Optimal Pharmacologic Treatment of Heart Failure With Preserved and Mildly Reduced Ejection Fraction: A Meta-analysis

JAMA Netw Open. 2022 Sep 1;5(9):e2231963. doi: 10.1001/jamanetworkopen.2022.31963.


Importance: In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF).

Objective: To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF.

Data sources: A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021.

Study selection: Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF.

Data extraction and synthesis: Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model.

Main outcomes and measures: The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model.

Results: In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes.

Conclusions and relevance: The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.

Publication types

  • Meta-Analysis

MeSH terms

  • Adrenergic beta-Antagonists / therapeutic use
  • Angiotensin Receptor Antagonists / pharmacology
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Angiotensins / pharmacology
  • Angiotensins / therapeutic use
  • Bayes Theorem
  • Glucose
  • Heart Failure* / drug therapy
  • Humans
  • Mineralocorticoid Receptor Antagonists / therapeutic use
  • Neprilysin / pharmacology
  • Neprilysin / therapeutic use
  • Receptors, Angiotensin / therapeutic use
  • Sodium / pharmacology
  • Sodium / therapeutic use
  • Sodium-Glucose Transporter 2 / pharmacology
  • Sodium-Glucose Transporter 2 / therapeutic use
  • Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
  • Stroke Volume


  • Adrenergic beta-Antagonists
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Angiotensins
  • Mineralocorticoid Receptor Antagonists
  • Receptors, Angiotensin
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium
  • Neprilysin
  • Glucose