Research in context
Evidence before this study
We searched PubMed on Sept 17, 2020, using the search terms “febuxostat”, “allopurinol”, and “cardiovascular outcomes”. We searched, with no date or language restrictions, for reports of any randomised clinical trials comparing febuxostat with allopurinol in terms of cardiovascular outcomes in more than 500 participants. We found one trial, the CARES trial, which involved 6190 randomised patients with gout and coexisting major cardiovascular conditions and reported that febuxostat was non-inferior to allopurinol with respect to rates of adverse cardiovascular events. However, the risks of death from any cause (hazard ratio 1·22 [95% CI 1·01–1·47]) and of cardiovascular death (1·34 [1·03–1·73]) in a modified intention-to-treat analysis were higher in the febuxostat group than in the allopurinol group.
Added value of this study
The Febuxostat versus Allopurinol Streamlined Trial (FAST) was a large, multicentre, prospective, randomised, open-label, blinded-endpoint, non-inferiority trial to compare the cardiovascular safety of febuxostat versus allopurinol in patients with gout, at least one additional cardiovascular risk factor, and who were already being treated with allopurinol. The population studied was generally at lower cardiovascular risk than that in the CARES trial, with only about a third of patients in FAST having previous major cardiovascular comorbidity. Daily doses of febuxostat in FAST were higher (80 mg/day or 120 mg/day) than in CARES (40 mg/day or 80 mg/day), and dose ranges of allopurinol were wider in FAST (100–900 mg/day) than in CARES (200–600 mg/day). Only 5·8% of patients in FAST withdrew from all follow-up, and discontinuation of randomised treatment was less frequent (16·5% in the allopurinol group and 32·4% in the febuxostat group) than in the CARES trial (in which 45·0% of patients did not complete all trial visits and 56·6% of patients discontinued randomised treatment prematurely). FAST used record linkage to national health-care databases to complement other methods of reporting for the detection of hospitalisations and deaths. We found that febuxostat was non-inferior to allopurinol for the primary composite endpoint (hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death) during a median on-treatment period of 1324 days (IQR 870–1919; 3·63 years). In contrast to CARES, FAST found that treatment with febuxostat was not associated with an increase in cardiovascular death or all-cause death. Overall there were fewer deaths in the febuxostat group than in the allopurinol group.
Implications of all the available evidence
Although the CARES study suggested that febuxostat therapy might be associated with higher risks of all-cause death and cardiovascular death than allopurinol, FAST, with better ascertainment of events, found no increase in these risks.