Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial

Abstract

Context: The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.

Objective: To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009.

Design, setting, and participants: The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10,739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent.

Main outcome measures: The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death.

Results: The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older 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).

Conclusions: 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.

Trial registration: clinicaltrials.gov Identifier: NCT00000611.

Figure 1

Consort diagram of the WHI Hormone Therapy Estrogen-Alone Trial through extended follow-up * Data as of August 14, 2009. †Consent status as of August 14, 2009.

Figure 2

Effects of randomized assignment to conjugated equine estrogen vs. placebo on clinical outcomes during intervention phase and post-intervention in the Women’s Health Initiative Estrogen-alone Trial (details in Appendix 2 Table). ^aHazard ratios and 95% confidence intervals are shown for the intervention phase in green, the post-intervention period in red, and the overall period in black. The P-difference (shown in blue) tests whether the hazard ratio for the intervention phase equals the hazard ratio for the post-intervention period. ^bHazard ratios are derived from proportional hazards models stratified by prior disease (for outcomes where women were eligible for enrollment with and without the prevalent condition), age and dietary modification randomization group. Models for the overall 10.7 mean year follow-up period include a time dependent term for trial phase. For the intervention and overall phases, time to event equals 0 on date of randomization. For the postintervention phase, time to event equals 0 on February 29, 2004. Abbreviations: CABG, coronary artery bypass graft; CEE, conjugated equine estrogen; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; DVT, deep vein thrombosis; HR, hazard ratio; MI, myocardial infarction; PE, pulmonary embolism; PTCA, percutaneous transluminal coronary angioplasty.

Figure 3

Cumulative incidence of clinical outcomes by randomized assignment to conjugated equine estrogen or placebo during the intervention phase and post-intervention in the Women’s Health Initiative Estrogen-alone Trial (8 graphs) ^aShading represents quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the intervention ended on February 29, 2004). Darker shading corresponds to a quintile of time in which more women were still being followed; lighter shading corresponds to a quintile of time in which fewer women were still being followed depending on their date of randomization.

Figure 3

Cumulative incidence of clinical outcomes by randomized assignment to conjugated equine estrogen or placebo during the intervention phase and post-intervention in the Women’s Health Initiative Estrogen-alone Trial (8 graphs) ^aShading represents quintiles of duration of intended intervention and follow-up in the study population (elapsed time from randomization until the intervention ended on February 29, 2004). Darker shading corresponds to a quintile of time in which more women were still being followed; lighter shading corresponds to a quintile of time in which fewer women were still being followed depending on their date of randomization.

Figure 4

Cumulative annualized incidence rates^a, hazard ratios^b, and 95% confidence intervals for clinical outcomes in the Women’s Health Initiative Estrogen-alone Trial according to ten-year age groups^c at enrollment. ^a Annualized incidence rates were estimated for the overall follow-up period by dividing the number of events by the corresponding person-time for participants in each age strata. ^b Hazard ratios for the overall follow-up period are shown in the black squares. For comparison, hazard ratios for the intervention phase are shown in the open bars. ^cSample sizes at enrollment for each age and randomization group are as follows: age group 50–59, 1637 (CEE), 1673 (placebo); age group 60–69, 2387 (CEE), 2465 (placebo); age group 70–79, 1286 (CEE), 1291 (placebo). Abbreviations: CEE, conjugated equine estrogen; CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction.