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

Abstract

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. (ClinicalTrials.gov 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.

Figure 1

Proportion of women who took at least 80% of the study pills by treatment arm, the Women's Health Initiative estrogen-plus-progestin randomized trial

Figure 2

Estimated proportion of women free of coronary heart disease (CHD) under continuous adherence to the assigned treatment, the Women's Health Initiative estrogen-plus-progestin randomized trial

Appendix Figure

Proportion of women free of coronary heart disease (CHD)--intention-to-treat analysis, the Women's Health Initiative estrogen-plus-progestin randomized trial