Beta-Blockers to Reduce Mortality in Patients with Systolic Dysfunction A Meta-Analysis
Five of the 6 trials reported mortality caused by sudden death.3,11-14 Both MERIT-HF and CIBIS-II reported significant decreases in sudden death in patients receiving b-blocker therapy.3,12 Of the remaining 3 studies, the MDC trial showed a nonsignificant increase in sudden death,14 and CIBIS and US Carvedilo1 showed a nonsignificant decrease in sudden death.11,13 US Carvedilol had a larger RRR with respect to sudden death than MERIT-HF or CIBIS-II; however, statistical significance was not reached.13 Analysis revealed that these 5 trials were homogenous (Q=7.0) with respect to sudden death. When their results were pooled, a statistically significant reduction in the risk of sudden death was noted (ORMH=0.61; 95% CI, 0.5-0.75). All the included trials evaluated cardiovascular mortality as an end point; however, analysis revealed that the trials are heterogenous with respect to cardiovascular mortality (Q=12.7), and therefore a summary statistic would be misleading.
With analyses of the impact of disease severity and etiology of heart failure within the clinical trials, we attempted to determine the response of various subgroups to b-blocker therapy. Patients with NYHA class IV heart failure represented 3.6% and 17% of the MERIT-HF and CIBIS-II study populations, respectively. Subgroup analyses in these studies indicated that patients with NYHA class III heart failure had a nonsignificant but greater RRR in mortality than did those of NYHA class IV3,12 and II heart failure.3 US Carvedilol did not categorize patients according to NYHA class but rather stratified them on the basis of exercise test performance into mild, moderate, and severe categories. There was no difference in mortality benefit with b-blocker therapy between these 3 defined groups.13
The results of CIBIS-II, MERIT-HF, and US Carvedilol stratified by heart failure etiology indicated a decrease in mortality in patients with both ischemic and nonischemic heart failure. All 3 studies noted a significantly reduced mortality in patients with ischemic heart failure.3,12,13 US Carvedilol demonstrated a statistically significant decrease in mortality in patients with nonischemic heart failure receiving b-blocker therapy,13 while MERIT-HF and CIBIS-II did not.3,12
Discussion
Our findings indicate that there is a significant reduction in the risk of total mortality in patients receiving b-blocker therapy. US Carvedilol reported the largest RRR in mortality with b-blocker therapy in patients with heart failure13 compared with the other large trials that found a significant decrease in the risk of death.3,12 The RRR noted with carvedilol therapy approaches twice that reported with bisoprolol or extended-release metoprolol, although the absolute risk reductions are similar. The shorter study period employed in US Carvedilol compared with the other trials may provide some explanation for the large benefit noted, especially if the benefit of b-blocker therapy in this patient population is maximized early in the course of therapy. Also, the active run-in phase resulted in the withdrawal of 8.6% of the patients before randomization. Eliminating patients intolerant to carvedilol may have created the appearance of an elevated response to therapy compared with that seen in trials that did not employ an active run-in phase. Moreover, the patients included in US Carvedilol had a lower mean ejection fraction and a greater prevalence of nonischemic heart failure than the other clinical trials reviewed. The most intriguing potential explanation for the apparent greater mortality benefit with carvedilol compared with bisoprolol or metoprolol is the additional pharmacologic effects associated with carvedilol. In addition to b1-adrenergic blockade, carvedilol blocks a1- and b2-adrenergic receptors and has antioxidant effects.18 The contribution of these pharmacologic properties to the mortality benefit demonstrated with carvedilol therapy is currently unknown.
The limited number of patients with NYHA class IV heart failure enrolled in MERIT-HF make comparative benefit speculations unreliable. Also, the disease severity stratification used in US Carvedilol is not standardized, and the sample size representing the most severe patients was less than 10% of the study population. Based on the data currently available, it is not known if the magnitude of benefit with b-blocker therapy is related to disease severity.
The number of patients with nonischemic heart failure receiving b-blocker therapy was largest in MERIT-HF,3 followed by US Carvedilol13 and CIBIS-II.12 Of these, US Carvedilol was the only trial to demonstrate a statistically significant decrease in mortality in patients with nonischemic heart failure receiving b-blocker therapy.13 This may indicate that greater benefit can be derived with carvedilol than with bisoprolol or metoprolol therapy in patients with nonischemic heart failure. Further data are needed to fully assess the impact of heart failure etiology on mortality following b-blocker therapy.
Sudden death, which is often attributed to ventricular tachycardia or fibrillation,19 is a major cause of mortality in patients with heart failure. Although large trials evaluating metoprolol and carvedilol reported a significant reduction in sudden death,3,12 the use of concomitant antiarrhythmic medications varied between each trial evaluated. For example, approximately 15% of patients in CIBIS-II were receiving therapy with amiodarone,12 which has been shown to decrease the occurrence of sudden death in patients with heart failure.20 However, amiodarone therapy was evenly distributed between patients receiving bisoprolol and placebo12 and would not be expected to have a untoward effect on the assessment of sudden death.
