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1758 THE NEW ENGLAND JOURNAL OF MEDICINE June 29, 1995

MEDICAL PROGRESS

REVIEW ARTICLES

THE PRIMARY PREVENTION OF CORONARY HEART DISEASE IN WOMEN

J

ANET

W. R

ICH

-E

DWARDS

, S

C

.D.,J

O

A

NN

E. M

ANSON

, M.D., D

R

.P.H.,C

HARLES

H. H

ENNEKENS

, M.D., D

R

.P.H.,

AND

J

ULIE

E. B

URING

, S

C

.D.

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 andWomens Hospital and Harvard Medical School; and the Department of Epide-miology, 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 ofHealth. Dr. Rich-Edwards is the recipient of an Institutional National ResearchService Award (HL-07575) from the National Heart, Lung, and Blood Institute. Dr.Manson is the recipient of a MerckSociety for Epidemiologic Research award.

C

ORONARY heart disease has long been recog-nized as the leading cause of death among mid-

dle-aged men, but it is an equally important cause ofdeath and disability among older women. By the age of60 years, only 1 in 17 women in the United States hashad a coronary event, as compared with 1 in 5 men. Af-ter the age of 60, however, coronary heart disease is theprimary cause of death among women. In this agegroup, one in four women, as well as one in four men,die of coronary heart disease.

1

The annual numbers ofAmerican women and men who have myocardial in-farctions are shown in Figure 1.

2

Although the rates ofmortality from coronary heart disease have been fallingsince the 1960s, the rate of decline has been sloweramong women than among men since 1979.

3

Most of the risk factors for coronary heart diseaseand the strategies for preventing disease among menare also important for women.

4

However, the magni-tude of their effects may be different. In addition, thereare risk factors and preventive strategies that areunique to women. In this article, we review the mainrisk factors and preventive strategies for coronaryheart disease among women (Table 1).

R

ISK

F

ACTORS

AND

P

REVENTIVE

S

TRATEGIES

FOR

W

OMEN

AND

M

EN

Cigarette Smoking

Cigarette smoking is the leading preventable causeof death among men and women in the United States.A large body of evidence has consistently indicated thatthe risk of coronary heart disease is two to four timeshigher among women who are heavy smokers (usually

defined as those who smoke 20 or more cigarettes perday) than among women who do not smoke.

34

More-over, there is a clear doseresponse relation: as com-pared with nonsmokers, even light smokers (womenwho smoke one to four cigarettes per day) have morethan twice the risk of coronary disease.

6

Fortunately, after the cessation of smoking, the riskof coronary heart disease in both women and men be-gins to decline within a matter of months and falls tothe level of the risk among nonsmokers within three tofive years after cessation, regardless of the amountsmoked, the duration of the habit, or the age at cessa-tion.

6,8,34

Although the prevalence of smoking amongU.S. women declined from 34 percent in 1965 to 24percent in 1991, the rate of cessation of smoking is low-er among women than among men.

35

In lieu of quittingor cutting back, women may switch to low-yield ciga-rettes with reduced tar, nicotine, and carbon monoxide.The epidemiologic evidence, however, indicates thatsmokers of low-yield cigarettes are at no lower risk forcoronary heart disease than those who smoke higher-yield brands.

36

Cholesterol

Most of the research on cholesterol and coronaryheart disease has involved middle-aged men, amongwhom a 2 to 3 percent decline in the risk of coronaryheart disease has been associated with every 1 per-cent reduction in the serum cholesterol level.

37

Ex-trapolation of these findings to women has been ques-tioned,

38,39

because estrogens affect the lipid profile.

40

However, 9 of 10 prospective observational studies havereported a positive association between total cholester-ol levels and coronary heart disease in women.

41-50

Anincreased level of high-density lipoprotein (HDL) cho-lesterol is a particularly strong predictor of a decreasedrisk of coronary heart disease in women.

41,43,44

HDLcholesterol was second only to age as a predictor ofdeath from cardiovascular causes among women in theLipid Research Clinics Follow-up Study.

