Assessment of Cardiovascular Risk in Older Patients with Gout Initiating Febuxostat versus Allopurinol: A Population-Based Cohort Study

Background —Hyperuricemia and gout are associated with increased risk of cardiovascular disease (CVD). Xanthine oxidase inhibitors (XOI), allopurinol and febuxostat, are the mainstay of urate lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. Methods —Using U.S. Medicare claims data (2008-2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among gout patients aged ≥65 years. The primary outcome was a composite endpoint of hospitalization for myocardial infarction (MI) or stroke. Secondary outcomes were individual endpoints of hospitalization for MI, stroke, coronary revascularization, new and recurrent heart failure (HF), and all-cause mortality. We used propensity score (PS) matching with a ratio of 1:3 to control for confounding. We estimated incidence rates (IR) and hazard ratios (HR) for primary and secondary outcomes in the PS-matched cohorts of febuxostat and allopurinol initiators. Results —We included 24,936 febuxostat initiators PS-matched to 74,808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate (IR) per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. HR for the primary outcome was 1.01 (95%CI 0.94-1.08) in the febuxostat compared to allopurinol groups. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of HF exacerbation (HR 0.94, 95%CI 0.91-0.99) in febuxostat initiators. The HR for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95%CI 0.56-2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. Conclusions —Among a cohort of 99,744 older Medicare patients with gout, overall there was no difference in the risk of MI, stroke, new onset HF, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for over 3 years versus allopurinol for over 3 years. The risk of HF exacerbation was slightly lower in febuxostat initiators.