Association of frailty and pre-frailty with cardiovascular mortality: a meta-analysis of 26 cohort studies.

Objective: This meta-analysis evaluated the association of frailty and pre-frailty with cardiovascular mortality in cohort studies. While frailty is a recognized predictor of poor outcomes, the prognostic role of pre-frailty-a critical intermediate stage-remains less clear. We assessed their associations with cardiovascular mortality, explored heterogeneity, and examined the robustness of findings through publication bias analyses. Methods: Cohort studies published up to 2025 were systematically searched. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using random-effects models. Heterogeneity was assessed using the I 2 statistic. Subgroup analyses and meta-regression were performed to explore sources of heterogeneity, but no single factor fully explained the high variability observed (I 2 > 80%). Publication bias was evaluated using funnel plots and statistical tests, with no significant bias detected. Results: Twenty-six cohort studies involving over 4 million participants were included. Frailty was significantly associated with higher cardiovascular mortality (HR = 2.11, 95% CI: 1.86-2.40), and pre-frailty also conferred elevated risk (HR = 1.80, 95% CI: 1.46-2.23). Despite substantial heterogeneity (I 2 > 80%), subgroup analyses and meta-regression did not identify a clear source. No publication bias was found. Conclusion: Frailty and pre-frailty are consistently associated with increased cardiovascular mortality, emphasizing their value for early risk identification and preventive strategies. Given the observational nature and residual heterogeneity, findings should be interpreted cautiously, and future research is needed to establish standardized assessment tools and test targeted interventions. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD420251109559.