The phase IV CARES study enrolled patients with gout and a history of major cardiovascular disease, and found higher risks of cardiovascular and all-cause mortality in those treated with febuxostat than in those who received allopurinol.
An EU review of the CARES findings has recommended that healthcare professionals avoid treatment with febuxostat in patients with pre-existing major cardiovascular disease (eg, myocardial infarction, stroke, or unstable angina), unless no other therapy options are appropriate. Clinical guidelines for gout and hyperuricaemia recommend treatment with febuxostat only when allopurinol is contraindicated or not tolerated.
The randomised, double-blind CARES study followed 6190 patients for a median of 32 months. The primary endpoint was time to first occurrence of major adverse cardiovascular events, a composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and unstable angina with urgent coronary revascularisation.
The primary endpoint occurred at similar rates in the febuxostat and allopurinol groups. In the secondary analysis, the incidence of cardiovascular deaths was higher in the febuxostat group than in the allopurinol group (4.3% vs 3.2%; hazard ratio 1.34, 95% CI 1.03–1.73). The incidence of all-cause mortality was also higher with febuxostat than with allopurinol (7.8% vs 6.4%; hazard ratio 1.22, 95% CI 1.01–1.47), which was mainly driven by the higher rate of cardiovascular deaths in the febuxostat group.
Febuxostat, at doses of 80mg and 120mg, is indicated for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence, of tophus or gouty arthritis). Febuxostat at a dose of 120mg is indicated for the prevention and treatment of hyperuricaemia in adults undergoing chemotherapy for haematologic malignancies who are at intermediate to high risk of tumour lysis syndrome.