Background/Purpose: Febuxostat and allopurinol are uric acid lowering agents. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency (EMA) recommended a post-authorization study comparing the cardiovascular (CV) safety of febuxostat versus allopurinol.

Methods: We did a prospective, randomized, open-label, blinded endpoint (PROBE) trial of febuxostat versus allopurinol in patients with chronic symptomatic hyperuricaemia (gout) in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, were currently treated with allopurinol, and had at least one additional cardiovascular risk factor. After increasing allopurinol dose if necessary to achieve serum uric acid (SUA) levels < 0·357 mmol/L (< 6 mg/dL), patients were randomly assigned to continue allopurinol (at optimised dose) or start febuxostat at a dose of 80mg daily, increasing to 120mg, if necessary, to achieve serum uric acid level < 0·357 mmol/L. A short washout period (7-21 days) was included before randomized therapy was started. The primary outcome was the composite of hospitalisation for non-fatal myocardial infarction/biomarker positive acute coronary syndrome, non-fatal stroke or cardiovascular death. The hazard ratio (febuxostat versus allopurinol) in a Cox proportional hazards model was assessed for non-inferiority (limit of 1·3) in an on-treatment (OT) analysis and then by intention to treat (ITT). This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728).

Results: 6128 patients (mean age 71, 85·3% male, 33·4% prior established CV disease) were randomised to receive allopurinol (n=3065) or febuxostat (n=3063) and were followed up for a median of 4 years during which 5·5% and 6·2% respectively withdrew from all follow up. In both the on-treatment and intention-to-treat analyses, febuxostat was non-inferior to allopurinol for incidence of the primary endpoint (OT analysis: febuxostat 172 patients [1·72 events per 100 patient years]; allopurinol 241 patients [2·05 events per 100 patient years]; hazard ratio 0·85 [95% CI 0·70-1·03], p< 0·001; ITT analysis: febuxostat 256 patients [2·05 events per 100 patient years], allopurinol 285 patients [2·29 events per 100 patient years]; hazard ratio 0·89 [95% CI 0·75-1·06], p< 0·001). 222 (7·2%) patients died in the febuxostat group compared to 263 deaths (8·6%) in the allopurinol group.

Conclusion: Febuxostat was non-inferior to allopurinol therapy for the primary cardiovascular outcome. Long-term use of febuxostat was not associated with an increased risk of death compared with allopurinol.

Funding: Menarini provided funding. The University of Dundee was the sponsor and Menarini had no involvement in the running of the study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/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/