What are the considerations for using allopurinol or febuxostat in patients with heart failure?

Allopurinol vs. Febuxostat in Heart Failure Patients

Allopurinol is strongly recommended as the first-line urate-lowering therapy for patients with heart failure and hyperuricemia due to its better cardiovascular safety profile compared to febuxostat. 1

General Considerations for Urate-Lowering Therapy in Heart Failure

• Hyperuricemia is common in heart failure patients, often resulting from loop diuretic therapy and renal dysfunction 1
• Elevated uric acid levels are associated with poor prognosis in heart failure 1
• Xanthine oxidase inhibitors (allopurinol and febuxostat) are the preferred agents for treating hyperuricemia in heart failure patients 2, 1

Allopurinol in Heart Failure

• Allopurinol is strongly recommended as the first-line urate-lowering therapy for all patients, including those with heart failure and moderate-to-severe chronic kidney disease 2, 1
• Start with a low dose (≤100 mg/day, and lower in patients with CKD) with subsequent dose titration to target serum urate levels <6 mg/dL 2, 3
• Dose titration should occur by increasing in 100 mg increments every 2-5 weeks until target uric acid level is reached 3, 1
• The maximum FDA-approved dose is 800 mg/day, though higher doses may be required in some patients 3, 1
• Allopurinol remains effective and safe even in patients with moderate-to-severe CKD, though starting doses should be lower (50 mg/day in stage 4 or worse CKD) 3

Febuxostat in Heart Failure

• Febuxostat should be considered a second-line agent in heart failure patients due to cardiovascular safety concerns 2, 1
• The FDA-mandated CARES trial showed febuxostat was associated with higher risk of cardiovascular-related death and all-cause mortality compared to allopurinol 2, 1
• Switching to an alternative oral urate-lowering therapy is conditionally recommended for patients taking febuxostat with a history of cardiovascular disease or new cardiovascular events 2
• When initiating febuxostat, start at a low dose (≤40 mg/day) with subsequent dose titration 2
• Some conflicting evidence exists, with a smaller study suggesting febuxostat might be more effective than allopurinol for treating patients with chronic heart failure and hyperuricemia 4
• The FAST trial (2020) found febuxostat to be non-inferior to allopurinol with respect to cardiovascular endpoints 5, but this contradicts the CARES trial findings

Special Considerations

Cardiovascular Risk Assessment

• Patients with pre-existing cardiovascular disease should preferentially receive allopurinol over febuxostat 2, 1
• FDA has issued a black box warning for febuxostat regarding increased risk of cardiovascular death 2
• A 2023 analysis of the FDA Adverse Event Reporting System found febuxostat may increase cardiovascular toxicity compared to allopurinol in gout patients 6

Renal Function Considerations

• Both allopurinol and febuxostat are strongly recommended over probenecid for patients with moderate-to-severe CKD (stage ≥3) 2
• Allopurinol dosage should be adjusted according to creatinine clearance in patients with renal impairment 3, 1
• If target serum uric acid levels cannot be achieved with appropriate allopurinol dosing in patients with renal impairment, carefully consider the risks and benefits of switching to febuxostat 1

Prophylaxis During Initiation

• Concurrent prophylaxis against gout flares (colchicine, NSAIDs, or prednisone) is strongly recommended when starting any urate-lowering therapy 2, 1
• For heart failure patients, colchicine is preferred over NSAIDs as prophylaxis, since NSAIDs can cause fluid retention and worsen heart failure 1
• Continue prophylaxis for 3-6 months rather than <3 months 2

Monitoring Recommendations

• Monitor serum urate levels every 2-5 weeks during dose titration and every 6 months once the target is achieved 3, 1
• Target serum urate level is <6 mg/dL in all gout patients, with a lower target of <5 mg/dL for patients with severe gout 3
• Be vigilant for signs of allopurinol hypersensitivity syndrome, particularly in patients of Asian descent or those with severe renal impairment 2, 1
• Consider HLA-B*5801 testing prior to starting allopurinol in high-risk populations (Han Chinese, Korean, Thai, or African American patients) 2, 3

Common Pitfalls to Avoid

• Do not use NSAIDs for gout attacks in heart failure patients whenever possible 1
• Avoid starting at high doses of either allopurinol or febuxostat, as this increases the risk of acute gout flares 2, 3
• Do not discontinue urate-lowering therapy during acute gout attacks; continue therapy while treating the acute attack 2
• Be cautious with diuretic therapy in gout patients with heart failure, as it may aggravate hyperuricemia 1