Cardiovascular safety of febuxostat

The FAST trial, reported by Isla Mackenzie and colleagues,1Mackenzie IS Ford I Nuki G et al.Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial.Lancet. 2020; 396: 1745-1757Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar found that febuxostat therapy did not increase the risk of all-cause death or cardiovascular death, which differs from the results of the CARES trial.2White WB Saag KG Becker MA et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout.N Engl J Med. 2018; 378: 1200-1210Crossref PubMed Scopus (342) Google Scholar One of the main differences in the FAST trial was the use of a lead-in phase and, as a result, the lower rates of treatment discontinuation (32·4% in the febuxostat group and 16·5% in the allopurinol group) and better quality of follow-up (6·2% of patients in the febuxostat group and 5·5% in the allopurinol group withdrawing from follow-up) than that of the CARES trial. The use of the lead-in phase might affect external validity by excluding non-complying patients who are common in real-world settings and who are included in the CARES trial.2White WB Saag KG Becker MA et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout.N Engl J Med. 2018; 378: 1200-1210Crossref PubMed Scopus (342) Google Scholar It also might affect internal validity by exaggerating the intention-to-treat effect estimate and the risk of unblinding bias as half of the patients switched from allopurinol to febuxostat. Notably, the treatment discontinuation rate was higher in the febuxostat group (32·4%) than in the allopurinol group (16·5%), with most withdrawals from the febuxostat group occurring in the first 6 months. The imbalanced treatment discontinuation rates might be due to the use of the lead-in phase. A significant increase of hospitalisation for arrhythmia was found in the febuxostat group, with no evidence of ischaemia. Did the hospitalisation for arrhythmia happen more frequently in patients who discontinued treatment? Did it happen within a short period after switching or discontinuing treatment? It would be informative if the authors reported these results. The 2020 American College of Rheumatology guideline for the management of gout conditionally recommends switching to an alternative agent for urate-lowering therapy for patients taking febuxostat with a history of cardiovascular disease or a new cardiovascular disease-related event.3FitzGerald JD Dalbeth N Mikuls T et al.American College of Rheumatology guideline for the management of gout.Arthritis Care Res (Hoboken). 2020; 72: 744-760Crossref PubMed Scopus (111) Google Scholar The increased mortality within 30 days of discontinuation of febuxostat in the CARES trial should be emphasised,2White WB Saag KG Becker MA et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout.N Engl J Med. 2018; 378: 1200-1210Crossref PubMed Scopus (342) Google Scholar which might be due to the abrupt increase in serum urate concentration, with subsequent free urate crystal formation in the cardiovascular system (leading to a possible cardiovascular gout attack).4Ghang B Ahn SM Kim J Kim Y-G Lee C-K Yoo B Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the CARES trial.Rheumatology (Oxford). 2020; 59: 1439-1440Crossref PubMed Scopus (6) Google Scholar If there is an association between increased hospitalisation for arrhythmia and switching or discontinuing treatment, it, together with the high mortality within the first month of discontinuation of febuxostat in the CARES trial,2White WB Saag KG Becker MA et al.Cardiovascular safety of febuxostat or allopurinol in patients with gout.N Engl J Med. 2018; 378: 1200-1210Crossref PubMed Scopus (342) Google Scholar should prompt a consideration of the risk of switching urate-lowering therapy. I declare no competing interests. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trialFebuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol. Full-Text PDF Cardiovascular safety of febuxostat – Authors' replyWe thank Jasvinder Singh and Chuanhui Xu for their Correspondences. Singh asks about equivalent doses and urate concentrations. In the FAST study,1 before randomisation, a third of participants had their allopurinol dose adjusted upwards to achieve the target urate concentration. Those randomly assigned to the allopurinol group then remained on this dose, whereas those randomly assigned to the febuxostat group received 80 mg, increasing to 120 mg if required. Thus, it is not surprising that urate concentrations did not change much after randomisation in the allopurinol group, whereas febuxostat, given at almost exclusively 80 mg doses, was much more potent at lowering urate concentrations than allopurinol was at the optimised dose. Full-Text PDF Cardiovascular safety of febuxostatWe congratulate Isla Mackenzie and colleagues on publishing the FAST study1 and eloquently highlighting differences in inclusion criteria between FAST and the CARES study.2,3 A few questions remain. Full-Text PDF