Citations

To determine if dehydroepiandrosterone (DHEA) replacement improves insulin secretion, insulin action, and/or postprandial glucose metabolism, 112 elderly subjects with relative DHEA deficiency ingested a labeled mixed meal and underwent a frequently sampled intravenous glucose tolerance test before and after 2 years of either DHEA or placebo. Despite restoring DHEA sulphate concentrations to values observed in young men and women, the changes over time in fasting and postprandial glucose concentrations, meal appearance, glucose disposal, and endogenous glucose production were identical to those observed after 2 years of placebo. The change over time in postmeal and intravenous glucose tolerance test insulin and C-peptide concentrations did not differ in men treated with DHEA or placebo. In contrast, postmeal and intravenous glucose tolerance test change over time in insulin and C-peptide concentrations were greater (P < 0.05) in women after DHEA than after placebo. However, since DHEA tended to decrease insulin action, the change over time in disposition indexes did not differ between DHEA- and placebo-treated women, indicating that the slight increase in insulin secretion was a compensatory response to a slight decrease in insulin action. We conclude that 2 years of replacement of DHEA in elderly men and women does not improve insulin secretion, insulin action, or the pattern of postprandial glucose metabolism.

Background The Detect Supraventricular Tachycardia (Detect SVT) trial was a randomized single blind study in subjects receiving a dual chamber implantable cardioverter defibrillator (ICD). The primary goal was to evaluate whether dual chamber enhancements result in greater discrimination between supraventricular tachycardia (SVT) and ventricular episodes when compared to ventricular-only enhancements. Purpose The purpose of this report is to describe our experiences from an analytic perspective, including overall study design, the value of blinded episode review, and the statistical analysis plan. Methods The Detect SVT study was a parallel group study, with blinded central review of all arrhythmia episodes occurring over a six-month period. The primary response was the proportion of inappropriate detections (SVT episodes that are inappropriately classified as ventricular by the device). Results A parallel group design was essential as unplanned crossovers were very differential. The blinded review of episodes was a major use of resources, with over 2300 episodes observed. This review did not materially alter the findings, however, the avoidance of any perceived bias was a major strength. The value of collecting large numbers of episodes on a single subject was found to be minimal. A Kaplan–Meier analysis of the number of SVT episodes until first inappropriate detection was found to add additional information. Limitations The recommendations reported here relate to cardiac arrhythmia trials, or other studies with very similar endpoints. These observations are based on the results of a single trial and should be confirmed in other studies. Conclusions The parallel group design was essential, as was accounting for within-subject correlation in the analysis. The blinded review process was also important, but significant resources could be saved by closing-out episode collection after a fixed number of episodes. Lessons learned from the Detect SVT trial may prove useful to others designing trials in this active research area.

Soluble guanylate cyclase is a heterodimeric enzyme with a prosthetic heme group that, on binding of its main ligand, NO, generates the second messenger cGMP. Unlike conventional nitrovasodilators, the novel direct NO- and heme-independent soluble guanylate cyclase activator BAY 58-2667 is devoid of non-cGMP actions, lacks tolerance development, and preferentially activates NO-insensitive heme-free or oxidized soluble guanylate cyclase. BAY 58-2667, therefore, represents a novel therapeutic advance in mediating vasodilation. To date, its cardiorenal actions in congestive heart failure (CHF) are undefined. We, therefore, hypothesized that BAY 58-2667 would have beneficial preload- and afterload-reducing actions in experimental severe CHF together with renal vasodilating properties. We assessed the cardiorenal actions of intravenous administration of 2 doses of BAY 58-2667 (0.1 and 0.3 μg/kg per minute, respectively) in a model of tachypacing-induced severe CHF. In CHF, BAY 58-2667 dose-dependently reduced mean arterial, right atrial, pulmonary artery, and pulmonary capillary wedge pressure (from baseline 19±1 to 12±2 mm Hg). Cardiac output (2.4±0.3 to 3.2±0.4 L/min) and renal blood flow increased. Glomerular filtration rate and sodium and water excretion were maintained. Consistent with cardiac unloading, atrial and B-type natriuretic peptide decreased. Plasma renin activity ( P =0.31) and aldosterone remained unchanged ( P =0.19). In summary, BAY 58-2667 in experimental CHF potently unloaded the heart, increased cardiac output and renal blood flow, and preserved glomerular filtration rate and sodium and water excretion without further neurohumoral activation. These beneficial properties make direct soluble guanylate cyclase stimulation with BAY 58-2667 a promising new therapeutic strategy for cardiovascular diseases, such as heart failure.