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


METHODS
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.


METHODS
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.


METHODS
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.


METHODS
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.
Hulley
Stephen
S
Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, San Francisco, CA 94143-0560, USA. shulley@epi.ucsf.edu
Furberg
Curt
C
Barrett-Connor
Elizabeth
E
Cauley
Jane
J
Grady
Deborah
D
Haskell
William
W
Knopp
Robert
R
Lowery
Maureen
M
Satterfield
Suzanne
S
Schrott
Helmut
H
Vittinghoff
Eric
E
Hunninghake
Donald
D
D000368:Aged; D001660:Biliary Tract Diseases / Q000453:epidemiology* / Q000601:surgery; D001662:Biliary Tract Surgical Procedures / Q000706:statistics & numerical data; D002423:Cause of Death; D003327:Coronary Disease / Q000453:epidemiology; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D050723:Fractures, Bone / Q000453:epidemiology*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000627:therapeutic use; D009369:Neoplasms / Q000453:epidemiology*; D017698:Postmenopause; D011655:Pulmonary Embolism / Q000453:epidemiology; D012307:Risk Factors; D016019:Survival Analysis; D013923:Thromboembolism / Q000453:epidemiology*; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000453:epidemiology
D004966:Estrogens, Conjugated (USP); D017258:Medroxyprogesterone Acetate