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© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Nature reviews | Rheumatology Febuxostat is noninferior to allopurinol with respect to rates of adverse cardiovascular events in patients with gout and cardiovascular disease, according to results from a new, doubleblind trial. However, in this trial, febuxostat was also associated with a higher risk of allcause and cardiovascular mortality than allopurinol. Gout is associated with an increased risk of cardiovascular disease and is characterized by increased levels of circulating serum urate (hyperuricaemia), which can be managed with uratelowering therapies such as allopurinol and febuxostat. “A small increase in cardiovascular events had been observed during the development of febuxostat compared with allopurinol,” remarks corresponding author William B. White. “This imbalance led to a concern among regulators in the USA and a large cardiovascular outcome study was mandated,” he continues. To determine whether febuxostat was non inferior to allopurinol, the CARES trial was conducted. In this trial, 6,190 patients with gout and a history of major cardiovascular disease were randomly assigned to receive either febuxostat or allopurinol, and were followed for a median of 32 months. “Of note, the dose of allopurinol was higher in the study than typically used in clinical practice but adjusted for renal dysfunction,” explains White. “This strategy resulted in much closer serum uric acid levels for the two treatment groups.” By the end of the study, the primary outcome — a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent revascularization for unstable angina — had occurred in a similar proportion of patients in both groups: 10.8% of patients in the febuxostat group and 10.4% of patients in the allopurinol group. “Unexpectedly, the rate of cardiovascular death (and allcause mortality) was significantly higher in the febuxostat group compared with in the allopurinol group,” explains White. This surprising finding was confirmed in a prespecified analysis of the events that occurred during treatment or within 30 days after treatment discontinuation, although the underlying mechanisms were unclear. White says that his group is currently performing additional analyses on patient subgroups to evaluate the effects of various factors (such as coadministration of medications, drug dosage, rates of gout flare and baseline kidney function) on cardiovascular end points and mortality. “These analyses might further our understanding of the benefit to risk ratio of febuxostat in special patient populations with gout,” explains White. “This study will influence gout management guidelines [and] there is now a need to reconsider where febuxostat sits in the order of uratelowering therapies,” states rheumatologist Lisa Stamp, who was not involved in the study. “Physicians need to discuss the risks and benefits of any uratelowering drug with patients and make a shared decision about which therapy is best for an individual patient. This study adds some support to using allopurinol at higher doses than many physicians would currently use to obtain target urate levels,” she concludes. Jessica McHugh G O U T