Greenberg, Barry

Abstract Clinical trial Data and Safety Monitoring Boards (DSMBs) have a primary obligation of ensuring study participant safety, while maintaining trial integrity. The role of DSMBs is expanding, and ideally should include post-hoc reporting of deliberative processes related to clinically important safety issues or factors that could impact on future trial designs. We describe how the TOPCAT DSMB detected, investigated, and adjudicated an unexpectedly large renal adverse event signal midway through the trial, and offer general guidelines for dealing with similar unanticipated occurrences in future trials. The detection of a greater than expected incidence of deterioration in renal function, occurring in 6.1% of patients in the spironolactone arm compared with 3.9% in the placebo arm (P = 0.009), led to an in-depth DSMB review of associated study medication withdrawals and adverse events. The trial continued uninterrupted throughout the review, which reached the conclusions that spironolactone-associated renal dysfunction did not compromise overall patient safety or interfere with a perceived efficacy signal. Although no discrete mechanism for the spironolactone-associated renal adverse event signal was identified, likely possibilities are discussed. In clinical trials, DSMBs and co-ordinating centres should have the resources to detect, investigate, and adjudicate unexpected safety issues, with goals of ensuring patient safety and preserving the potential for detection of therapeutic effectiveness. In TOPCAT, spironolactone-associated renal dysfunction emerged as a potentially trial-threatening adverse event and, although clinically important, did not lead to compromise of patient safety, trial interruption, termination, or apparent loss of treatment effectiveness.

The fourth Leon Thal Symposium (LTS2010) was convened in Toulouse, France, on November 3, 2010. This symposium reviewed design parameters that are necessary to develop comprehensive national databases on healthy aging. Such datasets offer the potential to serve as the foundation for a systems‐approach to solve the dual public health problems of: (1) early detection of people who are at elevated risk for Alzheimer's disease, and (2) the development of interventions to delay onset of, or prevent, late‐life dementia. The symposium considered three interrelated components of a National Database for Longitudinal Studies on Healthy Aging as follows: (a) a registry of healthy aging adults; (b) refined computer‐based assessments for data gathering, including assessments of behavioral/memory changes associated with aging that are appropriate for broad use in nonexpert settings; and (c) high performance computing/supercomputer‐based approaches for health data modeling and mining.

Background— β-Blockers improve survival and reduce hospitalization in chronic heart failure (CHF) by biologically improving left ventricular ejection fraction (LVEF). However, a good predictor of improvement with this therapy has not been identified. This substudy of BEST examined whether myocardial contractile reserve, as determined by dobutamine stress echocardiography, predicts improvement in LVEF. Methods and Results— Seventy-nine patients with class III/IV CHF underwent dobutamine stress echocardiography before treatment with bucindolol (n=41) or placebo (n=38). Regional wall motion score index (WMSI) was calculated as the sum of the scores in each segment divided by the total number of segments visualized. WMSI was compared with change in LVEF after 3 months of therapy as determined by gated radionuclide scan. Change in WMSI correlated inversely with change in LVEF after 3 months of bucindolol ( r =−0.72, P <0.0001) and was the most significant multivariate predictor of change in LVEF ( P =0.0002). Patients with contractile reserve had demographics similar to those of patients without contractile reserve, including RVEF, LVEF, systolic blood pressure, and CHF duration. However, patients without contractile reserve had higher baseline plasma norepinephrine levels (687±333 versus 420±246 pg/mL, P <0.05) and greater decrease in plasma norepinephrine in response to bucindolol (−249±171 versus −35±277 pg/mL, P <0.05). Conclusions— This study suggests a direct relationship between contractile reserve and improvement in LVEF with β-blocker therapy in patients with advanced CHF. Patients without contractile reserve have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may experience greater sympatholytic effects from bucindolol.