Cardiovascular Disease in Women

Epidemiology

There is a significantly lower age-specific risk of CHD in women than men. Risk of death due to CHD in women is roughly similar to that of men 10 years younger. Despite their marked advantage in age-specific risk of CHD death, the greater likelihood of survival of women to advanced ages produces nearly equal numbers of actual deaths due to CHD in men and women. In 1993 CHD claimed the lives of 239 701 women (48.9% of all CVD deaths) and 250 362 men (51.1% of all CVD deaths).²

In the Cardiovascular Health Study, the prevalence of myocardial infarction (MI) in older women was 9.7% for those aged 65 through 69 years and 17.9% for those 85 years and older. Of particular concern is that nearly two thirds of sudden deaths due to CHD in women in the Framingham Heart Study occurred in those with no previous symptoms of disease compared with about half the sudden deaths in men.² Treatment efforts in women may be less likely to be effective in reducing the death rate because the majority of cases may never reach a hospital. For these women, primary prevention is likely to be the only practical solution.

Substantial ethnic differences in CHD deaths in women exist, although data are sparse for minorities other than blacks. CHD death rates are 34% higher for black women than white women, compared with a 5% higher rate for black men compared with white men. Declines in CHD death rates also show gender and ethnic variations. Death rates in men declined more steeply in the 1980s and 1990s, and rates in white women declined more rapidly than those in black women during the same period.² The reasons for these differences remain unclear but may be related to differences in reporting, access to care, detection biases, and competing risks. In addition, higher prevalence of certain risk factors in black women (particularly diabetes and obesity) may explain their increased risk of CHD.

Ethnic differences in CHD are even more perplexing for Hispanics. Death rates for CVD and CHD have been reported to be markedly lower for Mexican-American men compared with white men, but this advantage has not been demonstrated for Mexican-American women.⁴ Prevalence of ECG-defined MI shows similar trends with comparable rates among women in the two ethnic groups but higher rates in non-Hispanic white men compared with Hispanic men. More recent data from the Corpus Christi Heart Project demonstrate higher hospitalization rates for heart attacks and incident MI in Mexican-Americans compared with non-Hispanic whites for both men and women. This same study demonstrated a higher case-fatality after MI in Mexican-Americans and women compared with non-Hispanic whites and men, respectively.⁵

Risk Factors and Primary Prevention

The major risk factors for CHD in women are cigarette smoking, hypertension (including isolated systolic hypertension), dyslipidemia, diabetes mellitus, obesity, sedentary lifestyle, and poor nutrition. Although most risk factors for CHD are similar in men and women, gender differences have been documented, particularly diabetes and dyslipidemia. The prevalence, magnitude of effect, and gender differences in identified risk factors for CHD are summarized below.

Cigarette smoking remains the leading preventable cause of CHD in women, with more than 50% of MIs among middle-aged women attributable to tobacco.⁶ The magnitude of excess risk, a twofold to fourfold elevation, is similar in women and men.⁷ Risk of CHD begins to decline within months of smoking cessation and reaches the level of persons who have never smoked within 3 to 5 years.⁸ Although the prevalence of smoking among US women declined from 34% in 1965 to 24% in 1991, smoking cessation rates have declined more slowly among women than men.⁹ On the basis of current trends, it is estimated that by the year 2000 smoking rates will be higher in women (23%) than in men (20%).¹⁰ These changing demographics of smoking, particularly the unfavorable smoking patterns among younger women, may contribute substantially to the future burden of CHD on women, as well as other smoking-related illnesses.

Epidemiological studies document a strong association between high levels of both systolic and diastolic blood pressure (BP) and risk of CHD in both women and men.¹¹ Among US adults older than 45 years, 60% of white women and 79% of African-American women were classified as having hypertension (defined as either taking antihypertensive medication or having systolic BP≥140 mm Hg or diastolic BP >90 mm Hg). In the most recent National Health and Nutrition Examination Survey (NHANES III, 1988-1991), approximately one half of identified hypertensive subjects were receiving treatment with antihypertensive medication, but only about 21% had hypertension that was well controlled (BP <140/90).¹¹ Of particular concern for older women is isolated systolic hypertension, which is estimated to affect 30% of women older than 65.¹²

In the Systolic Hypertension in the Elderly Program (SHEP), in which women constituted 57% of the study population, antihypertensive therapy resulted in a 25% reduction in CHD and a 36% reduction in stroke in both sexes combined.¹³ For severe diastolic hypertension (diastolic BP ≥110), the benefits of medication are large and obvious for both sexes. For mild to moderate hypertension (diastolic BP = 90 to 109 mm Hg), a meta- analysis of randomized drug-treatment trials found reductions of 14% in nonfatal CHD, 42% in stroke, and 21% in vascular mortality in both sexes combined.¹⁴ A recent subgroup meta-analysis based on the database of seven trials from the Individual Analysis of Antihypertensive Intervention Trials (INDANA), in which primarily β-blockers and thiazide diuretics were used, shows a significant effect for stroke and major CVD events in women. The relative risk reduction did not differ between men and women.¹⁵ Weight reduction and dietary interventions also have important roles in prevention and treatment of hypertension.¹¹

Increased total serum cholesterol and low-density lipoprotein (LDL) cholesterol are risk factors for CHD in both women and men. From 1980 to 1991 more than 50% of women older than 55 years had serum cholesterol levels that were considered high (>240 mg/dL).¹⁶ In a recent meta-analysis, these lipids predicted CHD mortality in women younger than 65 but not in older women.¹⁷ A low level of high-density lipoprotein (HDL) cholesterol, however, was a risk factor for CHD in both younger and older women and was a stronger predictor of CHD mortality in women than in men. The role of triglycerides in CHD risk remains controversial, but observational studies suggest they may be a particularly important risk factor in women and the elderly, the majority of whom are women.¹⁸

Limited data are available from randomized trials of lipid-lowering therapy for primary prevention of CHD in women. In an overview of three such trials that included women (two using dietary therapy and one using medication), no evidence for reduction in CHD or total mortality was observed in the treated groups.¹⁹ In contrast, secondary prevention trials of lipid-lowering therapy in women with CHD suggest substantial benefit of treatment and significant undertreatment of postmenopausal women with CHD (discussed elsewhere in this statement).

