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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. [ABSTRACT FROM AUTHOR]

Background: Heart failure is associated with ventricular tachyarrhythmias (VT/VF). Fluid accumulation during worsened heart failure may trigger VT/VF. Increased intrathoracic impedance has been correlated with fluid accumulation during heart failure. Implanted defibrillators capable of daily measures of intrathoracic impedance allow correlation of impedance with occurrence of VT/VF. We hypothesized that VT/VF episodes are preceded by decreases in intrathoracic impedance. The goal was to identify the relationship of intrathoracic impedance measured by implanted cardioverter defibrillators to the occurrence of VT/VF. Method: Implanted defibrillator follow-up data were obtained retrospectively. Those with Medtronic OptiVol (Medtronic Inc., Minneapolis, MN, USA), storing averaged daily and reference impedance values, were reviewed for VT/VF episodes. Impedance changes in the week leading up to VT/VF were analyzed. Results: A total of 317 VT/VF episodes in a cohort of 121 patients’ follow-up data were evaluated. Averaged daily intrathoracic impedance declined preceding 64% of VT/VF episodes, with an average decline of 0.46 ± 0.35 Ohms from the day before the VT/VF episodes. However, the mean values of the averaged daily and reference impedance did not change significantly. A novel measure, ΔTI, the sum of the daily differences between the averaged daily and reference impedance, was negative preceding 66% of VT/VF episodes (P < 0.001). The mean ΔTI was −4.0 ± 1.3 Ohms, which was significantly lower than the theoretically expected value of zero Ohms (P < 0.01). Conclusion: (1) Averaged daily impedance declined preceding 64% of VT/VF episodes, but the overall decline was of small magnitude; (2) a novel measure, ΔTI, was negative preceding 66% of VT/VF episodes, and significantly below zero. (PACE 2010; 33:960–966) [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate myocardial diastolic function in patients with beta-thalassemia major (β-TM) using pulsed-tissue Doppler imaging (TDI) and flow propagation (VP), in relation to BNP levels. Methods: We enrolled 192 consecutive patients with β-TM (88 men (25 ± 6 years) and 104 women (26 ± 6 years), with normal left ventricular (LV) systolic function. By TDI, diastolic myocardial velocities were sampled at the lateral section of the mitral annulus (Smv, Emv, Amv). From the apical four-chamber view diastolic transmitral flow velocities, including measures of E- and A-waves were performed. The propagation velocity of early flow into the LV cavity was measured by color M-mode Doppler. Plasma BNP levels were measured in all patients. Results: A nonlinear relationship was found between BNP levels and E/A ratio (beta coefficient for the second-order term = 1.4 ± 0.4, P = 0.001). We also found a positive association of BNP levels with Amv (r = 0.28, P = 0.023), and a reverse with Smv (r =−0.59, P = 0.01) and Emv/Amv (r =−0.36, P = 0.019). Moreover, an inverse relationship was observed between BNP and Vp (r =−0.43, P = 0.012) levels. Finally, a strong positive linear relationship was found between E/Vp ratio and BNP levels (r = 0.76, P < 0.001). Conclusion: A U-curved association of E/A ratio of transmitral Doppler velocity was revealed with BNP levels, while the tissue Doppler of the Emv/Amv of the mitral annulus movement showed a negative linear association with BNP levels. [ABSTRACT FROM AUTHOR]

Congestive heart failure affects millions of Americans, and thousands of new cases are reported each year. The prognosis continues to be grim. Most deaths in heart failure patients can be attributed to low-output states (pump failure) and arrhythmias (sudden). Attempts have been made to decrease the incidence of pump failure deaths by using contractility agents that, in most cases, have been shown to be detrimental. The results of trials using beta blockers are encouraging. Vasodilators have made a positive impact on outcome. However, the use of pharmacologic antiarrhythmic agents to decrease sudden death has failed to improve survival. Studies with implantable devices are ongoing and will provide an answer to the question of whether a reduction in sudden death will translate into a reduction of all-cause mortality. Antiplatelet and antithrombotic agents appear to be favor-able, and revascularization is recommended when feasible. [ABSTRACT FROM AUTHOR]

A double-blind, randomized, placebo-controlled study was conducted to test the peak and trough antianginal and antiischemic monotherapy efficacy and safety of a new extended-release formulation of nisoldipine (nisoldipine Coat Core [Bayer Corporation], 20 mg, 40 mg, and 60 mg once daily compared to placebo). Study patients had a history of chronic, stable angina pectoris, exercise-induced angina in association with ST segment depression, and exercise test reproducibility. Of the 483 patients enrolled in the study, results were valid for safety analysis for 312 and for efficacy analysis for 284. There was a statistically significant improvement in total exercise time at both peak and trough for patients taking 20 mg and 60 mg of nisoldipine compared with patients taking placebo, but the group taking 60 mg was not better than the group taking 20 mg (33.9 and 33.7 seconds, respectively, at trough). The results were similar for the secondary endpoints (time to onset of angina and time to 1 mm ST segment depression). No correlation was evident between plasma nisoldipine levels and total exercise duration. Headache and peripheral edema were the most frequently reported adverse events and were dose related. There were no discontinuations due to adverse events in patients randomized to the 20-mg nisoldipine group. No deaths occurred while patients were receiving active nisoldipine therapy. Therapy with this extended-release formulation of nisoldipine is an effective once-daily treatment for chronic stable angina pectoris. It represents one of the few dihydropyridine calcium channel antagonists that has shown efficacy when administered as monotherapy to patients with angina. [ABSTRACT FROM AUTHOR]