Cardiovascular Risk Increases After Stopping Xanthine Oxidase Inhibitors
Overview
This cohort study analyzed a large national claims database and found that recent discontinuation of xanthine oxidase inhibitors (XOis) in gout patients is associated with an increased risk of acute cardiovascular events, including myocardial infarction and ischemic stroke. The findings suggest a potential withdrawal effect that elevates cardiovascular risk shortly after stopping therapy.
Background
Xanthine oxidase inhibitors, such as allopurinol and febuxostat, are widely used to lower serum uric acid in gout and hyperuricemia. Beyond urate control, XOis may reduce cardiovascular risk by modulating oxidative stress and endothelial function. Prior trials indicated increased cardiovascular mortality after febuxostat use, particularly when patients discontinued therapy, raising concerns about a withdrawal syndrome. However, real-world data on cardiovascular outcomes following XOi cessation remain limited.
Data Highlights
Characteristic
Continued XOi Use
Discontinued XOi
Population
Adults with gout initiating XOi
Adults with gout initiating XOi
Exposure Assessment
Any XOi supply in prior 90 days
No XOi supply in prior 90 days
Outcome
Acute myocardial infarction or ischemic stroke
Acute myocardial infarction or ischemic stroke
Follow-up Period
Days 121–180 post-XOi initiation
Days 121–180 post-XOi initiation
Statistical Model
Cox proportional hazards with time-varying exposure
Cox proportional hazards with time-varying exposure
Key Findings
Discontinuation of XOis within 90 days was associated with a significantly increased hazard of acute cardiovascular events compared to continued use.
The study excluded patients with prior cardiovascular events to isolate incident risk after XOi cessation.
Adjustment for colchicine use, a potential cardioprotective agent, did not eliminate the observed association.
Baseline comorbidities and demographic factors were balanced between groups after weighting, supporting robustness of findings.
The risk elevation was observed during days 121 to 180 after XOi initiation, highlighting a critical window post-cessation.
Clinical Implications
Clinicians should be aware that stopping xanthine oxidase inhibitors in gout patients may increase the risk of acute cardiovascular events. Careful consideration and monitoring are warranted when discontinuing these agents, especially in patients with cardiovascular risk factors. Strategies to mitigate withdrawal-related cardiovascular risk should be explored.
Conclusion
This large retrospective cohort study provides evidence that recent discontinuation of xanthine oxidase inhibitors is linked to increased acute cardiovascular events, underscoring the importance of sustained therapy or close cardiovascular monitoring after cessation.
References
CARES Trial and Post Hoc Analyses (2018-2020) -- Cardiovascular Safety of Febuxostat and Allopurinol
Systematic Review on XOi Cardiovascular Effects (2021) -- Cardiovascular Protection Associated with Xanthine Oxidase Inhibitors
Inpatient Cohort Study on XOi Discontinuation (2022) -- Increased Mortality Following XOi Withdrawal
