Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II)

Context  The Heart and Estrogen/progestin Replacement Study (HERS) was a randomizedtrial of estrogen plus progestin therapy after menopause. Objective  To examine the effect of long-term postmenopausal hormone therapy oncommon noncardiovascular disease outcomes. Design and Setting  Randomized, blinded, placebo-controlled trial of 4.1 years' duration(HERS) and subsequent open-label observational follow-up for 2.7 years (HERSII), carried out between 1993 and 2000 in outpatient and community settingsat 20 US clinical centers. Participants  A total of 2763 postmenopausal women with coronary disease and averageage of 67 years at enrollment in HERS; 2321 women (93% of those surviving)consented to follow-up in HERS II. Intervention  Participants were randomly assigned to receive 0.625 mg/d of conjugatedestrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo(n = 1383) during HERS; open-label hormone therapy was prescribed at personalphysicians' discretion during HERS II. The proportions with at least 80% adherenceto hormones declined from 81% (year 1) to 45% (year 6) in the hormone groupand increased from 0% (year 1) to 8% (year 6) in the placebo group. Main Outcome Measures  Thromboembolic events, biliary tract surgery, cancer, fracture, andtotal mortality. Results  Comparing women assigned to hormone therapy with those assigned to placebo,the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolismdeclined from 2.66 (95% confidence interval CI], 1.41-5.04) during HERS to1.40 (95% CI, 0.64-3.05) during HERS II (P for timetrend = .08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and3 of the 73 women with thromboembolism died within 30 days due to pulmonaryembolism. The overall RH for biliary tract surgery was 1.48 (95% CI, 1.12-1.95);for any cancer, 1.19 (95% CI, 0.95-1.50); and for any fracture, 1.04 (95%CI, 0.87-1.25). There were 261 deaths among those assigned to hormone therapyand 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjustedand as-treated analyses did not alter our conclusions. Conclusions  Treatment for 6.8 years with estrogen plus progestin in older womenwith coronary disease increased the rates of venous thromboembolism and biliarytract surgery. Trends in other disease outcomes were not favorable and shouldbe assessed in larger trials and in broader populations.