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. this parameter was 44.4% (Figure 1). The per - centage of patients at target, whereas only 4 re - centage reduction of sUA concentration, com - ported comparisons of sUA reduction versus pared with baseline values was reported in 8 baseline values (Figure 3). studies and it was equal to 33.8% (Figure 2). Overall, febuxostat resulted superior over al - lopurinol at the doses tested both in terms of Benzbromarone probability to achieve the recommended target of Only four studies reported the proportion of pa - sUA (odds ratio: 2.64, 95% confidence interval tients at target of sUA and the reduction of sUA 1.74-4.01) and percentage reduction of uricaemia concentration with benzbromarone. Overall, the (mean difference: 13.08; 95% confidence inter - pooled analysis of data suggested that 81.8% (95% val 7.6-18.55) (Figure 3). CI: 73.5-88.1) of patients could achieve the sUA target with this molecule, which is also associated Efficacy CKD Patients with a 55.3% reduction (46.3-64.4) in uricaemia Two of the identified studies allowed a com - versus baseline values. However, the low number parison of febuxostat and allopurinol in patients of studies reporting this parameter and the overall with CKD: the APEX trial 15 and the CONFIRMS low number of patients enrolled in all studies (n= trial 16 . Figure 4 reports the pooled analysis of the 310) may not allow to retrieve definitive conclu - proportion of patients with renal dysfunction sions on these two efficacy outcomes. In addition, who achieved the target level of sUA, showing only 129 patients were treated with benzbromarone. an advantage for febuxostat also in this setting (for this meta-analysis we were forced to use a Febuxostat Versus Allopurinol fixed-effect model because we had available only All the 8 studies which included both a febux - two studies). Only one study on 36 patients, 17 ostat and an allopurinol treatment arm were used of whom assigned to benzbromarone, explored to calculate a pooled summary effect of the dif - the efficacy of benzbromarone in patients with ference between the two drugs in terms of per - renal dysfunction 17 .

986 Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis

A

B

Figure 3. Comparison, in terms of odds ratio, between febuxostat and allopurinol in studies comparing the two drugs. A) pro - portion of patients who achieved target levels of sUA. B) percentage reduction of uricaemia.

987 C. Borghi, F. Perez-Ruiz

Figure 4. Pooled analysis of the proportion of patients with renal dysfunction who achieved the target level of sUA.

Safety stricted use due to safety (benzbromarone) and We also conducted an explorative analysis efficacy (probenecid) concerns 18,19 . comparing the cumulative occurrence of adverse It can be remarked that efficacy data of allop - events of any grade with febuxostat and allopuri - urinol are drawn only from clinical studies in nol (data on the safety of benzbromarone con - comparison with febuxostat, although allopurinol cerned a lower number of patients and were not had been marketed for decades before febuxostat considered for this sub-analysis). development. This may be explained by the fact Odds ratios were also obtained for the proba - that clinical trials, as designed nowadays, were bility of any adverse event (febuxostat vs. allop - not performed at that time. urinol) from 6 of the 8 studies comparing the two When comparing allopurinol and febuxostat in drugs, and a pooled summary effect was pro - terms of proportion of patients at target and per - duced. Overall, the odds ratio for the incidence centage reduction of sUA compared with baseline of adverse events favored febuxostat over allop - values, febuxostat at doses > 40 mg/day was su - urinol (OR 0.85; 95% confidence interval: 0.75- perior to allopurinol 300 mg/day, in line with pre - 0.97) (Figure 5). vious analysis 20 . Of note, while patients treated with febuxostat received different dosages mainly ranging from 10 to 80 mg/day (4 studies included Discussion febuxostat 120 mg/day); allopurinol was used at the maximum dosage of 300 mg/day in 98% of This systematic review explored the efficacy cases in interventional trials, reflecting the most of ULTs in the treatment of gout. Overall, it ap - commonly prescribed dose in clinical practice 21 . peared that only the two xanthine oxidase in - Indeed a retrospective analysis conducted on hibitors, allopurinol and febuxostat had been ex - nearly 5 million patients with gout, revealed that tensively explored (scant data have been pub - allopurinol was prescribed at an average daily lished on topiroxostat, a medication only labelled dose ≤300 mg in about 95% of the patients ana - in Japan), whereas the uricosuric agent benzbro - lyzed 21 . Noteworthy, the recently-published LAS - marone and probenecid had been investigated SO study 22 suggested that significant proportions only in a limited number of studies, carried out of patients do not achieve target sUA levels when on low numbers of subjects, and both are of re - treated with such doses of allopurinol.

