The primary prevention of coronary heart disease in women: An overview

The prevalence of hypertension increases as women age. Under the age of 50, men have, on average, a systolic blood pressure 7 mm Hg higher than women. By age 60, however, systolic blood pressures are greater in women than in men.5 Over the age of 75, hypertension has an estimated prevalence of 80% in women.6,7

The association between hypertension and CHD has been clearly shown for women. Although both systolic and diastolic blood pressures affect CHD risk, systolic blood pressure has been shown to be the more significant risk factor.8 Studies such as the Nurses’ Health Study showed that, even after adjusting for diabetes, smoking, and high cholesterol levels, women with increased blood pressure had four times the relative risk of myocardial infarction (MI) and more than seven times the risk of fatal coronary events.9 Other studies have found a threefold to fourfold increased risk of CHD in women with high blood pressure.10-12

Interventions to decrease blood pressure have proven effective in lowering cardiovascular risk. Modest reductions in blood pressure through lifestyle changes, such as increasing physical activity, reducing weight, decreasing alcohol intake, and decreasing salt intake, can have a significant effect on risk reduction.13 Although no randomized controlled trials of medical therapy for hypertension have been limited to women, several studies have included a significant proportion of women. The Hypertension and Detection Follow-up Program,14 the Swedish Trial in Old Patients with Hypertension,15 and the Systolic Hypertension in Elderly16 studies have all shown a 19%14 to 55%15 reduction in CHD events with blood pressure treatment.

Despite the known cardiovascular benefits of blood pressure reduction, even in the setting of known CHD, women have inadequate blood pressure control. In their 1995 study of 135 women after coronary artery bypass graft surgery, Allen and Blumenthal found that the mean systolic and diastolic blood pressures were higher 6 months after surgery compared with presurgical values.17 In the recent baseline data from the Women’s Health Initiative, only 36.1% of women with high blood pressure had adequate blood pressure control, and as many as 71% of women older than age 70 had inadequate blood pressure control (these results are based on the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI definition of hypertension).18 Thus, further studies are needed to elucidate the barriers that may exist in treating hypertension in women.

Diabetes

It has been well established that diabetes is a major risk factor for CHD. Studies have clearly shown that the increased risk of CHD is greater for diabetic women than for diabetic men.19-22 Furthermore, diabetic women are more likely to die after an MI than men.23,24

The reasons for this discrepancy between men and women with diabetes are not entirely clear. Some of the excess risk may be explained by the lower rates of CHD for nondiabetic women in comparison to nondiabetic men. In addition, compared with nondiabetic women, women with diabetes have higher rates of other CHD risk factors, such as hypertension and high cholesterol, thus increasing their overall risk for heart disease. However, this only partially explains the excess CHD risk found in diabetic women compared with diabetic men. After controlling for other CHD risk factors, the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe study found that women with diabetes still had an increased risk of cardiovascular disease mortality compared with diabetic men.22

There is increasing evidence to suggest a continuous linear relationship between blood glucose levels and macrovascular disease, such as CHD.25 Although no randomized controlled intervention trials have been limited to women with type 2 diabetes, it can be inferred from observational studies that tight control of blood glucose levels and the modification of other CHD risk factors will decrease the rate of CHD in women. In January 2004, the American Diabetes Association set the following goals for diabetic patients: glycosylated hemoglobin less than 7%, blood pressure below 130/80 mm Hg, and low-density lipoprotein (LDL) cholesterol level less than 100 mg/dL.26 Given the excess mortality among diabetic women compared with diabetic men, studies need to be conducted in women to determine whether more stringent guidelines should be recommended.

Cholesterol

Observational studies, such as the Framingham study, have clearly established the association between hyperlipidemia and CHD risk.27-32 Studies also suggest a difference between men and women among the various lipoprotein levels and risk of CHD. Furthermore, cholesterol values change differently for men and women with age. Under the age of 20, cholesterol levels are comparable in men and women. From ages 20 to 55, men have, on average, higher total cholesterol values. After age 55, cholesterol levels in women rise, with an increase in both total cholesterol and LDL cholesterol levels. Although high-den-sity lipoprotein (HDL) cholesterol levels decrease slightly after menopause, throughout their lifetime, women have, on average, higher HDL values compared with men.33

