A Systematic Review and Network Meta-Analysis of Pharmacological Treatment of Heart Failure With Reduced Ejection Fraction

Jasper Tromp, MD, PHD; Wouter Ouwerkerk, PHD; Dirk J. van Veldhuisen, MD, PHD; Hans L. Hillege, MD, PHD; A. Mark Richards, MBCHB, PHD; Peter van der Meer, MD, PHD; Inder S. Anand, MD; Carolyn S.P. Lam, MBBS, PHD; Adriaan A. Voors, MD, PHD


JACC Heart Fail. 2022;10(2):73-84. 

In This Article

Abstract and Introduction


Objectives: This study sought to estimate and compare the aggregate treatment benefit of pharmacological therapy for heart failure (HF) with reduced ejection fraction.

Background: The estimated treatment effects of various combinations of contemporary HF medical therapies are not well characterized.

Methods: We performed a systematic network meta-analysis, using MEDLINE/EMBASE and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between January 1987 and January 2020. We included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRAs), digoxin, hydralazine-isosorbide dinitrate, ivabradine, angiotensin receptor–neprilysin inhibitors (ARNi), sodium glucose cotransporter-2 inhibitors (SGLT2i), vericiguat, and omecamtiv-mecarbil. The primary outcome was all-cause death. We estimated the life-years gained in 2 HF populations (BIOSTAT-CHF [BIOlogy Study to TAilored Treatment in Chronic Heart Failure] and ASIAN-HF [Asian Sudden Cardiac Death in Heart Failure Registry]).

Results: We identified 75 relevant trials representing 95,444 participants. A combination of ARNi, BB, MRA, and SGLT2i was most effective in reducing all-cause death (HR: 0.39; 95% CI: 0.31–0.49); followed by ARNi, BB, MRA, and vericiguat (HR: 0.41; 95% CI: 0.32–0.53); and ARNi, BB, and MRA (HR: 0.44; 95% CI: 0.36–0.54). Results were similar for the composite outcome of cardiovascular death or first hospitalization for HF (HR: 0.36; 95% CI: 0.29–0.46 for ARNi, BB, MRA, and SGLT2i; HR: 0.44; 95% CI: 0.35–0.56 for ARNi, BB, MRA, and omecamtiv-mecarbil; and HR: 0.43; 95% CI: 0.34–0.55 for ARNi, BB, MRA, and vericiguat). The estimated additional number of life-years gained for a 70-year-old patient on ARNi, BB, MRA, and SGLT2i was 5.0 years (2.5–7.5 years) compared with no treatment in secondary analyses.

Conclusions: In patients with HF with reduced ejection fraction, the estimated aggregate benefit is greatest for a combination of ARNi, BB, MRA, and SGLT2i.


Heart failure (HF) remains a major cause of mortality and hospitalization globally, despite advances in pharmacological treatment.[1] Successes of early clinical trials established angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) as the foundation for the pharmacological treatment of HF with reduced ejection fraction (HFrEF).[2,3] In the last decade, treatment options for HFrEF increased with the addition of sacubitril/valsartan (ARNi) and ivabradine.[4,5] Results of trials published in the past year showed that treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) empagliflozin[6] and dapagliflozin,[7–9] soluble guanylase cyclase stimulator vericiguat,[10] and cardiac-specific myosin activator omecamtiv-mecarbil[11] can further improve outcomes in HFrEF.

Continued success in treatment of HFrEF has led to important challenges for clinicians who are left with multiple effective treatment options for their patients.[12,13] Earlier trials were performed largely sequentially—showing incremental benefit of novel pharmacological therapy on top of existing treatment—but recent trials were performed in parallel.[6,8,10,11] Results of more recent trials cannot guide sequencing of therapy or determine the most beneficial combination of pharmacotherapy. Network-meta-analyses allow for comparisons between different combinations of therapies to compare differences in the aggregate treatment effects. Information on the optimal cumulative benefit of treatment can help physicians and patients in their shared decision for therapy. An underlying assumption is that therapies have an additive effect. This is plausible for ARNi, SGLT2i, vericiguat, and omecamtiv-mecarbil, because they potentially target different disease pathways. Therefore, we conducted a systematic review and network meta-analysis to estimate and compare the aggregate treatment benefit of pharmacological therapy for HFrEF.