Combined Postmenopausal Hormone Therapy and Cardiovascular Disease: Toward Resolving the Discrepancy between Observational Studies and the Women's Health Initiative Clinical Trial
ABSTRACT 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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ABSTRACT: The primary objective of this study was to compare the biodistribution and pharmacokinetic profile of 17-β-estradiol (17-βE) on systemic delivery using either the cationic or the CREKA-peptide-modified (Cysteine-Arginine-Glutamic-acid-Lysine-Alanine) omega-3-fatty acid oil containing nanoemulsion system in vivo in the wild type C57BL/6 mice. Higher blood concentrations of 17-βE, higher accumulation in the tissues of interest - heart and aorta, and higher accumulation within the other tissues - liver and kidney was observed on delivering 17-βE using the CREKA-peptide-modified nanoemulsion system (AUClast in plasma - 263.89±21.81min*%/injected dose/ml) as compared to the cationic nanoemulsion (AUClast in plasma - 20.2±1.86min*%/injected dose/ml) and solution form (AUClast in plasma - 44.9±1.24min*%/injected dose/ml) respectively. Both, the cationic nanoemulsion and the CREKA-peptide-modified nanoemulsion showed a higher relative targeting efficiency of 4.57 and 4.86 respectively for 17-βE than the relative targeting efficiency of 1.78 observed with the solution form. In conclusion, since the maximum exposure (highest AUClast for plasma and tissues) for 17-βE was observed with the CREKA-peptide-modified nanoemulsion system, the study shows that CREKA-peptide-modified nanoemulsion system was the most suitable vehicle for systemic delivery of 17-βE in the wild type C57BL/6 mice.Journal of Controlled Release 04/2014; 180. DOI:10.1016/j.jconrel.2014.02.009 · 7.26 Impact Factor
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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 · 1.06 Impact Factor
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ABSTRACT: To assess the relationship between closer monitoring of depressed patients during high-risk treatment periods and death from suicide, using two analytic approaches. VA patients receiving depression treatment between 1999 and 2004. First, a case-control design was used, adjusting for age, gender, and high-risk days (1,032 cases and 2,058 controls). Second, an instrumental variable (IV) approach (N=714,106) was used, with IVs of (1) average monitoring rates in the VA facility of most use and (2) monitoring rates of VA facilities weighted inversely by distance from patients' residences. The case-control approach indicated a modest increase in suicide risk with each additional visit (odds ratio=1.02; 95 percent confidence interval=1.002, 1.04). The "facility used" IV estimate indicated near zero change in risk (0.0008 percent increase; p=.97) with each additional visit, while the distance-weighted IV estimate indicated a 0.032 percent decrease in risk (p=.29). An alternative analysis assuming a threshold effect of ≥4 visits during high-risk periods also showed a decrease (0.15 percent; p=.08) using the distance IV. The IV approach appeared to address the selection bias more appropriately than the case-control analysis. Neither analysis clearly indicated that closer monitoring during high-risk periods was significantly associated with reduced suicide risks, but the distance-weighted IV estimate suggested a potentially protective effect.Health Services Research 10/2010; 45(5 Pt 1):1205-26. DOI:10.1111/j.1475-6773.2010.01132.x · 2.49 Impact Factor