Combined Estrogen plus Progestin Replacement Therapy Increased Heart Disease and Breast Cancer Risk among Postmenopausal Women with Intact Uteruses Rossouw JE, Anderson GL, Prentice RL, et al.

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.

Before this trial, epidemiologic observational studies had suggested health and survival benefits primarily involving cardiovascular disease in women who took postmenopausal hormone therapy. The Heart and Estrogen/progestin Replacement Study (HERS) had shown in a randomized, controlled trial that such hormone therapy was not beneficial for secondary prevention in women who already had established coronary heart disease (3), but the role of postmenopausal hormone therapy in primary prevention of heart disease remained unknown.

Answering this question was the focus of the Women's Health Initiative (WHI). The WHI investigators recruited 16 608 healthy women with intact uteruses (50 to 79 years of age; mean age, 63.3 years; 84% white) from 40 U.S. clinical centers and conducted a randomized trial to determine the effects of hormone therapy with combined estrogen plus progestin. Participants were randomly assigned to receive 0.625 mg of conjugated equine estrogen per day plus 2.5 mg of medroxyprogesterone per day in a single pill or placebo. The patients had no history of breast cancer, only 7.7% had a history of coronary heart disease, and 12% had vasomotor symptoms at baseline.

The primary outcomes were incident coronary disease and invasive breast cancer. A secondary outcome measure was a global index that summarized risks and benefits, including stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, and total mortality. The trial was stopped after an average follow-up of 5.2 years (range, 3.5 to 8.5 years) because the risk for invasive breast cancer in the combined hormone therapy group exceeded the predetermined termination threshold.

At trial termination, 58% of participants in the hormone therapy group and 62% in the placebo group were still taking the study drug. Intention-to-treat analyses showed that the combined hormone therapy group had higher rates of invasive breast cancer (38 events per 10 000 compared with 30 events per 10 000 in the placebo group) and coronary heart disease (37 events per 10 000 compared with 30 events per 10 000 in the placebo group). The global index was also higher in the combined hormone therapy group (hazard ratio, 1.15 [CI, 1.03 to 1.28]); this group had a higher incidence of stroke and pulmonary embolism in particular. The combined hormone therapy group did, however, have lower rates of colorectal cancer and hip fracture. Total mortality was the same in the 2 groups. Overall, the findings were consistent across all subgroups based on age, race, risk status, or previous disease, with the exception of invasive breast cancer. For the latter outcome, an interaction occurred between study treatment and previous hormone therapy use; in women who took postmenopausal hormone therapy for 5 to 10 years, the hazard ratio for breast cancer increased to 4.61

Abstract reprinted from Annals of Internal Medicine, April 6, 2004

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