Vitamin E and cardiovascular health: does sex matter?

THE CRITICAL IMPORTANCE OF PREVENTIVE MEDICINE for all people has long been recognized, as documented in the writings of Hippocrates and Osler. Moreover, in preventive health, it is clear that sex matters, as the 2001 Institute of Medicine report concluded after reviewing the basis for biological differences in health. The goal of preventing cardiovascular disease is similar in men and women. However, the strategies and recommendations to achieve this goal differ, as exemplified in the 2004 American Heart Association Guidelines for Cardiovascular Disease Prevention in Women. Although it is increasingly well known and appreciated that heart disease is the leading cause of death in both women and men, it is also true that researchers are increasingly discovering sex differences in how cardiovascular disease may be prevented and treated. All prevention, as well as treatment, involves some degree of balancing benefit and risk. The attractiveness of a particular strategy depends on the magnitude of the risk/ benefit ratio. Put simply, it is difficult to improve the health of individuals who largely (apparently) have nothing wrong with them. Yet from a societal viewpoint, it is still reasonable to recommend a preventive therapy to individuals at very low risk; even though individual patient benefits are very small, the population benefits are huge. This principle is applied in legislation mandating use of childhood vaccines. However, this strategy only works if the possible risks are trivial—even a low risk of harm (eg, Guillain-Barre syndrome from swine flu shots) cannot be justified. Sex-specific benefits and risks can differ for many reasons, such as that the incidence and prevalence of coronary heart disease are lower in women than in men until after the sixth decade. For example, according to recent data from the Women’s Health Study (WHS), aspirin provides no benefit in healthy women (except in the subgroup of those aged 65 years or older), even though previous studies have shown abenefit inhealthymen.Similarly, like studies inmen,numerous statin trials in the last decade have not shown a benefit on total or coronary heart disease mortality in women. In this issue of JAMA, Lee et al report on another promising prevention strategy, vitamin E, which earlier epidemiologic and observational studies suggest provides cardiovascular benefits in men and women. Vitamin E is a powerful biological antioxidant that can protect cells against the ravages of free radicals. Thus, there has been great interest in the value of vitamin E for preventing heart disease and cancer. Vitamin E is found in vegetable oils, nuts, green leafy vegetables, and fortified cereals, among other foods. So how does vitamin E supplementation compare with other primary prevention strategies for women? Until publication of the Heart and Estrogen/progestin Replacement Study (HERS) in 1998, followed by the Women’s Health Initiative (WHI) a few years later, postmenopausal hormone therapy was the most popular primary prevention strategy for women. Hormone therapy has plausible pathophysiological mechanisms for cardiovascular risk reduction, such as lipid lowering and favorable vascular effects. In addition, epidemiologic and observational studies have suggested a benefit of hormone therapy on cardiovascular disease. However, after randomized controlled trials showed no benefit on total or cardiovascular mortality and in fact found increased cardiovascular events in the first year of use, hormone therapy has plummeted from 90 million US prescriptions annually between 1999 and 2002 to a drug with a black box warning on its label. Like hormone therapy, vitamin E has plausible mechanisms and data from observational studies to support a meaningful role in prevention of cardiac disease. Data from approximately 90 000 women in the Nurses’ Health Study showed a 30% to 40% decrease in heart disease for women taking vitamin E supplements, after adjustment for risk factors for coronary disease and use of other antioxidant nutrients. In this issue of JAMA, Lee et al report their findings from the WHS on the effects of 600 IU of vitamin E vs placebo every other day in 39 876 healthy women followed up for an average of 10 years. The investigators found no benefit