medwireNews: Results of the CARES trial indicate that febuxostat is associated with a higher risk for all-cause and cardiovascular mortality than allopurinol among patients with gout and a history of cardiovascular disease.
The publication of the trial results in The New England Journal of Medicine follows a safety alert that was issued by the US FDA in November 2017 on the basis of these findings.
William White (University of Connecticut School of Medicine, Farmington, USA) and co-investigators randomly assigned patients with gout and a history of major cardiovascular disease to receive daily treatment with febuxostat 40 mg, with a dose increase to 80 mg for patients with serum urate levels above 6.0 mg/dL, or to receive allopurinol with dosing based on kidney function.
After a median 32 months of follow-up, there was no significant difference in the occurrence of the primary endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization – between the 3098 patients receiving febuxostat and the 3092 patients in the allopurinol group, at rates of 10.8% and 10.4%, respectively.
However, patients receiving febuxostat were a significant 22% more likely to die from any cause than those taking allopurinol, with rates of 7.8% versus 6.4%, and this was due to “an imbalance in cardiovascular deaths” between the two groups, report the researchers.
Indeed, the rate of cardiovascular death was 4.3% in the febuxostat group and 3.2% in the allopurinol group, translating into a significant 34% increased risk with febuxostat.
The CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial was “conducted as an FDA requirement” to establish whether febuxostat is noninferior to allopurinol in relation to cardiovascular safety following the results of placebo-controlled trials suggesting a “modestly higher rate” of cardiovascular events with febuxostat, explain White and colleagues.
They note that the mechanisms underlying the increased risk for death among febuxostat-treated patients are “unclear,” given that adjudicated rates of nonfatal cardiovascular events were comparable between the groups, and preclinical studies of febuxostat demonstrated no toxic cardiovascular effects related to heart rhythm and function.
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