LDL cholesterol seems to be a less potent risk factor for CHD in women compared with men. This is especially true for women aged 65 and older. A workshop conducted by the National Heart, Lung, and Blood Institute (NHLBI) pooled data from 22 US and international cohort studies and provided information on over 86,000 women. For women aged 65 and older, an LDL cholesterol value 160 mg/dL or higher conferred a relative risk of 1.13 for a CHD event compared with women with LDL cholesterol less than 140 mg/dL. For women younger than 65 years of age with LDL cholesterol levels of 160 mg/dL or greater, the relative risk

of a CHD event was 3.27 compared with those with LDL cholesterol values lower than 140 mg/dL.34 Studies also show a more potent associa-

tion between HDL cholesterol and CHD risk in women.28,32,35,36 Corti

and colleagues found that women older than 71 years with HDL cholesterol values above 60 mg/dL had half the risk of CHD compared with women with HDL cholesterol values lower than 35 mg/dL, after controlling for all other CHD risk factors.37 Furthermore, data from the NHLBI study showed that, for women older than age 65, HDL cholesterol was the only significant lipid predictor for CHD.38 Studies also suggest that increased triglyceride levels may be an important risk factor for CHD in women. In a study of 24,535 women and 25,058 men by Stensvold and colleagues, cardiovascular mortali-ty increased with increasing tri-

glyceride values for women but not for men.39

Secondary prevention studies clearly show a risk reduction of CHD with cholesterol treatment for both men and women.40-42 Although primary prevention studies have shown risk reduction of CHD in men, there have been no primary prevention studies of cholesterol treatment limited to women.43 Of the five primary prevention HMG-CoA reductase inhibitor (statin) intervention trials that have included women, only four have assessed risk reduction by sex (table), and only one showed a statistically significant decrease in CHD risk for women.44-48 However, the women in this study all had diabetes and thus represented a very high-risk group.

There have been two primary prevention dietary intervention trials that have included women.49,50 In both cases, no statistically significant reduction in CHD risk was seen with intervention. The usefulness of this information is limited, however, because neither study attempted to enroll patients with high cholesterol levels. Furthermore, in the study by Frantz and colleagues, dietary intervention did not follow recommendations by the National Cholesterol Education Program.50

For women at above-average risk for heart disease, aggressive management of high cholesterol levels is necessary for CHD risk reduction. However, there is currently no evidence to support aggressive lipid management in the average-risk

and below-average-risk female patient. Given the sex differences in the magnitude of CHD risk among the various lipoproteins, gender-specific intervention trials need to be conducted to better understand the role of cholesterol treatment in the prevention of heart disease in women.

Smoking

Cigarette smoking has been linked to CHD in women since 1976, when Mann and colleagues published a case-control study showing that women who smoked more than 34 cigarettes per day had a sevenfold increased risk of coronary events.51 In 1987, the Nurses’ Health Study reported that cigarette smoking was linked to an increased risk of fatal and nonfatal MI in a dose-dependent manner. An estimated 58% of all CAD events in this study were attributable to smoking; that figure increased to 91% among the heaviest smokers (≥ 45 cigarettes/day).52 Other studies have found similar associations.1,53-57 For those who quit, cardiovascular risk returned to that of nonsmokers by 3 to 5 years.58

Although smoking has been linked to numerous adverse health outcomes, men have higher quit rates than women. From 1965 to 1990, the rates of smoking in men declined by 18%; however, only a 9% decline was shown for women.59 There are several reasons smoking cessation rates are lower for women than for men. Women in general are less likely to associate smoking with negative health risks.60 Although lung cancer surpasses breast cancer as the number one cancer killer of women, women still fear breast cancer as their greatest health risk and are also much less likely to fear heart disease.61 Women also have a harder time quitting. In the 1995 Community Intervention Trial for Smoking Cessation, women were found to have much lower quit rates than men.60 The authors offered several reasons for this apparent disparity. Women, more than men, use smoking as a coping mechanism. Nicotine results in a state of euphoria and an increased state of alertness that may enhance psychological addiction, which may explain the increased prevalence of smoking among women with high levels of stress and depression.60

It is clear that smoking increases the risk of CHD and that cessation of smoking decreases this risk. Given the lower quit rates among women, sex-specific intervention trials may help to address the barriers to smoking cessation in women.

