Coronary heart disease in postmenopausal recipients of estrogen plus progestin therapy: does the increased risk ever disappear? A randomized trial

Ann Intern Med. 2010 Feb 16;152(4):211-7. doi: 10.7326/0003-4819-152-4-201002160-00005.


Background: Estrogen plus progestin therapy increases the risk for coronary heart disease (CHD) in postmenopausal women. However, this increased risk might be limited to the first years of use and to women who start therapy late in menopause.

Objective: To estimate the effect of continuous estrogen plus progestin therapy on CHD risk over time and stratified by years since menopause.

Design: Women's Health Initiative randomized, double-blinded, placebo-controlled trial. ( registration number: NCT00000611)

Setting: 40 U.S. clinical centers.

Patients: 16 608 postmenopausal women with an intact uterus at baseline from 1993 to 1998.

Intervention: Conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo.

Measurements: Adherence-adjusted hazard ratios and CHD-free survival curves estimated through inverse probability weighting.

Results: Compared with no use of hormone therapy, the hazard ratio for continuous use of estrogen plus progestin therapy was 2.36 (95% CI, 1.55 to 3.62) for the first 2 years and 1.69 (CI, 0.98 to 2.89) for the first 8 years. For women within 10 years after menopause, the hazard ratios were 1.29 (CI, 0.52 to 3.18) for the first 2 years and 0.64 (CI, 0.21 to 1.99) for the first 8 years, and the CHD-free survival curves for continuous use and no use of estrogen plus progestin crossed at about 6 years (CI, 2 years to 10 years).

Limitation: The analysis may not have fully adjusted for joint determinants of adherence and CHD risk. Sample sizes for some subgroup analyses were small.

Conclusion: No suggestion of a decreased risk for CHD was found within the first 2 years of estrogen plus progestin use, including in women who initiated therapy within 10 years after menopause. A possible cardioprotective effect in these women who initiated therapy closer to menopause became apparent only after 6 years of use.

Primary funding source: National Heart, Lung, and Blood Institute.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Coronary Disease / epidemiology*
  • Coronary Disease / prevention & control
  • Disease-Free Survival
  • Double-Blind Method
  • Estrogen Replacement Therapy / adverse effects*
  • Estrogens, Conjugated (USP) / adverse effects*
  • Female
  • Humans
  • Medication Adherence
  • Medroxyprogesterone Acetate / adverse effects*
  • Middle Aged
  • Postmenopause / drug effects*
  • Proportional Hazards Models
  • Risk Factors
  • Time Factors


  • Estrogens, Conjugated (USP)
  • Medroxyprogesterone Acetate

Associated data