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Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II)

Stephen Hulley, MD, MPH; Curt Furberg, MD, PhD; Elizabeth Barrett-Connor, MD; Jane Cauley, PhD; Deborah Grady, MD, MPH; William Haskell, PhD; Robert Knopp, MD; Maureen Lowery, MD; Suzanne Satterfield, MD; Helmut Schrott, MD; Eric Vittinghoff, PhD; Donald Hunninghake, MD; for the HERS Research Group

JAMA. 2002;288:58-64.

Context  The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized trial of estrogen plus progestin therapy after menopause.

Objective  To examine the effect of long-term postmenopausal hormone therapy on common 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 (HERS II), carried out between 1993 and 2000 in outpatient and community settings at 20 US clinical centers.

Participants  A total of 2763 postmenopausal women with coronary disease and average age 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 conjugated estrogens plus 2.5 mg of medroxyprogesterone acetate (n = 1380) or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group and increased from 0% (year 1) to 8% (year 6) in the placebo group.

Main Outcome Measures  Thromboembolic events, biliary tract surgery, cancer, fracture, and total mortality.

Results  Comparing women assigned to hormone therapy with those assigned to placebo, the unadjusted intention-to-treat relative hazard (RH) for venous thromboembolism declined from 2.66 (95% confidence interval [CI], 1.41-5.04) during HERS to 1.40 (95% CI, 0.64-3.05) during HERS II (P for time trend = .08); it was 2.08 overall for the 6.8 years (95% CI, 1.28-3.40), and 3 of the 73 women with thromboembolism died within 30 days due to pulmonary embolism. 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 therapy and 239 among those assigned to placebo (RH, 1.10; 95% CI, 0.92-1.31). Adjusted and as-treated analyses did not alter our conclusions.

Conclusions  Treatment for 6.8 years with estrogen plus progestin in older women with coronary disease increased the rates of venous thromboembolism and biliary tract surgery. Trends in other disease outcomes were not favorable and should be assessed in larger trials and in broader populations.

Author Affiliations: Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco (Drs Hulley, Grady, and Vittinghoff); Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (Dr Furberg); Division of Epidemiology, Department of Family and Preventive Medicine, University of California, San Diego (Dr Barrett-Connor); Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); Department of Medicine, Stanford University, Stanford, Calif (Dr Haskell); Department of Medicine, University of Washington School of Medicine, Seattle (Dr Knopp); University of Miami School of Medicine, Miami, Fla (Dr Lowery); Department of Preventive Medicine, University of Tennessee, Memphis (Dr Satterfield); College of Public Health and Medicine, University of Iowa, Iowa City (Dr Schrott); and Departments of Medicine and Pharmacology, University of Minnesota, Minneapolis (Dr Hunninghake).

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