Time-varying cardiovascular risk of febuxostat vs. allopurinol in gout: a one-stage meta-analysis

Whether febuxostat is associated with an increased cardiovascular risk compared with allopurinol in patients with gout remains controversial, with major randomized trials reporting conflicting results. This study aims to perform a comprehensive meta-analysis using reconstructed individual participant data (IPD) to evaluate the time-varying cardiovascular and mortality risk of febuxostat vs. allopurinol in gout. We conducted a one-stage individual participant data meta-analysis. PubMed, Embase and Cochrane Library were searched up to November 2025 for randomized controlled trials and propensity score-matched observational studies reporting Kaplan-Meier curves for cardiovascular risk or all-cause mortality. Individual patient data were reconstructed from published curves. Time-varying hazard ratios (HRs) were estimated using a mixed-effects Cox model with treatment-by-time interaction across pre-specified intervals (0-12, 12-24, 24-48, >48 months). Four studies (n = 19 090) were included. Analysis revealed significant time-varying effects. For cardiovascular risk, HRs were 0.89 (95% CI 0.79-0.99) at 0-12 months, 0.58 (0.50-0.68) at 12-24 months, 0.86 (0.74-0.99) at 24-48 months and 1.09 (0.81-1.46) after >48 months. For all-cause mortality, HRs were 0.70 (0.62-0.79), 0.39 (0.33-0.45), 0.75 (0.65-0.86) and 1.02 (0.77-1.34) across the same intervals, respectively. The cardiovascular and mortality risk of febuxostat relative to allopurinol is time-dependent, showing a significant early reduction that attenuates over time. These findings advocate for a time-aware approach to clinical management and monitoring.