The most effective combination of pharmacological therapy for heart failure with reduced ejection fraction: a network meta-analysis of randomized controlled trials

Abstract

Background: 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 most effective combination of pharmacological therapy 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 death, 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.

Results: We included 49 RCTs involving 90,529 participants with HFrEF. For reducing all-cause mortality, the combination of angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), and sodium-glucose co-transporter-2 inhibitors (SGLT2i) was most effective (RR, 0.46; 95% CI, 0.32-0.66). For CV death, the combination of ACEI, BB, MRA, and Vericiguat showed the highest efficacy (RR, 0.34; 95% CI, 0.12-0.90). Regarding reducing HHF, the combination of ACEI, BB, MRA, and SGLT2i as well as the combination of ACEI, BB, MRA, and Ivabradine were equally the most effective (both RR, 0.27; 95% CI, 0.18-0.39).

Conclusion: This study provides robust evidence supporting the use of combination therapies in HFrEF management, with newer agents offering incremental benefits when added to established guideline-directed medical therapy.

Keywords: Heart failure with reduced ejection fraction; Meta-analysis; Pharmacological interventions; Randomized controlled trials.

Fig. 1

The flowchart of trial selection. HFpEF, heart failure with preserved ejection fraction; CENTRAL, Cochrane Central Register of Controlled Trials

Fig. 2

Network graphs of pharmacological treatments for heart failure with reduced ejection fraction in terms of all-cause death(A), cardiovascular death (B), and hospitalization for heart failure (HHF) (C). SGLT2i, sodium-glucose co-transporter-2 inhibitors; H-ISDN, Hydralazine and Isosorbide Dinitrate; ACEI, angiotensin II converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin II receptor-neprilysin inhibitors; BB, beta blocker; MRA, mineralocorticoid receptor antagonists; Iva, Ivabradine; Ver, Vericiguat; Ome, Omecamtiv

Fig. 3

Forest plots of frequentist standard network meta-analysis (NMA) and additive component NMA (CNMA) of pharmaceutical treatments for risk of all-cause death in patients with HFrEF. RR, risk ratio; CI, confidence interval; SGLT2i, sodium-glucose co-transporter-2 inhibitors; H-ISDN, Hydralazine and Isosorbide Dinitrate; ACEI, angiotensin II converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin II receptor-n eprilysin inhibitors; BB, beta blocker; MRA, mineralocorticoid receptor antagonists; Iva, Ivabradine; Ver, Vericiguat; Ome, Omecamtiv

Fig. 4

Forest plots of frequentist standard network meta-analysis (NMA) and additive component NMA (CNMA) of pharmaceutical treatments for risk of cardiovascular death in patients with HFrEF. RR, risk ratio; CI, confidence interval; SGLT2i, sodium-glucose co-transporter-2 inhibitors; H-ISDN, Hydralazine and Isosorbide Dinitrate; ACEI, angiotensin II converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin II receptor-neprilysin inhibitors; BB, beta blocker; MRA, mineralocorticoid receptor antagonists; Iva, Ivabradine; Ver, Vericiguat; Ome, Omecamtiv

Fig. 5

Forest plots of frequentist standard network meta-analysis (NMA) and additive component NMA (CNMA) of pharmaceutical treatments for risk of hospitalization for heart failure in patients with HFrEF. RR, risk ratio; CI, confidence interval; SGLT2i, sodium-glucose co-transporter-2 inhibitors; H-ISDN, Hydralazine and Isosorbide Dinitrate; ACEI, angiotensin II converting enzyme inhibitors; ARB, angiotensin II receptor blockers; ARNI, angiotensin II receptor-neprilysin inhibitors; BB, beta blocker; MRA, mineralocorticoid receptor antagonists; Iva, Ivabradine; Ver, Vericiguat; Ome, Omecamtiv