Background/Purpose: The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES) trial demonstrated that major cardiovascular (CV) outcomes on febuxostat versus allopurinol in patients with gout and CV disease were comparable but that rates of CV mortality were higher on febuxostat. We evaluated the CV outcomes in those patients with chronic kidney disease (CKD) according to the need for up-titration of dose aimed at achieving serum urate (sUA) levels < 6 mg/dl.

Methods: Fifty-three percent of the study population in CARES (n = 3267) had moderately impaired kidney function (CKD 3, estimated creatinine clearance (eCRCL) < 60 ml/min and ≥ 30 ml/min). Febuxostat patients received 40 mg daily, increased to 80 mg at Week 4 if the sUA was ≥ 6.0 mg/dL at Week 2, regardless of kidney function. Allopurinol patients received 200 mg to 400 mg for CKD 3, or 300 mg to 600 mg when the eCRCL was ≥ 60 ml/min, increased in 100 mg increments each month until the sUA was < 6.0 mg/dL. The rates of the primary composite endpoint and its 4 components were analyzed according to final dose requirements in patients with CKD 3.

Results: There were 1636 CKD 3 patients randomized to febuxostat and 1631 to allopurinol in CARES.  In these patients, the final dose of febuxostat was 40 mg in 59% and 80 mg in 41% whereas the final dose of allopurinol was 200 mg in 41%, 300 mg in 28%, and 400 mg in 31% of patients.  At baseline, CKD 3 patients who required up-titration of dose to achieve serum urate levels < 6 mg/dl for both febuxostat and allopurinol were slightly younger, had greater serum urate levels and higher rates of tophi and higher rates of congestive heart failure compared to those patients not requiring up-titration of dose (p < 0.05) (Table 1). In patients with CKD 3, higher proportions of patients in the febuxostat group achieved the targets of < 6 and < 5 mg/dL compared to allopurinol at most time points during the trial and the incidence of gout flares was comparable for the 2 treatment arms (febuxostat, 47.9% and allopurinol 43.9%, overall). The incidence of CV events was greater in the patients who required higher doses and was driven by CV mortality rates; however, these results were similar for both febuxostat and allopurinol (Table 2).

Conclusion: CV event rates, driven by CV mortality, were greater in patients with moderately impaired kidney function who required up-titration of both febuxostat and allopurinol. However, these findings occurred in association with greater gout and CV disease burden, particularly heart failure, a comorbidity linked to increases in subsequent CV mortality.