43

Whereas more than 10,000 men with preexisting cor-onary heart disease have been enrolled in trials of cho-lesterol reduction,

51-54

just over 400 women have beenincluded in such secondary-prevention trials.

55-59

Evenin these small trials, however, lowering low-density lip-oprotein (LDL) cholesterol levels and raising HDL cho-lesterol levels were shown to impede the progression ofatherosclerosis in women as well as in men.

55,56

Trialshave suggested that reduction of lipid levels reduces therisk of subsequent myocardial infarction in women withpreexisting coronary heart disease, although these stud-ies 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 apparent-ly healthy women are equally limited.

60

Only 5800 of

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Vol. 332 No. 26 MEDICAL PROGRESS 1759

the more than 30,000 participants enrolled in pri-mary-prevention trials of cholesterol reduction havebeen women.

9,60,61

None of these studies have had ade-quate statistical power to estimate the effect of alteredcholesterol profiles on the risk of coronary heart dis-ease in healthy women. Although the data from ran-domized trials have yet to provide definitive evidencethat lowering cholesterol levels reduces the risk of cor-onary heart disease in healthy women, the consistencyof observational data suggests that interventions to

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

Hypertension

As in men, the strong association between elevatedblood pressure and coronary heart disease in womenhas been demonstrated by a number of prospectivestudies.

62-65

Although the benefits of medication in thetreatment of severe hypertension are great and obviousfor both men and women, the benefit of treating mild-to-moderate hypertension (i.e., diastolic blood pressurebetween 90 and 114 mm Hg) has been debated. Ameta-analysis of randomized drug-treatment trials in-volving a total of 37,000 subjects, 47 percent of whomwere women, evaluated therapy of three to six yearsduration for mild-to-moderate hypertension. A meandecrease of 6 mm Hg in diastolic pressure significantlyreduced overall mortality from vascular disease by 21percent, fatal and nonfatal stroke by 42 percent, andfatal and nonfatal coronary heart disease by 14 per-cent.

66

Inclusion of three subsequently published trials,each with a sample in which approximately 60 percentof the subjects were women, demonstrated an evengreater reduction in coronary heart disease (about 16percent).

9

The four randomized trials of drug treatment formild-to-moderate hypertension in which women wereseparately assigned to treatment

67-70

have reported a9 to 30 percent reduction in the incidence of all cardio-vascular events among women, yet only one trial hasreported a decrease in the incidence of coronary heart

Figure 1. Annual Incidence of Myocardial Infarction in Women

Estim

ated

Num

ber o

f Per

sons

(thou

sand

s)500

400

300

200

100

029 44 45 64 65

Age (yr)

MenWomen

123,000

3000

424,000

136,000

440,000

374,000

and Men in the United States.The data, which are from the Framingham Heart Study, areadapted from the American Heart Association,

2

with the permis-sion of the publisher.

*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 hypothesizedinteractions among factors. As Rothman has noted, because of the manifold causal pathways that lead to chronic disease, the total of the proportion of disease attributableto various causes is not 100 percent but infinity.

5

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

I

NTERVENTION

S

OURCE

OF

D

ATA

ON

W

OMEN

E

STIMATED

M

EAN

R

EDUCTION

IN

R

ISK

OF

C

ORONARY

H

EART

D

ISEASE

*

Smoking cessation Prospective observational studies in women

6-8

50 to 80% within 3 to 5 yearsReduction in serum cholesterol level Two randomized trials of drug and dietary

intervention (each with 52% women, some with prior coronary heart disease)

9,10

Trials in men

4

Insufficient data to provide estimates for women

2 to 3% for every 1% reduction in serum cho-lesterol

Treatment of hypertension Meta-analysis of randomized drug trials (50% women)

11

16% after 3 to 6 years of treatment

Unblinded randomized trials of nonpharmaco-logic interventions (30 to 60% women)

Unknown

Treatment of isolated systolic hypertension One randomized trial (57% women)

