The WHI Randomized Trials: Is Menopausal Hormone Therapy Associated with Long-Term Mortality?
The original WHI trials were designed to assess risk vs benefits of menopausal hormone therapy
Double-blinded, placebo-controlled, randomized clinical trials, conducted among US postmenopausal women aged 50 to 79 years at enrollment using the following 2 drug regimens
Conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for women with an intact uterus
CEE alone for women with hysterectomy
The CEE plus MPA trial was stopped early (after 5.6 years) due to an increased risk of breast cancer and overall risks exceeding benefits
CEE-alone trial was stopped after 7.2 years due to an increased risk of stroke
Postintervention follow up has been ongoing
Manson et al. (JAMA, 2017) report the extended follow up on all-cause and cause-specific mortality with attention to age
Postintervention follow up study of the two WHI studies (1993-1998)
Total 27,347 postmenopausal women ages 50 to 79 years were recruited at 40 US clinical centers
16,608 women with a uterus received daily oral CEE (0.625 mg) plus MPA (2.5 mg) or placebo
10,739 women with hysterectomy received daily oral CEE (0.625 mg) alone or placebo
Primary outcome: All-cause mortality
Cause-specific mortality (cardiovascular disease cancer and other major causes)
18 year follow up in 2 trials separately and combined (pooled)
Pooled cohort: 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])
CEE plus MPA: HR 1.02 (95% CI, 0.96-1.08)
CEE alone: HR 0.94 (95% CI, 0.88-1.01)
Pooled cohort: HR 1.00 (95% CI, 0.92-1.08)
Total cancer mortality
Pooled cohort: HR 1.03 (95% CI, 0.95-1.12)
Pooled cohort: HR 0.95 (95% CI, 0.88-1.02)
results did not differ significantly between trials
Comparing younger women (50-59 years) to older women (70-79 years) in the pooled cohort for all-cause mortality
During intervention phase: all-cause mortality reduced compared to older women
ratios of HRs 0.61 (95% CI, 0.43-0.87)
During cumulative 18-year follow-up: no difference seen in all-cause mortality compared to older women
ratios of HRs 0.87 (95% CI, 0.76-1.00)
No significant difference between trials
There was no long-term association between hormone replacement and all-cause or cause-specific mortality during a follow up period of 18 years in women who used combination estrogen plus progestin for 5.6 or estrogen-alone group for 7.2 years
Limitations include specific hormone replacement formulations and therefore results may not be generalizable
Cause-specific mortality results should be considered exploratory because multiple smaller subgroups were analyzed
The accompanying editorial states that this present study supports the recently released 2017 NAMS guidance and women should be reassured and hormone therapy appears “safe and efficacious”.
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