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This editorial refers to ‘Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy’†, by S. Kojima et al., on page 1778.

Ever since the observation of Cannon et al.  1 more than half a century ago that almost half of all hypertensive patients have hyperuricaemia, there has been increasing recognition of the link between uric acid, cardiovascular (CV) disease (CVD),2 and chronic kidney disease (CKD).3  ,  4 Numerous observational studies have shown that the risk of CV mortality is higher in people with gout and, conversely, that CVD/CKD patients often have elevated serum uric acid levels and are at increased risk of gout (Figure 1).

Disentangling association from causality is exceedingly difficult. However, defining the evidence regarding the pathogenic impact of uric acid levels is seminal because of its potential implications regarding the prevention and treatment of CVD and CKD.

Some studies have shown that lowering uric acid levels with allopurinol may improve CV conditions, such as hypertension,5 heart failure,6 and CKD,7 but the level of evidence for causality remains low. The recent CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial8 demonstrated that treatment with febuxostat resulted in overall rates of major CV events (a composite of non-fatal myocardial infarction, non-fatal stroke, urgent revascularization for unstable angina, and death because of CV causes) comparable to those of allopurinol in patients with high CV-risk gout, although CV death and deaths from any cause were higher on febuxostat. Among a cohort of 99 744 older Medicare patients with gout, Zhang and colleagues9 reported no difference in the risk of myocardial infarction, stroke, new-onset heart failure, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. With exposure exceeding 3 years, mortality for febuxostat vs. allopurinol also may have increased. However, neither the observational study by Zhang et al. nor the CARES trial had a placebo control group. Therefore, neither trial allows us to conclude that there was an increase in mortality due to febuxostat per se. As a consequence of the CARES data, a black box warning was mandated by the Food and Drug Administration (FDA) in February 2019, with the recommendation to use febuxostat only in patients who have failed on or do not tolerate allopurinol.10

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FAST TRACK CLINICAL RESEARCH > Editorial
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