Cardiovascular Safety of Febuxostat vs. Allopurinol in Gout Patients with Cardiovascular Diseases: A Target Trial Emulation

Guidelines recommend febuxostat and allopurinol as first-line urate-lowering therapies (ULTs) for gout, yet the cardiovascular safety of febuxostat remains debated, with conflicting randomized trials (CARES, FAST) results and limited real-world evidence in high-risk patients. This target trial emulation study evaluated the long-term cardiovascular safety of febuxostat vs. allopurinol in gout patients with preexisting cardiovascular disease (CVD) using US collaborative electronic health records. We included 7555 propensity-score matched (42 covariates) pairs of adults aged ≥ 50 years initiating either febuxostat or allopurinol. The primary outcome of our study was the occurrence of major adverse cardiovascular events (MACE) and the secondary outcome was all-cause mortality. During a 10-year follow-up period (median 1,558 days), MACE risk was comparable (HR: 1.027; 95% CI: 0.978-1.079) between the two groups. Febuxostat was associated with modestly increased all-cause mortality (HR: 1.125; 95% CI: 1.039-1.217). Risk elevations were consistent across subgroups (White race, males, nonsmokers, etc.). Sensitivity analyses confirmed robustness. Findings suggest cautious febuxostat use in CVD patients, guiding personalized prescribing based on racial and lifestyle factors.