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Context The Women's Health Initiative (WHI) trial of estrogen plus progestin vs placebo was stopped early, after a mean 5.6 years of follow-up, because the overall health risks of hormone therapy exceeded its benefits. Objective To report health outcomes at 3 years (mean 2.4 years of follow-up) after the intervention was stopped. Design, Setting, and Participants The intervention phase was a double-blind, placebo-controlled, randomized trial of conjugated equine estrogens (CEE) 0.625 mg daily plus medroxyprogesterone acetate (MPA) 2.5 mg daily, in 16 608 women aged 50 through 79 years, recruited by 40 centers from 1993 to 1998. The postintervention phase commenced July 8, 2002, and included 15 730 women. Main Outcome Measures Semi-annual monitoring and outcomes ascertainment continued per trial protocol. The primary end points were coronary heart disease and invasive breast cancer. A global index summarizing the balance of risks and benefits included the 2 primary end points plus stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes. Results The risk of cardiovascular events after the intervention was comparable by initial randomized assignments, 1.97% (annualized rate) in the CEE plus MPA (343 events) and 1.91% in the placebo group (323 events). A greater risk of malignancies occurred in the CEE plus MPA than in the placebo group (1.56% [n = 281] vs 1.26% [n = 218]; hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.04-1.48). More breast cancers were diagnosed in women who had been randomly assigned to receive CEE plus MPA vs placebo (0.42% [n = 79] vs 0.33% [n = 60]; HR, 1.27; 95% CI, 0.91-1.78) with a modest trend toward a lower HR during the follow-up after the intervention. All-cause mortality was somewhat higher in the CEE plus MPA than in the placebo group (1.20% [n = 233] vs 1.06% [n = 196]; HR, 1.15; 95% CI, 0.95-1.39). The global index of risks and benefits was unchanged from randomization through March 31, 2005 (HR, 1.12; 95% CI, 1.03-1.21), indicating that the risks of CEE plus MPA exceed the benefits for chronic disease prevention. Conclusions The increased cardiovascular risks in the women assigned to CEE plus MPA during the intervention period were not observed after the intervention. A greater risk of fatal and nonfatal malignancies occurred after the intervention in the CEE plus MPA group and the global risk index was 12% higher in women randomly assigned to receive CEE plus MPA compared with placebo. Trial Registration clinicaltrials.gov Identifier: NCT00000611

Background: The aim of this study was to determine the magnitude and significance of the associations between coronary artery calcium (CAC) and different measures of blood pressure among postmenopausal women. Methods: Subjects were a subset of women aged 50 to 59 at baseline in the Women’s Health Initiative (WHI) clinical trial of conjugated equine estrogen (CEE) who underwent a one-time computed tomography (CT) scan of the chest following the end of the trial to determine CAC. At the baseline WHI clinic visit, CEE trial participants provided data on a wide range of factors to include blood pressure measurements which were measured twice with the participant in the seated position using a conventional mercury sphygmomanometer and appropriately sized cuffs. Results: The sample consisted of 1,064 women with a mean age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score > 0 was 47%, while the prevalence of a CAC score >= 10 and > 100 was 39 and 19%, respectively. There was a linear association between the log-odds of any CAC and SBP while there was a curvilinear and inverse association with DBP that was independent of CVD risk factors and blood pressure medication status. For any value of diastolic blood pressure, the probability of CAC increased with higher levels of SBP. Conversely, for any given value of SBP, the probability of any CAC decreased with higher levels of DBP. Those with a PP >= 55 mmHg had nearly a two-fold higher odds for having any CAC (Odds Ratio: 1.95, 95% CI: 1.24 – 3.06) while individuals with isolated systolic hypertension (SBP >= 140 and DBP < 90) had a 73% higher odds for CAC (95% CI: 1.03 – 2.90, p = 0.04) independent of other risk factors and blood pressure medication status. There was no significant associations between mean arterial pressure and CAC. Conclusions: In postmenopausal women over the age of 50 years, both SBP and DBP are relevant for determining the risk for coronary artery calcium. Notably, higher levels of pulse pressure and systolic blood pressure were strong determinants of CAC, while diastolic blood pressure was inversely related. Consequently, isolated systolic hypertension may be relevant in women. These results may be of clinical relevance for the prevention of coronary artery disease. This research has received full or partial funding support from the American Heart Association, AHA National Center.

To define frailty using simple indicators; to identify risk factors for frailty as targets for prevention; and to investigate the predictive validity of this frailty classification for death, hospitalization, hip fracture, and activity of daily living (ADL) disability.Prospective study, the Women's Health Initiative Observational Study.Forty U.S. clinical centers.Forty thousand six hundred fifty-seven women aged 65 to 79 at baseline.Components of frailty included self-reported muscle weakness/impaired walking, exhaustion, low physical activity, and unintended weight loss between baseline and 3 years of follow-up. Death, hip fractures, ADL disability, and hospitalizations were ascertained during an average of 5.9 years of follow-up.Baseline frailty was classified in 16.3% of participants, and incident frailty at 3-years was 14.8%. Older age, chronic conditions, smoking, and depressive symptom score were positively associated with incident frailty, whereas income, moderate alcohol use, living alone, and self-reported health were inversely associated. Being underweight, overweight, or obese all carried significantly higher risk of frailty than normal weight. Baseline frailty independently predicted risk of death (hazard ratio (HR)=1.71, 95% confidence interval (CI)=1.48-1.97), hip fracture (HR=1.57, 95% CI=1.11-2.20), ADL disability (odds ratio (OR)=3.15, 95% CI=2.47-4.02), and hospitalizations (OR=1.95, 95% CI=1.72-2.22) after adjustment for demographic characteristics, health behaviors, disability, and comorbid conditions.These results support the robustness of the concept of frailty as a geriatric syndrome that predicts several poor outcomes in older women. Underweight, obesity, smoking, and depressive symptoms are strongly associated with the development of frailty and represent important targets for prevention.

ContextThe Women's Health Initiative (WHI) trial of estrogen plus progestin was stopped early because of adverse effects, including an increased risk of stroke in the estrogen plus progestin group.ObjectiveTo assess the effect of estrogen plus progestin on ischemic and hemorrhagic stroke and in subgroups, and to determine whether the effect of estrogen plus progestin was modified by baseline levels of blood biomarkers.DesignMulticenter double-blind, placebo-controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow-up of 5.6 years. Baseline levels of blood-based markers of inflammation, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and 513 controls.InterventionsParticipants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n = 8506) or placebo (n = 8102).Main Outcome MeasuresOverall strokes and stroke subtype and severity were centrally adjudicated by stroke neurologists.ResultsOne hundred fifty-one patients (1.8%) in the estrogen plus progestin and 107 (1.3%) in the placebo groups had strokes. Overall 79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the intention-to-treat hazard ratio (HR) for estrogen plus progestin vs placebo was 1.31 (95% confidence interval [CI], 1.02-1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08-2.08). The HR for ischemic stroke was 1.44 (95% CI, 1.09-1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43-1.56). Point estimates of the HRs indicate that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C supplements, blood-based biomarkers of inflammation, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen plus progestin on stroke risk.ConclusionsEstrogen plus progestin increases the risk of ischemic stroke in generally healthy postmenopausal women. Excess risk for all strokes attributed to estrogen plus progestin appeared to be present in all subgroups of women examined.