Obesity and sedentary lifestyle are parallel, interrelated epidemics in the United States that contribute to increased risk of CHD. The prevalence of obesity has increased among both men and women in the United States in the past decade; currently about one third of adult women (or 34 million) are classified as obese.²⁰ Moreover, 60% of both men and women have no regular physical activity.²¹ Obesity, particularly abdominal adiposity, is an important risk factor for CHD in women.^{22 23} Although most of the epidemiological studies of exercise and CHD have been conducted in men, most studies in women suggest a comparable 50% risk reduction among active women compared with sedentary women.²⁴ Recent evidence suggests that even moderate-intensity activity, including brisk walking, is associated with substantial reduction in CHD risk.²⁵ These findings support the 1995 federal exercise guidelines endorsing 30 minutes of moderately intense physical activity most days of the week,²⁶ a program that should be feasible and safe for most of the population.

Regular exercise and maintenance of healthy weight should also help reduce insulin resistance and the risk of non–insulin-dependent diabetes mellitus, which appears to be an even stronger risk factor for CHD in women than in men.²⁷ Diabetes is associated with a threefold to sevenfold elevation in CHD risk among women, compared with a twofold to threefold elevation among men; this gender-based difference may be due to a particularly deleterious effect of diabetes on lipids and blood pressure in women.²⁷ Diabetes is the fourth leading cause of death among black women and third among Hispanic women aged 45 to 74 years and American-Indian women aged 65 to 74 years. It is also the second leading cause of death in Pima Indian women. Approximately half of all deaths in persons with non–insulin dependent diabetes mellitus are due to heart disease, the majority of which is ischemic heart disease.²⁸

Increasing research and knowledge related to nutrition have led to identification of several dietary factors that influence CHD risk. The epidemiological evidence is compelling: diets low in saturated fat and high in fruits, vegetables, whole grains, and fiber are associated with a reduced risk of CHD.²⁹ Trans fatty acids have recently been linked to adverse lipid profiles and an increased risk of CHD.³⁰ The role of other fatty acids, including monounsaturated, polyunsaturated, and marine omega-3 fatty acids, remains controversial. Moderate intake of alcohol is related to reduction of CHD but may raise blood pressure and increase risk of breast cancer. ³¹

Genetic factors are also important determinants of CHD risk in both men and women, but they are not modifiable and thus are not further addressed here. Recently identified thrombotic, hemostatic, and inflammatory markers for CHD have promising roles in predicting risk of vascular events, but their clinical usefulness in the general population remains largely unknown.

Pharmacological interventions, including antiplatelet therapy and postmenopausal hormone replacement therapy, are appropriate in selected patients. In primary prevention the balance of benefits and risks of aspirin prophylaxis among women remains unknown and awaits the results of the ongoing Women’s Health Study, the only randomized trial of aspirin in usual-risk women. Antioxidant vitamin supplements, particularly vitamin E and homocysteine-lowering agents such as folate and B6, have promising roles in prevention of CHD, but conclusive evidence awaits the results of several ongoing randomized clinical trials.³² Early surgical menopause is linked to increased risk of CHD, which appears to be negated by the use of estrogen therapy.³³ The role of postmenopausal hormone therapy in prevention and treatment of CHD is discussed in detail elsewhere in this report.

In summary, epidemiological studies and randomized clinical trials provide compelling evidence that CHD is largely preventable.⁸ Pharmacological intervention has a role in primary prevention for selected patients. However, a major emphasis should be placed on lifestyle modifications, including smoking cessation, regular physical activity, maintenance of healthy weight, and consumption of a diet low in saturated fat and high in fruits and vegetables. Further studies on the potential benefits of stress reduction and psychosocial interventions are indicated.

Diagnosis

The diagnosis of CHD presents a greater challenge in women compared with men. Gender differences in the clinical presentation of ischemic heart disease and diminished accuracy of diagnostic tools, in part due to the lower prevalence of CHD in women, may contribute to the difficulty. Elucidation of the cause of chest pain and an increased awareness of atypical symptoms of CHD in women are needed. In addition, diagnosis of unrecognized ischemia is of interest in women because of the high fatality rate associated with first MIs.

Historically, chest pain has not been perceived to be of great prognostic value in women. This is based partly on follow-up reports from the Framingham study indicating that women developed chest pain more often than men, but it rarely progressed to MI.³⁴ In the same population the predictive value of angina was increased among older subsets of women.³⁵ In the Coronary Artery Surgery Study (CASS), half of all women undergoing arteriography for suspected CHD did not have significant obstruction.³⁶ Refinement of the diagnosis as definite angina, probable angina, or nonspecific chest pain may improve the predictive value of symptoms. Women with classical angina pectoris had a 71% probability of angiographic evidence of disease compared with 36% of women with probable angina. Nonspecific chest pain syndromes in women have an excellent prognosis and are rarely associated with significant disease on arteriography.³⁷

Syndrome X, defined as exertional angina, a positive response to exercise testing and angiographically normal coronary arteries occurs predominantly in postmenopausal women. Although chest pain may be typical for angina, conventional antianginal therapy may not successfully treat symptoms. Long-term survival rates are not reduced in women with syndrome X.³⁸

Despite the limited prognostic value of chest pain, it remains the most common initial manifestation of CHD in women. In the Myocardial Infarction Triage and Intervention (MITI) Project,³⁹ nearly 90% of women with MI had chest pain as a feature of initial clinical presentation, similar to that of men. In contrast, women with MI were significantly more likely than men to present with upper abdominal pain, dyspnea, nausea, and fatigue. Chest pain and possible atypical symptoms of angina should be pursued in women, given the appropriate clinical context and based on the underlying probability of disease. A recent review of the evaluation of chest pain in women suggests that it is possible to stratify patients into broad categories of low, intermediate, and high likelihood of disease on the basis of the existence of minor and major determinants of CHD to make diagnostic testing more cost-efficient and informative.⁴⁰

The choice and interpretation of an array of noninvasive procedures poses unique challenges in women. Factors that influence gender differences in the accuracy of diagnostic testing include a lower prevalence of CHD and multivessel disease compared with men, sex-based differences in the pathophysiology of coronary disease and its relation to risk factors, altered referral patterns for men versus women, and features intrinsic to the testing procedure itself.^{41 42}

Gender-specific considerations related to diagnostic test performance may influence the choice of procedures used to evaluate chest pain syndromes in women. Electrocardiographic (ECG) stress testing in women has a lower sensitivity and specificity compared with men, not only because of gender differences in prevalence and extent of disease but also because women are less likely to achieve an adequate heart rate response and more likely to have repolarization abnormalities.⁴³ In addition, hormone replacement therapy may induce a false-positive ST-segment depression, thereby reducing the specificity of ECG exercise testing in women.⁴⁴

