• Vincenzo De Marzo, Gianluigi Savarese, Lucia Tricarico, Sofia Hassan, Massimo Iacoviello, Italo Porto, and Pietro Ameri.
• Department of Internal Medicine, University of Genova, Genova, Italy.
• J. Intern. Med. 2022 Aug 1; 292 (2): 333-349.

BackgroundFollowing the availability of new drugs for chronic heart failure (HF) with reduced ejection fraction (HFrEF), we sought to provide an updated and comparative synthesis of the evidence on HFrEF pharmacotherapy efficacy.MethodsWe performed a Bayesian network meta-analysis of phase 2 and 3 randomized controlled trials (RCTs) of medical therapy in HFrEF patient cohorts with more than 90% of the participants with left ventricular ejection fraction less than 45% and all-cause mortality reported.ResultsSixty-nine RCTs, accounting for 91,741 subjects, were evaluated. The step-wise introduction of new drugs progressively decreased the risk of all-cause death, up to reaching a random-effects hazard ratio (HR) of 0.43 (95% credible intervals [CrI] 0.27-0.63) with beta blockers (BB), angiotensin-converting enzyme inhibitors (ACEi), and mineralocorticoid receptor antagonist (MRA) versus placebo. The risk was further reduced by adding sodium-glucose cotransporter-2 inhibitors (SGLT2i; HR 0.38, 95% CrI 0.22-0.60), ivabradine (HR 0.39, 95% CrI 0.21-0.64), or vericiguat (HR 0.40, 95% CrI 0.22-0.65) to neurohormonal inhibitors, and by angiotensin receptor-neprilysin inhibitor (ARNI), BB, and MRA (HR 0.36, 95% CrI 0.20-0.60). In a sensitivity analysis considering the ARNI and non-ARNI subgroups of SGLT2i RCTs, the combination SGLT2i + ARNI + BB + MRA was associated with the lowest HR (0.28, 95% CrI 0.16-0.45 vs. 0.40, 95% CrI 0.24-0.60 for SGLT2i + BB + ACEi + MRA). Consistent results were obtained in sensitivity analyses and by calculating surface under the cumulative ranking area, as well as for cardiovascular mortality (information available for 56 RCTs), HF hospitalization (45 RCTs), and all-cause hospitalization (26 RCTs).ConclusionsCombination medical therapy including neurohormonal inhibitors and newer drugs, especially ARNI and SGLT2i, confers the maximum benefit with regard to HFrEF prognosis.© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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