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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]

Abstract: The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and meta-analyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union. [Copyright &y& Elsevier]

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the β1-adrenergic receptor (β1AR), a β-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, β1-Arg-389 had respective 2.8 ± 0.3- and 4.3 ± 2.1-fold greater agonist-promoted contractility vs. β1-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The β-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 ± 80 vs. 115 ± 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that β1AR-389 variation alters signaling in multiple models and affects the β-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome. [ABSTRACT FROM AUTHOR]

Presents the roundtable discussion by cardiac specialists and pharmacologists, which was convened on August 18, 2003, regarding the results of the Carvedilol or Metoprolol European Trial. Background on adrenergic dysfunction and mechanisms in heart failure; Differences among the trials related to the severity of illness of the subjects; Dose-response relationship of receptor-blocking drugs from the intrinsic way receptors function.

The Digitalis Investigation Group (DIG) trial reported that digoxin provided no overall mortality benefit and only a modest reduction in hospitalizations among patients with heart failure and depressed left ventricular systolic function. The clinical outcomes associated with digoxin therapy at different serum concentrations in the DIG trial have not been assessed. Our objective was to assess variations in serum digoxin concentration (SDC) and their association with mortality and hospitalization in patients with heart failure. Post hoc analysis of the randomized, double-blinded, placebo-controlled DIG trial, conducted from August 1991 to December 1995, with the main analysis restricted to men with a left ventricular ejection fraction of 45% or less (n = 3782). Patients randomly assigned to receive digoxin were divided into 3 groups based on SDC at 1 month (0.5-0.8 ng/mL, n = 572; 0.9-1.1 ng/mL, n = 322; and ≥1.2 ng/mL, n = 277) and compared with patients randomly assigned to receive placebo (n = 2611). All-cause mortality at a mean follow-up of 37 months. Results: Higher SDCs were associated with increased crude all-cause mortality rates (0.5-0.8 ng/mL, 29.9%; 0.9-1.1 ng/mL, 38.8%; and ≥1.2 ng/mL, 48.0%; P = .006 for trend). Patients with SDCs of 0.5 to 0.8 ng/mL had a 6.3% (95% confidence interval [CI], 2.1%-10.5%) lower mortality rate compared with patients receiving placebo. Digoxin was not associated with a reduction in mortality among patients with SDCs of 0.9 to 1.1 ng/mL (2.6% increase; 95% CI, - 3.0% to 8.3%), whereas patients with SDCs of 1.2 ng/mL and higher had an 11.8% (95% CI, 5.7%-18.0%) higher absolute mortality rate than patients receiving placebo. The association between SDC and mortality persisted after multivariable adjustment (SDC 0.5-0.8 ng/mL hazard ratio [HR] 0.80, 95% CI, 0.68-0.94; SDC 0.9-1.1 ng/mL HR 0.89, 95% CI, 0.74-1.08; SDC ≥1.2 ng/mL HR 1.16, 95% CI, 0... [ABSTRACT FROM AUTHOR]

Objectives: We sought to describe the United States and the rest of the world (ROW) outcomes from the major β-blocker heart failure (HF) trials. Background: HF trials have demonstrated differences in outcomes by geographic region. Methods: Randomized, double-blind, placebo-controlled studies that evaluated β-blockers in HF patients, had a primary endpoint of mortality, and enrolled U.S. patients were included. Relative risk (RR) was calculated for patients enrolled in the United States and ROW. Meta-analysis of the combined mortality rates was performed using the Cochran-Mantel-Haenszel statistic, stratified by study. Results: A total of 8,988 patients were enrolled in the MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), and BEST (β-Blocker Evaluation of Survival Trial) combined; 4,198 (46.7%) were from the United States. In the U.S. cohort, the RR reduction for each β-blocker was of smaller magnitude than in the overall cohort and no longer significant, whereas in the ROW subgroup, the mortality benefit for β-blockade persisted. In the pooled analysis (n = 11,635), the RR of death was reduced by 23% (p < 0.001) with β-blockade compared with placebo. In contrast, the mortality reduction associated with β-blockade in the U.S. cohort was small and not statistically significant (RR: 0.92, 95% confidence interval [CI]: 0.82 to 1.02, p = 0.11). The survival benefit persisted in the ROW cohort (RR: 0.64, 95% CI: 0.56 to 0.72, p < 0.001). Conclusions: Among patients enrolled in the United States, β-blockade was associated with a lower magnitude of survival benefit, whereas the ROW response was similar to the total study population. This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance. [Copyright &y& Elsevier]