Sensitivity and specificity of pharmacological or exercise treadmill testing is enhanced by added imaging techniques. Myocardial perfusion imaging with thallium 201 has improved sensitivity over conventional treadmill testing, but breast tissue attenuation of radioactivity may lead to a false-positive test result in women.⁴⁵ Attenuation artifacts may be reduced and specificity increased with the use of newer high energy agents such as technetium 99m Sestamibi and simultaneous ECG-gated single-photon emission computed tomography (SPECT), but data are limited in women.⁴⁶ Radionuclide ventriculography is of limited prognostic value in women because of a reduced left ventricular response to exercise compared with men.⁴⁷ In contrast, exercise echocardiography may be a valuable diagnostic tool in women. It is more specific than exercise electrocardiography and is considered a cost-effective approach to diagnosis of CHD in women.⁴⁸

These data suggest gender has a significant impact on the accuracy of widely available diagnostic tests and should be a consideration in the choice and interpretation of noninvasive tests. Emerging data on electron beam computed tomography, a noninvasive screening technique that detects coronary calcium, suggest minimal gender differences in diagnostic and prognostic usefulness.⁴⁹ Recent advances in development of three-dimensional imaging with magnetic resonance or positron emission tomography hold promise for women because they may overcome some of the inherent test-related limitations described above; however, these are still considered experimental.⁵⁰ As new techniques are developed to help detect CHD, gender-specific information about test efficacy will need to be provided to clinicians. Follow-up evaluation and management should be based on both pretest and posttest probability of disease in women.

Prognosis and Revascularization

Several reports have documented a worse prognosis for women with CHD than for men with CHD, which likely reflects increased severity of illness at presentation, increased age, and comorbidity in women. In the Framingham study the initial case fatality rate for MI was greater in women compared with men, and within 1 year after infarction, 44% of women died, compared with 27% of men.⁵¹ In addition, the proportion of first events occurring as sudden death rose more sharply with age in women than in men in this cohort. Data from the more recent Multicenter Investigation of the Limitation of Infarct Size (MILIS) study has also documented a more adverse prognosis in women after MI compared with their male counterparts, even after adjustment for differences in risk.⁵² In-hospital mortality was 13% for women versus 7% for men. Cumulative mortality at 48 months was 36% for women versus 21% for men, with the poor prognosis among women largely due to a high mortality rate in black women (48%).

Observations from placebo control groups of large-scale clinical trials, such as the International Study of Infarct Survival (ISIS-1) trial of atenolol, confirm a greater 1-week mortality for women compared with men (7.5% versus 3.7%).⁵³ ISIS-4, which compared captopril with placebo in patients receiving thrombolytic agents after MI, also suggested an increased short- and long-term mortality in women.⁵⁴ The 30-day mortality rate in women was double that of men in the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) study of tissue type plasminogen activator.⁵⁵ Women were shown to have a 60% greater mortality than men 35 days after presentation to the hospital with acute MI in the Fibrinolytic Therapy Trialists study meta-analysis.⁵⁶ In contrast, the outcome of women and men with unstable angina and non–Q-wave MI was found to be similar in the Thrombolysis in Myocardial Ischemia (TIMI) III B Registry despite less extensive disease and better left ventricular function.⁵⁷ However, older age and more comorbidity among women may have attenuated these benefits.

Reported differences in mortality rates among studies may reflect differences in the baseline characteristics of the populations studied as well as methodological considerations related to whether short-term, long-term, or cumulative mortality is examined. Furthermore, gender differences in mortality in the postthrombolytic era may potentially reflect gender differences in utilization and responsiveness to cardiovascular revascularization and aggressiveness of postinfarction risk reduction.

Use of diagnostic and therapeutic cardiovascular modalities may be related to gender differences in morbidity and mortality. Data from the Myocardial Infarction Triage and Intervention (MITI) registry suggest that the gender gap in mortality due to acute MI is associated with a lower likelihood of women receiving acute cardiovascular interventions.³⁹ In this community hospital trial, women had twice the in-hospital mortality of men and were half as likely to undergo acute catheterization, angioplasty, thrombolysis, or coronary bypass surgery. In contrast, women with unstable angina or non–Q-wave MI in the TIMI III Registry had similar risk for an adverse event at 6 weeks compared with men despite being less likely to undergo revascularization.⁵⁸ In area hospitals participating in the Atherosclerosis Risk in Communities (ARIC) study, women hospitalized for an MI were less likely to have coronary angiography, bypass graft surgery, and thrombolytic therapy than men, even after adjusting for several clinical and demographic variables.⁵⁹ This may not necessarily represent underuse in women, because evidence for a gender difference in the appropriateness of use of cardiovascular procedures has not been clearly demonstrated.⁶⁰ Recently, women in New York state have had a higher rate of bypass surgery when compared with women in Ontario, but it is unclear if this translates into a survival benefit.⁶¹

Gender differences in the efficacy of myocardial revascularization procedures could also explain a more adverse prognosis in women, but data are limited due to a lack of randomized clinical trials that include large numbers of women. The mortality benefit of thrombolytic therapy in men and women was found to be equivalent in the GUSTO-I trial; however, women had a higher stroke rate.⁶² Reinfarction and reocclusion of an initially patent infarct-related artery tended to be more common in women but were not statistically different from men.⁶³ With respect to percutaneous transluminal coronary angioplasty (PTCA), women have an excellent long-term prognosis after a successful procedure, similar to that observed in men.^{64 65 66} However, procedural morbidity and mortality for PTCA is three times higher for women.⁶⁷ Newer revascularization procedures such as atherectomy and stents have been less well studied in women and men.

CASS⁶⁸ demonstrated a similar rate of bypass grafting for men and women. The 15-year survival rate approached 50% for men and women with initial medical treatment. A greater survival rate was associated with surgical treatment for men (52%) versus women (48%), which was attributable to differences in operative mortality. Differences in functional class, age, and size of coronary arteries as well as a greater likelihood of emergent surgery have explained a gender differential in operative mortality in some studies but not others.^{69 70 71} Women have been sicker at the time of bypass surgery but show similar patterns of recovery and improvements in psychosocial and physical functioning after bypass surgery.^{72 73}

It has been suggested that gender differences in mortality related to CHD no longer exist after adjustment for differences in age, risk factors, and interventions.^{74 75 76 77 78} Although this may be important from an explanatory point of view, from the perspective of public health the fact remains that women have a worse prognosis and die more often than men after a heart attack or bypass surgery.

