Pharmacologic Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis (JACC December 2025- 2)-Article: Pharmacologic Treatment of Heart Failure with Reduced Ejection Fraction: An Updated Systematic Review and Network Meta-Analysis

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

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This 2025 systematic review and network meta-analysis by van Essen et al. encompasses 89 randomized controlled trials (RCTs) with over 103,000 patients to evaluate pharmacologic treatments for heart failure with reduced ejection fraction (HFrEF). It updates prior analyses by incorporating recent large RCTs, including the VICTOR trial evaluating vericiguat. The study focuses on all-cause mortality as the primary outcome, with cardiovascular death and composite cardiovascular death or heart failure hospitalization as secondary endpoints.<br /><br />Key findings confirm that the established quadruple therapy regimen—angiotensin receptor–neprilysin inhibitors (ARNi), β-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i)—remains most effective, reducing all-cause mortality by 61% compared to placebo (HR 0.39; 95% CI: 0.32-0.49). This therapy also increased life expectancy by approximately 5.3 years in 70-year-old patients and 7.8 years in 50-year-olds versus no treatment.<br /><br />Adding vericiguat to create a quintuple therapy further reduced all-cause mortality (HR 0.35; 95% CI: 0.27-0.45) and cardiovascular mortality, translating to an additional survival gain of about 0.7 years beyond the quadruple regimen. However, this incremental benefit is exploratory, derived from a secondary endpoint in a single trial, warranting cautious interpretation.<br /><br />Individual drug analyses revealed hydralazine–isosorbide dinitrate, MRAs, and ARNi as notably associated with reduced mortality. Sensitivity analyses affirmed the robustness of quadruple therapy benefits despite variations in study periods or baseline therapies.<br /><br />The study highlights that comprehensive pharmacotherapy substantially improves survival and reduces morbidity in HFrEF. It underscores the established quadruple therapy as foundational while recognizing vericiguat’s potential added value. Limitations include reliance on single-trial data for vericiguat’s incremental benefit, potential biases from trial populations versus real-world settings, and assumptions of sustained medication adherence.<br /><br />In conclusion, this extensive meta-analysis reinforces the mortality and morbidity benefits of quadruple therapy for HFrEF patients, with vericiguat offering a modest additional survival advantage that requires further validation. These findings support guideline-directed comprehensive treatment to optimize patient outcomes.

Keywords

heart failure with reduced ejection fraction

HFrEF

quadruple therapy

angiotensin receptor–neprilysin inhibitors

β-blockers

mineralocorticoid receptor antagonists

sodium-glucose cotransporter 2 inhibitors

vericiguat

all-cause mortality

network meta-analysis