Highlights from

ACR 2020

ACR Convergence 2020

Virtual 5 - 9 November 2020

No increased cardiovascular risk of febuxostat compared with allopurinol

In the previous CARES trial, concerns were raised regarding the cardiovascular safety of febuxostat. The post-licensing FAST study determined that febuxostat was non-inferior with respect to cardiovascular events compared with allopurinol treatment for gout.

The current post-authorisation study was initiated as suggested by the EMA to obtain data about cardiovascular (CV) safety of febuxostat in comparison to allopurinol, 2 possible treatments for hyperuricaemia [1]. Previously, the CARES trial had raised concern in terms of CV risk with febuxostat that led to changes in treatment recommendations.

The FAST trial is a multinational, prospective, open-label, non-inferiority, blinded endpoint study. Included were 6,128 adults aged >60 years with an ongoing treatment of allopurinol for gout, who also had ≥1 additional CV risk factor. After patients had been treated to a target urate level of <0.357 mmol/L (<6 mg/dL), they were randomly assigned to continue allopurinol at their necessary dose, or start 80 mg febuxostat daily with increasing dosage to 120 mg daily to meet the target uric acid level, after allowing for a wash-out period for allopurinol of 1-3 weeks.

The primary endpoint was based on a composite of major cardiac events: hospitalisation for non-fatal stroke, non-fatal myocardial infarction, biomarker-positive acute coronary syndrome, or CV death. To determine non-inferiority with a cut-off hazard ratio of 1.3, a Cox model was used for an on-treatment (OT) analysis as well as for the intention-to-treat (ITT) population.

Most participants (85.3%) were male. Their baseline mean age was 71 and 33.4% had previously been diagnosed with CV disease. Randomisation was performed 1:1, median follow-up time was 4 years in the study and 3.6 years on treatment. As for events, febuxostat was non-inferior to allopurinol with significant differences in both the OT and ITT analyses (P<0.001). The OT result for all-cause mortality was nominally lower for febuxostat with an HR of 0.75 (95% CI 0.59-0.95) but was not significant in the ITT analysis (HR 0.84; 95% CI 0.71-1.01). Both analyses for CV death demonstrated insufficient evidence to conclude that the groups were statistically significantly different.

Regarding serious adverse events (SAEs), there were 222 (7.2%) deaths in the febuxostat and 263 (8.6%) in the allopurinol group and 59.4% of the allopurinol recipients experienced at least 1 SAE under allopurinol versus 57.3% treated with febuxostat.

In summary, febuxostat was determined non-inferior to allopurinol in both the OT and ITT analyses. ”In contrast to previous studies, there was no evidence of increased mortality with febuxostat and we believe that regulators should review febuxostat licensing restrictions,” Prof. Thomas MacDonald (University of Dundee, UK) concluded his talk.

  1. MacDonald T, et al. Long Term Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Chronic Gout: The Febuxostat versus Allopurinol Streamlined Trial (on Behalf of the FAST Investigators. L08, ACR Convergence 2020 Virtual Annual Meeting, 5-9 November 2020.

Top image: @ iStockPhoto: Wavebreakmedia

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.