Obesity

Obesity is associated with the CHD risk factors of diabetes, hypertension, and high cholesterol levels. Studies also show that obesity is an independent risk factor for CHD, particularly in women.62-66 In two prospective analyses of the Nurses’ Health Study, the relative risk of CHD, adjusted for age and smoking, increased with increasing body mass index (BMI). Women with a BMI of 32 kg/m2 or greater had a relative risk of 4.1 versus those with a BMI less than 19 kg/m2.

Although there is no evidence that weight reduction alone reduces the risk of CHD, weight reduction improves glucose control, blood pressure, and lipid profiles. Given the growing epidemic of obesity, effective weight loss and maintenance of ideal body weight need to be continually emphasized by physicians to their patients.

Exercise

Numerous epidemiological studies have shown the beneficial effects of physical activity on CHD risk reduction for both men and women.67-70 The largest study was conducted by Manson and colleagues and involved 70,000 postmenopausal women.70 A strong inverse association between increasing physical activity and risk of cardiovascular events was shown, even after controlling for other CHD risk factors. Walking briskly or exercising vigorously for at least 2.5 hours per week conferred a 30% risk reduction in cardiovascular events; however, prolonged sitting was associated with a significant increase in cardiovascular risk.70

Given the health benefits of exercise and the health risks of a sedentary lifestyle, physicians should encourage moderate exercise as an important strategy for CHD risk reduction in women.

Aspirin

Aspirin irreversibly inhibits platelet aggregation, which likely accounts for the role of aspirin in the primary and secondary prevention of CHD. For both men and women, studies have shown that aspirin can decrease the risk of subsequent vascular events, proving the benefit of aspirin for secondary prophylaxis.71,72

The role of aspirin for primary prevention of CHD in women is less clear. Data from both observational and prospective trials are conflicting and limited. Three observational trials that investigated the use of aspirin as primary prophylaxis for CHD have included women. The Nurses’ Health Study showed a significant risk reduction for CHD in women who took aspirin; the other two trials, however, did not show a significant decrease in risk.73-75

Five major prospective trials have evaluated aspirin as primary prevention for CHD. Only two of these trials, the Hypertension Optimal Treatment (HOT) study and Primary Prevention Project (PPP), included women. Although there was a significant decrease in fatal and nonfatal MIs of 36% in the HOT study, when the data were stratified by sex, the decrease in risk was not significant in women.76,77 The PPP trial showed a decrease in cardiovascular events by 23% with aspirin use; however, subgroup analysis by sex was not performed.78

Meta-analysis of the data from the five major prospective primary prevention trials shows that the net benefit of aspirin increases with increasing cardiovascular risk.79,80 Therefore, the decision to initiate aspirin therapy should be based on the assessment of absolute cardiovascular risk for each individual patient. A 2002 review by Lauer on the use of aspirin for the primary prophylax-

is of CHD suggested that aspirin should be initiated for patients with a Framingham 10-year risk score of 15% or greater who do not have contraindications to its use.81 Patients with a 10-year risk of 6% or less should not receive aspirin, and those with a 10-year risk of 7% to 14% should be considered on an individual basis.81 Because the data used for this algorithm are mainly derived from studies involving men, the algorithm is most appropriate for men 50 to 65 years of age. The risk—benefit ratio may vary by sex, and further randomized controlled trials involving women are needed prior to making recommendations for the use of aspirin for the primary prevention of CHD in average-risk women. It is expected that data from the Women’s Health Study, a randomized, double-blind, placebo-controlled trial designed to assess the benefits and risks of low-dose aspirin and vitamin E for the pri-mary prevention of cardiovascular disease and cancer, will help guide physicians regarding the risks and benefits of aspirin use for women.82

Conclusion

Although CHD mortality rates have been declining over the last few decades, this decline has been greater for men than for women.13 In addition, compared with men, women who survive the initial cardiac event have higher rates of reinfarction and subsequent death.52

Given the increasing prevalence of heart disease with age and that women older than age 75 make up the fastest growing portion of the population, strategies to prevent CHD are paramount to the health of women.83 Modifiable risk factors for heart disease prevention include control of hypertension, control or prevention of diabetes, cessation of smoking, prevention of weight gain, and increase in physical activity. For women at above-average risk for heart disease, the aggressive man