Effects of Febuxostat on Mortality and Cardiovascular Outcomes

Abstract

Objective: To investigate the association between using febuxostat and cardiovascular events. Methods: Systematic search of randomized controlled trials was performed using PubMed/MEDLINE, Cochrane review, and EMBASE databases through April 17, 2019. Meta-analysis was performed using random effect model and estimates were reported as risk difference (RD) with 95% CIs. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. The main outcomes of interest were cardiovascular mortality and all-cause mortality. Results: A total of 15 randomized controlled trials (16,070 participants) were included. The mean AE SD age was 58.1AE11.7 years. At the median follow-up of 6.4 months, use of febuxostat was not associated with statistically significant risk of cardiovascular mortality (RD, 0.12%; 95% CI,-0.25% to 0.49%; I 2 ¼48%; low certainty evidence), all-cause mortality (RD, 0.20%; 95% CI,-0.28% to 0.68%; I 2 ¼60%; very low certainty evidence), major adverse cardiovascular events (RD, 0.40%; 95% CI,-0.34% to 1.13%; I 2 ¼26%; low certainty evidence), myocardial infarction (RD,-0.06%; 95% CI,-0.29% to 0.17%; I 2 ¼0%; moderate certainty evidence), stroke (RD, 0.10%; 95% CI,-0.15% to 0.35%; I 2 ¼0%; moderate certainty evidence), or new-onset hypertension (RD, 1.58%; 95% CI,-0.63% to 3.78%; I 2 ¼58%; very low certainty evidence). These findings were consistent in patients with existing cardiovascular disease. Conclusion: This meta-analysis suggested that use of febuxostat was not associated with higher risk of mortality or adverse cardiovascular outcomes in patients with gout and hyperuricemia. The results were limited by low to moderate certainty of evidence.

Cardiovascular Safety of Febuxostat in Patients With Gout or Hyperuricemia

“…A systematic review and meta-analysis of Mayo Clinic included 15 RCTs including more than 100,000 patients with gout and hyperuricemia and showed that there was no significant risk of cardiovascular events including mortality with febuxostat compared with controls. 41 The last included study was in 2019, therefore not including the FAST trial. Like previously published systematic reviews and meta-analyses on the cardiovascular safety of febuxostat compared with allopurinol, the authors included MACE forest plot studies where MACE was neither defined nor its components mentioned.…”

“…Like previously published systematic reviews and meta-analyses on the cardiovascular safety of febuxostat compared with allopurinol, the authors included MACE forest plot studies where MACE was neither defined nor its components mentioned. [41][42][43] This could result in underestimation or overestimation of results and misinterpretation of the cardiovascular safety of febuxostat. In addition, Gao colleagues 44 published a systematic review and meta-analysis in 2021 on trials including retrospective, cohort, and observational studies.…”

“…A systematic review and meta-analysis of Mayo Clinic included 15 RCTs including more than 100,000 patients with gout and hyperuricemia and showed that there was no significant risk of cardiovascular events including mortality with febuxostat compared with controls 41 . The last included study was in 2019, therefore not including the FAST trial.…”

“…The last included study was in 2019, therefore not including the FAST trial. Like previously published systematic reviews and meta-analyses on the cardiovascular safety of febuxostat compared with allopurinol, the authors included MACE forest plot studies where MACE was neither defined nor its components mentioned 41–43 . This could result in underestimation or overestimation of results and misinterpretation of the cardiovascular safety of febuxostat.…”

Past, present and future of xanthine oxidase inhibitors: design strategies, structural and pharmacological insights, patents and clinical trials

“…36 In November 2017, the FDA put a boxed warning to clinicians and patients due to the increased risk of cardiovascular complications and deaths by this drug. 37,38 Topiroxostat was approved in June 2013 as a xanthine oxidase inhibitor for the management of gout and hyperuricemia. 39 It also causes gouty arthritis and liver dysfunction like effects.…”