Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women's Health Initiative Randomized Trials

Abstract

Importance: Health outcomes from the Women's Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.

Objective: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women's Health Initiative hormone therapy trials.

Design, setting, and participants: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.

Interventions: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).

Main outcomes and measures: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.

Results: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

Conclusions and relevance: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.

Trial registration: clinicaltrials.gov Identifier: NCT00000611.

Figure 1. Flow of Participants in the Women's Health Initiative Trials of Postmenopausal Hormone Therapy vs Placebo Through Extended Follow-up

During the postintervention and extension phases, fewer than2%of women in the conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) trial and fewer than 4% of women in the CEE-alone trial reported use of hormone therapy. NDI indicates National Death Index.

Figure 2. Mortality Outcomes in the Women's Health Initiative Hormone Therapy Trials During the 18-Year Cumulative Follow-up

The 18-year follow-up is cumulative, indicating the intervention plus extended postintervention phases of the 2 trials (median, 17.7 [interquartile range {IQR}, 16.6-18.6] years in the conjugated equine estrogens [CEE] plus medroxy progesterone acetate [MPA] trial; median, 17.7 [IQR, 16.5-18.7] years in the CEE-alone trial; and median,17.7 [IQR,16.6-18.6] years in the pooled analysis). ^aCardiovascular disease (CVD) mortality includes deaths due to myocardial infarction, coronary heart disease, stroke, heart failure, peripheral vascular disease, venous thromboembolism, and other major causes of CVD death. ^bThe P value corresponding with a test of heterogeneity between trial-specific hazard ratios (HRs) was .05 or less; therefore, the pooled estimate and HR (95% CI) are not reported. ^cIndicates other mortality outcomes that were known but were not due to Alzheimer disease or other dementia, chronic obstructive pulmonary disease (COPD), or accident or injury.

Figure 3. Mortality Outcomes During the Intervention Phase According to 10-Year Age Groups at Randomization

Reported values indicate the duration of follow-up for the intervention phase (median, 5.6 [interquartile range {IQR}, 4.9-6.5] years in the conjugated equine estrogens [CEE] plus medroxyprogesterone acetate [MPA] trial; median, 7.2 [IQR, 6.5-8.2] years in the CEE-alone trial; and median, 6.3 [IQR, 5.3-7.3] years in the pooled analysis). Age groups indicate participant ages at randomization. HR indicates hazard ratio. ^aP values based on a test for trend of interaction between the randomization group and the age group. ^bCardiovascular disease (CVD) mortality includes deaths due to myocardial infarction, coronary heart disease, stroke, heart failure, peripheral vascular disease, venous thromboembolism, and other major causes of CVD death. ^c Indicates mortality outcomes not due to CVD or cancer.

Figure 4. Mortality Outcomes During the 18-Year Cumulative Follow-Up According to 10-Year Age Groups at Randomization

The 18-year follow-up is cumulative, indicating the intervention plus extended postintervention phases of the 2 trials (median, 17.7 [interquartile range {IQR}, 16.6-18.6] years in the conjugated equine estrogens [CEE] plus medroxyprogesterone acetate [MPA] trial; median, 17.7 [IQR, 16.5-18.7] years in the CEE-alone trial; and median,17.7 [IQR,16.6-18.6] years in the pooled analysis). HR indicates hazard ratio. ^aP values based on a test for trend of interaction between the randomization group and the age group. ^bCardiovascular disease (CVD) mortality includes deaths due to myocardial infarction, coronary heart disease (CHD), stroke, heart failure, peripheral vascular disease, venous thromboembolism, and other major causes of CVD death. ^c Indicates mortality outcomes not due to CVD or cancer.