Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial

University of Pittsburgh, Pittsburgh, Pennsylvania, United States
American Journal of Epidemiology (Impact Factor: 5.23). 10/2005; 162(5):404-14. DOI: 10.1093/aje/kwi223
Source: PubMed


Observational research on postmenopausal hormone therapy suggests a 40-50% reduction in coronary heart disease incidence among women using these preparations. In contrast, the Women's Health Initiative clinical trial of estrogen plus progestin found an elevated incidence over a 5.6-year intervention period through July 7, 2002. Toward explaining this discrepancy, the authors analyzed data from this trial, which included 16,608 postmenopausal women aged 50-79 years, and corresponding data from 53,054 women in the Women's Health Initiative observational study, 33% of whom were estrogen-plus-progestin users at baseline. Estrogen-plus-progestin hazard ratio estimates for coronary heart disease, stroke, and venous thromboembolism in the observational study were 39-48% lower than those in the clinical trial following age adjustment. However, hazard ratios tended to decrease with increasing time from initiation of estrogen-plus-progestin use, and observational study hazard ratio estimates are heavily weighted by longer-term use while clinical trial hazard ratio estimates reflect shorter-term use. Following control for time from estrogen-plus-progestin initiation and confounding, hazard ratio estimates were rather similar for the two cohorts, although there was evidence of some remaining difference for stroke. These analyses have implications for both the design and the analysis of observational studies.

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    • "The cardioprotective benefits of 17-βE have been reported in several pre-clinical models [4] [5] [6]. While observational studies have reported about 50% reduced incidences of coronary artery disease in postmenopausal women receiving hormone therapy, the results from clinical trials evaluating hormone replacement therapy have always shown large discrepancies and limited success in the treatment of the disease [7] [8] [9]. Current research is now focused on designing techniques for improved delivery of this hormone [10]. "
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    Journal of Controlled Release 04/2014; 180(1). DOI:10.1016/j.jconrel.2014.02.009 · 7.71 Impact Factor
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    • "Also, common reasons for taking nutritional supplements include the belief that these preparations may prevent chronic diseases, such as cardiovascular disease, osteoporosis, and cancer [16, 17], raising the specter of “confounding by indication”, which may tend to offset any “healthy supplement user” bias. Here, as in our earlier WHI combined CT and OS analyses of postmenopausal hormone therapy [18–23], our analyses allow for outcome-specific residual confounding in the OS. In effect, these combined CT and OS analyses allow an entirely separate overall HR from the OS versus the CT, so that OS data are used very conservatively to strengthen analysis of temporal HR variation patterns. "
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    ABSTRACT: The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D(3) daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer. INTRODUCTION: This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality. METHODS: WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS). RESULTS: Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38-1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44-0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive. CONCLUSION: Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.
    Osteoporosis International 12/2012; 24(2). DOI:10.1007/s00198-012-2224-2 · 4.17 Impact Factor
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    • "While this covers many practical situations, other patterns of the hazard ratio are possible. When the tests indicate a lack of fit for the model of Yang & Prentice (2005), it is possible to remedy the situation by considering larger classes of semiparametric models to incorporate an even wider range of hazard ratio patterns. Also, in addition to the two-sample case considered here, adjustment for covariates may be considered. "
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    ABSTRACT: The short-term and long-term hazard ratio model includes the proportional hazards model and the proportional odds model as submodels, and allows a wider range of hazard ratio patterns compared with some of the more traditional models. We propose two omnibus tests for checking this model, based, respectively, on the martingale residuals and the contrast between the non-parametric and model-based estimators of the survival function. These tests are shown to be consistent against any departure from the model. The empirical behaviours of the tests are studied in simulations, and the tests are illustrated with some real data examples.
    Scandinavian Journal of Statistics 09/2012; 39(3). DOI:10.2307/41679812 · 0.87 Impact Factor
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