Past
use of oral contraceptives and cardiovascular disease: a meta-analysis in
the context of the Nurses Health Study. Am J Obstet Gynecol 1990;163:
285-91.

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