CARES results cast doubts on the cardiovascular safety of febuxostat for gout

By Liz Meszaros, MDLinx
Published March 16, 2018

Key Takeaways

In patients with gout and cardiovascular disease (CVD), treatment with febuxostat for 2 years or longer may significantly increase the risk of death—specifically cardiovascular (CV) death—compared with allopurinol, according to results from the CARES trial, presented at the American College of Cardiology’s 67th Annual Scientific Session, held March 10-12 in Orlando, FL. The study was published simultaneously in the New England Journal of Medicine.

"This finding was entirely unexpected, and we’re at a loss at this time to explain why this finding was seen," said lead author William B. White, MD, professor of medicine, Calhoun Cardiology Center, University of Connecticut School of Medicine, Farmington, CT. "The results were consistent across many subgroups; there was no evidence of a relationship with age, sex, race or ethnicity, history of CVD, or duration or severity of the gout."

Febuxostat is a xanthine oxidase inhibitor that is approved for the treatment of chronic gout and hyperuricemia. In early clinical trials, febuxostat effectively lowered serum urate levels, but slightly elevated the risk for adverse CV events. The US Food and Drug Administration (FDA) approved the drug for gout in 2009, with the stipulation that a robust trial be undertaken to assess long-term CV outcomes.

The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial was conducted to meet the FDA requirements to determine whether febuxostat was noninferior to allopurinol in major CV events in patients with both gout and CVD.

A randomized, double-blind, allopurinol-controlled study, CARES was conducted in 320 centers throughout North America. The primary endpoint was time from randomization to first occurrence of any one of a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke, and urgent revascularization due to unstable angina.

Dr. White and colleagues included 6,190 subjects (mean age: 65 years; 84% male; 70% Caucasian; average duration of gout: 12 years), who were randomized to treatment with febuxostat or allopurinol, and followed for up to 6.5 years (median follow-up: 32 months).

At baseline, major CV conditions included acute myocardial infarction (39%), hospitalization for unstable angina (28%), stroke (14%), and peripheral arterial disease (13%).

By the end of the study, results indicated that febuxostat was not inferior to allopurinol. At this time, 656 primary endpoint events had occurred in 7.8% of febuxostat subjects vs 7.7% of those treated with allopurinol (HR: 1.00; 95% CI: 0.82-1.22; P=0.99).

Cardiovascular death occurred in significantly more patients treated with febuxostat (2.0% vs 1.3%, respectively; HR: 1.49; 95% CI: 1.01-2.22; P=0.047), but results for nonfatal MI, nonfatal stroke, and urgent revascularization were not significantly different. The incidence of death from any cause was also similar (3.0% vs 2.3%, respectively; P=0.14).

Upon individual analysis of each endpoint, however, researchers found that patients treated with febuxostat had a 34% higher rate of death due to CV causes, and a 22% higher rate of all-cause mortality.

A full 45% of patients chose to discontinue treatment before the study’s end, and the elevated risk of death in those who stopped taking febuxostat was diminished. More patients died, however, after discontinuing their assigned treatment than when actively taking the drug.

Increased risk of death was consistent when demographics and comorbid conditions were taken into account, but researchers found two differences: in patients treated with febuxostat, both those who did not regularly take aspirin and those who regularly took nonsteroidal anti-inflammatory drugs (NSAIDs) had a higher risk of mortality compared with those taking aspirin or not taking regular NSAIDs.

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

Dr. White and fellow researchers plan to continue analyzing their results to help determine which treatment for gout is optimal in patients with both CV disease and chronic kidney disease (CKD). In the approximately 50% of patients with a history of CKD in the CARES trial, mortality was roughly equal for those taking febuxostat and those taking allopurinol. Further studies are also being conducted in Europe, and these may help better identify the potential risks and benefits of febuxostat in patients with CV risk factors who do not yet have CVD.

The CARES study was funded by Takeda Development Center Americas.

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