In a recent article, published in The New England Journal of Medicine, the rates of major cardiovascular events with febuxosat were similar to allopurinol in patients with gout and concomitant cardiovascular disease. However, the mortality rates either due to cardiovascular deaths or any other cause were higher with febuxostat than allopurinol.
Prior to this study, limited data was available on the cardiovascular safety profile of xanthine oxidase inhibitors. Febuxostat and allopurinol had shown a similar effect on serum urate levels and gout flare rates. To address the safety profile of xanthine oxidase inhibitors, Dr. White and his colleagues conducted the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial, which was the largest cardiovascular safety trial in gout patients.
The CARES trial was a non-inferiority trial that randomized 6190 patients with gout to receive febuxostat or allopurinol. The primary endpoint was a composite of death due to cardiovascular causes, nonfatal MI, nonfatal stroke, and urgent revascularization due to unstable angina. Patients received study drugs for 2 years and were followed up for a maximum of 7 years.
“The impact of the results of CAREs are yet to be determined – the primary prescribers of gout drugs are internists and rheumatologists, not cardiologists. These physicians certainly will be concerned by the results of CARES but there may be patients in whom the benefit to risk is still acceptable for these providers.”-Dr. William White, M.D.
Febuxostat was non inferior to allopurinol in the occurence of the primary endpoint. In a prespecified analysis, results were consistent for events that occurred during the treatment phase. However, febuxostat increased the risk of cardiovascular mortality and all cause mortality by 34% and 22%, respectively.
The authors acknowledged that discontinuation of medications and loss to follow up were the major limitations of the study. More than half of the patients discontinued the study drug, and 45% discontinued follow up.
When asked for comment, Dr. White, a cardiologist from the University of Connecticut Health told Cardiology Now, “Of note, those patients on NSAIDs and colchicine had higher rates of mortality on febuxostat than those not on these agents. In addition, there was a lower number of deaths in patients taking low dose aspirin versus those not taking aspirin.” He added, “The subgroup analyses were interesting but not definitive. We are exploring these data at this time to better understand the covariates of these 3 subgroups.”
When asked about the impact of the study on clinical practice, Dr. White stated, “The impact of the results of CAREs are yet to be determined – the primary prescribers of gout drugs are internists and rheumatologists, not cardiologists. These physicians certainly will be concerned by the results of CARES but there may be patients in whom the benefit to risk is still acceptable for these providers.” He mentioned that patients with high benefit to risk ratio may include those with chronic kidney disease who are unable to take allopurinol and patients with hypersensitivity to allopurinol (skin reactions such as Steven Johnson Syndrome). The study did not show an increase in mortality amongst these high-risk groups with febuxostat use, as compared to allopurinol. However, more data is required to make a definitive declaration of the cardiovascular safety of febuxostat in comparison with allopurinol.