Pharmacological Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis.

Background: In 2022, our network meta-analysis showed that a combination of β-blockers, angiotensin receptor-neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2i) was most effective in reducing all-cause mortality in heart failure with reduced ejection fraction (HFrEF). This study updates the treatment benefit by including additional large randomized controlled trials (RCTs) since 2022, including the Vericiguat Global Study in Participants with Chronic Heart Failure (VICTOR) trial.

Objectives: To evaluate and compare regimens of pharmacotherapy in patients with HFrEF.

Methods: We searched MEDLINE, EMBASE, and Cochrane CENTRAL for RCTs in patients with HFrEF through April 2025. Using frequentist network meta-analysis, we estimated hazard ratios (HRs) for all-cause mortality (primary outcome), cardiovascular death, and the composite of cardiovascular death or heart failure hospitalization (secondary outcomes). Absolute benefits were quantified as life-years gained using BIOSTAT-CHF and ASIAN-HF cohort data.

Results: The analysis included 103,754 patients across 89 randomized controlled trials. Relative to placebo, quintuple therapy with ARNi, β-blockers, MRA, SGLT2i, and vericiguat most effectively reduced all-cause mortality (HR 0.35, 95% confidence interval [CI]: 0.27-0.45), followed by quadruple therapy with ARNi, β-blockers, MRA and SGLT2i (0.39, 95% CI: 0.32-0.49). For a representative 70-year-old patient, quadruple therapy (ARNi/β-blockers/MRA/SGLT2i) provided 5.3 additional life-years (95% CI: 2.8-7.7 years) versus no treatment, while quintuple therapy (ARNi/β-blockers/MRA/SGLT2i/vericiguat) provided 6.0 additional life-years (95% CI: 3.7-8.4).

Conclusions: This analysis reinforces the substantial mortality and morbidity benefit associated with the currently recommended quadruple therapy regimen-angiotensin receptor-neprilysin inhibitors (ARNi), β-blockers, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter-2 inhibitors (SGLT2i)-in patients with HFrEF. The addition of vericiguat may provide an incremental survival gain of approximately 0.7 years beyond that achieved with quadruple therapy. However, these results should be regarded as exploratory, as they are derived from a secondary endpoint of a single trial.