Twenty-three RCTs (n=19,209) were included in the review, reporting a total of 2,720 deaths. There was some discrepancy in patient numbers between the tables and the text. Sample sizes ranged from 50 to 3,047.
There was statistically significantly lower mortality in the groups treated with beta-blockers than in the control groups (relative risk 0.76, 95% CI: 0.68, 0.84) with evidence of moderate heterogeneity (I2 = 30%, p = 0.09).
The magnitude of the survival benefit was significantly affected by the choice of beta-blocker. Metoprolol (relative risk 0.70, 95% CI: 0.58, 0.83), carvedilol (relative risk 0.66, 95% CI: 0.51, 0.87) and bisoprolol (relative risk 0.71, 95% CI: 0.61, 0.83) showed statistically significantly reduced death rates compared to placebo, but the comparisons were statistically non-significant for bucindolol, nebivolol and atenolol. The survival benefit for bucindolol was significantly lower (36% lower survival, 95% CI: 9%, 69%) than that for carvedilol. Results for other comparisons were also reported.
There was a statistically significant relationship between heart rate reduction and beta-blocker survival benefit (p = 0.01), with trials in the tertile with the greatest reductions in heart rate (median 15 beats/minute) showing greater survival benefits with beta-blockade (relative risk 0.64, 95% CI: 0.48, 0.86) than those in the tertile with the least reductions in heart rate (median eight beats/minute) (relative risk 0.91, 95% CI: 0.83, 0.99). Inclusion of heart rate reduction as a variable reduced heterogeneity to an I2 value of 0%. Meta-regression showed that for every five beats/minute reduction in heart rate with beta-blocker treatment the relative risk for death was reduced by 18% (95% CI: 6%, 29%). A Monte Carlo sensitivity analysis produced an even greater estimate of the impact of heart rate reduction. No evidence of confounding by other variables was found in the meta-regression.
There was no statistically significant effect of beta-blocker dosing on mortality. The relative risk for death in the 15 trials where patients received high doses of beta-blockers was 0.74 (95% CI: 0.64, 0.86) compared with 0.78 (95% CI: 0.63, 0.96) in those where they received low doses of beta-blockers.