988 Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis

In addition, febuxostat was associated, al - the other and, allopurinol seems less effective though in an explorative-only analysis, with a and may be contraindicated 29-32 . In the above-de - lower incidence of adverse events compared with scribed meta-analysis, febuxostat appeared asso - allopurinol. Evidence collected to date on this is - ciated with a lower risk of adverse events com - sue shows mixed results 20,23 . In terms of efficacy pared with allopurinol, although this advantage on sUA levels, the present findings are in line was less evident than that reported for efficacy with previous systematic reviews that showed the outcomes 28 . Moreover, a very recent retrospec - superiority of febuxostat over allopurinol in tive study 33 which utilized 2009 to 2012 medical achieving target levels of sUA 24-26 . In addition, and pharmacy claims and laboratory data from a the analysis of a large (>13,000) population of large US database, evaluated by a propensity patients with gout treated with allopurinol in analysis, analyzed 2015 patients taking febuxo - clinical practice showed that the proportion of stat and 14,025 on allopurinol. A higher propor - subjects who reached the sUA target levels was tion of febuxostat users attained sUA goals of low, and the adherence to this molecule remained <6.0 mg/dl (56.9% vs. 44.8%; p<0.001) and <5.0 poor 27 . These findings were also consistent, and mg/dl (35.5% vs. 19.2%; p<0.001), respectively. even more evident, in patients with renal dys - Similar observations were made for overall function, a common condition in gouty patients. propensity score-matched cohorts that included Of note, a recent meta-analysis of 7 studies on both treatment-naïve and current users (n=932 chronic kidney disease patients has shown that each). The Authors of this work concluded that pooled prevalence estimates of chronic kidney febuxostat was more effective than allopurinol at disease stage ≥3 in people with gout was 24%; at the doses currently used in USA (40 mg/day for the same time, in this analysis gout was associat - febuxostat in 83% users and 300 mg/day or low - ed with chronic kidney disease (pooled adjusted er for allopurinol in 97% users) in lowering sUA odds ratio 2.41, 95% confidence interval 1.86 to in gout patients. As a further confirmation of the 3.11) 28 . In gout patients with renal insufficiency, superior efficacy of febuxostat, another recent a number of molecules (febuxostat, rasburicase, “real-world” study 34 suggested that patients benzbromarone) may be considered effective; on switched from allopurinol to febuxostat are more

Figure 5. Pooled analysis of incidence of adverse events in studies comparing febuxostat and allopurinol.

