Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: another story of the CARES trial

OBJECTIVES: The Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES) trial suggested a higher risk of cardiovascular (CV) death from febuxostat than from allopurinol. However, a significant number of patients died after discontinuation of febuxostat or allopurinol. We investigated whether major adverse cardiovascular events (MACE) and CV death were increased because of discontinuation of febuxostat or allopurinol using the CARES trial data. METHODS: We compared the MACE that occurred during administration and after discontinuation in the initial phase after discontinuation, and we compared the CV and non-CV mortality rates in the initial phase after discontinuation to determine the impact of discontinuation of febuxostat or allopurinol. RESULTS: Among 6190 patients, the incidence rate per 100 person-years for MACE was 3.11 during administration and 6.71 after discontinuation. MACE was significantly increased after discontinuation compared with that during administration within 1 month (HR 7.40; 95% CI 5.38 to 10.17) and 6 months (HR 5.22; 95% CI 4.26 to 6.39). In the analysis excluding death induced by adverse events that occurred up to 1 day after the last medication, the CV mortality rate was higher than the non-CV mortality rate within 6 months (45.7% vs 27.9%, p=0.0001). In addition, changes in serum uric acid levels from baseline to the last measurement before discontinuation were significantly associated with higher MACE risk after drug discontinuation (HR 1.14; 95% CI 1.04 to 1.26). CONCLUSIONS: MACE and CV death were increased in the initial stage after discontinuation of febuxostat or allopurinol in patients with gout.