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Despite increasing prevalence of heart failure (HF) in patients with preserved ejection fraction (PEF), there are no available therapies proven to reduce morbidity and mortality. Aldosterone, a potent stimulator of myocardial and vascular fibrosis, may be a key mediator of HF progression in this population and is therefore an important therapeutic target. The TOPCAT trial is designed to evaluate the effect of spironolactone, an aldosterone antagonist, on morbidity, mortality, and quality of life in patients with HF-PEF. Up to 3,515 patients with HF-PEF will be randomized in double-blind fashion to treatment with spironolactone (target dose 30 mg daily) or matching placebo. Eligible patients include those with age ≥50 years, left ventricular ejection fraction ≥45%, symptomatic HF, and either a hospitalization for HF within the prior year or an elevated natriuretic peptide level (B-type natriuretic peptide ≥100 pg/mL or N-terminal pro–B-type natriuretic peptide ≥360 pg/mL) within the 60 days before randomization. Patients with uncontrolled hypertension and those with known infiltrative or hypertrophic cardiomyopathy are excluded. The primary end point is the composite of cardiovascular death, hospitalization for HF, or aborted cardiac arrest. Key secondary end points include quality of life, nonfatal cardiovascular events, and new-onset atrial fibrillation. Ancillary studies of echocardiography, tonometry, and cardiac biomarkers will provide more insight regarding this understudied population and the effects of spironolactone therapy. TOPCAT is designed to assess definitively the role of spironolactone in the management of HF-PEF.

Baseline data collected on each patient at randomisation in controlled clinical trials can be used to describe the population of patients, to assess comparability of treatment groups, to achieve balanced randomisation, to adjust treatment comparisons for prognostic factors, and to undertake subgroup analyses. We assessed the extent and quality of such practices in major clinical trial reports. A sample of 50 consecutive clinical-trial reports was obtained from four major medical journals during July to September, 1997. We tabulated the detailed information on uses of baseline data by use of a standard form. Most trials presented baseline comparability in a table. These tables were often unduly large, and about half the trials inappropriately used significance tests for baseline comparison. Methods of randomisation, including possible stratification, were often poorly described. There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear. Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference. Two-thirds of the reports presented subgroup findings, but mostly without appropriate statistical tests for interaction. Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power. Clinical trials need a predefined statistical analysis plan for uses of baseline data, especially covariate-adjusted analyses and subgroup analyses. Investigators and journals need to adopt improved standards of statistical reporting, and exercise caution when drawing conclusions from subgroup findings.

In this trial, 3445 patients with heart failure and a preserved ejection fraction were assigned to spironolactone or placebo. At a mean of 3.3 years, there was no significant difference in death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Many patients with heart failure have a normal or near-normal left ventricular ejection fraction. 1 – 4 Such patients share common signs and symptoms, as well as an impaired quality of life and a poor prognosis, with patients who have heart failure and a reduced ejection fraction. 5 – 8 However, the benefit of most medical therapies for heart failure is limited to those with a reduced ejection fraction, generally 40% or less. 1 , 2 , 9 The lack of favorable evidence from clinical-outcome trials involving patients with heart failure and a preserved left ventricular ejection fraction is reflected in current guidelines, which offer no specific . . .

The use of platelet transfusions to prevent bleeding in patients with thrombocytopenia due to chemotherapy or other causes of marrow suppression is widespread, but the optimal number (dose) of platelets is unsettled. In this randomized trial, three doses of platelets were studied: the usual dose, half the usual dose, and twice the usual dose. No major differences in bleeding complications were found among the three groups, but more transfusions were given in the lowest-dose group to prevent bleeding. In this randomized trial, three doses of platelets were studied: the usual dose, half the usual dose, and twice the usual dose. No major differences in bleeding complications were found among the three groups, but more transfusions were given in the lowest-dose group to prevent bleeding. The optimal number of platelets in a prophylactic platelet transfusion is controversial. 1 , 2 A standard dose for adults is considered to be approximately 3×10 11 to 6×10 11 platelets. 3 Higher doses than these could potentially result in superior hemostasis, 4 but a lower dose might be equally effective while conserving the platelet supply. Two randomized trials with limited enrollment — one of 111 patients 5 and the other of 119 patients 6 — have compared a low dose of platelets to the standard dose. In both trials, the two doses prevented bleeding to a similar degree. We conducted a randomized trial of prophylactic platelet transfusions . . .

