Jacques E. Rossouw

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Womens Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

The women's health initiative recruitment methods and results

One of the most challenging aspects of the Women’s Health Initiative (WHI) was the recruitment of more than 161,000 women for this long-term prevention trial and observational study. The WHI had many enrollment goals that made recruitment efforts formidable (1). These included the recruitment of postmenopausal women, a group seldom targeted for clinical trials; enrolling minority groups in at least the same proportion as they existed in the general population; and enrolling women willing to participate in a long-term (8–12 year) study. The success of the WHI in meeting these goals can be attributed to several factors: the experience gained from prior studies, such as the National Cancer Institute (NCI)-sponsored Women’s Health Trial (2), the subsequent Women’s Health Trial Feasibility Study in Minority Populations (3), and the Postmenopausal Estrogen/Progestin Interventions Trial (4); detailed planning by the WHI investigators; the dedication of recruiters, staff, and investigators at the clinical centers; and, a social and political climate that enhanced women’s interest in health research. Prior to the WHI, few large-scale prevention or clinical trials focused on postmenopausal women. Indeed, until recently, relatively little emphasis was placed on the recruitment of women of any age into such studies (5). However, during the last decade, a number of forces have come together to change this situation. The stance that women

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS Postmenopausal women (N = 36 282) who were enrolled in a Womens Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin.

CONTEXT The Womens 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.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction

Summary Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance1,2. When MI occurs early in life, the role of inheritance is substantially greater1. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families3–8 whereas common variants at more than 45 loci have been associated with MI risk in the population9–15. Here, we evaluate the contribution of rare mutations to MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes where rare coding-sequence mutations were more frequent in cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare, damaging mutations (3.1% of cases versus 1.3% of controls) were at 2.4-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). This sequence-based estimate of the proportion of early MI cases due to LDLR mutations is remarkably similar to an estimate made more than 40 years ago using total cholesterol16. At apolipoprotein A-V (APOA5), carriers of rare nonsynonymous mutations (1.4% of cases versus 0.6% of controls) were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase15,17 and apolipoprotein C318,19. When combined, these observations suggest that, beyond LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative

Background— The Women’s Health Initiative (WHI) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women. The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke. This report provides a thorough analysis of the stroke finding using the final results from the completed trial database. Methods and Results— The WHI Estrogen Alone hormone trial is a multicenter, double-blind, placebo-controlled, randomized clinical trial in 10 739 women aged 50 to 79 years who were given daily conjugated equine estrogen (CEE; 0.625 mg; n=5310) or placebo (n=5429). During an average follow-up of 7.1 years, there were 168 strokes in the CEE group and 127 in the placebo group; 80.3% of strokes were ischemic. For all stroke the intention-to-treat hazard ratio [HR] (95% CI) for CEE versus placebo was 1.37 (1.09 to 1.73). The HR (95% CI) was 1.55 (1.19 to 2.01) for ischemic stroke and 0.64 (0.35, 1.18) for hemorrhagic stroke. The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk, including younger and more recently menopausal women and in women with prior or current use of statins or aspirin. Conclusions— CEE increases the risk of ischemic stroke in generally healthy postmenopausal women. The excess risk appeared to be present in all subgroups of women examined, including younger and more recently menopausal women. There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke.

Benefits and Risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause

The authors further analyzed results from the Womens Health Initiative randomized trials (1993-2004) of conjugated equine estrogens, with or without medroxyprogesterone acetate, focusing on health benefits versus risks among women who initiated hormone therapy soon after menopause. Data from the Womens Health Initiative observational study (1993-2004) were included in some analyses for additional precision. Results are presented here for incident coronary heart disease, stroke, venous thromboembolism, breast cancer, colorectal cancer, endometrial cancer, or hip fracture; death from other causes; a summary global index; total cancer; and total mortality. Hazard ratios for breast cancer and total cancer were comparatively higher (P < 0.05) among women who initiated hormone therapy soon after menopause, for both regimens. Among these women, use of conjugated equine estrogens appeared to produce elevations in venous thromboembolism and stroke and a reduction in hip fracture. Estrogen plus progestin results among women who initiated use soon after menopause were similar for venous thromboembolism, stroke, and hip fracture but also included evidence of longer-term elevations in breast cancer, total cancer, and the global index. These analyses provide little support for the hypothesis of favorable effects among women who initiate postmenopausal estrogen use soon after menopause, either for coronary heart disease or for health benefits versus risk indices considered.

