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Free PDF Download Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2016; 20: 983-992 Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis C. BORGHI 1, F. PEREZ-RUIZ 2 1University of Bologna, Bologna, Italy 2Servicio de Reumatologìa, Hospital Universitario Cruces, Instituto de Investigaciòn Biomédica BioCruces, Vizcaya, Spain Abstract. – OBJECTIVE: In patients with Introduction gout, serum uric acid (sUA) concentrations should be lowered at least below the target of 6 Gout represents the most frequent inflammatory mg/dL (even below 5 mg/dL in patients with se - joint disease in the general population 1, and it vere gout). To achieve this goal, urate lowering largely contributes to healthcare burden 2. medications (ULMs) should be considered. Cur - Monosodium urate deposition due to longstanding rently-used ULMs include xanthine-oxidase in - hyperuricemia leading to urate crystal formation in hibitors such as allopurinol, febuxostat, as well tissues represents the pathophysiological mecha - as available uricosuric agents. However, evi - 3 dence comparing these agents remains scant. nism of gout . Recent evidence suggests that the We have conducted a systematic review and mean serum urate (sUA) levels in the general pop - meta-analysis to retrieve evidence on the clini - ulation are increasing worldwide, due to a number cal trials on the above-mentioned drugs in the of factors such as the “epidemic” of overweight treatment of gout. MATERIALS AND METHODS: and obesity in developed countries, as well as the The following shifts in diet with overconsumption of foods rich in efficacy outcomes were considered in the meta- 4-6 analysis: (1) % of patients meeting the therapeu - purines, alcohol, fructose-sweetened soft drinks , tic target for sUA level (<6 mg/dl) and (2) percent - in addition to the use of diuretic drugs to treat co - age reduction in sUA concentration at the end of morbid conditions. Of note, patients with gout of - the study compared with baseline values. An ex - ten present comorbid conditions in addition to obe - plorative analysis on safety was also conducted. RESULTS: sity, such as cardiovascular diseases, arterial hy - In total, 16 papers concerned pertension, diabetes mellitus, and chronic kidney febuxostat, 15 allopurinol, 4 benzbromarone 7 and none involved probenecid. disease (CKD) . There is evidence suggesting that Overall, 70.7% of patients reached the target increased sUA may be a risk factor also of these 8-10 of sUA with febuxostat therapy; the reduction conditions . The management of hyperuricemia in sUA was 45.3%. Corresponding figures with thus represents the key strategy in the treatment of allopurinol were 44.4% and 33.8%, respectively. gout and, potentially, of associated diseases. The number of patients on benzbromarone A number of guidelines are available to im - (N=129) was too low to retrieve definitive find - prove gout management and reduce hyper - ings. The advantage for febuxostat over allop - 11-14 urinol was evident also in patients with renal uricemia . In particular, sUA should be gener - dysfunction. Safety analysis favored febuxostat ally lowered below the target of 6 mg/dL, and over allopurinol (OR 0.85; 95% CI: 0.75-0.97). even further below 5 mg/dL in patients with se - CONCLUSIONS: On the basis of the reported vere gout 11,12 . To achieve this goal, urate lower - data, febuxostat can play a major role in the ing therapies (ULTs) should be considered and treatment of hyperuricaemia and gout. Febuxo - discussed with patients prescribed as soon as di - stat is a suitable pharmacological option for first line treatment of gout, given its established agnosis of gout is established. Currently-used efficacy and safety, documented in a high num - ULTs include xanthine-oxidase inhibitors such ber of clinical studies and in daily practice. as allopurinol, febuxostat, and topiroxostat (la - belled only in Japan), as well as uricosuric Key Words: agents, such as benzbromarone and probenecid. Gout, Urate lowering therapy, Febuxostat, Allopuri - nol, Benzbromarone. However, evidence directly comparing these two classes of drugs remains scant. Corresponding Author: Claudio Borghi, MD; e-mail: [email protected] 983 C. Borghi, F. Perez-Ruiz We have conducted a systematic review and assessed when appropriate with the Pearson 2 meta-analysis to retrieve evidence on the clinical and evaluated with the I 2 statistics; I 2 >50% was trials on the most widely-used of the above-men - taken as the criterion for the use of a random-ef - tioned drugs in the treatment of gout. fect model. All these analyses were performed on overall rates and overall weighted mean reduc - tions, thus mixing reported outcomes for differ - Materials and Methods ent dosage arms when necessary (9 out of 16 studies, n=9718, investigated recommended dos - Literature searches were conducted on es of febuxostat 80 or 120 mg/day as approved in PubMed with the following keywords: hyper - Europe). Between-study variances were