Background/Purpose:  About one-third of patients with recurrent calcium oxalate (CaOx) stones have hyperuricosuria as a urinary risk factor. Febuxostat (FEB), a newer xanthine oxidase inhibitor (XOI), may be superior to allopurinol (ALLO) in stone prevention. ALLO treatment has been shown to reduce the incidence of recurrent CaOx stones in hyperuricosuric stone formers (SF). We studied whether FEB would reduce 24h urinary uric acid (uUA) excretion and prevent stone formation and pre-existing stone growth.

Methods:  In this 6-month, double-blind, multicenter, randomized, controlled trial, hyperuricosuric (>700 mg/d) adult subjects with a history of CaOx stones and ≥1 3-mm stone in its longest in-plane diameter as seen by multidetector computed tomography (MDCT) were randomized to receive daily FEB 80 mg, ALLO 200 or 300 mg (based on baseline Ccr), or PBO. Patients were excluded if they had a history of gout or secondary hyperuricemia, if they had received ALLO within the past 2 years or ever received FEB. Primary end-point was percent change from baseline (CFB) to month 6 in 24h uUA; secondary end-points were percent CFB in size of index stone, CFB in number of stones and in 24h creatinine clearance (Ccr).

Results: Of 99 subjects enrolled, 86 completed the study. Key baseline characteristics were balanced. Most subjects were men (86%), had a mean lifetime history of 10.9 stone episodes, mean largest stone diameter of 9.9 mm and a mean number of stones 5.7 on MDCT. Normal renal function was present in 97% of patients (mean baseline Ccr was 147 mL/min/1.73m²). Mean baseline serum urate (sUA) was 6.3 mg/dL, 24h urine calcium excretion was 272.2 mg/d, and 24h uUA was 952.7 mg/d. FEB led to significantly greater reduction from baseline in 24h uUA than either PBO or ALLO. Reductions in stone size and number with FEB were not statistically greater than with ALLO or PBO. In all groups, there were no statistically significant changes in 24h Ccr and serum creatinine did not change. Rates of adverse events (AE) were similar across the treatments groups. One patient in the placebo group experienced a serious AE of nephrolithiasis, but remained in the study.

Conclusion:  FEB 80 mg lowered 24h uUA significantly more than ALLO 300 mg in SF with hyperuricosuria. Neither XOI was associated with significantly reduced stone number or size compared with PBO after 6 months of treatment. Extended duration of FEB treatment leading to greater 24h uUA reductions may demonstrate improved prevention of CaOx stone recurrence.

mean±SD; ^aP=0.003 vs ALLO; ^b,c P<0.001 vs PBO and ALLO, respectively.