Outcomes after Stopping Conjugated Equine Estrogens in Postmenopausal Women

The effects of conjugated equine estrogens (CEEs) on the incidence of chronic disease among postmenopausal women with prior hysterectomy were evaluated in the Women’s Health Initiative Estrogen-Alone Trial. The double-blind, placebo-controlled, randomized trial intervention was stopped 1 year early (after a mean follow-up of 7.1 years) due to an increased risk of stroke as well as little likelihood of altering the balance of risk to benefit by the planned termination date. Previous reports of this trial were limited to outcomes that occurred during the intervention phase. Researchers recently conducted a preplanned analysis on postintervention data through a mean follow-up of 10.7 years. The analysis had 3 objectives: (1) assess the long-term effects of the CEE intervention on health outcomes, (2) determine whether effects of CEE on health outcomes differed between the intervention and postintervention periods, and (3) determine if previously identified suggestions of age-specific differences in effects of CEE on health outcomes persisted after stopping the intervention. Results of the analysis were reported in the Journal of the American Medical Association [2011;305(13):1305-1314]. During the intervention phase of the trial, 0.625 mg/day of CEE was compared with placebo in 10,739 women 50 to 79 years of age in the United States. Follow-up continued after the planned trial completion date among surviving participants who provided written consent (n=7645). The primary outcome measures were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included stroke, pulmonary embolism, colorectal cancer, hip fracture, and death in addition to the 2 primary outcomes. Among women in the CEE group, the postintervention risk (annualized rate) for CHD was 0.64% compared with 0.6% among women in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25); for invasive breast cancer, the risk for women in the CEE group was 0.26% compared with 0.34% for women in the placebo group (HR, 0.75; 95% CI, 0.51-1.09). For total mortality, the risk among women in the CEE group was 1.47% compared with 1.48% for women in the placebo group (HR, 1.00; 95% CI, 0.84-1.18). During the postintervention follow-up period, the risk of stroke was no longer elevated among women in the CEE group; among women in the CEE group, the risk was 0.36% compared with 0.41% among women in the placebo group (HR, 0.89; 95% CI, 0.64-1.24). The risk of deep vein thrombosis was lower during the postintervention follow-up period: 0.17% among women in the CEE group compared with 0.27% among those in the placebo group (HR, 0.63; 95% CI, 0.41-0.98). The risk of hip fracture did not differ significantly from the earlier analysis: 0.36% among women in the CEE group compared with 0.28% among women in the placebo group (HR, 1.27; 95% CI, 0.88-1.82). Lower breast cancer incidence persisted over the entire follow-up period (0.27% in the CEE group vs 0.35% in the placebo group; HR, 0.77; 95% CI, 0.62-0.95). Compared with older women, health outcomes were more favorable for younger women for CHD (P=.05 for interaction), total myocardial infarction (P=.007 for interaction), colorectal cancer (P=.04 for interaction), total mortality (P=.04 for interaction), and global index of chronic diseases (P=.009 for interaction). In summary, the researchers commented, “Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.”