Background: The medical treatments of chronic heart failure have made remarkable progress in recent years. It is crucial to determine the optimal drug combination based on current evidence.Methods: A search of PubMed, EMBASE, and Cochrane CENTRAL databases was conducted for studies on angiotensin receptor-neprilysin inhibitors (ARNIs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and ivabradine (IVA) between 1987 and 2021. The network meta-analysis was performed to compare the efficacy of drug therapies in heart failure with reduced ejection fraction (HFrEF).Results: Forty-eight randomized controlled trials (RCTs), which overall included 68,074 patients with HF and left ventricular ejection fraction (LVEF) ≤ 40%, were identified and included in the network meta-analysis. The efficacies of 13 intervention classes, including monotherapies or combinations of ACEI, ARB, ARNI, BB, MRA, SGLT2i, IVA, and placebo, on hospitalization for HF, cardiovascular mortality, and all-cause mortality were compared. Among the 13 included interventions, ARNI+BB+MRA, SGLT2i+ACEI+BB+MRA, and IVA+ACEI+BB+MRA were found to be best in terms of all three outcomes. Compared with placebo, these three drug combinations were associated with significant reductions in the risk of all-cause death, cardiovascular mortality and hospitalization for HF.Conclusions: ARNI+BB+MRA, SGLT2i+ACEI+BB+MRA, and IVA+ACEI+BB+MRA were the top three therapies for patients with HFrEF. The increasing use of combinations of conventional and novel drugs contributed to progressive reductions in hospitalization and mortality in patients with HFrEF.

ImportanceIn 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).ObjectiveTo compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF.Data SourcesA 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 SelectionRandomized 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 SynthesisData 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 MeasuresThe 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.ResultsIn 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 RelevanceThe 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.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were developed as antidiabetic agents, but accumulating evidence has shown their beneficial effects on the cardiovascular system. Analyses of the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) suggested that these benefits are independent of glycemic control. Several large-scale outcome trials of SGLT2i also showed cardiovascular benefits in nondiabetic patients, strengthening this perspective. Extensive animal and clinical studies have likewise shown that mechanisms other than the antihyperglycemic effect underlie the cardiovascular benefits. Recent clinical guidelines recommend the use of SGLT2i in patients with type 2 diabetes mellitus and cardiovascular diseases because of the proven cardiovascular protective effects. Since the cardiovascular benefits are independent of glycemic control, the therapeutic spectrum of SGLT2i will likely be extended to nondiabetic patients.