12

25%Maintenance of normoglycemia in diabetic

patientsRandomized trials in progress Insufficient data to provide estimates for

women or menAvoidance of obesity Prospective observational studies in women

13-15

35 to 60% for women at ideal weight, as com-pared with obese women

Physical activity Small prospective and retrospective observational

16-20

studies in women50 to 60% for physically active women, as

compared with sedentary womenSmall-to-moderate daily alcohol intake Prospective and retrospective observational

studies in women

20-25

Approximately 50% for women and men, as compared with nondrinkers

Prophylactic low-dose aspirin Prospective and retrospective observational studies in women

26-29

Inconsistent data on women

Antioxidant-vitamin supplementation Prospective observational studies in women

30,31

Insufficient dataPostmenopausal hormone-replacement

therapyMeta-analysis of observational studies in

women

32

44% with estrogen alone

One randomized prospective study

33

Data also suggest a reduction in risk factors with estrogenprogestin therapy




disease.

71

Although the reduction in blood pressureachieved in these short-term trials led to the expectedreduction in the incidence of stroke, it may be neces-sary to maintain reduced blood pressure for manyyears to realize the 20 to 25 percent reduction in coro-nary heart disease hypothesized on the basis of obser-vational studies.

72

There are few data that indicatewhether the side effects of antihypertensive drugs arethe same in women and men.

73

The control of blood pressure through dietary inter-vention and weight loss has been moderately successfulin groups in which 30 to 60 percent of the patients werewomen.

74-76

None of these trials of nonpharmacologictreatment of hypertension, however, have reported re-sults separately for women.

There is evidence suggesting that preeclampsia,which occurs in 5 to 10 percent of pregnancies, maypredict subsequent coronary heart disease. Withoutinformation on blood pressure before and after preg-nancy, it is difficult to distinguish preeclampsia andpregnancy-induced hypertension (unaccompanied byproteinuria) from chronic hypertension. Studies havethus far relied on a physicians diagnosis of preeclamp-sia rather than the strict definition adopted by theAmerican College of Obstetrics and Gynecology.

77

Somecasecontrol studies have reported an association be-tween physician-diagnosed preeclampsia and subse-quent coronary heart disease that appears to be inde-pendent of hypertension.

78-80

It is not known whetherpregnancy-induced hypertension is associated with cor-onary heart disease. Because of the possible diagnosticconfusion among preeclampsia, pregnancy-induced hy-pertension, and chronic hypertension, studies withclear case definitions are needed.

Of particular concern in older women is isolated sys-tolic hypertension, an indication of the loss of arterialelasticity. More prevalent among women than men, iso-lated systolic hypertension is estimated to affect ap-proximately 30 percent of women over 65 years old.

81

Several studies have linked isolated systolic hyperten-sion with an elevated risk of death from stroke

82

or cor-onary heart disease.

83,84

In the Systolic Hypertension inthe Elderly Program, in which women accounted for 57percent of the study population, antihypertensive treat-ment resulted in a 36 percent reduction in the inci-dence of stroke and a 25 percent reduction in that ofcoronary heart disease.

12

Diabetes Mellitus

Diabetes is an even stronger risk factor for coronaryheart disease in women than in men. Mortality rates forcoronary heart disease are three to seven times higheramong diabetic women than among nondiabetic wom-en, as compared with rates that are two to four timeshigher among diabetic men than among those withoutdiabetes.

85-88

Diabetes exacerbates the effects of knowncoronary risk factors and may impair estrogen binding,negating the protection against coronary heart disease

that endogenous estrogens confer on premenopausalwomen.

89

Although it is not yet clear whether strictglycemic control reduces the risk of coronary heart dis-ease, there is promising evidence that intensive treat-ment of insulin-dependent diabetes slows the develop-ment of other diabetic complications.

90

At present,however, recommendations for diabetic patients relyon the modification of other risk factors. Because ciga-rette smoking, hypertension, and obesity act in synergywith diabetes,

86

control of these risk factors yieldsgreater reductions in the risk of myocardial infarctionin patients with diabetes than in the nondiabetic popu-lation.