Adjunctive Drug Therapy and Secondary Prevention

The role of pharmacological therapy on the outcome of acute MI was recently reviewed.^{79 80 81} Conclusions related to gender differences in treatment efficacy are limited because the number of women in many postinfarction intervention trials has been small, probably because of upper age restrictions (as low as 65 years) where prevalence of CHD increases in women.⁸² Clinicians may refer to the ACC/AHA guidelines for the acute management of patients with MI, including drug therapy, that were published in 1996.⁸³ Treatment with β-blockers is associated with a 21% reduction in mortality, a 30% decrease in sudden death, and a 25% lower reinfarction rate,^{84 85} with reportedly similar benefits in women and men in some studies.³⁷

The Survival and Ventricular Enlargement (SAVE) study demonstrated that long-term therapy with an angiotensin-converting enzyme (ACE) inhibitor decreased mortality and morbidity among MI survivors with left ventricular dysfunction (ejection fraction ≤40%)⁸⁶ and found the beneficial effect of β-blockers was additive in these patients who often are not prescribed β-blockers.^{81 87} ACE inhibitor therapy was associated with a decreased rate of reinfarction in both the SAVE trial and Studies of Left Ventricular Function (SOLVD), suggesting potential antiatherogenic qualities of ACE inhibitors.^{88 89 90} Short-term ACE inhibitor therapy (<3 months) should be considered for patients with no contraindications, and treatment may be continued up to 3 years in patients with left ventricular dysfunction.⁷⁹

Calcium channel blockers, antiarrhythmic drugs, or intravenous magnesium are not recommended as standard therapy during or after an acute MI because they have not demonstrated a conclusive reduction in mortality in randomized trials.⁷⁹ Nitrates may be considered for symptomatic relief of ischemic chest pain during or after MI. Few data are available to examine gender differences in quality of life or potential adverse side effects of many of these medications, and future research should address this issue.

In high-risk women with prior occlusive vascular events, lifestyle modifications and therapeutic interventions (discussed in the section on primary prevention) are applicable and of heightened importance. Women at high baseline risk of CHD have the most to gain from using the risk-reduction strategies above. For some interventions, such as aspirin therapy and cholesterol-lowering medications, the evidence for benefit in secondary prevention among women is much stronger than the evidence for primary prevention. A meta-analysis of randomized trials of aspirin documented that among both men and women with prior vascular disease, aspirin treatment reduced risk of subsequent cardiovascular events by about 25%.⁹¹

Lipid-lowering therapy also appears to provide substantial benefit in secondary prevention in women.¹⁸ Although data are limited (six trials have included women with CHD and hyperlipidemia), these studies suggest a >50% reduction in CHD mortality among the treated women.¹⁸ In the Cholesterol and Recurrent Events study, the one trial of patients with CHD and “normal” cholesterol levels, pravastatin therapy was associated with an even greater reduction (46%) in major coronary events among women than among men (20%).⁹² These data support the recent National Cholesterol Education Program recommendations for an LDL cholesterol treatment goal of <100 mg/dL for both men and women with CHD.⁹³

According to a recent report from the multicenter Heart and Estrogen-Progestin Replacement Study (HERS) trial, women with CHD have been substantially undertreated for cholesterol elevations.⁹⁴ In this study, <10% of women were within the ATP-II treatment goal of 100 mg/dL. The potential role of postmenopausal hormone replacement therapy in secondary prevention is addressed elsewhere. Stress reduction, relaxation, and psychosocial support show promise in reducing vascular events in patients with established coronary disease, but data are limited.⁹⁵

Cardiac Rehabilitation

A recent secondary prevention consensus panel of the AHA found compelling scientific evidence that comprehensive risk factor interventions in patients with CHD extend overall survival, improve quality of life, decrease the need for interventional procedures, and reduce the incidence of subsequent MI.⁹⁶ Cardiac rehabilitation is a key step initiating the process of risk reduction and restoration of functional capacity after a heart attack or revascularization. It is an established treatment that includes exercise training, risk factor modification, and psychosocial and vocational counseling.⁹⁷ Studies that have included women suggest they have similar improvements in functional capacity and other outcomes compared with men.^{98 99 100}

Despite the well-documented benefit of cardiac rehabilitation, utilization rates are extremely low. In a recent national survey on gender differences in cardiac rehabilitation programs after MI, women were found to be less likely to enroll in a program (6.9% versus 13.3%) or to undergo postbypass surgery (20.2% versus 24.6%) than men.¹⁰¹ In addition to lower program attendance, dropout rates are greater for women.⁹⁹ The reasons for gender differences in participation in cardiac rehabilitation remain unclear but may be partly related to the degree of encouragement by the attending physician.⁹⁸ Preferences for specific program features have suggested a lack of pain and fatigue during exercise as an important program feature, whereas convenience factors were rated as less important among women.¹⁰² Future research should identify patient-, physician-, and program-related barriers that limit use of cardiac rehabilitation services by women. Previous work has shown that post-MI patients not enrolled in cardiac rehabilitation programs receive less aggressive risk factor management; therefore, the issue of participation in cardiac rehabilitation is critical for women because they have a worse prognosis after cardiac events compared with men.¹⁰³

Epidemiology

Stroke represents a significant healthcare burden for our society. It is the third leading cause of death in the United States and the leading cause of disability, with an estimated direct cost of $41 billion per year.² Healthcare costs increase dramatically as stroke severity increases, with greatest costs occurring for those patients with subarachnoid hemorrhages,^{104 105 106} the only subtype of stroke more common in women than in men.¹⁰⁷ Strokes account for half of acute neurological hospitalizations. It is estimated that approximately 3 890 000 stroke victims are alive today, 52 percent of whom are women.² Stroke survivors are at greater risk of dementia and disability than men and women without a history of stroke.¹⁰⁸

The overall prevalence of stroke is higher in men than in women but increases with age in both gender groups.¹⁰⁸ Results from the Cardiovascular Health Study show that prevalence for women aged 70 to 74 is 2.1% and increases to 7.8% for those aged 85 and older.¹⁰⁹ There is also an ethnic difference in stroke prevalence among women. In the NHANES III (1988-1991) data, the crude prevalence of stroke was 1.9% for white women, 2.5% for African-American women, and 0.8% for Mexican-American women.¹⁰⁹ The age-adjusted prevalence of stroke is also higher in blacks than in whites, and data suggest that blacks suffer more severe strokes.¹¹⁰

