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Writing Group for the Women's Health Initiative Investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial. JAMA. 2002;288(3):321–333. doi:10.1001/jama.288.3.321
Writing Group for the Women's Health Initiative Investigators: Jacques E. Rossouw, MBChB, MD, National Heart, Lung, and Blood Institute, Bethesda, Md; Garnet L. Anderson, PhD, Ross L. Prentice, PhD, Andrea Z. LaCroix, PhD, and Charles Kooperberg, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Marcia L. Stefanick, PhD, Stanford University Clinical Center, Stanford, Calif; Rebecca D. Jackson, MD, Ohio State University Clinical Center, Columbus; Shirley A. A. Beresford, PhD, Fred Hutchinson Cancer Research Center, Seattle, Wash; Barbara V. Howard, PhD, MedStar Research Institute, Washington, DC; Karen C. Johnson, MD, MPH, University of Tennessee, Memphis; Jane Morley Kotchen, MD, Medical College of Wisconsin, Milwaukee; Judith Ockene, PhD, University of Massachusetts Medical School, Worcester.
Context Despite decades of accumulated observational evidence, the balance of
risks and benefits for hormone use in healthy postmenopausal women remains
Objective To assess the major health benefits and risks of the most commonly used
combined hormone preparation in the United States.
Design Estrogen plus progestin component of the Women's Health Initiative,
a randomized controlled primary prevention trial (planned duration, 8.5 years)
in which 16608 postmenopausal women aged 50-79 years with an intact uterus
at baseline were recruited by 40 US clinical centers in 1993-1998.
Interventions Participants received conjugated equine estrogens, 0.625 mg/d, plus
medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n
Main Outcomes Measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial
infarction and CHD death), with invasive breast cancer as the primary adverse
outcome. A global index summarizing the balance of risks and benefits included
the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer,
colorectal cancer, hip fracture, and death due to other causes.
Results On May 31, 2002, after a mean of 5.2 years of follow-up, the data and
safety monitoring board recommended stopping the trial of estrogen plus progestin
vs placebo because the test statistic for invasive breast cancer exceeded
the stopping boundary for this adverse effect and the global index statistic
supported risks exceeding benefits. This report includes data on the major
clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal
95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with
286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85)
with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63
(0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases;
hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes,
0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite
outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial
and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for
combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28)
for the global index. Absolute excess risks per 10 000 person-years attributable
to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more
PEs, and 8 more invasive breast cancers, while absolute risk reductions per
10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
The absolute excess risk of events included in the global index was 19 per
10 000 person-years.
Conclusions Overall health risks exceeded benefits from use of combined estrogen
plus progestin for an average 5.2-year follow-up among healthy postmenopausal
US women. All-cause mortality was not affected during the trial. The risk-benefit
profile found in this trial is not consistent with the requirements for a
viable intervention for primary prevention of chronic diseases, and the results
indicate that this regimen should not be initiated or continued for primary
prevention of CHD.
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