The Women's Health Initiative (WHI) multicentre primary prevention trial 1 randomized 16 608 postmenopausal women aged 50 -70 years to receive either conjugated equine estrogen (CEE) 0.625 mg/d plus medroxyprogesterone acetate (MPA) 2.5 mg/d or placebo. The planned duration of the trial was 8.5 years, but it was terminated early after a mean follow-up of 5.2 years. The follow-up of clinical events occurred every 6 months. The study protocol required annual mammograms. The estimated hazard ratios were as follows: coronary heart disease (CHD) 1.29 (95% CI 1.02 to 1.63), breast cancer 1.26 (1.00 to 1.59), stroke 1.41 (1.07 to 1.85), pulmonary embolism 2.13 (1.39 to 3.25), colorectal cancer 0.63 (0.43 to 0.92), endometrial cancer 0.83 (0.47 to 1.47), hip fracture 0.66 (0.45 to 0.98). For total mortality the hazard ratio was 0.98 (0.82 to 1.18). Absolute health risks per 10 000 person-years were as follows: CHD events 7, strokes 8, pulmonary embolisms 8, invasive breast cancers 8. Absolute risk reductions were as follows: colorectal cancer 6, hip fractures 5. The absolute excess risk of events was 19 per 10 000 person-years.
An observational follow-up of WHI studies 3 examined total and cause-specific cumulative during the cumulative 18-year follow-up with prespecified analyses by 10-year age group based on age at time of randomization. Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years), mortality follow-up was available for more than 98%. 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 to 1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02, 95% CI 0.96 to 1.08); and with CEE alone, the HR was 0.94, 95% CI 0.88 to 1.01). HR for cardiovascular mortality was 1.00 (95% CI 0.92 to 1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality 1.03 (95% CI 0.95 to 1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes 0.95 (95% CI 0.88 to 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 to 0.87) during the intervention phase and the ratio was 0.87 (95% CI 0.76 to 1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.
A secondary analysis of the WHI studies 4 explored the effects of HRT on risk of cardiovascular disease by age or years since menopause began. For women with less than 10 years since menopause began, the HR for CHD was 0.76 (95% CI 0.50 to 1.16); 10 to 19 years, 1.10 (95% CI 0.84 to 1.45); and 20 or more years, 1.28 (95% CI 1.03 to 1.58) (P for trend = .02). The estimated absolute excess risk for CHD for women within 10 years of menopause was -6 per 10 000 person-years; for women 10 to 19 years since menopause began, 4 per 10 000 person-years; and for women 20 or more years from menopause onset, 17 per 10 000 person-years. For the age group of 50 to 59 years, the HR for CHD was 0.93 (95% CI 0.65 to 1.33) and the absolute excess risk was -2 per 10 000 person-years; 60 to 69 years, 0.98 (95% CI 0.79 to 1.21) and -1 per 10 000 person-years; and 70 to 79 years, 1.26 (95% CI 1.00 to 1.59) and 19 per 10 000 person-years (P for trend = .16). Hormone therapy increased the risk of stroke (HR 1.32; 95% CI 1.12 to 1.56). Risk did not vary significantly by age or time since menopause. There was a nonsignificant tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50-59 years; 1.05 for 60-69 years, and 1.14 for 70-79 years; P for trend = .06).
A extended poststopping phases of the WHI trials 2 reported the extended 13 years postintervention follow-up. During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (HR 1.18; 95% CI 0.95 to 1.45), for invasive breast cancer (HR 1.24; 95% CI 1.01 to 1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR 1.28, 95% CI 1.11 to 1.48). The risks and benefits were more balanced during the CEE alone intervention: for CHD (HR 0.94; 95% CI 0.78 to 1.14) and for invasive breast cancer (HR 0.79; 95% CI 0.61 to 1.02). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index. Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials.
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