estimat - uricemia, gout, febuxostat, allopurinol, ed with the Restricted Maximum Likelihood Es - benzbromarone, and probenecid as labelled timator. Analyses were performed with the ULMs at the moment of the search. It included metafor package in the R Statistical Computing papers published through March 2015 with no environment [see www.R-project.org/]. lower date limit on the search results. The stud - ies included in the analysis were both interven - Retrieved Papers: an Overview tional and non-interventional studies of In total, 37 potentially relevant study publica - prospective and retrospective nature; we also tions were retrieved and the full-text was exam - considered studies with naturalistic design. ined for compliance with eligibility criteria. The criteria for including studies in the present Fourteen studies failed to meet the criteria (7 review were as follows: baseline hyperuricemic were duplicate reports of the same study, 6 did (sUA ≥ 7.0 mg/dl) adults (aged ≥18 years), with not report the outcomes of interest, 1 assessed gout, and at least one of the study outcomes as - only a combined treatment). Among the remain - sessed after treatment with one of the drugs com - ing 23 studies: 8 were related to febuxostat only; mercialized at the time of analysis for the treat - 8 included an allopurinol and a febuxostat treat - ment of gout: allopurinol, benzbromarone, febux - ment arm; 3 were related to allopurinol only; 4 ostat or probenecid. Efficacy outcomes considered included both an allopurinol and a benzbro - for this review were: (1) proportion of patients marone treatment arm. meeting the therapeutic target for sUA level, de - In total, 16 papers concerned febuxostat thera - fined as < 6 mg/dl, and (2) percentage reduction in py, 15 allopurinol treatment, 4 benzbromarone sUA concentration at the end of the study com - therapy and none involved probenecid. An out - pared with baseline values. Papers on combination line of the main characteristics and results col - of two ULTs were not considered. An explorative lected from the identified studies on febuxostat analysis on safety was also conducted. and allopurinol is provided in Tables I and II. Statistical Analysis Proportions of patients reaching target were Efficacy outcomes obtained from each treatment arm or subgroup reported in the studies and a pooled estimate was Febuxostat calculated via a random-effects logistic regres - All the 16 studies including febuxostat treat - sion, according to a Binomial-Normal model. ment arms reported the proportion of patients Summary estimates of mean sUA reduction per - reaching therapeutic target. Overall, the pooled centage were also obtained pooling the raw per - analysis showed that, in the identified studies, centage reduction means by fitting an inverse- 70.7% of patients reached the target of sUA with variance weighted, random-effects, linear model. febuxostat therapy (Figure 1). These two analyses were conducted separately Eight studies reported the percentage reduc - for each drug. tion of sUA concentration with febuxostat, over - Reported treatment comparison effect-sizes all showing a 45.3% reduction at the end of the between allopurinol and febuxostat, when avail - study with respect to baseline values (Figure 2). able, were pooled in terms of odds-ratios, for pa - tients-at-target rates, and mean differences, for Allopurinol sUA reduction percentage, respectively; the sum - Fourteen studies reported the proportion of pa - mary effect-size was obtained using a weighted tients who reached the target level of sUA with random-effects linear model heterogeneity was allopurinol. Overall, the pooled percentage of 984 Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis Table I. Summary of the main data collected from the interventional studies*. Time span Total n. of % patients at Average Number of (years) patients SUA target sUA Drug studies (6 mg/dl) reduction Allopurinol (dose was ≤300 mg/day 8 2005-2014 1667 41.61% 33-36% in 7/8 studies, with 1622 subjects) Febuxostat (dose was ≤ 120 mg/day, n=3635) 10 2005-2014 3635 65.03% 33.8-52% *Data not referred to the whole body of studies, because not always available. Data on benzbromarone are not reported as only very few studies are available on this drug (n=129 patients treated with benzbromarone) Figure 1. Pooled analysis of proportion of patients who achieved target values of sUA (≤ 6 mg/dl). Table II. Summary of the main data collected from observational studies. Time span Total n. of % patients at Average Number of (years) patients SUA target sUA Drug studies reduction Allopurinol (dose was ≤300 mg/day in >24900 patients) 3 2014-2015 26820 30.57 NA Febuxostat (dose was ≤ 120 mg/day, n=7544) 6 2011-2015 7544 45.54 44.7 (1 study) *Data not referred to the whole body of studies, because not always available. NA: Not available; 985 C. Borghi, F. Perez-Ruiz Figure 2. Pooled analysis of percentage reduction of SUA concentration compared with baseline values.
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