An allopurinol dose escalation strategy for patients with gout was associated with a small increase in all-cause mortality when compared against a static dosing strategy, results of a recent observational study show.

Allopurinol dose escalation was also associated with small, but not statistically significant, increases in cardiovascular- and cancer-related mortality, investigators said in a report published in Arthritis & Rheumatology .

Those finding suggest that allopurinol dose escalation is “unlikely to improve survival as currently prescribed in real-life practice characterized by limited dose increases,” wrote Brian W. Coburn, PhD, and his coauthors in the division of rheumatology at the University of Nebraska, Omaha.

Dr. Coburn and his colleagues had hypothesized that dose escalation would instead be associated with lower cause-specific cardiovascular and cancer mortality, compared with static dosing, according to the report.

However, a minority of dose-escalated patients achieved serum urate goal. Thus, inadequate escalation may have obscured any potential mortality benefit associated with the treatment strategy, the investigators suggested.

Current guidelines recommend starting gout patients on a low dose of allopurinol (100 mg/day or less) and then titrating up the dose slowly.

“While randomized, controlled trials of urate-lowering therapies have used static dosing strategies, such strategies are suboptimal and should now be considered unethical,” they wrote.

The researchers’ 10-year, observational, active-comparator study included 6,428 U.S. veterans with gout receiving allopurinol according to a dose escalation strategy, and 6,428 matched individuals not treated with an escalation approach.

Dose escalators had significantly increased all-cause mortality (hazard ratio, 1.08; 95% confidence interval, 1.01-1.17). Similar, but not statistically significant, effect sizes were seen for cardiovascular mortality (HR, 1.08; 95% CI, 0.97-1.21) and cancer mortality (HR, 1.06; 95% CI, 0.88-1.27), the investigators reported.

However, only 10% of dose-escalation patients received allopurinol in doses exceeding 300 mg daily, and only about one-third achieved a serum urate goal of less than 6.0 mg/dL after 2 years, they found.

“Patients receiving urate-lowering therapy dose escalation were only rarely escalated to levels typically required for proper gout control,” the investigators said.

Inadequate dose escalation amounts to “clinical inertia” that limited the ability of the study to show how optimal dose escalation may affect mortality, the investigators said.

“This appears to be particularly relevant since gout patients receiving dose escalation and achieving serum urate goal appeared to have lower cardiovascular mortality in sensitivity analyses,” they noted.

There was a 7% reduction in cardiovascular mortality in a sensitivity analysis limited to dose escalators who achieved goal, though that finding did not reach statistical significance, Dr. Coburn and his coinvestigators reported (HR, 0.93; 95% CI, 0.76-1.14).

“Taken together, these results add to the persistent uncertainty regarding the role of urate-lowering therapy in reducing mortality risk,” the investigators concluded.

The study was supported by a Rheumatology Research Foundation Health Professional Research Preceptorship, a University of Nebraska Medical Center Graduate Fellowship Grant, and the Nebraska Arthritis Outcomes Research Center. No information was provided on author disclosures.

SOURCE: Coburn B et al. Arthritis Rheumatol. 2018 Mar 7. doi: 10.1002/art.40486.