Impact of Severe Polypharmacy on Survival in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Background: Polypharmacy is highly prevalent in patients with heart failure (HF), but the prognostic significance of severe polypharmacy remains uncertain. This systematic review and meta-analysis evaluated its association with all-cause mortality in adults with HF. Methods: PubMed, MEDLINE, Embase, Scopus and the Cochrane Library were searched from inception through August 2026. Observational studies assessing severe polypharmacy (the highest medication-burden category in each study; ≥9 to ≥15 medications) and all-cause mortality in adults with HF were eligible. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Leave-one-out sensitivity analyses and post hoc threshold-specific analyses were performed. Risk of bias and certainty of evidence were assessed using the Newcastle–Ottawa Scale (NOS) and GRADE, respectively. The protocol was registered in PROSPERO (CRD420261507517). Results: Nine studies included 44,213 patients. Severe polypharmacy was not significantly associated with all-cause mortality (HR 1.04, 95% CI 0.86–1.26; p = 0.67; I2 = 79%). NOS scores ranged from 6 to 9. Leave-one-out HRs ranged from 0.996 to 1.097, with all 95% CIs including 1. In six studies defining severe polypharmacy as ≥10 medications, the pooled HR was 1.15 (95% CI 1.00–1.32; p = 0.054; I2 = 37.8%). Certainty of evidence was very low because of serious inconsistency and imprecision. Conclusions: No statistically significant association was identified, but very low certainty of evidence precludes firm conclusions, and clinically important associations cannot be excluded. Medication count should be interpreted alongside treatment appropriateness and clinical complexity.