Early Quadruple Therapy in HFrEF: A Systematic Review and Pooled Analysis of Mortality and Hospital Utilisation Versus ≤Triple Therapy

Abstract

Background and Purpose: Despite advances in guideline-directed medical therapy (GDMT), heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality. The 2021 ESC and 2022 AHA/ACC/HFSA guidelines recommend early initiation of quadruple therapy (ARNI, β-blocker, MRA, SGLT2i). However, evidence comparing early quadruple therapy with conventional triple therapy (ACEi/ARB/ARNI + β-blocker + MRA) in real-world settings remains limited. This study aimed to evaluate the impact of early quadruple GDMT on clinical outcomes in HFrEF.

Methods: We conducted a systematic review and pooled analysis following PRISMA 2020 guidelines. MEDLINE, Embase, CENTRAL, and Web of Science were searched (Jan 2014–Mar 2025). Eligible studies compared early quadruple therapy (initiated ≤4 weeks of diagnosis) with ≤triple therapy in adult HFrEF patients, reporting outcomes ≥90 days. Risk of bias was assessed using ROB2/ROBINS-I. Random-effects (DerSimonian–Laird) and fixed-effect models were used; heterogeneity assessed via I² statistic.

Results: Two observational studies (n = 2,584) were included. Early quadruple therapy significantly reduced the 30-day composite of all-cause mortality/readmission (RR 0.73, 95% CI 0.55–0.97; I² = 0%), in-hospital mortality (RR 0.29, 95% CI 0.15–0.56), and hospital stay duration (mean difference –2.6 days). Twelve-month HF-related admissions were lower with quadruple therapy (RR 0.51, p = 0.02). There was no significant increase in hypotension, hyperkalaemia, or acute kidney injury. Sensitivity analyses confirmed result robustness.

Conclusions: Early initiation of quadruple therapy in HFrEF is associated with significant reductions in short-term mortality, readmissions, and hospital utilisation, without increased adverse effects. While promising, these findings are based on two moderate-risk, non-randomised studies. Larger prospective trials are needed to validate these outcomes and support widespread implementation.

Keywords: HFrEF, quadruple therapy, SGLT2i, guideline-directed therapy, outcomes, systematic review