The incidence of stroke is about 19% higher in men than in women and increases with age (AHA, unpublished data, 1996). Among older adults the gender differences disappear after adjustment for age.¹¹¹ However, the incidence of ischemic stroke for persons with a history of transient ischemic attacks (TIA) is higher in women than in men.¹¹² Seasonal effects on the incidence of stroke in men and women have been suggested but not confirmed by all studies (AHA, unpublished data, 1996).^{113 114 115}

Although the lifetime risk of stroke is higher in men, women are more likely to die of stroke, probably due to their older age at its occurrence and their longer life expectancy. Over an entire lifetime, about 16% of women will die of stroke, whereas only 8% of men will die of stroke.¹¹⁶ However, mortality rates over the last decades have been declining for both men and women. From 1984 through 1994 the mortality rate declined by 19.8%, although the actual number of deaths has been on the rise since 1993. ² Results from the WHO MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) project show a decline in case-fatality rates over a 5- to 6-year period through 1990 for 13 of 17 populations for men and 15 of 17 populations for women.¹¹⁷

Age and ethnicity are important predictors of survival among stroke victims. Mortality associated with stroke is higher in blacks than in whites.¹¹⁰ Results from the National Longitudinal Mortality Study¹¹⁸ showed that 5-year cumulative mortality rates from strokes (ICD-9-430-438) among three ethnic groups differed according to age at occurrence. Among the younger women, aged 45 through 59, mortality was highest among blacks (0.36%), followed by Hispanics (0.14%) and non-Hispanic whites (0.12%). Among all ethnic groups there were increasing stroke mortality rates with increasing age, but the greatest rate of change occurred in non-Hispanic white women. By age 75 and older, stroke mortality had increased to 3.92% in non-Hispanic white women, 4.07% in black women, and 1.85% in Hispanic women. These data suggest that excess stroke mortality observed in black women is attributable to the increased mortality that occurs at younger ages. For non-Hispanic white women, 5% of fatal strokes occur from ages 45 to 59, and 74% occur at age 75 and older.¹¹⁸

Risk Factors

Many identifiable risk factors for ischemic stroke in both men and women have been fairly consistent over epidemiological studies. They include hypertension, smoking, diabetes mellitus, ischemic heart disease, atrial fibrillation, and TIAs.^{112 119 120 121 122} Most epidemiological studies have not provided gender-specific relative risks. However, Davis¹⁰⁷ identified risk factors or conditions, some of which are rare but nonetheless uniquely associated with stroke in women: fibromuscular dysplasia, choriocarcinoma, mitral annular calcification, current pregnancy, migraine, mitral valve prolapse, antiphospholipid syndrome, Takayasu’s arteritis, retinocochleocerebral vasculopthathy, and systemic lupus erythematosis. (The relationship between hormone use and stroke is addressed elsewhere in this report.)

Hypertension is clearly a major risk factor for stroke, with a 46% increase in stroke risk for every 7.5 mm Hg increase in diastolic blood pressure.¹²³ In black women the risk of developing hypertension is more than twice that of white women.¹²⁴ Several randomized placebo-controlled trials for treatment of hypertension in elderly women have shown substantial benefits for stroke morbidity and mortality. For example, both SHEP and the Swedish Trial in Old Patients (STOP) demonstrated reductions in stroke incidence among women who received the active drug for treatment of hypertension.^{12 125} Yet the results of several other randomized clinical trials suggest that treatment in women may not offer the same protection against stroke that it does in men, and further studies are needed to specifically address treatment issues in women.¹²⁶

Current smoking habits are related to stroke risk for both men and women even after adjustment for age, gender, and hypertension.¹²⁷ In the Finnmark Study, the adjusted relative risk for smoking was 1.64 for men and 2.12 for women.¹²⁸ In the Nurses’ Health Study, smoking increased the relative risk for ischemic stroke by a factor of 2.5 and for subarachnoid hemorrhage by 4.9. Results from this cohort study also demonstrate a reduction in risk for ischemic stroke with smoking cessation.^{107 129}

Diabetes mellitus is associated with a doubling of ischemic stroke risk.¹¹² One study among stroke patients with hypertension has shown diabetes is a significant predictor of ischemic stroke compared with hemorrhagic stroke in women but not in men.¹³⁰ When all types of stroke are considered, data from the Framingham study yield an (adjusted) relative risk of 1.4 in men and 1.7 in women for the presence of diabetes.¹³¹ Not only does diabetes increase stroke risk, it increases severity and mortality associated with stroke.¹³²

A number of studies have demonstrated increased risk of stroke associated with coronary diseases and conditions. Among older adults in the Cardiovascular Health Study, a significantly greater risk of stroke was associated with abnormal left ventricular wall motion and increased left ventricular mass, carotid stenosis, and atrial fibrillation.¹¹¹ Another population-based longitudinal study found a number of coronary factors to convey an increased risk for ischemic stroke: congestive heart failure, angina pectoris, MI, ischemic heart disease, mitral valve disease, left ventricular hypertrophy, and atrial fibrillation. Investigators found that risk of stroke for normotensive persons with persistent atrial fibrillation was seven times greater than risk for normotensive persons without atrial fibrillation.¹¹² Results from the Framingham Study indicate that risk of stroke associated with atrial fibrillation is greater in women than in men (RR 3.16 versus 1.83).¹³¹ Other studies have shown that younger patients with nonvalvular atrial fibrillation in the absence of other risk factors are not at increased risk of stroke.^{133 134 135}

TIAs convey considerable risk for subsequent stroke.¹²² It is estimated that each year 50 000 Americans experience TIAs, and one third will experience a stroke (AHA, unpublished data, 1996). The risk of stroke is 13 to 14 times greater during the first year after a TIA and about 7 times greater during the first 5 years. However, risk is modified by age and subtype of TIA. Those with hemispheric TIA along with carotid stenosis >70% have a 40% increased risk of stroke during the next 2 years. Younger patients and those with isolated monocular visual symptoms have a lower risk.¹³⁶ One group of investigators reported that, over a long period of follow-up, risk of stroke for both men and women among those with TIAs was more than fivefold that of those without TIAs; risk decreased with age; a history of TIA resulted in more then twice the risk for women than for men.¹¹²

