Written by: Didem Saygin, Emily Peninger, Laarni Quimson, Marco Lopez-Velazquez, Kichul Ko – University of Chicago Fellowship Program
Based on: Mackenzie IS and the FAST Study Group. 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 Nov 28;396(10264):1745-1757.
Gout is the most common inflammatory arthritis affecting 4% of adults1. Hyperuricemia, a feature of gout, is associated with increased risk of cardiovascular (CV) disease. There are currently only two FDA-approved xanthine oxidase inhibitors for urate lowering therapy (ULT) in gout: allopurinol and febuxostat. Initial trials of gout comparing febuxostat with placebo/allopurinol suggested a higher rate of CV event with febuxostat. In this population with an already increased risk for CV disease, these results led to a blackbox warning for CV events with febuxostat and a change in recommendations for ULT in gout treatment guidelines.
The FAST trial is a large study conducted in Europe to assess the CV safety of febuxostat compared with allopurinol4. The study was a prospective, randomized, open-label, blinded endpoint, non-inferiority multi-center trial of febuxostat vs allopurinol. Eligible patients were 60 years or older, had gout, required ULT and had at least one CV risk factor. Patients who had a myocardial infarction (MI) or stroke in the previous six months, or class III/IV heart failure were excluded from the study. A total of 6128 patients were randomized to receive allopurinol vs febuxostat. The primary outcome was a composite of hospitalization for non-fatal MI or biomarker positive acute coronary syndrome, non-fatal stroke or death due to CV event. The study showed that febuxostat was non-inferior to allopurinol with respect to the primary outcome as well as secondary outcomes including CV death, all-cause death, hospitalization for non-fatal MI or biomarker positive acute coronary syndrome, and hospitalization for heart failure or transient ischemic attack based on both intention-to-treat and on-treatment analyses.
Implications for Patients, Providers, & Researchers
Current implications: Given the frequency of gout, increased risk of CV events in these patients and limited ULT options, the clinical implications of the FAST trial are undoubtedly large. The results of this study inform both patients and physicians regarding the CV safety of febuxostat compared to allopurinol. These results are particularly helpful in choosing a ULT for patients with gout who have CV risk factors and patients for whom allopurinol is contraindicated or not tolerated.
Future implications: The FAST trial provides a high-quality evidence for the FDA to consider removing the blackbox warning of febuxostat and for a change in future gout treatment guidelines.
Will FAST trial Win its First Round Match-up?
We believe that the FAST trial will easily win its first-round match-up against the ACR 2020 gout guidelines as the trial actually helps to clarify the uncertainties regarding CV safety of febuxostat and provides important results to inform newer gout guidelines with more robust evidence. The ACR guidelines may make some runs with a barrage of different shots with their numerous recommendations of varying degrees of evidence. However, the ‘analytics’ strongly favor high efficiency shots near the basket which the FAST trial provides with its high-quality data and straight-to-answer-the-question approach.
Could FAST trial Win it All?
The FAST trial can really win it all given the impact of its results. There are certainly heavy challenges that can come from novel therapies for systemic diseases with their jaw-dropping moves. Nonetheless, when it comes to efficiency and volume of shots made, the FAST trial can score high on both counts as a large randomized study that can affect countless gout patients with CV risks.
- M Chen-Xu, et al. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71:991-999.
- IS Mackenzie, et al. Long-term cardiovascular safety of compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomized, open-label, non-inferiority trial. Lancet. 2020;396:1745-1757