Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin

Abstract

The Women's Health Initiative trial of estrogen plus progestin was a double blind, placebo-controlled, randomized study that evaluated a combination of 0.625 mg of conjugated equine estrogens (CEE) and 2.5 mg of medroxyprogesterone acetate (MPA) daily in 16,608 women 50-79 years of age. The trial was stopped after 5.6 years of follow-up because of the lack of overall health benefit and an increased risk of invasive breast cancer. The postintervention phase began in mid 2002 and averaged 2.4 years of follow-up. Participants were monitored semiannually. The increased risk of cardiovascular disease events observed in women assigned to CEE or MPA treatment was not apparent in the postintervention phase. The annualized risk level was 1.97% in the CEE or MPA group and 1.91% in placebo recipients. The risk of malignant disease was greater in the CEE or MPA group than in the placebo group (1.56% versus 1.26%); the hazard ratio (HR) was 1.24, with a 95% confidence interval (CI) of 1.04-1.48. The HR for breast cancer was 1.27 (95% CI, 0.91-1.78). During follow-up after the intervention there was a moderate trend toward a lower HR. All-cause mortality was somewhat higher in the CEE or MPA group than in placebo recipients. A global index of risks and benefits was unchanged from the time of randomization. This index included, in addition to the two primary end-points of coronary heart disease and breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death from other causes. A major implication of this postintervention study is that women who receive combined estrogen and progestin therapy must be closely observed after treatment ends because of a sustained increase in the risk of malignant disease including breast cancer.