ACR CONVERGENCE 2020—The results of a post-authorization study comparing the cardiovascular safety of febuxostat vs. allopurinol were presented in a late-breaking abstract session at the ACR’s fully virtual annual meeting on Monday, Nov. 9.
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Cardiologist Thomas MacDonald, MD, FRCP, MBChB, clinical professor (teaching and research) of molecular and clinical medicine, University of Dundee School of Medicine, Scotland, U.K., presented the results from the so-called FAST study: “We did a prospective, randomized, open-label, blinded endpoint (PROBE) trial of febuxostat vs. allopurinol in patients with chronic gout in the U.K., Denmark and Sweden,” he said.1
“As you all know, febuxostat and allopurinol are uric acid-lowering agents,” he said. Concerns about the cardiovascular safety of febuxostat have been raised, so the European Medicines Agency (EMA) recommended a post-authorization study. “The FDA [U.S. Food & Drug Administration] had also requested such a study, the CARES study, and it actually reported increased cardiovascular and all-cause deaths leading to an FDA warning and changes in treatment recommendations.”2
Between Dec. 20, 2011, and Jan. 26, 2018, 6,128 patients (mean age 71; 85.3% male; 33.4% with prior established cardiovascular disease) were randomized to receive allopurinol (n=3,065) or febuxostat (n=3,063), and were followed up for a median of four years, during which 5.5% and 6.2%, respectively, withdrew from all follow-up. “So this was really a long-term study,” he said.
Eligible patients were 60 years or older, were already being treated with allopurinol and had at least one additional cardiovascular risk factor. “We excluded strokes and MIs in the past six months, and severe heart failure,” Prof. MacDonald said.
“Allopurinol was increased—we titrated people up—if they weren’t at target at screening, and we did that by increasing the allopurinol dose at 100 mg every two weeks until they reached target or the maximum recommended dose … to achieve a serum uric acid level of less than 0.357 mmol/L [<6 mg/dL],” he said.
Patients were randomly assigned to continue allopurinol (at the optimized dose) or to start febuxostat at a dose of 80 mg daily, increasing to 120 mg, if necessary, to achieve a serum uric acid level of <0.357 mmol/L.
The primary outcome was the composite of hospitalization for non-fatal myocardial infarction/biomarker positive acute coronary syndrome, non-fatal stroke or cardiovascular death. This was ascertained via clinician or patient reports and by national healthcare records, post-mortem and death certification. The hazard ratio (febuxostat vs. allopurinol) in a Cox proportional hazards model was assessed for non-inferiority (limit of 1.3) in an on-treatment analysis and then by intention to treat.