Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis

In the Estrogen Replacement and Atherosclerosis trial, a randomized, double-blind, placebo-controlled study, 309 postmenopausal women with angiographically confirmed coronary artery disease (CAD) were assigned to receive estrogen alone, estrogen plus medroxyprogesterone acetate, or placebo and were reassessed approximately 3 years later. Participants had one or more epicardial coronary arteries with luminal stenosis of at least 30%. Estrogen therapy consisted of 0.625 mg of conjugated equine estrogen (Premarin), and the combined treatment contained the same amount of estrogen plus 2.5 mg of medroxyprogesterone acetate. The interval between angiographic assessments averaged 3.2 years. Mean age at the beginning of the study was 66 years. There were no significant demographic or clinical differences among the 248 women included in the comparative angiographic analysis. Unopposed estrogen therapy correlated with a 20.9% reduction in plasma low-density lipoprotein cholesterol, compared with a 16.5% decline with estrogen plus medroxyprogesterone and a 1.3% drop in the placebo group. Both forms of active treatment were associated with significantly greater increases in high-density lipoprotein cholesterol (18.8 and 14.2%, respectively) compared with placebo (6.8%). Treated women also had increased triglyceride levels, but these levels did not differ significantly from those in the placebo group. Adjusting for baseline measurements, average minimum coronary artery diameters at follow-up were 1.87 mm in women given estrogen alone, 1.84 mm in women given combined hormone treatment; and 1.87 mm in placebo recipients. New lesions developed in 30, 20, and 33% of subjects, respectively. Nine women died of CAD during follow-up, and 19 had nonfatal myocardial infarcts. Rates of clinical cardiovascular events were similar in all groups. Venous thromboembolism occurred in five women given unopposed estrogen, two receiving combined treatment, and one receiving placebo. No endometrial cancer emerged during follow-up, but endometrial hyperplasia was more frequent in women given unopposed estrogen. Just over half of these women had heavy or persistent vaginal bleeding, and eight underwent dilation and curettage. Fractures were more than twice as common in placebo recipients than in those assigned to hormone treatment, but the difference was not statistically significant. The investigators believe that women with heart disease should not expect to gain cardiovascular benefit from use of conjugated estrogen, either alone or in combination with medroxyprogesterone acetate, and this probably can be extended to other forms of estrogen and progestin. It remains possible that estrogen is effective for the primary prevention of coronary heart disease, although this remains to be documented. At present it is most appropriate to use other measures, including lipid-lowering agents, to prevent CAD or slow its progress.