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

JACC Heart Fail. 2022 Feb;10(2):73-84. doi: 10.1016/j.jchf.2021.09.004. Epub 2021 Dec 8.


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.

Keywords: heart failure; network meta-analysis; pharmacotherapy.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiotensin Receptor Antagonists / therapeutic use
  • Heart Failure* / drug therapy
  • Humans
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Network Meta-Analysis
  • Stroke Volume


  • Angiotensin Receptor Antagonists
  • Mineralocorticoid Receptor Antagonists