Polypharmacy as an independent predictor of heart failure hospitalization and mortality in HFrEF patients

Background Polypharmacy is highly prevalent in patients with heart failure with reduced ejection fraction (HFrEF), driven by multimorbidity, older age, and the need for multiple guideline-directed medical therapies (GDMT). Excessive medication burden may increase the risk of adverse events, reduce adherence, and worsen clinical outcomes. This study aimed to evaluate the prognostic effect of polypharmacy in patients with HFrEF. Methods Prospective, single-centre study that included consecutive de novo HFrEF patients followed in a HF-specialised outpatient clinic from 2019 to 2024. Medication burden was categorised as <5 drugs (no polypharmacy), 5–9 drugs (polypharmacy), and ≥10 drugs (hyper-polypharmacy). The primary endpoint was a composite of HF hospitalisation and all-cause mortality. Survival analyses were performed using Kaplan–Meier curves, and multivariable Cox regression assessed the independent prognostic effect of medication burden. Statistical significance was defined as p<0.05. Results A total of 262 patients were included (mean age 65.6 ± 15.4 years; 70.6% male), with a mean follow-up of 3.1 years. Medication burden was high (mean 8.4 ± 2.4 drugs), with 171 patients (65.3%) classified as having polypharmacy and 77 (29.4%) hyper-polypharmacy. Compared with the polypharmacy group, patients with hyper-polypharmacy were older (70.8 vs 63.3 years, p<0.001), had lower creatinine clearance (60.1 vs 74.1 mL/min, p<0.001), higher NT-proBNP concentrations (3337 vs 2414 pg/mL, p=0.012), and higher frailty scores (CFS 3.6 vs 3.1, p<0.001). The composite endpoint occurred in 17.5% of patients with polypharmacy and 32.5% with hyper-polypharmacy. Kaplan–Meier analysis showed progressively lower event-free survival with increasing medication burden. In multivariable Cox regression, hyper-polypharmacy independently predicted the composite endpoint (HR 2.1; 95% CI 1.21–5.37; p=0.003), after adjustment for age, renal function, NT-proBNP and frailty. Conclusion Polypharmacy and hyper-polypharmacy were common and associated with significantly worse event-free survival in patients with HFrEF. Although HF severity and GDMT use were similar between groups, patients with higher medication burden were older, frailer, had poorer renal function and higher NT-proBNP. Hyper-polypharmacy independently predicted heart failure hospitalisation and mortality, underscoring the need for structured medication review and strategies to reduce treatment burden in HFrEF patients.