Objectives: The aim of this study was to evaluate the mode of death in patients with advanced chronic heart failure (HF) and intraventricular conduction delay treated with optimal pharmacologic therapy (OPT) alone or OPT with biventricular pacing to provide cardiac resynchronization therapy (CRT) or CRT + an implantable defibrillator (CRT-D). Background: Limited data are available on mode of death in advanced HF. No data have existed on mode of death in these patients who also have an intraventricular conduction delay and are treated with CRT or CRT-D. Methods: Using prespecified definitions and source materials, seven cardiologists assessed mode of death among the 313 deaths that occurred in the Comparison of Medical, Pacing, and Defibrillation Therapies in Heart Failure (COMPANION) trial. Results: A primary cardiac cause was present in 78% of deaths. Pump failure (44.4%) was the most common mode of death followed by sudden cardiac death (SCD) (26.5%). Compared with OPT, CRT-D significantly reduced the number of cardiac deaths (38%, p = 0.006), whereas CRT alone was associated with a non-significant 14.5% reduction (p = 0.33). Both CRT and CRT-D tended to reduce pump failure deaths (29%, p = 0.11 and 27%, p = 0.14, respectively). The CRT-D significantly reduced SCD (56%, p = 0.02), but CRT alone did not. Conclusions: Pump failure deaths are the predominant mode of death in patients with advanced HF and are modestly reduced by both CRT and CRT-D. Only CRT-D reduced SCD and thus produced a favorable effect on cardiac mortality. [Copyright &y& Elsevier]

Introduction: Beta-blockers lower the risk for developing atrial fibrillation (AF) in heart failure (HF) with reduced ejection fraction. Bucindolol is a nonselective beta-blocker/mild vasodilator with the unique properties of sympatholysis and ADRB1 Arg389 inverse agonism. GENETIC-AF, a pharmacogenetic guided rhythm control intervention trial of bucindolol versus metoprolol succinate for the prevention of recurrent AF or atrial flutter (AFL), included a pre-specified AF burden (AFB) sub-study. Methods: The AFB cohort included 69 HF patients with reduced (< 0.50) left ventricular ejection fraction (LVEF), symptomatic paroxysmal or persistent AF, ADRB1 Arg389Arg genotype, and continuous rhythm monitoring via insertable cardiac monitor (N=43) or implanted therapeutic devices (N=26) to evaluate AFB. The substudy primary endpoint was time to first event of AFB ≥6 hours per day or death during a 24-week period after establishing sinus rhythm. Results: Patients had paroxysmal (36%) or persistent (64%) AF and 67% underwent electrical cardioversion prior to the start of efficacy follow-up. Mean LVEF was 0.34 ± 0.08, and 23%, 57%, and 20% had NYHA class I/II/III symptoms at baseline, respectively. For the primary endpoint, the HR was 0.75 (95% CI: 0.43, 1.32) by the prespecified AFB criteria and 0.69 (95% CI: 0.38, 1.23) by clinic-based 12-lead ECGs. In the U.S. population (N=42), the HR was 0.49 (95% CI: 0.24, 1.04) by AFB criteria and 0.41 (95% CI: 0.19, 0.90) as determined by ECG. The AFB endpoint occurred a median of 6.5 days prior to clinical AF/AFL (p <0.0001). Conclusions: AFB of 6 hours per day, previously associated with an increased rate of HF hospitalizations, has high predictive accuracy for clinical AF/AFL, can be used to reinforce the validity of clinical AF endpoint detection and has potential as a surrogate marker of impending clinical AF episodes. Trends for bucindolol benefit compared to metoprolol were observed with both rhythm monitoring methodologies. [ABSTRACT FROM AUTHOR]