The WHI Randomized Trials: Is Menopausal Hormone Therapy Associated with Long-Term Mortality?

PURPOSE:

  • 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

METHODS:

  • 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)

RESULTS:

  • All-cause mortality
    • 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)
  • Cardiovascular mortality
    • 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)
  • Other causes
    • 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

CONCLUSION:

  • 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”.

Learn More – Primary Sources:

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

Menopausal Hormone Therapy: Understanding Long-term Risks and Benefits (JAMA Editorial)