OBJECTIVES: Evidence for the efficacy of pharmacological therapies for heart failure with reduced ejection fraction (HFrEF) is growing. However, there is no consensus on the most effective treatment for HFrEF. This study aimed to evaluate the comparative efficacy of pharmacological treatments in patients with HFrEF.

METHODS: We systematically searched Medline, Embase, and CENTRAL up to Feb 2022, to include randomized controlled trials (RCTs) that evaluated the efficacy of pharmacological treatment among adults (≥18 years) with a diagnosis of HFrEF (defined by a left ventricular ejection fraction ≤ 45%). The outcomes of interest included all-cause mortality, cardiovascular (CV) death, and hospitalization for heart failure (HHF). A random network meta-analysis using a frequentist framework model was employed to calculate the pooled risk ratio (RR) with 95% confidence interval (CI) and rank the treatments using the surface under the cumulative ranking curve score (P-score).

RESULTS: We included 53 RCTs involving 105,498 participants with HFrEF. Sacubitril/valsartan (ARNI) + beta-blocker (BB) was found to be the most effective treatment for decreasing the risk of all-cause mortality (RR, 0.53; 95%CI, 0.37-0.75), followed by angiotensin-converting enzyme inhibitors (ACEi)+BB+renin inhibitor (RI) (0.57 [0.40-0.80]), and ACEI+BB+digoxin (0.58 [0.40-0.85]). Similarly, ARNI+BB had the highest probability to be the effective treatment for reducing the risk of CV death (0.49 [0.35-0.69]), followed by ACEi+BB+RI (0.57 [0.40-0.80]), and ACEI+BB (0.61 [0.47-0.77]). For the risk of HHF, ACEi+BB+digoxin was the most effective treatment (0.38; [0.25-0.57]), followed by ARNI (0.39; [0.25-0.57]), and ARNI+BB (0.41 [0.27-0.62]).

CONCLUSIONS: In patients with HFrEF, different medication regimens may have better efficacy than others for reducing all-cause mortality and CV death (e.g., ARNI+BB) and HHF (e.g., ACEI+BB+ digoxin).