Beta-Blockers to Reduce Mortality in Patients with Systolic Dysfunction A Meta-Analysis
Quality Assessment
Each study was evaluated using the instrument designed by Jadad and colleagues16 that rates study quality from 0 (worst) to 5 (best). Two of the 6 clinical trials identified received a score of5,11,14 while the remaining 4 received a score of4,3,9,12,13 The reasons for lower scores included a lack of description of the randomization process13 or of which patients withdrew from the trials.3,9,12
Analysis of Data
We critically analyzed the mortality end points of each study. Two independent reviewers calculated relative risk, relative risk reduction (RRR), absolute risk reduction, and number needed to treat (NNT) for total mortality. The NNT is a numerical representation of the number of patients that must be treated to prevent 1 adverse outcome (in this case death) in the population studied for the duration of the trial. Direct comparisons of NNT between studies should be avoided; since the benefit cannot be assumed to have occurred in even increments throughout the trial, the NNT serves only as an alternate form of data presentation. The results of these 4 calculations are provided in an effort to allow for additional assessment of the clinical trials evaluated.
Homogeneity of effect was assessed by calculating a Q statistic, where the number of degrees of freedom is equal to the number of trials included in the analysis minus 1. A P value of less than .05 was considered statistically significant. The pooled estimate of effect was calculated using the Mantel-Haenszel method, which assumes a fixed effect model. The variance of the individual risk assessments, the weight of each study, and ultimately the summary odds ratio (OR) and 95% confidence interval (CI) were calculated for mortality end points when studies were homogenous using this method as previously described.17
Results
Study Characteristics
Of those identified, 2 trials each evaluated bisoprolol (the Cardiac Insufficiency Bisoprolol Study [CIBIS]11 and the Cardiac Insufficiency Bisoprolol Study II [CIBIS-II]12), carvedilol (the Australia/New Zealand Heart Failure Research Collaborative Trial [ANZ]9 and the US Carvedilol Heart Failure Program [US Carvedilol]13), and metoprolol (the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure [MERIT-HF]3 and the Metoprolol in Dilated Cardiomyopathy [MDC]14 trial). A total of 9335 patients were enrolled in the 6 trials.3,9,11-14 With an average 7.5% withdrawal rate during the active run-in phases,9,13,14 9171 patients were ultimately randomized to receive either b-blocker or placebo therapy. The average withdrawal rate after randomization was 15.8% for patients receiving active treatment compared with 17.2% for patients receiving placebo (P >.05 for each individual trial).3,9,11-14
Patient Characteristics
There were no statistically significant differences between the baseline characteristics of the patients receiving active treatment versus placebo. The mean age of patients was 60 years, with an average of 78% men. All patients were receiving pharmacologic treatment for their heart failure before study enrollment. Although the studies used various ejection fraction requirements, the average ejection fraction ranged from 22% to 29%.3,9,11-14 In all studies the majority of patients had New York Heart Association (NYHA) class II or III heart failure.3,9,11-14Table 1 shows the study characteristics for each included clinical trial and the baseline characteristics of enrolled patients.
End Points
Mortality offers an objective and clear end point for clinical trials. It supersedes other safety and efficacy end points.1Table 2 provides a summary of selected mortality end points and the notation of the statistical significance of the end point in each trial. The calculated risk reduction demonstrated for total mortality in trials generating a statistically significant mortality benefit is given.
A statistically and clinically significant decrease in mortality was reported in CIBIS-II, US Carvedilol, and MERIT-HF. These clinical trials included a total of 7732 patients receiving 1 of 3 different b-blockers.3,12,13 A nonsignificant reduction in total mortality was noted in patients receiving b-blocker therapy in CIBIS-I and ANZ,9,11 while a nonsignificant increase in total mortality was reported in patients receiving b-blocker therapy in the MDC trial.14 These clinical trials included a total of 1439 patients and were not powered to assess this end point.9,11,14
Analysis revealed that the 6 clinical trials are homogenous in total mortality (Q=9.3). This indicates that the trials are measuring an effect of the same size and that differences in issues such as study design and patient population would not be expected to have an appreciable impact on the outcome of meta-analysis. When the results of all 6 trials were pooled, a statistically significant reduction in the risk of total mortality was noted (ORMH=0.66; 95% CI, 0.58-0.75). The Figure 1 is a representation of the effect of b-blocker therapy on total mortality.