Recently, attention has turned to hematologic factors, including hematocrit and white blood cell counts,¹³⁷ infections and inflammations,¹³⁸ psychosocial factors,^{139 140} and lifestyle¹⁴¹ as risk factors for stroke. Inconsistent results of homocyst(e)ine as a risk factor have been reported.^{142 143 144} Risk of stroke has been noted to be inversely related to stature among both men and women.¹²⁸ Elevated serum creatinine has been documented as a significant risk factor in men, regardless of hypertensive status; studies in women are lacking.¹⁴⁵ The presence of clinical proteinuria was seen as a significant predictor of thromboembolic and hemorrhagic stroke in a Finnish cohort of men and women.¹⁴⁶

Treatment

To date there are no specific recommendations for treatment of stroke in women, and recommendations for acute interventions for women and men appear to be the same.¹²² For all stroke victims, early detection and treatment are vital. Thrombolytic therapy with r-TPA for acute ischemic stroke can be effective for ischemic stroke patients when administered early in the course of the event.¹⁴⁷ Recently, a panel of the American Heart Association Stroke Council reviewed the clinical trials of thrombolytic drugs and established guidelines for management of patients with acute ischemic stroke.¹⁴⁸ The guidelines call for early administration of r-TPA when the time of stroke onset can be ascertained reliably and with some specific exclusions. Ten percent of patients with acute stroke develop hemorrhage with r-TPA. The panel also considered the need for careful attention to ancillary care measures and management of bleeding complications, and these are outlined in the guidelines. Although treatment after the acute stage should focus on the patient’s particular risk factor profile and the pathogenesis of the stroke, most care will include the use of antiplatelet aggregating or antithrombotic agents such as aspirin, ticlopidine, or warfarin.¹⁴⁸ Secondary prevention may include aspirin for both men and women. The Chinese Acute Stroke Trial (CAST)¹⁴⁹ has shown that early administration of aspirin (within 48 hours of stroke onset) reduces stroke-related death and recurrence. While women and men both received equal benefit with aspirin therapy in this trial of secondary prevention,¹⁴⁹ the efficacy of aspirin use for primary stroke prevention in women remains questionable.¹⁵⁰ In patients with TIA and atrial fibrillation, adjusted dose warfarin may prevent stroke.¹⁵¹

Women who have symptomatic carotid stenosis of 70% to 99% may benefit from the combination of carotid endarterectomy and aspirin therapy. The risk of a second stroke is 26% at 2 years in those on antiplatelet therapy alone, compared with 9% with antiplatelet therapy combined with endarterectomy.¹⁵²

Epidemiology

Peripheral artery disease is more prevalent in women than generally appreciated, but estimates vary greatly according to the diagnostic criteria applied. Prevalence and incidence rates do not differ significantly by gender, although incidence rates in women lag behind those in men in a pattern similar to that for coronary disease.¹⁵³ The incidence of peripheral artery disease increases sharply with age regardless of the criteria applied. In the Framingham study, age-specific incidence accelerated rapidly in women.¹⁵³ Intermittent claudication is not a very sensitive indicator of disease; when used as the sole criterion, it yields prevalence rates of just 2% to 3%.^{154 155} Absence of pulses is also not a sensitive indicator.¹⁵⁴ Data from a variety of studies clearly show that the risk of cardiovascular events associated with decrements in peripheral vascular function is continuous.

Besides claudication, commonly used criteria for diagnosing peripheral arterial disease include an ankle/brachial index (ABI); <0.9 determined by the ratio of systolic BP at the posterior tibial artery at the level of the ankle divided by the brachial artery pressure; flow velocity deficits measured by Doppler; the absence of posterior tibial or dorsalis pedis pulses; and intermittent claudication. In studies in which at least two of these criteria were used, prevalence rates ranged from 6% to 20%.^{156 157} Asymptomatic patients have survival rates that are not significantly different from those with symptoms, suggesting that claudication is not a reliable marker for severity of disease.¹⁵⁸ Thus, when peripheral artery disease is considered a problem only in the presence of claudication, the majority of the population at risk is discounted. The ABI and measurements with a hand-held Doppler in an outpatient setting can reliably diagnose the majority of peripheral artery disease.¹⁵⁹

Risk Factors

Smoking is the most consistently associated risk factor, and prevalence rates in nonsmokers are less than half that of smokers.¹⁵⁷ Other risk factors include glucose intolerance, increased body mass index, elevated blood pressure, and elevated fibrinogen.^{157 160 161} The association between peripheral artery disease and lipids is less definitive. In the Cardiovascular Health Study, total and LDL cholesterol were inversely associated with ABI in women but not men.¹⁶⁰ The San Luis Valley and Edinburgh studies found an association between total cholesterol and peripheral artery disease,^{157 162} whereas there was no association in the Rancho Bernardo Study, in which peripheral artery disease was strongly associated with elevated triglycerides.¹⁶¹ Except for the importance of smoking, the risk factor profile common in peripheral artery disease shares features with the metabolic syndrome¹⁶³ : glucose intolerance with low HDL cholesterol and often normal levels of LDL cholesterol, with a large fraction of the LDL cholesterol in a dense, more atherogenic form.¹⁶⁴ An association with the metabolic syndrome in persons whose total and LDL cholesterol levels are normal may explain the inconsistent associations for lipids.

The degree of overlap in risk factors between peripheral artery disease and other major atherosclerotic CVD varies considerably by population and the diagnostic criteria applied. In the Cardiovascular Health Study peripheral artery disease was associated with increased carotid wall thickness, abnormal cardiac wall motion, and major electrocardiographic abnormalities.¹⁶⁰ The Atherosclerosis Risk in Communities Study found peripheral artery disease to be the most important predictor of carotid thickness.¹⁶⁵ In the Rancho Bernardo Study, a history of coronary disease or stroke was more than twice as common in women with peripheral artery disease than in women with normal peripheral arteries.¹⁶⁴ Similarly, 25% of women with a history of coronary disease or stroke had peripheral artery disease, compared with an 11% prevalence of peripheral artery disease in women without this history.¹⁶⁴ Typically, the more detailed the assessment of the arterial tree, the greater the concordance between peripheral arterial, coronary, and cerebrovascular diseases. The concordance of diagnoses ranges from about 20% to 60% for noninvasive measures to as much as 90% with angiography.¹⁶⁶

Peripheral artery disease itself is a strong risk factor for other cardiovascular events and mortality. There is a threefold to fourfold increase in relative risk for all-cause mortality associated with peripheral arterial disease^{158 167} that does not differ by gender.¹⁵⁸ The relative risk for cardiovascular death is between 4 and 6, and the relative risk for CHD death is between 4 and 7.^{158 167} Moreover, adjustment for risk factors and exclusion of persons with a history of other CVD at baseline does not attenuate these risks, suggesting that once manifested, the disease itself is an independent predictor of survival.¹⁵⁸

