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PREMPRO STUDY STOPPED: RISKS AND BENEFITS OF ESTROGEN PLUS
PROGESTIN IN HEALTHY POSTMENAPOSUALl WOMEN
Principal Results From the Women's Health Initiative
Randomized Controlled Trial
Journal of American Medical Association
Risks and Benefits of Estrogen Plus Progestin in Healthy
Postmenopausal Women
Principal Results From the Women's Health Initiative
Randomized Controlled Trial
Writing Group for the Women's Health Initiative Investigators
Context: Despite decades of accumulated observational
evidence, the balance of risks and benefits for hormone use in
healthy postmenopausal women remains uncertain.
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 = 8102).
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.
JAMA. 2002;288:321-333
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