Meta-Analysis of Large-Scale Randomized Trials to Determine the Effectiveness of Inhibition of the Renin-Angiotensin Aldosterone System in Heart Failure

Abstract

Renin-angiotensin-aldosterone system (RAAS) inhibition is 1 of the most effective strategies for the management of heart failure with reduced systolic function. However, trials that included patients with preserved systolic function have not shown a clear beneficial effect. Pooling evidence from several heart failure trials provides the opportunity to better assess the differential effects of RAAS inhibition across the continuum of systolic function. The authors searched MEDLINE for large-scale trials published from 1966 to March 2014 that compared RAAS inhibitors against placebos. Studies were eligible for inclusion if they were conducted in heart failure populations with either clinical signs of heart failure or reduced ejection fractions. Inverse variance-weighted fixed-effects meta-analysis was used to pool outcomes of interest, with metaregression used to test for trends. In 16 trials with 54,621 randomized heart failure participants, RAAS inhibition reduced the risks for hospitalization for heart failure by 20% (relative risk [RR] 0.80, 95% confidence interval [CI] 0.77 to 0.83), cardiovascular mortality by 14% (RR 0.86, 95% CI 0.83 to 0.90), and all-cause mortality by 11% (RR 0.89, 95% CI 0.85 to 0.92). However, proportional effects decreased with increasing mean left ventricular ejection fraction (LVEF) for all outcomes (p for trend <0.01). Although there was no significant proportional effect on cardiovascular and all-cause mortality in trials with a mean LVEF >50%, RAAS inhibition was still found to decrease the risk for heart failure hospitalization in patients with preserved LVEFs (RR 0.88, 95% CI 0.80 to 0.97). In conclusion, the relative beneficial effects of RAAS inhibition in heart failure decreases with increasing left ventricular systolic function. Nonetheless, RAAS inhibition significantly reduces the risks for all-cause mortality and cardiovascular mortality in patients with moderately reduced LVEFs and the incidence of hospitalization in patients with preserved left ventricular function.