In patients with gout and co-existing cardiovascular disease, febuxostat is noninferior to allopurinol in the rates of major cardiovascular events, but febuxostat is associated with higher risks for all-cause and cardiovascular mortality.

At the request of the FDA, William B. White, MD, of the University of Connecticut School of Medicine in Farmington, and colleagues conducted a double-blind, randomized trial to assess the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES, NCT01101035). A total of 6190 patients with gout and cardiovascular disease from 320 centers in North America were randomly assigned to receive febuxostat, a nonpurine xanthine oxidase inhibitor, or allopurinol, a purine base analogue, for a median of 2 years. Allopurinol doses were adjusted according to kidney function. Febuxostat was administered at 40 mg once daily and only increased to 80 mg if serum urate level exceeded 6.0 mg per dL. In the event of gout flare, colchicine therapy typically was started.

More than half (56.6%) of patients discontinued the trial, and 45.0% did not complete follow-up over a median of 32 months, according to results published online in the New England Journal of Medicine. The study’s main endpoint — cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization — occurred in 10.8% of the febuxostat group and 10.4% of the allopurinol group. The confidence interval of the hazard ratio did not cross a prespecified threshold, demonstrating that febuxostat is noninferior to allopurinol.

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The all-cause and cardiovascular mortality risks were 22% and 34% higher in the febuxostat group, respectively, compared with the allopurinol group. The higher all-cause mortality risk stemmed from an excess of cardiovascular deaths in the febuxostat group, according to the investigators.

“The mechanism underlying this risk of death is unclear,” Dr White and his team stated. “Preclinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism. In addition, the rates of adjudicated nonfatal events, including myocardial infarction, coronary revascularization, arrhythmias, and hospitalization for heart failure, were similar in the febuxostat group and the allopurinol group.”

The investigators ruled out concomitant use of aspirin or nonsteroidal anti-inflammatory drugs as major factors.

The CARES trial was funded by Takeda Development Center Americas, which manufactures febuxostat.

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White WB, Saag KG, Becker MA, et al. Cardiovascular safety of ebuxostat or allopurinol in patients with gout. New Engl J Med. DOI: 10.1056/NEJMoa1710895 [Published online March 12, 2018]