Treatment

Smoking cessation is essential for any patient still smoking when peripheral artery disease is recognized. Antiplatelet therapy may be effective in reducing adverse outcomes.^{168 169} Surgery is indicated for severe disease and may reduce direct sequelae of poor peripheral circulation, but, just as for coronary disease, a comprehensive program of atherosclerotic risk reduction and exercise is necessary to reduce risk of other cardiovascular events. Despite ambiguity about the association between lipids and peripheral artery disease, lipid-lowering therapy is likely to be protective.¹⁷⁰

Oral Contraceptives

Case reports suggesting an increased risk of MI and stroke almost immediately followed the introduction in 1960 of oral contraceptives, which typically contained 150 μg estradiol. Between 1968 and 1988 the average dose of estradiol in US-made oral contraceptives decreased from 70 to 35 μg; today some oral contraceptives contain less than 20 μg of estradiol. More recently, third-generation progestins, such as desogestrel or gestodene (unlike earlier progestins), lower LDL and raise HDL cholesterol.¹⁷¹ Prescribing patterns have also changed, following recognition that oral contraceptives raise blood pressure and pose additional risk in older women who smoke cigarettes. These changes in products and their use would be expected to reduce the cardiovascular risks associated with oral contraceptives. Obviously, only recent case-control studies can quantitate risks associated with current formulations and prescribing practices. The most remarkable of these efforts is the 1989-1993 World Health Organization (WHO) Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception, a case-control study conducted in 21 centers in nine countries (in Africa, Asia, Europe, and Latin America).^{172 173} In the WHO study, hospitalized case subjects and control subjects underwent a standard interview to assess current and past use of oral contraceptives, cigarette smoking, history of hypertension, and whether or not blood pressure was measured before prescription.

The WHO Study reported the association between current use of oral contraceptives and acute MI in more than 300 cases and age-matched controls.¹⁷⁴ The overall odds ratio for MI was 5.01 (95% confidence interval, 2.54 to 9.90) in Europe and 4.78 (2.52 to 9.07) in developing countries. The absolute risk in nonsmoking women younger than 35 years was low, however: approximately 3 per million woman years. The risk was dramatically increased in older women who smoked, approximately 400 per million woman years, and in women with known hypertension whose blood pressure was not checked before prescription. Risk was not associated with dose or duration of use of estrogen and did not persist after oral contraceptives were discontinued.

Between 1991 and 1994, MI and use of oral contraceptives were compared with a California database.¹⁷⁵ Most women were using low-dose oral contraceptives (<50 μg). After adjusting for major heart disease risk factors, the odds of MI in current oral contraceptive users compared with nonusers was 1.65 (95% CI=0.45 to 6.06). The odds ratio for prior use was not increased. The authors concluded that oral contraceptives do not increase the risk of heart attack in women who do not have risk factors for heart disease.

In the WHO study, more than 95% of stroke cases were classified as ischemic or hemorrhagic on the basis of a CT scan, MRI, or cerebral angiography performed within 3 weeks of the stroke. About 13% of all strokes in 20- to 44-year-old women in Europe and 8% in developing countries were attributable to oral contraceptives.¹⁷³ Current use of oral contraceptives carried a nearly threefold increased odds of stroke in Europe (OR=2.99) and in non-European (developing) countries (OR=2.93).¹⁷² The odds ratios were lower in younger women, women who did not smoke, and women whose blood pressure had been checked before oral contraceptive prescription. However, the odds ratios exceeded 10 for women who had a history of hypertension. In Europe the odds ratio was less with oral conceptives containing <50 μg estradiol compared with higher-dose preparations (OR=1.53 versus 5.30), but no dose-related differences in stroke risk were seen in developing countries, possibly reflecting lower levels of CVD risk factors in these women. Risk was not increased with increasing duration of use or past use.

From 1985 to 1989 a case-control study of cerebral thromboembolism in 320 Danish women aged 15 to 44 years also found evidence for an estrogen dose-response effect, even among women taking low-dose regimens.¹⁷⁶ In multivariate analysis, pills containing 50 μg estrogen were associated with an odds ratio for cerebral embolism of 2.9 compared with 1.1 for pills containing 30 to 40 μg estrogen. No increased risk was demonstrable with progestin-only pills.

Hemorrhagic stroke was also associated with oral contraceptive use in the WHO Study.¹⁷³ The excess risk was statistically significant in developing countries (OR=1.75) but not in Europe (OR=1.38). Women younger than 35 who used oral contraceptives had no increased risk of stroke, while women with a history of hypertension had a 10-fold to 15-fold increased risk. Odds ratios among current cigarette smokers exceeded 3. Dose of estrogen, type of progestin, and duration of use were unrelated to risk of hemorrhagic stroke.

A California case-control study of over 1 million women conducted in a prepaid health plan between 1991 and 1994¹⁷⁷ found no statistically significant excess risk of ischemic or hemorrhagic stroke associated with low-dose (<50 μg) estrogen oral contraceptives, although the upper bound of the 95% confidence intervals was 2.5. The authors postulate that the low risk reflects the low prevalence of hypertension and cigarette smoking in this cohort.

In the WHO Study,¹⁷⁸ the risk of venous thromboembolism (VTE) was increased threefold to fourfold in oral conceptive users compared with nonusers. An unexpected higher risk in women using third-generation progestins led to a secondary analysis using data from nine countries and adding community controls in one center.¹⁷⁹ For the progestins levonorgestrel, desogestrel, and gestodene, adjusted odds ratios for VTE in women taking combined low estrogen (<35 μg estradiol) were 3.4, 7.3, and 10.2, respectively, compared with nonusers.

The discovery that intrinsic coagulation factors play an important role in oral contraceptive-associated VTE¹⁸⁰ has unquestionably been the most novel and exciting discovery in this field. Epidemiological studies have shown that the factor V Leiden mutation increases risk of VTE between five times and ten times. In the presence of the mutation, the risk of VTE associated with second- and third-generation oral contraceptives increased 30 times. A research group from the Netherlands¹⁸¹ has shown that second- and, to a greater extent, third-generation oral contraceptives induce resistance to the body’s natural anticoagulation system (APC resistance). Women heterozygous for factor V Leiden who take oral contraceptives develop APC resistance as high as that seen in women who are homozygous for the factor V Leiden mutation. This information not only explains much about how the pill causes VTE but should make it possible to develop safer oral contraceptives and screening tests for women to detect coagulation defects.