Gestational diabetes, which develops in 3 percent ofpregnant women in the United States, may be a markerfor an increased risk of coronary heart disease. In long-term follow-up studies, more than a third of womenwith gestational diabetes subsequently had non-insulin-dependent diabetes,

91-93

as compared with the approx-imate 5 percent incidence of non-insulin-dependentdiabetes among women with normal pregnancies. Long-term follow-up has demonstrated a higher incidence ofinsulin resistance,

94

hypertension,

93

adverse lipid pro-files,

91

and abnormal electrocardiograms

91

in womenwith gestational diabetes than in those with normalpregnancies. Although there is little evidence to sug-gest that gestational diabetes is associated with a riskof coronary heart disease that is independent of therisk associated with overt diabetes mellitus, young wom-en with gestational diabetes may be suitable targets forearly preventive efforts.

Obesity

Direct positive associations between obesity and therisk of coronary heart disease have been demonstratedin a number of large, prospective cohort studies ofwomen.

13-15

In the Nurses Health Study, involving over120,000 middle-aged women, the risk of coronary heartdisease was over three times higher among the womenwith a body-mass index (expressed as the weight in kil-ograms divided by the square of the height in meters)of 29 or higher than among the lean women (body-mass index,

21).

15

Even the women who were mildlyto moderately overweight (body-mass index, 25 to 28.9)had nearly twice as high a risk of coronary heart dis-ease as the lean women.

15

Although a large portionof the excess risk is attributable to the influence of ad-iposity on blood pressure, glucose tolerance, and lipidlevels, after adjustment for these variables a moderateresidual effect persists that may be due to other mech-anisms.

15

Unfortunately, direct evidence that weight loss re-duces the risk of coronary heart disease is not yet avail-able because of the small numbers of subjects able tomaintain a reduced level of weight. Weight loss inwomen achieved by dieting either alone or in combina-tion with exercise does reduce blood pressure and LDLcholesterol levels.

95

Because weight loss is difficult to




achieve and maintain, prevention of obesity is critical.Women who maintain their ideal body weight have a 35to 60 percent lower risk of myocardial infarction thanwomen who become obese.

13-15

Several studies have suggested that excess abdomi-nal and upper-body fat may confer a particularly highrisk of coronary heart disease.

96

Cross-sectional andprospective studies have linked cardiovascular diseaseand its precursors to upper-body obesity an associ-ation that is independent of the degree of overall obe-sity.

97-101

The risk of coronary heart disease rises steeplyamong women whose waist-to-hip ratio is higher than0.8.

96

The increased lipolytic activity of intraabdominalfat has been associated with insulin resistance, reducedHDL cholesterol levels, hypertriglyceridemia, hyper-tension, and decreased sex hormonebinding globulinlevels.

102,103

Cross-sectional studies of women haveshown that abdominal adiposity is positively associatedwith cigarette smoking,

104,105

parity,

105,106

and weightcycling

106

and negatively related to physical activity.

105

Data are sparse, however, on the efficacy of approachesto reducing upper-body obesity or the potential cardio-vascular benefits of such weight reduction.

Physical Activity

Of the 43 epidemiologic studies that have been con-ducted since 1950 to assess the relation of exercise tocoronary heart disease, only 7 have included women.

107

Four prospective studies

16-18,108

and two casecontrolstudies

19,20

have analyzed and presented data on wom-en separately. The results of these analyses generallyindicate that physically active women have a 60 to 75percent lower risk of coronary heart disease than inac-tive women. These studies have been small, however,and the best estimate may be the 50 percent reductionin risk derived from a meta-analysis of studies basedlargely on men.

109

A cross-sectional analysis of data from the HealthyWomen Study has shown associations between physicalactivity and reduced weight, lower blood pressure, andfavorable lipid and insulin profiles in perimenopausalwomen.

110

After three years of follow-up, the womenwho exercised more had gained less weight and had asmaller drop in HDL cholesterol levels than the moresedentary women. Physical activity, however, was notlinked to blood pressure or triglyceride, LDL choles-terol, or insulin levels, as it had been in the cross-sec-tional analysis.

111

An eight-year prospective study of3120 healthy women demonstrated associations betweenphysical fitness (assessed by treadmill testing) and re-duced rates of mortality from cardiovascular diseaseand from all causes. The age-adjusted rate of mortalityfrom cardiovascular disease among the most fit womenwas 0.8 per 10,000 person-years, as compared with 7.4per 10,000 person-years among the least fit women.

