Evaluation of Serum Urate Levels and the Clinical Manifestation of Gout with Cardiovascular Mortality from the CARES Trial

To investigate the relationship between serum urate (sUA) levels, gout flares, and tophi burden, with cardiovascular mortality after treatment with febuxostat or allopurinol in patients with gout from the CARES trial. Patients were randomly assigned to once-daily febuxostat (40 or 80 mg, based on sUA at Week 2) or allopurinol (dose titrated in 100 mg increments from 200-400 mg or 300-600 mg, based on kidney function). Key exploratory efficacy parameters were changes from baseline in sUA, gout flares, and tophus resolution in the overall population and subgroups of patients with and without cardiovascular mortality. Patients were treated with febuxostat (n = 3,098) or allopurinol (n = 3,092) for a median follow-up of 32 months (maximum 85 months). sUA levels were lower with febuxostat than allopurinol at most study visits in the overall population. There were no associations between sUA levels and cardiovascular mortality with febuxostat. Gout flares requiring treatment (per patient-year of exposure) were numerically higher within 1 year of treatment with febuxostat versus allopurinol (1.33 versus 1.20), but comparable thereafter and decreased across the study (>1 year: 0.35 versus 0.34; overall: 0.68 versus 0.63), irrespective of cardiovascular mortality. Overall, 20.8% of patients had ≥1 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of >50%. In CARES, febuxostat and allopurinol (≤600 mg doses) had comparable efficacy in patients with gout and cardiovascular disease, with no relationships between cardiovascular mortality and sUA, gout flares, or tophus resolution with febuxostat.