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Allopurinol was more effective than febuxostat (Uloric) in preventing incident renal disease among older Americans, a retrospective cohort study found.

In a propensity-matched multivariate analysis, patients on allopurinol had a 39% lower risk of developing renal disease (HR 0.61, 95% CI 0.49-0.77, P<0.0001) than those taking febuxostat, according to Jasvinder A. Singh, MD, and John D. Cleveland, MD, of the University of Alabama at Birmingham.

There also was a dose-response relationship, which supports causation versus association, according to the authors. For example, compared with 40 mg/day of febuxostat, the hazard ratios for incident renal disease were 0.75 (95% CI 0.65-0.86) for allopurinol in daily doses below 200 mg, 0.61 (95% CI 0.52-0.73) for 200-299 mg/day, and 0.48 (95% CI 0.41-0.55) for doses of 300 mg or higher, the researchers reported in .

"There has been a longstanding 'chicken or the egg' controversy regarding the relationship of hyperuricemia with renal disease," wrote Singh and Cleveland. Some have suggested that elevated uric acid is a result of progressive chronic kidney disease, while others have favored the notion that hyperuricemia is a causative factor in chronic kidney disease.

Some 80%-90% of U.S. patients with hyperuricemia are treated with allopurinol. However, because febuxostat more effectively reduces oxidative stress, which may play a role in kidney damage, the authors hypothesized that it was likely to be more protective against renal disease than allopurinol. They also noted that "a finding of greater renal protection with febuxostat or allopurinol [could] provide important evidence for preferring one medication to the other," the researchers stated.

Accordingly, they analyzed data from the 5% random sample of Medicare enrollees for 2006-2012, identifying 31,465 treatment episodes of new prescriptions for either drug in patients with no baseline renal disease.

Of these, 8,570 episodes ended in incident kidney disease, with 5,708 during allopurinol exposure and 302 during febuxostat use, and the remainder not occurring during exposure. The occurrence of renal disease was more common among individuals who were older, women, black, and who had higher Charlson-Romano comorbidity scores.

Crude incidence rates of renal disease were 192/1,000 person-years with allopurinol and 338/1,000 with febuxostat.

In the propensity-adjusted analysis, compared with use of febuxostat for 1-180 days, all durations of allopurinol use were associated with a significantly lower risk of incident renal disease.

In a sensitivity analysis that used a conventional multivariate model, there again was a decreased risk for renal disease among allopurinol users (HR 0.66, 95% CI 0.59-0.75, P<0.0001). Factors that were associated with a greater risk included older age, black race, and treatment with beta-blockers and diuretics.

And as was seen in the propensity-adjusted analysis, compared with febuxostat exposure of 1-180 days, all allopurinol treatment durations were associated with a lower risk.

"In this comparative effectiveness study of 5% random sample of U.S. Medicare beneficiaries 65 years or older, we were surprised to find that compared with febuxostat, allopurinol was independently associated with significantly lower hazard (39%) of incident renal disease (opposite to our hypothesis)," the researchers wrote.

It also was contrary to expectations that patients receiving allopurinol had higher scores on the Charlson-Romano comorbidity index, and therefore were sicker, rather than healthier, than those given febuxostat.

In addition, the lower risk was independent of age, sex, race, presence of gout and other medical comorbidities, and the use of treatments for gout, cardiovascular disease, or renal disease.

"Allopurinol differs from febuxostat in being a purine analog and nonselectively inhibiting xanthine oxidase and other enzymes in purine and pyrimidine pathways, which may possibly underlie these differences [in nephroprotection]," the researchers wrote.

They also pointed out that the doses typically used for gout are low, at a mean of 230 mg/day, and higher doses up to 600-800 mg/day might not only be more effective at urate lowering but might also be more effective for preventing renal disease.

They called for a randomized trial to confirm these findings, adding that "future studies should also assess whether renal protection with allopurinol differs by the underlying etiology of renal disease, that is, hypertension versus diabetes versus heart failure versus others."

Study limitations included its observation design in which there may be residual confounding.

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