What is the effect of Uloric (febuxostat) on the heart?

Uloric (Febuxostat) Effects on the Heart

Uloric (febuxostat) should be avoided in patients with cardiovascular disease due to increased risk of cardiovascular death and all-cause mortality compared to allopurinol. 1

Cardiovascular Safety Concerns

Evidence from Clinical Trials

• The CARES trial demonstrated that while febuxostat was non-inferior to allopurinol for the primary composite cardiovascular endpoint, it was associated with significantly higher rates of:

  • Cardiovascular death (hazard ratio 1.34) 2
  • All-cause mortality (hazard ratio 1.22) 2

• In contrast, the more recent FAST trial showed febuxostat was non-inferior to allopurinol with respect to cardiovascular outcomes and did not show increased mortality 3

Mechanism of Cardiac Effects

• Research suggests febuxostat may increase ventricular arrhythmogenesis through calcium handling dysregulation in cardiac cells 4
• Specifically, febuxostat exposure has been shown to generate dose-dependent irregular calcium transients through activation of the JNK pathway 4

Clinical Recommendations

For Patients Without Cardiovascular Disease

• Allopurinol remains the first-line urate-lowering therapy for most patients 1
• Febuxostat may be considered for patients who:
  • Cannot tolerate allopurinol due to hypersensitivity
  • Have severe renal impairment limiting allopurinol use

For Patients With Cardiovascular Disease

• The American College of Rheumatology conditionally recommends switching from febuxostat to an alternative oral urate-lowering therapy in patients with a history of cardiovascular disease 5, 1
• Patients currently taking febuxostat with ischemic heart disease should be switched to allopurinol when possible 1

Monitoring Recommendations

• For patients who must remain on febuxostat despite cardiovascular risk:
  • Implement enhanced cardiovascular monitoring
  • Monitor for symptoms of cardiovascular events
  • Consider lower doses when possible

Practical Considerations

• When initiating any urate-lowering therapy, concomitant anti-inflammatory prophylaxis should be used for 3-6 months to prevent gout flares 1
• Febuxostat is more effective than standard-dose allopurinol (300 mg/day) at decreasing serum urate levels, but this efficacy advantage does not outweigh the cardiovascular risk in patients with heart disease 1

Important Caveats

• The 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
• There are conflicting results between the CARES and FAST trials regarding cardiovascular mortality risk
• A meta-analysis found no significant difference in major cardiovascular events between febuxostat and allopurinol, but confirmed higher cardiovascular death with febuxostat 6