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.
The Women's Health Initiative [WHI] focuses on defining the risks and benefits of strategies that could potentially reduce the incidence of heart disease, breast and colorectal cancer, and fractures in postmenopausal women. Between 1993 and 1998, the WHI enrolled 161 809 postmenopausal women in the age range of 50 to 79 years into a set of clinical trials [trials of low-fat dietary pattern, calcium and vitamin D supplementation, and 2 trials of postmenopausal hormone use] and an observational study at 40 clinical centers in the United States.1 This article reports principal results for the trial of combined estrogen and progestin in women with a uterus. The trial was stopped early based on health risks that exceeded health benefits over an average follow-up of 5.2 years. A parallel trial of estrogen alone in women who have had a hysterectomy is being continued, and the planned end of this trial is March 2005, by which time the average follow-up will be about 8.5 years.
The WHI clinical trials were designed in 1991-1992 using the accumulated evidence at that time. The primary outcome for the trial of estrogen plus progestin was designated as coronary heart disease [CHD]. Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin.2-5 Hip fracture was designated as a secondary outcome, supported by observational data as well as clinical trials showing benefit for bone mineral density.6,7 Invasive breast cancer was designated as a primary adverse outcome based on observational data.3,8 Additional clinical outcomes chosen as secondary outcomes that may plausibly be affected by hormone therapy include other cardiovascular diseases; endometrial, colorectal, and other cancers; and other fractures.3,6,9
The effect of hormones on overall health was an important consideration in the design and conduct of the WHI clinical trial. In an attempt to summarize important aspects of health benefits vs risks, a global index was defined as the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism [PE], endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. Compared with total mortality, which may be too insensitive, this index assigns additional weight to the 7 listed diseases. Procedures for monitoring the trial involved semiannual comparisons of the estrogen plus progestin and placebo groups with respect to each of the elements of the global index and to the overall global index.
This report pertains primarily to estrogen plus progestin use among healthy postmenopausal women, since only 7.7% of participating women reported having had prior cardiovascular disease. During the course of the WHI trial, the Heart and Estrogen/progestin Replacement Study [HERS] reported its principal results.10 HERS was another blinded, randomized controlled trial comparing the same regimen of estrogen plus progestin with placebo among women with a uterus; however, in HERS, all 2763 participating women had documented CHD prior to randomization. The HERS findings of no overall effect on CHD but an apparent increased risk in the first year after randomization seemed surprising given preceding observational studies of hormone use in women with CHD.3 Subsequent to HERS, some investigators reanalyzed their observational study data and were able to detect an early elevation in CHD risk among women with prior CHD11-13 but not in ostensibly healthy women,14 prompting speculation that any early adverse effect of hormones on CHD incidence was confined to women who have experienced prior CHD events.
The WHI is the first randomized trial to directly address whether estrogen plus progestin has a favorable or unfavorable effect on CHD incidence and on overall risks and benefits in predominantly healthy women.
Detailed eligibility criteria and recruitment methods have been published.1 Briefly, most women were recruited by population-based direct mailing campaigns to age-eligible women, in conjunction with media awareness programs. Eligibility was defined as age 50 to 79 years at initial screening, postmenopausal, likelihood of residence in the area for 3 years, and provision of written informed consent. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months [12 months for 50- to 54-year-olds], had had a hysterectomy, or had ever used postmenopausal hormones. Major exclusions were related to competing risks [any medical condition likely to be associated with a predicted survival of