Hormone Replacement Therapy and Heart Disease
Replacing Dogma With Data
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In 1966, Dr Robert A. Wilson wrote an influential book entitled Feminine Forever that extolled the virtues of postmenopausal hormone replacement therapy (HRT).1 Over the next 3 decades, use of HRT to preserve the health and vitality of postmenopausal women became one of America’s most popular medical treatment paradigms. The enthusiasm for HRT was greatly enhanced by the perception that it could lower a woman’s risk for heart disease, perhaps by as much as 50%. This notion was fueled, in part, by the remarkably consistent finding from observational studies that postmenopausal users of HRT had substantially lower rates of cardiovascular events than non-users.2 Promising in vitro and animal model studies and favorable effects of HRT on cardiovascular risk factors added credibility to the observational study findings.3 By the mid-1990s, these cardiovascular and other data, coupled with effective relief of postmenopausal symptoms, helped make HRT the most frequently prescribed drug in the United States, despite the absence of any large, randomized clinical trials documenting its net clinical benefits or risks.
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In 1998, however, the HRT paradigm began to crumble with the release of the Heart and Estrogen/progestin Replacement Study (HERS). In this, the first major randomized clinical trial of HRT for secondary prevention of heart disease, there was no overall benefit of hormone treatment, but there was an unexpected pattern of increased risk during the first year of follow-up.4 Since then, 7 additional randomized clinical trials, testing a variety of hormone replacement regimens, also found no benefit of HRT on anatomic or clinical manifestations of atherosclerosis in women with established cardiovascular disease.5–9b In many of these trials, there was a persistent suggestion that HRT might indeed increase cardiovascular risk. Debates about the validity, generalizability, and proper interpretation of these trials resulted in numerous …