The gout drug febuxostat was shown to be noninferior to allopurinol for the primary outcome of the combined rate of fatal and nonfatal adverse events in patients with gout and established cardiovascular disease, according to results of the CARES trial. However, for the secondary endpoint of death from cardiovascular or any cause, there was a significantly increased risk. The trial, mandated by the U.S. Food and Drug Administration when the drug was approved because of a signal of an elevated risk of adverse cardiovascular events in early clinical trials, was presented by William B. White, MD, on Monday, March 12 in a Late-Breaking Clinical Trials session at ACC.18 in Orlando, FL. It was simultaneously published in the New England Journal of Medicine.

The median follow-up was 32 months (and as long as 6.5 years) in the 6,190 patients (84 percent men). The rate of the composite primary outcome (consisting of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or urgent revascularization due to angina) from the time from study drug randomization to first occurrence was similar in both treatment groups, meeting the study’s threshold for noninferiority of febuxostat to allopurinol.

However, there was a potential signal for increased mortality with febuxostat compared with allopurinol in the analysis of the individual endpoint components, with a 34 percent higher rate of death from cardiovascular causes and a 22 percent higher rate of death from any cause. Mortality rates with febuxostat and allopurinol were similar among the 50 percent of patients with a history of chronic kidney disease.

Approximately 45 percent of patients discontinued febuxostat before the study ended. Although the elevated risk of death was diminished in these patients, overall more patients died after stopping their assigned study drug than while taking it.

The increased risk of death was consistent across subgroups. Among patients receiving febuxostat, there was a higher risk of death in the patients who did not regularly take aspirin and those who regularly took nonsteroidal anti-inflammatory drugs (NSAIDs), compared with those taking aspirin or not taking NSAIDs. Yet, researchers caution that CARES was not designed to assess potential medication interactions.

“It is important to be careful when interpreting these findings; it doesn’t necessarily indicate there’s an interaction between these drugs and febuxostat,” White said. “It might have been that these patients had more active gout with more flares, for example.”

The investigators were not able to determine the reason for the surprising results and plan to further examine the data for insights into the optimal treatment for gout in patients with both cardiovascular disease and kidney disease. Ongoing studies in Europe are evaluating the risks and benefits of febuxostat in patients who have cardiovascular risk factors without established cardiovascular disease.

Keywords: ACC18, ACC Annual Scientific Session, Primary Prevention, Allopurinol, Hyperuricemia, Xanthine Oxidase, Peripheral Arterial Disease, Double-Blind Method, Proportional Hazards Models, Confidence Intervals, Random Allocation, Gout Suppressants, Gout, Angina, Unstable, Myocardial Infarction, Stroke, Comorbidity, Outcome Assessment, Health Care, Hospitalization

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