From the Guidelines
Febuxostat increases cardiovascular risk, particularly cardiovascular-related death and all-cause mortality, as evidenced by the FDA-mandated CARES trial 1. This medication, used to treat gout by inhibiting xanthine oxidase and reducing uric acid levels, has been associated with a higher risk of cardiovascular death compared to allopurinol in clinical trials 1. The increased risk may be related to febuxostat's effects on endothelial function, as xanthine oxidase inhibition can alter nitric oxide metabolism and vascular reactivity. Additionally, febuxostat may affect platelet function and promote a prothrombotic state in some patients. The medication might also influence inflammatory pathways that contribute to atherosclerosis progression. Some key points to consider when evaluating the cardiovascular risk of febuxostat include:
- The FDA has issued a black box warning for febuxostat regarding increased risk of cardiovascular death and all-cause mortality 1.
- Patients with existing cardiovascular disease are at particularly high risk, and physicians should consider alternative treatments for these individuals 1.
- Regular cardiovascular monitoring is recommended for patients who must use febuxostat, especially during the initial months of therapy when risk appears highest 1.
- The lack of an untreated control group in the CARES trial means the absolute CVD risk related to febuxostat is unknown 1.
- Observational studies have shown mixed results, with some demonstrating no increased risk of CVD or all-cause mortality associated with febuxostat initiation compared to allopurinol 1. However, the most recent and highest quality study, the CARES trial 1, suggests that febuxostat is associated with a higher risk of CVD-related death and all-cause mortality compared to allopurinol. Therefore, healthcare providers should engage in shared decision-making with patients, particularly those at high risk for CVD, when considering febuxostat for treatment 1.
From the Research
Cardiovascular Risk Associated with Febuxostat
- The relationship between febuxostat and cardiovascular risk is complex, with varying findings across different studies 2, 3, 4, 5, 6.
- A study published in 2020 found that febuxostat is non-inferior to allopurinol with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol 2.
- In contrast, a 2024 study found that febuxostat users had higher all-cause hospitalization, hospitalization for heart failure, and hospitalization for cardiovascular interventions compared to allopurinol users 3.
- A systematic review and meta-analysis published in 2019 found that febuxostat does not increase or decrease the risk of cardiovascular disease but may increase the risk of cardiovascular-related death 4.
- Another meta-analysis published in 2021 found that febuxostat use is not associated with increased risks of all-cause mortality, death from cardiovascular disease, or cardiovascular events 5.
- A population-based cohort study published in 2019 found that febuxostat users were at a significantly higher risk for heart failure hospitalization, atrial fibrillation hospitalization, and cardiovascular death compared to allopurinol users 6.
Key Findings
- Febuxostat may increase the risk of cardiovascular-related death 4.
- Febuxostat use is associated with a higher risk of heart failure hospitalization, atrial fibrillation hospitalization, and cardiovascular death compared to allopurinol use 3, 6.
- The relationship between febuxostat dose and cardiovascular risk is not fully understood, with some studies suggesting a dose-dependent increase in risk 6.
- Further studies are needed to investigate the mechanisms linking febuxostat to adverse cardiovascular outcomes 3, 6.