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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
[2002年11月25日 8時46分23秒]
先週骨粗鬆症学会に出てきました。印象に残ったのは、HRTです。以下の論文のように乳癌、脳
卒中が投与例で有意に多く効果もアレンドロネートと同等であることから、リウマチ医が第一選
択とするのは？？？と思いました。実際に第一人者の白木先生もアレンドロネートで消化器の副
作用が出た症例とかが適応なのではないか？と発言されていました。
1: JAMA 2002 Aug 21;288(7):872-81 Related Articles, Links
Postmenopausal hormone replacement therapy: scientific review.
Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD.
Oregon Health and Science University, Mail Code BICC 504, 3181 SW Sam Jackson
Park Rd, Portland, OR 97201, USA. nelsonh@ohsu.edu
CONTEXT: Although postmenopausal hormone replacement therapy (HRT) is widely
used in the United States, new evidence about its benefits and harms requires
reconsideration of its use for the primary prevention of chronic conditions.
OBJECTIVE: To assess the benefits and harms of HRT for the primary prevention
of cardiovascular disease, thromboembolism, osteoporosis, cancer, dementia, and
cholecystitis by reviewing the literature, conducting meta-analyses, and
calculating outcome rates. DATA SOURCES: All relevant English-language studies
were identified in MEDLINE (1966-2001), HealthSTAR (1975-2001), Cochrane
Library databases, and reference lists of key articles. Recent results of the
Women's Health Initiative (WHI) and the Heart and Estrogen/progestin
Replacement Study (HERS) are included for reported outcomes. STUDY SELECTION
AND DATA EXTRACTION: We used all published studies of HRT if they contained a
comparison group of HRT nonusers and reported data relating to HRT use and
clinical outcomes of interest. Studies were excluded if the population was
selected according to prior events or presence of conditions associated with
higher risks for targeted outcomes. DATA SYNTHESIS: Meta-analyses of
observational studies indicated summary relative risks (RRs) for coronary heart
disease (CHD) incidence and mortality that were significantly reduced among
current HRT users only, although risk for incidence was not reduced when only
studies that controlled for socioeconomic status were included. The WHI
reported increased CHD events (hazard ratio [HR], 1.29; 95% confidence interval
[CI], 1.02-1.63). Stroke incidence but not mortality was significantly
increased among HRT users in the meta-analysis and the WHI. The meta-analysis
indicated that risk was significantly elevated for thromboembolic stroke (RR,
1.20; 95% CI, 1.01-1.40) but not subarachnoid or intracerebral stroke. Risk of
venous thromboembolism among current HRT users was increased overall (RR, 2.14;
95% CI, 1.64-2.81) and was highest during the first year of use (RR, 3.49; 95%
CI, 2.33-5.59) according to a meta-analysis of 12 studies. Protection against
osteoporotic fractures is supported by a meta-analysis of 22 estrogen trials,
cohort studies, results of the WHI, and trials with bone density outcomes.
Current estrogen users have an increased risk of breast cancer that increases
with duration of use. Endometrial cancer incidence, but not mortality, is
increased with unopposed estrogen use but not with estrogen with progestin. A
meta-analysis of 18 observational studies showed a 20% reduction in colon
cancer incidence among women who had ever used HRT (RR, 0.80; 95% CI, 0.74-
0.86), a finding supported by the WHI. Women symptomatic from menopause had
improvement in certain aspects of cognition. Current studies of estrogen and
dementia are not definitive. In a cohort study, current HRT users had an age-
adjusted RR for cholecystitis of 1.8 (95% CI, 1.6-2.0), increasing to 2.5 (95%
CI, 2.0-2.9) after 5 years of use. CONCLUSIONS: Benefits of HRT include
prevention of osteoporotic fractures and colorectal cancer, while prevention of
dementia is uncertain. Harms include CHD, stroke, thromboembolic events, breast
cancer with 5 or more years of use, and cholecystitis.
[2002年11月25日 8時37分51秒]