Addressing Disparities in Health Care

Cardiovascular disease in women: Prevention, symptoms, diagnosis, pathogenesis

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Statins for primary prevention in women: Conflicting data

Given suggestions that statins may not be effective in women10 and the fact that women were underrepresented in earlier statin trials, a number of studies have examined this issue in the last several years.

The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin)10 enrolled patients who had no history of coronary artery disease and who had a C-reactive protein level equal to or greater than 2 mg/L and a low-density lipoprotein cholesterol level of less than 130 mg/dL. (Of note, these patients would not have met the criteria for receiving a statin for primary prevention according to the current Adult Treatment Panel guidelines.)

The women in the trial who received rosuvastatin had a 46% lower incidence of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes. In addition, a meta-analysis performed by the authors showed a one-third reduction of cardiovascular disease end points in women. However, there was no reduction in the mortality rate.

Reprinted from Kostis WJ, et al. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59:572–582, with permission from Elsevier.

Figure 1. Summary of statin trials in women, stratified by risk.

Other statin trials. A later meta-analysis of randomized primary prevention trials found that men and women derived similar benefit from statins in terms of cardiovascular disease end points and all-cause mortality (Figure 1),11 although five of the trials included a small number of secondary prevention patients. In contrast, a meta-analysis of only primary prevention patients showed no benefit of statin therapy in all-cause mortality, although the authors acknowledged that there were insufficient data to look specifically at women in this sample.12

A Cochrane review conducted before the JUPITER data were available concluded that there was insufficient evidence to prescribe statins for primary prevention in patients at low cardiovascular risk.13 However, an updated version that included results of the JUPITER trial concluded that there was a reduction in the rate of all-cause mortality and cardiovascular events in both men and women receiving a statin for primary prevention.14

Given these conflicting results, debate continues as to the benefit of statins for primary prevention, not only in women but in the population as a whole.15,16 The definition of high risk, in terms of comorbidities and lipid profile, also continues to evolve and will likely be an important factor in identifying women who will benefit from statin therapy for primary prevention.

Statin adverse effects. Much of the debate about statins for primary prevention stems from concern about the adverse effects of these drugs. In addition to myopathy, there have been reports of increased risks of new diabetes and cognitive impairment.16 In a post hoc analysis of the Women’s Health Initiative, the adjusted risk of diabetes was 48% higher in women taking a statin for primary prevention than in similar women not taking a statin.17 (This finding should be viewed with caution, since the data are observational.)

There has also been a question of whether women experience more side effects from statin therapy than men do. Although thin or frail women over age 80 are more susceptible to statin side effects, this finding has not been observed in younger women.18

Comment. In view of the data, it appears reasonable to consider statin therapy for primary prevention in women deemed to be at high risk based on the current guidelines. However, as always, one must consider whether the benefits outweigh the risks for the individual patient. More study is needed to better evaluate the utility of statin therapy in primary prevention.

Hormone therapy

Hormone therapy has received enormous attention in both the medical community and the public media. (Hormone therapy is either combined estrogen and progestin or estrogen alone, used to treat symptoms of menopause and to prevent osteoporosis in postmenopausal women. Here, we will discuss hormone therapy and not hormone replacement therapy, which is used specifically to treat premature menopause.)

The safety of estrogen-progestin combination therapy has been the subject of great debate since a Women’s Health Initiative study showed a trend toward a greater risk of cardiovascular disease in estrogen-progestin users.19

Women who received estrogen by itself showed no difference in cardiovascular risk compared with those who received placebo. Unopposed estrogen is rarely prescribed, since it increases the risk of endometrial cancer in women who have not undergone hysterectomy.20

Both unopposed estrogen and combination therapy have also been found to increase the risk of stroke,20 deep vein thrombosis, gallbladder disease, and certain forms of urinary incontinence.

Guidelines on hormone therapy. The USPSTF does not recommend hormone therapy to prevent chronic conditions, basing its decision on the findings from the Women’s Health Initiative.21 The American College of Cardiology and American Heart Association (ACC/AHA) 2007 guidelines advise against continuing hormone therapy in patients who present with acute coronary syndrome, although recommendations need to address a broader scope of primary and secondary prevention patients.

Does timing matter? There is a hypothesis that when hormone therapy is started may affect the cardiovascular risk. A secondary analysis of the Women’s Health Initiative study22 showed a trend towards less cardiovascular disease in women who started hormone therapy within 9 years of menopause, whereas those starting it later had a statistically significantly higher rate of cardiovascular mortality. However, all women had a higher risk of stroke while on hormone therapy, regardless of timing.22

A study of 1,006 healthy women age 45 to 58 whose last menstrual period was 3 to 24 months before enrollment found a statistically significant reduction in the composite end point of death, hospital admission for myocardial infarction, or heart failure with hormone therapy.23 There was no significant increase in breast cancer, deep vein thrombosis, or stroke after 10 years of randomized treatment.

A retrospective analysis of 71,237 postmenopausal women in the California Teachers Study also found a significant reduction in the rate of cardiovascular disease-related deaths with hormone therapy in younger women (ie, younger than age 65), but not in older women.24 The authors concluded that it may not just be the years after menopause but also the baseline age of the woman that may influence outcomes.

In view of these studies, there is increasing recognition that hormone therapy may, in fact, still be beneficial in terms of cardiovascular and all-cause mortality in carefully selected patients. The cardiovascular risk in women, specifically older women who have had a longer duration of menopause, should also be weighed against the potential benefits of therapy in terms of quality of life and symptom relief.

Trials under way include the Kronos Early Estrogen Prevention (KEEP) and Danish Osteoporosis Prevention (DOPS) studies. KEEP is a 4-year, double-blind, randomized controlled trial of hormone therapy in women within 3 years of menopause. DOPS is an open-label trial that includes more than 1,000 women with early menopause. The results of these trials will likely affect future recommendations.

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