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.
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).
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.
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