989 C. Borghi, F. Perez-Ruiz likely to achieve target SUA levels than those DRACT No.2014-005567-33; the CARES who continue on allopurinol. Moreover, a phar - study, NCT01101035; and the FAST study, macoeconomic study 35 indicates that febuxostat EUDRACT No: 2011-001883-23). may be a cost-effective alternative to allopurinol, especially for patients with more severe (stage 3- 4) CKD. Conclusions The uricosuric agent benzbromarone was asso - ciated with some efficacy in gouty patients; how - On the basis of reported data, febuxostat can ever, the efficacy of this drug, according to the play a major role in the treatment of hyperuri - requirements of the present analysis, was ex - caemia and gout. Febuxostat is a suitable phar - plored only in four studies, with an overall low macological option for first line treatment of number of patients, and therefore caution should gout, given its established efficacy and safety, be exerted when evaluating this finding. More - documented in a high number of clinical studies over, benzbromarone has been associated with and in daily practice. cases of fulminant and sometimes fatal hepato - toxicity 36,37 and, therefore, it was withdrawn from the market in several countries. ––––––––––––––––– –– Acknowledgements Besides its remarkable impact on the treat - ment of gout, some additional evidence has Editorial assistance was provided by Luca Giacomelli, PhD, suggested that febuxostat may exert some addi - Laura Brogelli, Marco Barbara and Ambra Corti, on behalf of Content Ed Net; this assistance was funded by Menarini tional favorable effects in terms of prevention International. of cardio-renal diseases. Preliminary data sug - gest that the treatment with febuxostat might –––––––––––––––– –-– –– alleviate atrial fibrillation 38 , reduce blood pres - Conflict of Interest sure, pulse wave velocity, and other cardiovas - The Authors declare that they have no conflict of interests. cular indexes 39,40 . In a randomized study on 141 patients with hyperuricemia undergoing cardiac surgery 39 , a 6-months treatment with febuxostat References in comparison to allopurinol improved sec - ondary endpoints related to CV and renal pro - 1) RODDY E, D OHERTY M. Epidemiology of gout. Arthri - tection. The serum creatinine (1.14±0.30 vs. tis Res Ther 2010; 12: 223. 1.26±0.39), urinary albumin (62.5±131.2 vs. 2) SMITH E, H OY D, C ROSS M, M ERRIMAN TR, V OS T, 163.2±233.8), oxidized low-density lipoprotein BUCHBINDER R, W OOLF A, M ARCH L. The global bur - den of gout: estimates from the Global Burden of (84.2±27.3 vs. 99.8±26.0), eicosapentaenoic Disease 2010 study. Ann Rheum Dis 2014; 73: acid/arachidonic acid ratio (0.46±0.35 vs. 1470-1476. 0.36±0.18), and high-sensitivity C-reactive pro - 3) DOHERTY M, J ANSEN TL, N UKI G, P ASCUAL E, P EREZ - tein were significantly better in the febuxostat RUIZ F, P UNZI L, S O AK, B ARDIN T. Gout: why is this group than in allopurinol treated patients curable disease so seldom cured? Ann Rheum (p<0.05 for all comparisons). Similar results Dis 2012; 71: 1765-1770. were obtained in patients with stage 3 chronic 4) DESIDERI G, C ASTALDO G, L OMBARDI A, M USSAP M, T ES - TA A, P ONTREMOLI R, P UNZI L, B ORGHI C kidney disease 41 , and the reno-protective effect . Is it time to of febuxostat has been also shown in long-term revise the normal range of serum uric acid lev - 42,43 40 els? Eur Rev Med Pharmacol Sci 2014; 18: 1295- studies . In a prospective study carried out 3067. in 17 patients with chronic tophaceous gout, 1 5) CHOI HK, A TKINSON K, K ARLSON EW, C URHAN G. Obe - year of treatment with febuxostat prevented the sity, weight change, hypertension, diuretic use, progression of arterial stiffening measured as and risk of gout in men: the Health Professionals’ carotid-femoral pulse wave velocity, while al - Follow-up Study. Arch Intern Med 2005; 165: lopurinol was not effective. The additional ben - 742-748. CHOI JW, F ORD ES, G AO X, C HOI HK efit of febuxostat treatment beyond gout could 6) . Sugar-sweet - ened soft drinks, diet soft drinks, and serum uric represent an interesting perspective for the acid level: the Third National Health and Nutrition overall treatment of patients with hyper - Examination Survey. Arthritis Rheum 2008; 59: uricemia and the results of several ongoing tri - 109-116. als comparing febuxostat and allopurinol are 7) BORGHI C, R OSEI EA, B ARDIN T, D AWSON J, D OMINICZAK awaited (e.g., the FORWARD study, EU - A, K IELSTEIN JT, M ANOLIS AJ, P EREZ -R UIZ F, M ANCIA G.

990 Urate lowering therapies in the treatment of gout: a systematic review and meta-analysis

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