From the Guidelines
Febuxostat should be used with caution in patients with cardiovascular disease due to potential increased risk of heart-related events, and switching to an alternative oral ULT agent is conditionally recommended for patients taking febuxostat with a history of CVD or a new CVD-related event. The FDA has issued a warning that febuxostat may increase the risk of heart-related death compared to allopurinol, another gout medication, as seen in the CARES RCT 1. Patients with a history of heart attack, stroke, or unstable angina should generally avoid febuxostat unless allopurinol is not an option. If febuxostat must be used in patients with cardiovascular risk factors, close monitoring is essential. The typical dosing is 40-80 mg once daily, with 40 mg being the recommended starting dose.
The cardiovascular risk appears to be related to febuxostat's mechanism of action as a xanthine oxidase inhibitor, which may affect nitric oxide metabolism and endothelial function. Patients taking febuxostat should be educated about recognizing symptoms of cardiovascular events such as chest pain, shortness of breath, or neurological changes, and should seek immediate medical attention if these occur. Regular cardiovascular assessments are recommended during febuxostat therapy, especially in the first few months of treatment. According to the 2020 American College of Rheumatology guideline for the management of gout, providers and patients should engage in shared decision-making when considering febuxostat for patients at high risk for CVD 1.
Some key points to consider when using febuxostat in patients with cardiovascular disease include:
- Close monitoring of cardiovascular risk factors
- Education on recognizing symptoms of cardiovascular events
- Regular cardiovascular assessments
- Consideration of alternative ULT agents
- Shared decision-making between providers and patients. The guideline conditionally recommends switching to an alternative ULT agent if available and consistent with other recommendations in the guideline for patients taking febuxostat with a history of CVD or a new CV event 1.
From the Research
Relationship Between Febuxostat and Cardiovascular Disease
The relationship between febuxostat, a xanthine oxidase inhibitor, and cardiovascular disease has been investigated in several studies.
- A systematic review and meta-analysis published in 2019 2 found that febuxostat does not increase or decrease the risk of cardiovascular disease, but may increase the risk of cardiovascular disease-related death.
- Another systematic review published in 2024 3 found that the data on cardiovascular safety of febuxostat were reassuring, but the quality of evidence was limited by concerns in most studies and heterogeneous cardiovascular outcomes.
- A multicenter, double-blind, noninferiority trial published in 2018 4 found that febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events, but all-cause and cardiovascular mortality were higher with febuxostat.
- A post hoc subgroup analysis published in 2022 5 found that febuxostat reduced the risk of adverse clinical outcomes in patients with hyperuricemia and cardiovascular disease.
- A network meta-analysis published in 2021 6 found that febuxostat was not associated with an increased risk of adverse cardiovascular events compared to allopurinol, and that compared to placebo, febuxostat and allopurinol may prevent adverse cardiovascular events, although the certainty of the evidence was low to moderate.
Key Findings
- Febuxostat may increase the risk of cardiovascular disease-related death 2, 4.
- Febuxostat is not associated with an increased risk of adverse cardiovascular events compared to allopurinol 3, 6.
- Febuxostat may reduce the risk of adverse clinical outcomes in patients with hyperuricemia and cardiovascular disease 5.
- The quality of evidence on the cardiovascular safety of febuxostat is limited by concerns in most studies and heterogeneous cardiovascular outcomes 3.
- Further studies are needed to draw conclusions on the cardiovascular safety of febuxostat in patients with severe cardiovascular disease 3, 4.