In summary, new oral contraceptives carry a greatly reduced risk of CVD complications compared with other high-dose preparations, but third-generation progestins appear to greatly increase risk of VTE. Overall, the risk/benefit ratio is excellent except for women who smoke.

Postmenopausal Estrogen Therapy

Unlike oral contraceptives, which are usually taken for a single purpose, postmenopausal estrogen is taken for a variety of reasons, ranging from relief of current symptoms to prevention of future osteoporotic fractures or CHD. In 1975 25 million prescriptions were written for noncontraceptive estrogen, primarily conjugated equine estrogen, in the United States; between 1982 and 1992 the number of prescriptions increased from 13.6 to 31.7 million.¹⁸²

Several reviews have summarized the results of prospective studies showing a remarkably consistent reduced risk of CHD^{183 184 185} and a somewhat less consistent reduced risk of stroke¹⁸⁶ in women using postmenopausal estrogen in the United States and Europe. Similar studies are not available for women of color or from developing countries. Because the risk of CHD exceeds the risk of all other estrogen-associated conditions combined in the United States, and because estrogen use has been associated with reduced mortality from all causes combined,¹⁸⁷ postmenopausal estrogen has been proposed as the standard of care in countries where heart disease is the leading cause of death and a major cause of morbidity in women.¹⁸⁵ Based on meta-analyses of studies, most from the United States,^{184 185} postmenopausal estrogen is associated with a 35% to 50% reduced risk of CHD. On the basis of a calculation of overall risks and benefits, a healthy woman at no particular increased risk for heart disease, cancer, or osteoporosis would gain on average 1 additional year of life.¹⁸⁵ As reviewed elsewhere,^{188 189} there are multiple mechanisms whereby estrogen might protect against CHD, including favorable changes in lipids, lipoproteins, fibrinogen and PAI-1, vasomotor effects, and antioxidant effects.

Despite the consistency and coherence of postmenopausal estrogen–associated cardioprotection, it is nevertheless possible that some or all of the association is an artifact explained by prescription, prevention, or compliance bias and differences in education and socioeconomic status.^{190 191} In a recent study,¹⁹² 232 women who had used estrogen since menopause for an average duration of 17 years had nearly 50% lower mortality from all causes than age-matched nonusers (95% CI=0.38-0.76); reduced mortality was largely due to less fatal CVD. A report from the Nurses’ Health Study ¹⁸⁷ showed a reduced risk of nearly every disease except breast cancer. A recent Markov analysis¹⁹³ postulated a 3-year increase in life expectancy associated with use of postmenopausal estrogen. Many studies in the United States have shown that women who are better educated and more affluent (well-established cardioprotective factors) are more likely to be prescribed postmenopausal estrogen and to take it. Recently this “healthy woman selection bias” has been strikingly documented by the Healthy Women’s Study,¹⁹⁴ which followed 355 premenopausal women through menopause. Women who later elected to take hormones were, when premenopausal, significantly more educated and had significantly more favorable levels of HDL cholesterol, blood pressure, fasting insulin, body weight, alcohol intake, and physical activity. Thus, the amount of protection attributed to estrogen may be exaggerated.

Nearly all of the studies describing cardiovascular protection included women using unopposed conjugated equine estrogen. Two recent US studies found similarly reduced cardiovascular risks for women taking estrogen plus a progestin, usually medroxyprogesterone acetate, suggesting that this combination is equally protective.^{195 196} These studies had relatively few events, however, and several new lines of evidence suggest that medroxyprogesterone acetate may mask or at least partially reverse estrogen-induced benefits. In the Postmenopausal Estrogen/Progestin Intervention (PEPI) study of 875 women,¹⁹⁷ a 3-year placebo-controlled randomized double blind trial, HDL cholesterol levels rose significantly more in women assigned to unopposed conjugated equine estrogen than in women assigned to conjugated equine estrogen plus continuous or cyclic medroxyprogesterone acetate. Other studies show that medroxyprogesterone acetate can have a particularly deleterious effect on estrogen-induced improvements in vascular reactivity and atherosclerosis. For example, recent studies in nonhuman primates showed that conjugated equine estrogen alone—but not estrogen combined with medroxyprogesterone acetate—improved vascular reactivity of coronary arteries¹⁹⁸ and prevented the progression of coronary artery atherosclerosis.¹⁹⁹

Although long suspected, no increased risk of VTE in women taking postmenopausal estrogen was convincingly demonstrated until 1996, when two case-control studies of VTE^{200 201} and one prospective study of pulmonary emboli²⁰⁰ were published concurrently. All showed remarkably similar threefold to fourfold increased risk associated with PME. Although the relative risk was high, the absolute risk was low, owing to the infrequency of events with or without hormone therapy.

Two major US trials have been designed to quantitate the cardioprotective effect of postmenopausal estrogen unconfounded by healthy woman selection bias. HERS is a 5-year randomized placebo-controlled secondary prevention trial of conjugated equine estrogen plus medroxyprogesterone acetate in women who already have CHD. This study of 2673 postmenopausal women is planned to end in 1998. Unopposed estrogen is not being evaluated. The Women’s Health Initiative (WHI), a placebo-controlled primary prevention trial in 27 500 postmenopausal women, is scheduled to complete randomization in 1998.²⁰³ The three major outcomes are CVD, osteoporosis, and breast cancer. Active treatments are conjugated equine estrogen alone for women without a uterus or conjugated equine estrogen plus continuous medroxyprogesterone acetate for women with an intact uterus, as compared with placebo. The WHI is planned to end in 2006. This trial will be the first to provide disease data in ethnic minority women on hormone therapy.

In summary, ongoing research suggests that estrogen replacement therapy reduces risk of CVD but may increase the risk of other diseases, including breast cancer and VTE. The potential benefits and risks need to be confirmed in randomized controlled clinical trials such as those now in progress, because no study can adjust properly for all the known and unknown selection factors that determine who takes estrogen. Until more definitive data are available, clinicians should individualize therapy based on a woman’s baseline risk for CVD and should weigh the potential net benefit on overall health. Emerging data suggest selective estrogen receptive modulators, also known as designer estrogens, may have beneficial effects on the cardiovascular system as well as bone without untoward effects on breast or endometrial tissue.²⁰⁴ However, the clinical effectiveness of newer hormonal agents for disease prevention remains to be established.