112

Thus, although there is scant direct evidence that phys-ical activity reduces the incidence of coronary heartdisease in women, the association between physical ac-

tivity and coronary risk factors suggests that such ben-efits would be apparent in large, long-term studies ofwomen.

Alcohol Consumption

Although heavy alcohol use increases the risk ofdeath from cardiovascular causes, there is a large bodyof evidence from both casecontrol studies

20,21

and co-hort studies

22-25

that low-to-moderate daily consump-tion of alcohol provides protection against coronaryheart disease in women as well as in men.

113

As com-pared with nondrinkers, women in the Nurses HealthStudy who consumed 10 to 15 g of alcohol per day (theequivalent of one 12-oz [355-ml] beer, one glass ofwine, or one drink of hard liquor daily) had a 40 per-cent reduction in the risk of coronary disease.

25

Otherinvestigators examining this association in women havereported estimated risk reductions of 30 to 70 percentamong moderate drinkers as compared with nondrink-ers.

20-23

Similar relative-risk estimates have been re-ported for men.

20,22,24,114

This apparent protective effectdoes not appear to depend on the type of alcoholic bev-erage consumed.

Several possible mechanisms for the protective roleof alcohol have been hypothesized, including increasedlevels of HDL cholesterol,

115

an increased ratio of pros-tacyclin to thromboxane,

116

increased levels of tissue-type plasminogen activator,

117

and reduced plateletaggregation.

118

Such antithrombotic effects of alcoholmay increase the risk of hemorrhagic stroke,

25

however,and even moderate alcohol consumption has beenlinked to hypertension.

119

Furthermore, alcohol con-sumption may increase the risk of breast cancer,120 andheavy consumption is the second leading preventablecause of all deaths in the United States.113 A recommen-dation that women drink moderate amounts of alcoholin order to prevent heart disease is therefore unwar-ranted. A better understanding of the mechanisms ofalcohols cardioprotective effect may suggest other in-terventions that mimic the benefits of alcohol withoutits deleterious consequences.

Low-Dose AspirinMeta-analyses of randomized trials involving people

with a history of occlusive vascular disease have dem-onstrated that aspirin reduces the incidence of subse-quent myocardial infarction, stroke, and death fromcardiovascular causes by about 25 percent in both menand women.121 Similarly, aspirin has a clear benefit inmen and women with acute evolving myocardial in-farction.122 In primary-prevention trials, the incidenceof a first myocardial infarction has been reduced by 33percent in men taking low doses of aspirin.121 The U.S.Preventive Services Task Force recommends aspirinfor the primary prevention of myocardial infarction inmen 40 years of age and older in whom the risk of my-ocardial infarction is sufficiently high to warrant risk-ing the possible adverse effects of the drug.123 No sim-




ilar recommendation has been made for women, sinceno completed primary-prevention trials have includedwomen.

The current data on aspirin for the primary preven-tion of coronary heart disease in women are limited tofour observational studies with inconsistent findings.Two studies demonstrated a reduced incidence of myo-cardial infarction among women who took aspirin,26,27one a possible adverse effect on ischemic heart dis-ease,28 and one no effect.29 To distinguish small-to-moderate effects of aspirin from other, unidentifieddifferences between the treatment and control groups,the only reliable design is a randomized trial of ade-quate size.124

The need for a randomized trial of aspirin in appar-ently healthy women is critical because the riskbenefitratio for aspirin may be different in women and in men.This issue is being addressed in the ongoing WomensHealth Study, a randomized trial of low-dose aspirin(100 mg on alternate days) among over 40,000 appar-ently healthy female health professionals 45 years ofage or older.125 Although aspirin may reduce the risk ofa first myocardial infarction, it may increase the riskof hemorrhagic stroke; the ratio of the incidence ofstroke to that of myocardial infarction is higher inwomen than in men.

