Allopurinol dose escalation is associated with a small increase in all-cause mortality, which suggests that dose escalation is unlikely to improve survival, according to the results of a 10-year, observational, active-comparator study published in Arthritis & Rheumatology.

Recent data suggest that hyperuricemia and gout are associated with increased mortality, while allopurinol use is associated with reduced mortality. However, it is not known whether there is a dose-dependent protective effect. Therefore, researchers from the Veterans Affairs Nebraska-Western Iowa Health Care System and the University of Nebraska Medical Center in Omaha used propensity score matching with Cox proportional hazards and competing risks regression to assess cause-specific mortality differences between allopurinol dose escalators and non-escalators.

Researchers included 6428 dose escalators and 6428 matched non-escalators in the analysis. A total of 2867 deaths occurred during the observation period, or 40.4 deaths per 1000 person-years.  Dose escalators experienced increased all-cause mortality (hazard ratio [HR], 1.08; 95% CI, 1.01-1.17) with similar effect sizes for cardiovascular mortality (HR, 1.08; 95% CI, 0.97-1.21) and cancer mortality (HR, 1.06; 95% CI, 0.88-1.27). However, neither observation reached statistical significance.


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The researchers noted that only 10% of patients received allopurinol doses >300 mg and only 31% achieved a serum urate goal of <6.0 mg/dL after 2 years. A sensitivity analysis limited to escalators achieving serum urate goal found a nonsignificant 7% reduction in cardiovascular mortality (HR, 0.93; 95% CI, 0.76-1.14).

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The investigators found no association between allopurinol dose escalation and improved survival. They noted that the findings were likely limited by suboptimal urate-lowering therapy dosing observed in dose escalators. The investigators noted that they were unable to make a definitive assessment and suggest that trial designs or interventions in day-to-day practice are necessary before a full evaluation of the potentially beneficial effects of dose escalation on mortality can be determined.

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Reference

Coburn BW, Michaud K, Bergman DA, Mikuls TR. Allopurinol dose escalation and mortality among patients with gout: a national propensity-matched cohort study [published online March 7, 2018]. Arthritis Rheumatol. doi:10.1002/art.40486