Efficacy and safety of quadruple therapy versus triple therapy in patients with heart failure with preserved ejection fraction: a propensity score-matched real-world study

Objective Although triple therapy has been recommended as foundational therapy for heart failure with preserved ejection fraction (HFpEF), residual risk remains high in affected patients. The efficacy of beta-blockers in HFpEF remains controversial. Methodology This single-center retrospective cohort study included 600 patients with HFpEF who received triple therapy (as defined per the study protocol) at Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, between January 2018 and January 2025. A 1:1 propensity score matching (PSM) approach was used to balance baseline confounding factors. The efficacy and safety of quadruple therapy were compared with those of triple therapy alone. The primary endpoint was the composite of heart failure hospitalization or cardiovascular death. Results After PSM, 360 patients were matched, with 180 patients in each group. During a median follow-up of 37.8 months, the incidence of the primary endpoint was significantly lower in the quadruple therapy group than in the triple therapy group [17.8% vs. 25.0%, hazard ratio (HR) = 0.678, 95% confidence interval (CI): 0.432–0.967, P = 0.035]. The quadruple therapy group had significantly lower rates of first heart failure hospitalization (14.4% vs. 20.6%, HR = 0.672, P = 0.030) and recurrent heart failure hospitalization (0.217 vs. 0.325 events per person-year, HR = 0.654, P = 0.015). Subgroup analyses showed that patients with concomitant coronary artery disease (HR = 0.591, P = 0.047) and baseline heart rate ≥70 beats per min (HR = 0.572, P = 0.045) derived greater benefit from quadruple therapy. A trend toward benefit was observed in patients with baseline LVEF of 50%–59%, but no significant interaction was detected. The overall safety profiles were comparable between the two groups. Conclusion In this real-world observational cohort of patients with HFpEF receiving triple therapy, quadruple therapy was associated with a lower risk of the composite of heart failure hospitalization or cardiovascular death, driven primarily by a reduction in heart failure hospitalizations. No statistically significant difference in cardiovascular or all-cause mortality was observed. The association appeared more prominent in patients with concomitant coronary artery disease and higher baseline heart rate in exploratory subgroup analyses. Given the observational design, these hypothesis-generating findings cannot establish causality and require prospective validation.