Allopurinol Dose Escalation and Mortality Among Patients With Gout: A National Propensity-Matched Cohort Study

Objectives Observational data suggests that hyperuricemia and gout are associated with increased mortality while allopurinol use is associated with reduced mortality. There may also be a dose-dependent protective effect. Our objective was to determine whether dose escalation is associated with cause-specific mortality. Methods In this 10-year observational, active-comparator study of U.S. Veterans with gout initiating allopurinol, we used propensity score matching with Cox proportional hazards and competing risks regression to assess cause-specific mortality differences between allopurinol dose escalators versus non-escalators. Results Among 6,428 dose escalators and 6,428 matched non-escalators, there were 2,867 deaths during observation (40.4 deaths per 1,000 person-years). Dose escalators experienced increased all-cause mortality (HR 1.08; 95% CI 1.01 to 1.17) with similar effect sizes for cardiovascular (HR 1.08; 95% CI 0.97 to 1.21) and cancer mortality (HR 1.06; 95% CI 0.88 to 1.27), albeit without reaching statistical significance. Dose escalation to achieve serum urate (SU) goal 300mg and 31% achieved SU goal after two years. In sensitivity analysis limited to escalators achieving SU goal, there was a non-significant 7% reduction in cardiovascular mortality (HR 0.93; 95% CI 0.76 to 1.14). Conclusion This is the largest study of allopurinol's effect on mortality and the first to use a rigorous active-comparator design. Dose escalation was associated with a small (<10%) increase in all-cause mortality, showing that allopurinol dose escalation is unlikely to improve survival as currently prescribed in real life practice characterized by limited dose increases. This article is protected by copyright. All rights reserved.