What alternative treatment can be used for a patient with symptomatic hyperuricemia who is intolerant to allopurinol (Zyloprim) or has contraindications to it, considering their impaired renal function and history of cardiovascular disease?

Febuxostat as an Alternative to Allopurinol in Patients with Renal Impairment and Cardiovascular Disease

Febuxostat is a reasonable alternative for patients with symptomatic hyperuricemia who are intolerant to allopurinol or have contraindications, particularly in the setting of impaired renal function, but it carries an FDA black box warning regarding cardiovascular risk that requires careful consideration in patients with established cardiovascular disease. 1, 2

First-Line Therapy Remains Allopurinol

• Allopurinol should be the first-line urate-lowering therapy even in patients with moderate-to-severe chronic kidney disease, starting at low doses (50-100 mg/day in renal impairment) and titrating upward to achieve target serum urate <6 mg/dL. 3, 4
• In patients with mild-moderate renal impairment, allopurinol may be used with close monitoring for adverse events, starting at a low daily dose (50-100 mg) and up-titrated to achieve the usual target of serum uric acid <6 mg/dL. 3
• Allopurinol demonstrates renoprotective effects in hyperuricemic patients with chronic kidney disease, with long-term treatment potentially slowing progression of kidney disease and reducing cardiovascular risk. 5, 6

When Febuxostat Becomes the Preferred Alternative

Febuxostat is specifically indicated as an alternative when:

• Allopurinol hypersensitivity or severe cutaneous adverse reactions occur, particularly in high-risk populations (patients with HLA-B*5801 haplotype, Korean patients with stage 3 or worse CKD, Han Chinese and Thai patients). 4
• Allopurinol fails to achieve target serum urate despite appropriate dose titration (up to 800 mg/day), with febuxostat demonstrating superior uric acid-lowering efficacy in head-to-head trials. 1, 7
• Severe renal impairment exists (eGFR <30 mL/min), where febuxostat can be used without dose adjustment while allopurinol would require significant dose reduction that may limit efficacy. 2, 4

Febuxostat Dosing and Efficacy in Renal Impairment

• Febuxostat can be used without dose adjustment regardless of CKD stage, starting at 40 mg daily and titrating to 80 mg daily (maximum dose) to achieve target serum urate <6 mg/dL. 2
• The 80 mg dose of febuxostat is superior to allopurinol 300 mg daily, achieving target serum uric acid <6 mg/dL in 67% versus 42% of patients. 2
• Febuxostat effectively lowers serum uric acid levels in patients with CKD and allopurinol-refractory hyperuricemia, with response rates above 70% maintained for 1 year without significant change in renal function. 7

Critical Cardiovascular Safety Considerations

The major limitation of febuxostat is cardiovascular risk:

• Febuxostat carries an FDA black box warning regarding cardiovascular risk, and the American College of Rheumatology conditionally recommends switching to an alternative urate-lowering therapy for patients taking febuxostat with a history of cardiovascular disease or new cardiovascular events. 2
• Shared decision-making between providers and patients is recommended when considering febuxostat for patients at high risk for cardiovascular disease. 2
• Network meta-analysis evidence suggests febuxostat is not associated with increased risk of adverse cardiovascular events compared to allopurinol, though the certainty of evidence ranges from very low to moderate. 8

Mandatory Flare Prophylaxis

• Anti-inflammatory prophylaxis is essential when initiating febuxostat, using colchicine 0.5-1 mg daily (dose-adjusted for renal function), low-dose NSAIDs if not contraindicated, or low-dose glucocorticoids for at least 6 months. 2
• Failing to provide prophylaxis is a major cause of treatment failure and patient non-adherence. 1

Common Pitfalls to Avoid

• Never combine febuxostat and allopurinol due to redundant mechanism of action and increased toxicity risk without therapeutic justification. 2
• Do not use 40 mg febuxostat as the final dose without checking serum uric acid, as most patients require 80 mg to achieve target serum urate <6 mg/dL. 2
• Avoid NSAIDs for flare prophylaxis in significant renal disease due to risk of further renal function impairment. 2
• Do not stop urate-lowering therapy during acute flares; continue the medication and add appropriate anti-inflammatory treatment. 1