CARDIOVASCULAR DISEASE IN POSTMENOPAUSAL WOMEN —

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 16 608 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 (0.901.17) 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 personyears. 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. Reprinted with permission from JAMA. 2002;288(3):321. the current recommendations for lipid lowering include statin use, as noted in the National Cholesterol Education Program Adult Treatment Panel III guidelines. If hormone therapy was instituted because of low bone mineral density for the prevention of osteoporosis, the use of hormone therapy versus alternatives, such as bisphosphonates or raloxifene, and their specific risks and benefits, should be explored. Currently, no evidence supports that hormone therapy improves urinary inconti nence, and it actually may cause this condition to worsen. I particularly want to emphasize that all of the information on which current decisions are being made were derived since 1998, the date of publication of the initial HERS study. Physicians and their patients must make decisions relative to 4 years of new and evolving information. ASiM: To date, have any additional notable new studies or publications other than the ones we have discussed shown harm or benefit from HRT? Dr Wenger: Until very recently, physicians have been dependent on information provided by a large number of observational studies and the meta-analyses of these studies that suggested cardiovascular benefit from HRT, which is why they had recommended hormone therapy for cardiovascular benefit in the past. In addition to the recent WHI and HERS II clinical trial data, newly published meta-analyses differ from the previous metaanalyses. One of these meta-analyses evaluates the value of HRT in the primary prevention of cardiovascular disease and coronary artery disease (CAD) by studying the potential explanatory variables of the relationship between HRT, CVD, and CAD. This meta-analysis adjusted for socioeconomic status, as well as other major CAD risk factors, and shows that with these adjustments, no benefit in the secondary or primary prevention of CVD events is seen. This meta-analysis’ methods differ from traditionally cited studies, but most importantly, its results are consistent with those of the recent randomized trials that have shown no cardiovascular benefit from HRT. Essentially, it highlights that differences previously described related to the characteristics of the women who were hormone users rather than to hormone use per se. Another recent meta-analysis produced comparable results. We are dealing with a rapidly changing landscape. Good scientific information continues to emerge from rigorous, ongoing clinical trials. Thus, physicians should counsel women regarding hormone therapy based on the most current and appropriate scientific information. Advanced Studies in Medicine ■ 713 CLINICIAN INTERVIEW CARDIOVASCULAR DISEASE OUTCOMES DURING 6.8 YEARS OF HORMONE THERAPY Heart and Estrogen/Progestin Replacement Study Follow-up (HERS II) Deborah Grady, MD, MPH; David Herrington, MD, MHS; Vera Bittner, MD; Roger Blumenthal, MD; Michael Davidson, MD; Mark Hlatky, MD; Judith Hsia, MD; Stephen Hulley, MD, MPH; Alan Herd, MD; Steven Khan, MD; L. Kristin Newby, MD; David Waters, MD; Eric Vittinghoff, PhD; Nanette Wenger, MD; for the HERS Research Group