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

OBJECTIVES: Whether febuxostat is associated with an increased cardiovascular risk compared to 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 versus allopurinol in gout. METHODS: 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). RESULTS: Four studies (n = 19,090) were included. Analysis revealed significant time-varying effects. For cardiovascular risk, HRs were 0.89 (95% CI 0.79 to 0.99) at 0-12 months, 0.58 (0.50 to 0.68) at 12-24 months, 0.86 (0.74 to 0.99) at 24-48 months, and 1.09 (0.81 to 1.46) after >48 months. For all-cause mortality, HRs were 0.70 (0.62 to 0.79), 0.39 (0.33 to 0.45), 0.75 (0.65 to 0.86), and 1.02 (0.77 to 1.34) across the same intervals, respectively. CONCLUSION: 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.