What is the role of febuxostat (xanthine oxidase inhibitor) in patients with ischemic heart disease (IHD)?

Febuxostat in Ischemic Heart Disease: Cardiovascular Risk Considerations

Patients with ischemic heart disease should avoid febuxostat due to increased risk of cardiovascular death and all-cause mortality compared to allopurinol, and should switch to alternative urate-lowering therapies when possible. 1

Cardiovascular Safety Concerns

Febuxostat carries significant cardiovascular risk in patients with pre-existing cardiovascular disease:

• The FDA-mandated CARES trial showed febuxostat was associated with higher risk of cardiovascular-related death and all-cause mortality compared to allopurinol in patients with gout and cardiovascular disease 1
• This risk led to an FDA black box warning for febuxostat 1
• The 2020 American College of Rheumatology (ACR) guidelines conditionally recommend switching from febuxostat to an alternative oral urate-lowering therapy in patients with a history of cardiovascular disease or new cardiovascular events 1

Management Algorithm for Patients with IHD Requiring Urate-Lowering Therapy

1. First-line therapy: Allopurinol is strongly recommended as the preferred first-line agent for all patients, including those with IHD 1

   • Start at low dose (≤100 mg/day, lower in CKD)
   • Gradually titrate to achieve target serum urate level <6 mg/dL

2. For patients currently on febuxostat with IHD:

   • Switch to allopurinol or alternative urate-lowering therapy 1
   • Implement shared decision-making if febuxostat must be continued due to treatment limitations
   • Monitor closely for cardiovascular symptoms

3. For patients who cannot tolerate allopurinol:

   • Consider uricosuric agents if renal function permits
   • If febuxostat must be used, implement enhanced cardiovascular monitoring
   • Weigh benefits of urate control against cardiovascular risks

Efficacy Considerations

Despite cardiovascular concerns, febuxostat does demonstrate efficacy in urate reduction:

• Febuxostat 80 mg/day is more effective than allopurinol 300 mg/day at decreasing serum urate levels 2
• No significant difference in efficacy between febuxostat 40 mg/day and allopurinol 300 mg/day 2

Recent Evidence and Utilization Trends

• A 2022 Austrian retrospective cohort study found febuxostat initiators had increased risk for nonfatal cardiovascular events or death compared to allopurinol users (adjusted HR 0.58,95% CI 0.53-0.63 for allopurinol vs. febuxostat) 3
• Following label changes and boxed warnings, real-world febuxostat utilization has decreased 4

Important Caveats and Considerations

• Interpretation of cardiovascular risk data is complicated by high dropout rates in the CARES trial, with many deaths occurring after urate-lowering therapy discontinuation 1
• Some observational studies show conflicting results regarding cardiovascular risk 1
• When initiating any urate-lowering therapy, concomitant anti-inflammatory prophylaxis (colchicine, NSAIDs, or prednisone) should be used for 3-6 months to prevent gout flares 1, 2
• Febuxostat may still be appropriate for patients without cardiovascular disease who cannot tolerate allopurinol due to hypersensitivity or severe renal impairment 2

In summary, for patients with ischemic heart disease requiring urate-lowering therapy, allopurinol should be the first choice, with careful consideration of alternatives if allopurinol cannot be used. The cardiovascular mortality risk associated with febuxostat makes it generally unsuitable for patients with established ischemic heart disease.