Antioxidant Vitamins

It has been hypothesized that antioxidants such asbeta carotene, vitamin E, and vitamin C may reducethe risk of cardiovascular disease.126 This belief is sup-ported by basic research, which has demonstrated thatthese vitamins inhibit either the oxidation of LDL cho-lesterol126 or its uptake into the coronary-artery en-dothelium.127 Epidemiologic data, although sparse, areconsistent with this hypothesis. Some but not all pro-spective observational studies in women,30,31 men,128and both sexes129,130 have indicated an inverse associa-tion between a high intake of antioxidant vitamins, ei-ther through diet or supplements, and the risk of coro-nary heart disease. In particular, the women with thehighest intakes of beta carotene30 and vitamin E31 werereported to have approximately a 25 percent lower riskof coronary heart disease than the women with the low-est intakes. Data on the possible protective role of vita-min C are inconsistent.31,130

The only completed randomized trials of antioxi-dant-vitamin supplementation in well-nourished peoplehave involved men, and the results are contradictory.In the Physicians Health Study, a subgroup of 333men with a history of chronic stable angina or coronaryrevascularization who were assigned to take 50 mg ofbeta carotene on alternate days had half as many ma-jor coronary events as similar men assigned to place-bo.131 In contrast, the Finnish Alpha-Tocopherol, BetaCarotene Cancer Prevention Study reported no reduc-tion in the incidence of coronary heart disease amongmiddle-aged male smokers randomly assigned to a reg-imen of daily supplements of beta carotene, vitamin E,

or both.132 In this trial, the very low dose of vitamin E(50 mg daily) may have been insufficient to yield thehypothesized cardiovascular benefits.133 Of concernwas an apparent increase in the risk of hemorrhagicstroke among the men taking vitamin E supplements.These results, though neither disproving the value ofantioxidant vitamins nor proving their harmful effects,do raise the possibility that the potential cardiovascu-lar benefits of antioxidant vitamins have been overesti-mated, and their potential adverse effects underesti-mated.

RISK FACTORS AND PREVENTIVE STRATEGIES UNIQUE TO WOMEN

MenopauseThe incidence of coronary heart disease in women

increases dramatically in middle age, which has led tothe speculation that menopause marks the end of aprotective effect of ovarian hormones on cardiovascu-lar disease. Indeed, women who had an early andabrupt menopause as a result of bilateral oophorectomyand who did not receive estrogen-replacement therapyhad a risk of coronary heart disease 2.2 times higherthan that of premenopausal women of the same age.134The women who received estrogen-replacement thera-py had no higher risk of coronary heart disease, andthey may even have had a lower risk than the premeno-pausal women.

No such sudden increase in the risk of coronaryheart disease accompanies the natural cessation of men-struation. This is not surprising, since menopausemarks only one moment in the gradual waning of ovar-ian function that spans more than a decade. The widelyheld belief that natural menopause signals an abruptincrease in cardiovascular risk is based on analyseswith a number of methodologic flaws.135 In fact, thenarrowing gap between rates of cardiovascular diseasein older men and those in older women is due in largepart to a decelerated increase in the rate of mortalityfrom coronary heart disease among men,136 as well asto earlier mortality among men than among women.

Postmenopausal Hormone-Replacement TherapyAlthough the effect of postmenopausal hormone-

replacement therapy on the overall health of women re-mains unclear, there is compelling evidence that suchtherapy reduces the risk of coronary heart disease. Areview of 31 observational studies estimated a statisti-cally significant 44 percent reduction in the risk of cor-onary heart disease among postmenopausal women re-ceiving estrogen-replacement therapy.32 This apparentprotective effect is biologically plausible, since estrogenhas been shown to reduce LDL cholesterol levels andincrease HDL cholesterol levels by 10 to 15 percent137and since it may have beneficial effects on the vascula-ture and endothelial function.138 Whereas estrogen maydecrease the risk of coronary heart disease, osteoporo-sis, and menopausal symptoms, however, it is a well-recognized cause of endometrial cancer and increases




the risk of gallbladder disease. Furthermore, the possi-ble influence of estrogen-replacement therapy on thedevelopment of breast cancer is not yet clear, althoughany increase in risk is likely to be small.139 Conclusiveanswers to these questions are forthcoming from theWomens Health Initiative, a large-scale, multicenter,randomized trial.

