Cardiovascular risk associated with polypharmacy in heart failure: a systematic review and meta-analysis

Polypharmacy is highly prevalent among patients with heart failure (HF), due to multimorbidity and guideline-directed pharmacotherapy. While polypharmacy aims to optimize management, it can increase the risk of drug-drug interactions and adverse drug events, which may compromise clinical outcomes. However, the evidence regarding the relationship between polypharmacy and cardiovascular (CV) outcomes in HF populations remains limited. The aim of this study was to determine the association between polypharmacy and adverse CV outcomes among patients with HF. A systematic review and meta-analysis were conducted to evaluate the association between polypharmacy and adverse CV outcomes in HF. Relevant studies were identified through searches of PubMed, Embase, and Web of Science. The primary outcomes included a composite CV endpoint and its individual components. Effect estimates, based on comparisons between the highest and lowest levels of polypharmacy, were pooled using random-effects models. Ten studies including 30 115 patients with HF were analyzed. Compared with those without polypharmacy, patients with polypharmacy had a significantly increased risk of the composite CV endpoint (HR: 1.27; 95% CI: 1.15-1.39). Notably, polypharmacy was linked to a higher risk of HF hospitalization (HR: 1.42; 95% CI: 1.28-1.56). No significant associations were found for CV death (HR: 1.07; 95% CI: 0.81-1.41) or all-cause mortality (HR: 1.05; 95% CI: 0.88-1.25). Polypharmacy in patients with HF was associated with increased risk of composite CV outcome and HF hospitalization, reflecting the complexity of managing multiple medications. These findings underscore the need for individualized medication reviews to minimize inappropriate prescribing and ensure continued delivery of evidence-based therapies. PROSPERO Registration Number CRD420251110556.