From the Guidelines
Febuxostat is associated with a higher risk of cardiovascular-related death and all-cause mortality compared to allopurinol, and its use should be approached with caution in patients with pre-existing cardiovascular disease. This medication, which is used to treat gout by lowering uric acid levels, carries an increased risk of cardiovascular events, as evidenced by the FDA-mandated CARES trial [ 1 ]. The CARES trial found that febuxostat was associated with a higher risk of CVD-related death and all-cause mortality compared with allopurinol, although there was no difference in the primary composite CVD end point [ 1 ]. Some key points to consider when evaluating the cardiovascular effects of febuxostat include:
- The lack of an untreated control group in the CARES trial means the absolute CVD risk related to febuxostat is unknown [ 1 ]
- A large observational study found no increased risk of CVD or all-cause mortality associated with febuxostat initiation compared with allopurinol [ 1 ]
- Another study using a managed care database demonstrated a lower risk of any major CVD event among febuxostat initiators than allopurinol initiators, although confounding by indication may not have been adequately addressed [ 1 ]
- The FDA has issued a black box warning for febuxostat due to a higher risk of cardiovascular death compared to allopurinol [ 1 ]
- Patients taking febuxostat should be monitored for cardiovascular symptoms such as chest pain, shortness of breath, or irregular heartbeat, and should seek immediate medical attention if these occur. Given these considerations, febuxostat should be used with caution in patients with cardiovascular disease, and allopurinol is generally preferred as first-line therapy for gout patients with cardiovascular comorbidities [ 1 ]. The typical dose of febuxostat is 40-80 mg once daily, but lower doses may be considered in patients with cardiovascular risk factors. Ultimately, providers and patients should engage in shared decision-making when considering febuxostat for patients at high risk for CVD [ 1 ].
From the Research
Cardiovascular Effects of Febuxostat
The cardiovascular effects of febuxostat have been studied in several clinical trials.
- Febuxostat is a urate-lowering therapy used to treat patients with gout, and its long-term use has been associated with a similar risk of cardiovascular events as allopurinol 2, 3.
- A multicentre, prospective, randomised, open-label, non-inferiority trial found that febuxostat was non-inferior to allopurinol with respect to the primary cardiovascular endpoint, which included hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome, non-fatal stroke, or cardiovascular death 2.
- Another study found that febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events, but all-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol 4.
- A meta-analysis of two randomised controlled trials found that there was no significant difference in the incidence of major adverse cardiovascular events, cardiovascular mortality, or all-cause mortality between febuxostat and allopurinol 3.
- A post hoc subgroup analysis of a clinical trial found that febuxostat reduced the risk of adverse clinical outcomes in patients with hyperuricemia and cardiovascular disease, including a significant reduction in all-cause mortality in the subgroup with cardiovascular disease 5.
Key Findings
- Febuxostat is non-inferior to allopurinol with respect to cardiovascular safety 2, 4.
- Febuxostat may have a similar cardiovascular profile to allopurinol in patients without atherosclerotic disease, but allopurinol may be associated with less cardiovascular mortality in patients with a history of cardiovascular disease 3.
- Febuxostat reduces the risk of adverse clinical outcomes in patients with hyperuricemia and cardiovascular disease, including a significant reduction in all-cause mortality in the subgroup with cardiovascular disease 5.