Febuxostat Black Box Warning: Cardiovascular Death Risk
The FDA black box warning for febuxostat warns of an increased risk of cardiovascular death and all-cause mortality compared to allopurinol, based on findings from the CARES trial. 1
What the Warning Means
The FDA-mandated CARES trial demonstrated that while febuxostat showed no difference in the primary composite cardiovascular endpoint compared to allopurinol, febuxostat was associated with higher cardiovascular-related death and all-cause mortality (driven by CV deaths) compared to allopurinol. 1 Importantly, there was no increased risk for the other secondary cardiovascular outcomes including:
- Nonfatal myocardial infarction
- Nonfatal stroke
- Urgent revascularization for unstable angina
Clinical Interpretation Challenges
The evidence is complicated by several factors:
- High dropout rate in CARES: The majority of deaths occurred after patients discontinued urate-lowering therapy, making causality uncertain 1
- No untreated control group: The absolute cardiovascular risk attributable to febuxostat remains unknown 1
- Conflicting observational data: A large observational study (not selected for CVD) showed no increased risk of CVD or all-cause mortality with febuxostat versus allopurinol 1
Clinical Recommendation Based on the Warning
For patients taking febuxostat with a history of cardiovascular disease or who develop a new cardiovascular event, switch to an alternative urate-lowering therapy agent (preferably allopurinol) if available and consistent with other clinical considerations. 1 This is a conditional recommendation from the 2020 ACR Gout Guidelines.
Key Practice Points:
- Engage in shared decision-making when considering febuxostat for patients at high cardiovascular risk 1
- The ACR guidelines note that patients may be willing to accept "some" incremental cardiovascular risk if the treatment adequately controls their gout 1
- Allopurinol remains the preferred first-line agent for all patients, including those with cardiovascular disease 1
Recent Meta-Analysis Findings:
More recent research supports the warning's validity, particularly in Asian populations. A 2024 meta-analysis found febuxostat associated with significantly increased risk of acute coronary syndrome (HR: 1.06) and atrial fibrillation (HR: 1.19) compared to allopurinol in Asian patients. 2 In Chinese subgroups specifically, febuxostat increased risk of acute decompensated heart failure, cardiovascular death, and all-cause mortality. 2
Common Pitfall to Avoid
Do not assume febuxostat is contraindicated in all patients with cardiovascular disease—the recommendation is conditional, not absolute. However, given the mortality signal and availability of allopurinol as an effective alternative, prioritize allopurinol as first-line therapy, reserving febuxostat for patients who cannot tolerate or have failed allopurinol.