Gout treatment with febuxostat: no higher cardiovascular mortality

A new evaluation of the risk for cardiovascular safety under treatment with febuxostat within a post-licensing study demonstrated no higher rates of cardiovascular mortality and major cardiovascular events when compared to allopurinol.

The current post-authorisation study was initiated as suggested by the EMA to obtain data about the cardiovascular (CV) safety of febuxostat in comparison to allopurinol, 2 possible treatments for hyperuricaemia [1]. Previously, the CARES trial (NCT01101035) had raised concerns regarding CV risk with febuxostat that led to changes in treatment recommendations [1,2]. However, given that CV disease risk factors are common in patients with gout, lingering doubts about ascribing such a CV risk to febuxostat persisted.

The FAST trial (ISRCTN72443728) is a multinational, prospective, randomised, parallel group, open-label, non-inferiority, blinded endpoint study [1]. 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 per day with increasing dosage to 120 mg daily to meet target uric acid level, after allowing for a washout 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 or biomarker-positive acute coronary syndrome, or CV death. To determine non-inferiority with a cut-off HR 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 not significant in the ITT analysis: HR 0.84 (95% CI 0.71–1.01). Both analyses for CV death also 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 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, L08, ACR Convergence 2020, 5-9 Nov.
2. White WB, et al. N Engl J Med. 2018;378:1200-10.

Posted on 18 January 202127 March 2024