The addition of a progestational agent to estrogen-replacement therapy may well decrease the risk of en-dometrial cancer, but whether the combined treatmentwill still provide protection against coronary heart dis-ease is unclear. Some observational studies have indi-cated that such combinations may be as beneficial asunopposed estrogen in reducing the risk of cardiovas-cular disease.140,141 The best evidence comparing es-trogen-replacement therapy with combined regimenscomes from the recently reported Postmenopausal Es-trogen/Progestin Interventions Trial.33 This random-ized, double-blind, placebo-controlled trial followed 875healthy postmenopausal women for three years to testthe effect of unopposed estrogen therapy and threecombined estrogenprogestin regimens on systolic bloodpressure and levels of HDL cholesterol, insulin, andfibrinogen. The combined regimens, as well as un-opposed estrogen therapy, increased HDL levels, de-creased LDL levels, and lowered fibrinogen levels, withlittle effect on insulin levels or blood pressure. Althoughestrogen alone raised HDL levels more than did the es-trogenprogestin regimens, the women taking unop-posed estrogen had an increased rate of endometrialhyperplasia. Each of three estrogenprogestin regi-mens raised HDL levels significantly higher than didplacebo. Cyclic micronized progesterone had a more fa-vorable effect on HDL levels than did medroxyproges-terone acetate. These findings strongly suggest a car-dioprotective benefit from estrogen alone or combinedwith progestin, particularly among women at high riskfor coronary heart disease, those who have preexistingcoronary heart disease, and those who have had a hys-terectomy.138

Oral ContraceptivesThe use of the older high-dose oral contraceptives in-

creased the risk of cardiovascular disease by raisingLDL cholesterol levels and lowering HDL cholesterollevels, reducing glucose tolerance, raising blood pres-sure, and promoting clotting mechanisms.142 The rela-tive risk of myocardial infarction was elevated amongwomen who used these oral contraceptives. However,the absolute risk of coronary heart disease, which israre in premenopausal women, was increased by only1 percent among oral-contraceptive users under theage of 40 years who did not smoke.143,144 Although fewdata have been accumulated on the safety of new low-dose formulations, the results of some recent casecon-trol studies suggest that oral contraceptives containinglower doses of steroids may carry less risk of coronaryheart disease.145

There was a clear and alarming synergy between the

previously used high-dose oral contraceptives and cig-arette smoking, leading to a dramatically elevated riskof myocardial infarction.143,146 Whether the risk is alsoelevated among smokers who use low-dose oral contra-ceptives and if so, to what degree is unclear.

Concern has been expressed that the atherogenic ef-fect of oral contraceptives may lead to an increased riskof coronary heart disease among older women whoused such contraceptives in the past. A meta-analysis of13 studies, however, concluded that there was no in-creased risk of coronary heart disease among past us-ers of oral contraceptives.147 There is a rapid return tothe base-line risk of cardiovascular disease amongwomen who have stopped using oral contraceptives,and the duration of their use does not affect the riskamong current users.142 These findings suggest that ashort-term mechanism, such as an increased risk ofthrombosis, explains most, if not all, of the increasein the risk of myocardial infarction among currentusers.147

CONCLUSIONSIt is clear that advising women to quit cigarette

smoking, avoid obesity, and increase their physical ac-tivity, as well as preventing and treating hypertension(including isolated systolic hypertension), will result insubstantial reductions in the risk of coronary disease.Furthermore, a reduction in the ratio of total cholester-ol to HDL cholesterol is likely to reduce the incidenceof coronary heart disease in women. More evidence isneeded to evaluate the overall balance between therisks and the prophylactic benefits of aspirin, small dai-ly amounts of alcohol, and antioxidant vitamins, as wellas low-dose oral contraceptives and postmenopausalhormone-replacement therapy. The results of studiesnow in progress will help establish more effective pro-grams for the primary prevention of coronary heart dis-ease in women. The clinical and public health chal-lenge remains to help women avoid or change harmfulelements of their lifestyles as a way of decreasing mor-tality from coronary heart disease, which remains theleading killer of women as well as men in the UnitedStates.

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