Comparison of the Framingham and Reynolds Risk Scores for Global Cardiovascular Risk Prediction in the Multiethnic Women's Health Initiative

Background— Framingham-based and Reynolds Risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort. Methods and Results— We selected a case-cohort sample of the multiethnic Womens Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 myocardial infarctions, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the Adult Treatment Panel III (ATP-III) score, the Reynolds Risk Score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with ≥10% risk in 6%, 10%, and 41% of women with the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models overestimated risk for coronary heart disease and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c statistic (0.765 versus 0.757; P=0.03), positive net reclassification improvement (NRI; 4.9%; P=0.02), and positive integrated discrimination improvement (4.1%; P<0.0001) overall, excluding diabetics (NRI=4.2%; P=0.01), and in white (NRI=4.3%; P=0.04) and black (NRI=11.4%; P=0.13) women. The Reynolds (NRI=12.9%; P<0.0001) and ATP-III (NRI=5.9%; P=0.0001) models demonstrated better discrimination than the Framingham CVD model. Conclusions— The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.

Women’s Ischemic Syndrome Evaluation Current Status and Future Research Directions: Report of the National Heart, Lung and Blood Institute Workshop: October 2–4, 2002 : Executive Summary

The WISE workshop was convened to review results from the Women’s Ischemic Syndrome Evaluation (WISE) study and other studies of ischemic heart disease to examine the nature and scope of gender differences in both chronic and acute cardiac ischemia, in terms of clinical manifestations, detection, and treatment. The purpose of the workshop was to provide recommendations to National Heart, Lung and Blood Institute that (1) address the need for improved diagnosis of ischemia and coronary artery disease (CAD) in women; (2) explore strategies for improved translation of promising research results into clinical practice; and (3) assess opportunities for effective educational strategies, including further refinement of the key messages for women with regard to risk factors and heart attack symptoms. CAD in women continues to be a major public health problem that represents a leading cause of death and disability.1–3 Among US women, more than a quarter of a million deaths per year are attributed to CAD, and this figure is expected to increase in the first decades of the 21st century as our population ages. The increased prevalence of obesity and diabetes in women is also expected to contribute to this increase in CAD. Women have a higher frequency of angina/chest pain than men; however, women have a lower prevalence of obstructive CAD compared with men with similar symptoms.4–6 Nevertheless, young women with obstructive CAD experience a significantly worse outcome compared with men with regard to prognosis after myocardial infarction,7 and older women with obstructive CAD often have …

Lipid-Lowering Interventions in Angiographic Trials

This analysis examines the pooled data from all 14 published randomized angiographic trials (with 16 treatment arms) by type of cholesterol-lowering intervention evaluated, and for all the trials combined. All interventions reduced low density lipoprotein (LDL) cholesterol levels (average reduction, 26%), whereas the effects on high density lipoprotein (HDL) cholesterol and triglycerides varied by type of intervention. Meta-analyses of the angiographic outcomes indicated that treatment reduced the odds for disease progression by 49%, increased the odds for no change by 33%, and increased the odds for regression by 219%. Cardiovascular events were reduced by 47%. Thus, lipid reduction is effective for modifying the angiographic outcome and for reducing the incidence of coronary artery disease events. All types of intervention (lifestyle, drugs, or surgery) had overall favorable effects on angiographic and clinical outcomes. There was no class effect for the statin group of drugs. Surgery (partial ileal bypass) had the most favorable angiographic outcome, possibly because of a longer duration of therapy. Trials with higher baseline LDL levels tended to have more favorable angiographic outcomes. Analyses of in-trial levels of LDL were confounded by baseline levels, and analyses of change in LDL levels in the treatment groups were confounded by not including zero change (i.e., no treatment). It is hypothesized that lowering LDL levels by 30 mg/dl (0.8 mmol/liter) is sufficient on average to modify the angiographic outcome, with modest gains from further reductions in LDL levels.