Despite the increasing acceptance of quality of life (QOL) as a critical endpoint in medical research, there is little consensus regarding the definition of this construct or how it differs from perceived health status. The objective of this analysis was to understand how patients make determinations of QOL and whether QOL can be differentiated from health status. We conducted a meta-analysis of the relationships among two constructs (QOL and perceived health status) and three functioning domains (mental, physical, and social functioning) in 12 chronic disease studies. Instruments used in these studies included the RAND-36, MOS SF-20, EORTC QLQ-30, MILQ and MQOL-HIV. A single, synthesized correlation matrix combining the data from all 12 studies was estimated by generalized least squares. The synthesized matrix was then used to estimate structural equation models. The meta-analysis results indicate that, from the perspective of patients, QOL and health status are distinct constructs. When rating QOL, patients give greater emphasis to mental health than to physical functioning. This pattern is reversed for appraisals of health status, for which physical functioning is more important than mental health. Social functioning did not have a major impact on either construct. We conclude that quality of life and health status are distinct constructs, and that the two terms should not be used interchangeably. Many prominent health status instruments, including utility-based questionnaires and health perception indexes, may be inappropriate for measuring QOL. Evaluations of the effectiveness of medical treatment may differ depending on whether QOL or health status is the study outcome.

OBJECTIVES: This investigation determined whether an in-home resistance training program achieved health benefits in older adults with disabilities. METHODS: A randomized controlled trial compared the effects of assigning 215 older persons to either a home-based resistance exercise training group or a waiting list control group. Assessments were conducted at baseline and at 3 and 6 months following randomization. The program consisted of videotaped exercise routines performed with elastic bands of varying thickness. RESULTS: High rates of exercise adherence were achieved, with 89% of the recommended exercise sessions performed over 6 months. Relative to controls, subjects who participated in the program achieved statistically significant lower extremity strength improvements of 6% to 12%, a 20% improvement in tandem gait, and a 15% to 18% reduction in physical and overall disability at the 6-month follow-up. No adverse health effects were encountered. CONCLUSIONS: These findings provide important evidence that home-based resistance exercise programs designed for older persons with disabilities hold promise as an effective public health strategy.

Background: Urinary mercury (U-Hg) excretion is a commonly used biomarker for mercury exposure from dental amalgam restorations. Objectives: Our goal was to determine the most efficient measure of dental amalgam exposure for use in analyses concerning U-Hg in children. Methods: We analyzed time-sensitive longitudinal amalgam exposure data in children randomized to amalgam restorations (n = 267) during the 5-year New England Children's Amalgam Trial. We calculated 8 measures of amalgam, evaluating current versus cumulative exposure, teeth versus surfaces, and total versus posterior occlusal amalgams. Urine samples collected during follow-up years 3-5 were analyzed for mercury excretion. Multivariate models for current and cumulative U-Hg excretion estimated associations between exposures and U-Hg. Results: At the end of follow-up, the average (± SD) cumulative exposure was 10.3 ± 6.1 surfaces and 5.7 ± 2.9 teeth ever filled with amalgam, corresponding to 30 ± 21 surface-years. Amalgam measures and U-Hg were moderately correlated. Of amalgam exposure measures, the current total of amalgam surfaces was the most robust predictor of current U-Hg, whereas posterior occlusal surface-years was best for cumulative U-Hg. In multivariate models, each additional amalgam surface present was associated with a 9% increase in current U-Hg, and each additional posterior occlusal surface-year was associated with a 3% increase in cumulative U-Hg excretion (p < 0.001). Conclusions: One single measure of amalgam exposure is insufficient. Studies of cumulative effects of mercury from amalgam exposure in children are likely to have improved validity and precision if time-sensitive amalgam exposure measures are used. In contrast, simple counts of current amalgam fillings are adequate to capture amalgam-related current U-Hg.

Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Interaction, defined as departure of disease rates from an additive model, can be measured by the relative excess risk due to interaction, or the attributable proportion due to interaction. Point estimates can be obtained using multiple logistic regression. Using simulated case-control data, we compare several confidence interval estimation techniques for these measures. These include a symmetrical interval based on the delta method estimate of the variance, and three types of bootstrap confidence intervals. One such bootstrap method has coverage closest to the nominal level and is the most evenly balanced with respect to the direction in which intervals miss the true value. The estimation methods are applied to data from an actual case-control study, and the results are interpreted in light of the simulation study.

In a trial involving nearly 1100 patients undergoing cardiac surgery, there were no significant differences in outcomes among patients receiving transfusions of red cells stored for 10 days or less as compared with outcomes in those receiving red cells stored for 21 days or more. The objective of red-cell transfusion is to increase oxygen delivery and improve clinical outcomes. However, in the United States, storage systems are licensed for up to 42 days on the basis of the estimated in vivo recovery of transfused red cells rather than on the basis of the clinical effectiveness of the transfusion. 1 During storage, red cells undergo numerous changes. 2 , 3 Some laboratory data suggest that red cells stored for longer periods may not traverse the microcirculation or deliver oxygen as effectively as those stored for shorter periods. 4 , 5 Several observational studies have assessed the association between the duration of . . .