The most recent findings from the Women’s Health Initiative study of short-term unopposed estrogen therapy suggest that after 10 years, the treatment neither increases nor decreases risks for coronary heart disease, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality, according to a report in the April 6 issue of JAMA.
This portion of the WHI study was halted early when interim analysis in 2004 showed an increased risk of stroke in women taking conjugated equine estrogens (CEE) compared with those taking placebo. "All previous reports of this trial were limited to outcomes occurring during the intervention phase. [Now] we report data on postintervention outcomes through a mean of 10.7 years of follow-up," said Andrea Z. LaCroix, Ph.D., of Fred Hutchinson Cancer Research Center, Seattle, and her associates (JAMA 2011;305:1305-14).
Andrea Z. LaCroix, Ph.D.
In the estrogen-only portion of the WHI study, 10,739 postmenopausal women who had undergone hysterectomy had been randomly assigned to receive either CEE or placebo. They were followed during this intervention phase for a median of 6 years, but the median "adherent time" – the interval during which the women actually took more than 80% of their study pills – was only 3.5 years because more than half stopped taking the pills even before the early halt of the trial.
Approximately 78% of the surviving study subjects (3,778 who took CEE and 3,867 who took placebo) agreed to participate in the extended follow-up reported here.
The increased risks of stroke, deep vein thrombosis, and pulmonary embolism that had been noted during the intervention phase did not persist during extended follow-up. In addition, active treatment, which had showed no effect on CHD risks during the intervention, continued to show no effect on CHD risks. For all cardiovascular events, the cumulative hazard ratio was 2.26% with active treatment and 2.12% with placebo, a nonsignificant difference.
Colorectal cancer incidence did not differ between women who received CEE and those who received placebo during the intervention phase, and this lack of effect persisted during extended follow-up.
Hip fracture risk had been reduced with CEE therapy during the intervention phase, but this benefit did not persist during the extended follow-up. Numerically, hip fracture incidence was slightly higher in the CEE group than in the placebo group.
Total mortality risk remained similar between the two study groups both during the intervention and during extended follow-up.
Only one benefit of CEE therapy that was seen during the intervention phase persisted in the extended follow-up and became statistically significant: Breast cancer incidence was 0.27% with active treatment and 0.35% with placebo. The researchers noted that these results differ from those of the other portion of the WHI trial in which subjects received combined estrogen-plus-progestin. In that study arm, active treatment impeded mammographic accuracy and was associated with significantly higher rates of breast cancer and breast cancer mortality, they noted.
The women’s age at commencing treatment showed a significant interaction with outcomes, both during the intervention phase and during extended follow-up. The results suggest that there may be greater benefit and safety for women who start CEE in their early 50s, and less benefit with more potential harm for women who are older when they begin treatment.
"Among younger women, no new safety concerns emerged and some risk reductions became apparent during the postintervention period. Among older women, risks of colorectal cancer, death, and the global index of chronic diseases were elevated over the cumulative follow-up period," Dr. LaCroix and her associates said.
The WHI was funded by the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs. Dr. LaCroix reported ties to Warner Chilcott, Sanofi-Aventis, Amgen, and Pfizer. Her associates reported ties to numerous other industry sources.