Febuxostat vs Allopurinol in Gout: Assessing the Implications of CV Safety

The US Food and Drug Administration (FDA) recently issued a public safety alert in response to the results of the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial,¹ which showed increased cardiovascular (CV) and all-cause mortality in patients with gout and established cardiovascular disease (CVD) who were treated with febuxostat therapy. 

No significant difference was reported, however, between febuxostat and allopurinol for the primary composite end point of major adverse CV events. According to a perspective published in Arthritis & Rheumatology,² the results of CARES do not support first-line use of febuxostat in urate-lowering therapy and raise new questions about when febuxostat should be considered during urate-lowering therapy for the treatment of gout.

The use of urate-lowering therapy is key to the long-term management of gout, with xanthine oxidoreductase inhibitor (XOI) therapy as the standard first-line approach. In this patient population, allopurinol is typically the first XOI used, but febuxostat is known to be an effective XOI treatment option that is often used when allopurinol is not well tolerated. Such data are particularly relevant because CV comorbidity is a common occurrence among patients with gout.

The investigators of the current analysis examined why the CARES trial was conducted, and they discussed other ongoing comparative studies of febuxostat vs allopurinol and their anticipated results. They note that CARES does not prove that the use of febuxostat increases the risk for CV mortality, but it does suggest an enhanced risk with febuxostat compared with allopurinol.

The results of CARES do not support the first-line use of febuxostat in urate-lowering therapy, raising questions with respect to the placement of febuxostat at various pharmacologic urate-lowering therapy decision tree branches. Alternatives to febuxostat treatment that are often effective include allopurinol dose escalation and uricosuric therapy alone or in combination with allopurinol. The FDA safety alert underscores the need for shared urate-lowering therapy decision making between clinicians and patients with gout, which should include a discussion on the CV safety of febuxostat.

The investigators concluded that both clinicians and patients should keep in mind that the results of CARES do not prove that treatment with febuxostat increases CV risk among patients with gout. Instead, the data suggest greater mortality risk with febuxostat compared with allopurinol in patients with preexisting CV disease. They emphasize that timely updates by relevant professional organizations are now needed to establish gout urate-lowering therapy management guidelines.

Please see original article for a full list of disclosures.

follow @RheumAdvisor

References

1. White WB, Saag KG, Becker MA, et al; CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout.  N Engl J Med. 2018;378(13):1200-1210.
2. Choi H, Neogi T, Stamp L, Dalbeth N, Terkeltaub R. Implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial and associated FDA public safety alert [published online June 5, 2018]. Arthritis Rheumatol. doi: 10.1002/art.40583