Uricosuric medications for chronic gout.
BACKGROUND
Uricosuric agents have long been used in the treatment of gout but there is little evidence regarding their benefit and safety in this condition.


OBJECTIVE
To assess the benefits and harms of uricosuric medications in the treatment of chronic gout.


METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2013), Ovid MEDLINE and Ovid EMBASE for studies to the 13 May 2013. We also searched the World Health Organization Clinical Trials Registry, ClinicalTrials.gov and the 2011 to 2012 American College of Rheumatology and European League against Rheumatism abstracts. WE considered black box warnings and searched drug safety databases to identify and describe rare adverse events.


METHODS
We considered all randomised controlled trials (RCTs) or quasi-randomised controlled trials (controlled clinical trials (CCTs)) that compared uricosuric medications (benzbromarone, probenecid or sulphinpyrazone) alone or in combination with another therapy (placebo or other active uric acid-lowering medication, or non-pharmacological treatment) in adults with chronic gout for inclusion.


METHODS
Two review authors independently selected the studies for inclusion, extracted data and performed a risk of bias assessment. Main outcomes were frequency of acute gout attacks, serum urate normalisation, study participant withdrawal due to adverse events, total adverse events, pain reduction, function and tophus regression.


RESULTS
The search identified four RCTs and one CCT that evaluated the benefit and safety of uricosurics for gout. One study (65 participants) compared benzbromarone with allopurinol for a duration of four months; one compared benzbromarone with allopurinol (36 participants) for a duration of nine to 24 months; one study (62 participants) compared benzbromarone with probenecid for two months and one study (74 participants) compared benzbromarone with probenecid. One study (37 participants) compared allopurinol with probenecid. No study was completely free from bias.Low-quality evidence from one study (55 participants) comparing benzbromarone with allopurinol indicated uncertain effects in terms of frequency of acute gout attacks (4% with benzbromarone versus 0% with allopurinol; risk ratio (RR) 3.58, 95% confidence interval (CI) 0.15 to 84.13), while moderate-quality evidence from two studies (101 participants; treated for four to nine months) indicated similar proportions of participants achieving serum urate normalisation (73.9% with benzbromarone versus 60% with allopurinol; pooled RR 1.27, 95% CI 0.90 to 1.79). Low-quality evidence indicated uncertain differences in withdrawals due to adverse events (7.1% with benzbromarone versus 6.1% with allopurinol; pooled RR 1.25, 95% CI 0.28 to 5.62), and total adverse events (20% with benzbromarone versus 6.7% with allopurinol; RR 3.00, 95% CI 0.64 to 14.16). The study did not measure pain reduction, function and tophus regression.When comparing benzbromarone with probenecid, there was moderate-quality evidence based on one study (62 participants) that participants taking benzbromarone were more likely to achieve serum urate normalisation after two months (81.5% with benzbromarone versus 57.1% with probenecid; RR 1.43, 95% CI 1.02 to 2.00). This indicated that when compared with probenecid, five participants needed to be treated with benzbromarone in order to have one additional person achieve serum urate normalisation (number needed to treat for an additional beneficial outcome (NNTB) 5). However, the second study reported no difference in the absolute decrease in serum urate between these groups after 12 weeks. Low-quality evidence from two studies (129 participants) indicated uncertain differences between treatments in the frequency of acute gout attacks (6.3% with benzbromarone versus 10.6% with probenecid; pooled RR 0.73, 95% CI 0.09 to 5.83); fewer withdrawals due to adverse events with benzbromarone (2% with benzbromarone versus 17% with probenecid; pooled RR 0.15, 95% CI 0.03 to 0.79, NNTB 7) and fewer total adverse events (21% with benzbromarone versus 47% with probenecid; pooled RR 0.43, 95% CI 0.25 to 0.74; NNTB 4). The studies did not measure pain reduction, function and tophus regression.Low-quality evidence based on one small CCT (37 participants) indicated uncertainty around the difference in the incidence of acute gout attacks between probenecid and allopurinol after 18 to 20 months' treatment (53% with probenecid versus 55% with allopurinol; RR 0.96, 95% CI 0.53 to 1.75). The study did not measure or report the proportion achieving serum urate normalisation, pain reduction, function, tophus regression, withdrawal due to adverse events and total adverse events.


CONCLUSIONS
There was moderate-quality evidence that there is probably no important difference between benzbromarone and allopurinol at achieving serum urate normalisation, but that benzbromarone is probably more successful than probenecid at achieving serum urate normalisation in people with gout. There is some uncertainty around the effect estimates, based on low-quality evidence from only one or two trials, on the number of acute gout attacks, the number of withdrawals due to adverse events or the total number of participants experiencing adverse events when comparing benzbromarone with allopurinol. However, when compared with probenecid, benzbromarone resulted in fewer withdrawals due to adverse events and fewer participants experiencing adverse events. Low-quality evidence from one small study indicated uncertain effects in the incidence of acute gout attacks when comparing probenecid with allopurinol therapy. We downgraded the evidence because of a possible risk of performance and other biases and imprecision.
Division of Rheumatology, University of British Columbia, 1650 Terminal Ave, Suite 206, Nanaimo, BC, Canada, V9S 0A3.
Alison S R
AS
Kydd
Rakhi
R
Seth
Rachelle
R
Buchbinder
Christopher J
CJ
Edwards
Claire
C
Bombardier
D000328:Adult; D000368:Aged; D000493:Allopurinol / Q000627:therapeutic use; D001553:Benzbromarone / Q000627:therapeutic use; D002908:Chronic Disease; D018849:Controlled Clinical Trials as Topic; D005260:Female; D006073:Gout / Q000097:blood / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011339:Probenecid / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D014527:Uric Acid / Q000097:blood; D014528:Uricosuric Agents / Q000009:adverse effects / Q000627:therapeutic use*
D014528:Uricosuric Agents; D014527:Uric Acid; D001553:Benzbromarone; D000493:Allopurinol; D011339:Probenecid