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The Exchange CARES Study Prompts FDA Boxed Warning on Febuxostat

CARES Study Prompts FDA Boxed Warning on Febuxostat

CARES Study Prompts FDA Boxed Warning on Febuxostat Posted By:
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On February 21, 2019, the US Food and Drug Administration (FDA) issued a boxed warning on febuxostat. This was a result of the CARES study published in the New England Journal of Medicine in March 2018, which looked at 6190 patients diagnosed with gout who also had established cardiovascular disease.

The conclusion stated, "Among patients with gout and cardiovascular disease, treatment with febuxostat resulted in overall rates of major cardiovascular events similar to those associated with allopurinol." However, "higher all-cause mortality, resulting from an imbalance in cardiovascular deaths, was observed with febuxostat than with allopurinol."

This was an unexpected finding in that the composite rate of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization due to unstable angina was 10.8% in the febuxostat group (n = 3098), compared to a 10.4% rate in the allopurinol group (n = 3092). It should be noted that doses of allopurinol were adjusted according to kidney function. For example, in a patient with an estimated creatinine clearance between 30 and 60 mL/minute who initially received 200 mg of allopurinol, the dose was increased in 100 mg increments until a serum urate level below 6.0 mg/dL or a total dose of 400 mg was reached. In those with eGFR >60 mL/min/1.73 m2, the maximum dose of allopurinol was 600 mg.

Urate-lowering therapies are commonly employed throughout general practice, as gout rates have increased over the past 20 years. With this new warning, our department is running a computer analysis of all patients on febuxostat with gout and cardiovascular disease. We are discussing the findings, reviewing the patient's prior exposure to allopurinol (if any), and assessing his or her risk of developing gout with any proposed switch. It should be noted that the differences in all-cause mortality between the febuxostat and allopurinol groups in CARES was quite small, and that the FDA did not pull febuxostat from the market. Febuxostat is an alternative for those sensitive or allergic to allopurinol.

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