The rates of adverse cardiac events are similar in patients with gout and cardiovascular disease treated with febuxostat and allopurinol, but all-cause and cardiovascular mortality were higher in patients taking febuxostat, a randomized, double-blind trial found.
Since prior clinical trials had suggested higher rates of cardiovascular events in patients taking febuxostat versus allopurinol, the FDA required a safety trial in patients with gout and cardiovascular disease. The resulting noninferiority study, the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial, was funded by Takeda Pharmaceuticals, which also participated in the trial's design, conduct, data collection, and analyses.
From April 2010 through May 2017, researchers enrolled participants from 320 North American sites. They randomly assigned 6,190 patients to receive febuxostat (n=3,098) or allopurinol (n=3,092) and followed them at regular outpatient visits for a median of 32 months. Doses of allopurinol, but not of febuxostat, were modified according to kidney function. In the allopurinol group, 21.8% of patients received 200 mg/d, 44.6% received 300 mg/d, 25.2% received 400 mg/d, 4.3% received 500 mg/d, and 4.1% received 600 mg/d. In the febuxostat group, the final adjusted dose was 40 mg/d in 61.0% of patients and 80 mg/d in 39.0%.
The prespecified noninferiority margin was a hazard ratio of 1.3 for the primary composite end point (first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina). The secondary safety end points included individual components of the primary end point in addition to a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. All-cause mortality was an additional safety end point. Results were published online on March 12 by the New England Journal of Medicine.
Overall, 56.6% of patients prematurely discontinued the trial regimen (57.3% in the febuxostat group and 55.9% in the allopurinol group), and 45% did not complete all follow-up visits. In a modified intention-to-treat analysis, the primary end point event occurred in 335 (10.8%) patients taking febuxostat and in 321 (10.4%) patients taking allopurinol (hazard ratio, 1.03; upper limit of the one-sided 98.5% CI, 1.23; P=0.002 for noninferiority).
The analysis of nonfatal secondary end points was consistent with the overall result. However, compared to the allopurinol group, the febuxostat group had higher risks of all-cause mortality (hazard ratio, 1.22; 95% CI, 1.01 to 1.47) and cardiovascular death (hazard ratio, 1.34; 95% CI, 1.03 to 1.73). The most common cause of cardiovascular mortality, sudden cardiac death, occurred in 83 patients (2.7%) in the febuxostat group and 56 patients (1.8%) in the allopurinol group.
The study authors noted limitations of the trial, such as the large proportion of participants who discontinued treatment during the trial, which could have biased results toward the null. They added that many patients were lost to follow-up, although the number was similar between groups and their baseline characteristics were similar to those who completed follow-up.