Oral contraception is known to increase the risk of venous thromboembolism, which presumably is a dose-related effect of estrogen. Although the estrogens generally used to treat postmenopausal women are only one-forth to one-fifth as potent as those in modern contraceptive preparations, recent observations suggest that the risk of deep venous thrombosis (DVT) and pulmonary embolism (PE) may be increased 2- to 4-fold. This study analyzed data from the Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled trial of whether 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate daily influences the risk of new coronary events in 2763 postmenopausal women with coronary heart disease. The trial was stopped after an average follow-up of 3.3 years for participants at increased risk of thromboembolism for any reason. Participants, whose average age was 67 years, had no history of venous thromboembolism.
In nearly 11,000 woman-years of follow-up, DVT or PE occurred at a rate of 6.2 per 1000 woman-years in the hormone-treated group and 2.3 per 1000 in placebo recipients, for a relative hazard of 2.7 (Fig. 1). Comparable results were obtained at all 20 participating clinical centers. Both DVT and PE, analyzed separately, were more prevalent in women taking hormone therapy. Two women, both of them treated, died of PE. The risk of PE seemed to decline during the course of the study, but that of DVT remained about the same. The only independent predictor of venous thromboembolism on multivariate analysis was age over 52 years at the last menses. Hormone therapy remained a significant predictor after adjusting for other factors. Women with a history of myocardial infarction were at a 2.1-fold higher risk of venous thromboembolism. The risk was increased more than 5-fold during the first 90 days after myocardial infarction. Warfarin use did not lower the risk, but few women took warfarin. Women who reported using aspirin during the trial period had a risk of thromboembolism 50 percent lower than that of others. Statin therapy (but not the use of other lipid-lowering agents) had a similar effect.
Women considering postmenopausal hormone replacement therapy should be aware of the increased risk of venous thromboembolism. Such treatment should be avoided in those at very high risk, including women with a history of venous thromboembolism, cancer, lower limb fracture, or immobilization.
Ann Intern Med 2000;132:689-696