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Clinical Therapeutics/Volume 35, Number 2, 2013

Efficacy and Tolerability of Febuxostat in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis

Peng Ye, MD; Shumin Yang, MD; Wenlong Zhang, MD; Qiong Lv, MD; Qingfeng Cheng, MD; Mei Mei, MD; Ting Luo, MD; Lulu Liu, MD; Shumei Chen, MD; and Qifu Li, MD, PhD

Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

ABSTRACT Background: Febuxostat has been approved for the treatment of hyperuricemia in patients with/without gout. Objectives: This meta-analysis and systematic re- view assessed the efficacy and tolerability of febuxostat in hyperuricemic patients with/without gout. Methods: Major electronic databases were searched for articles of all publication years (up to February 2012), as were the Web sites of the American College of Rheumatology, the European League Against Rheu- matism, and the Chinese State Food and Drug Admin- istration, and clinicaltrials.gov for unpublished stud- ies. Only randomized, controlled trials (RCTs) were included. Results: Ten trials were included. A significantly greater proportion of patients achieved the target se- rum urate level (sUA 6.0 mg/dL) at the final visit in the febuxostat group compared with the placebo (OR 235.73; P 0.01) and allopurinol groups (OR 3.14; P 0.01). In subgroup analysis, the proportion of patients who achieved target sUA at the final visit was significantly greater in the febuxostat-treated group (40 mg/d) compared with the allopurinol-treated group (100 –300 mg/d) (50.9% vs 45.6%; OR 1.25; 95% CI, 1.05–1.49; P 0.01). As the dosage was increased (40, 80, 120 mg/d), the proportion of pa- tients who achieved target sUA in the febuxostat- treated group increased gradually (50.9%, 71.4%, 82%, respectively). There was no significant difference in the occurrence of adverse events (AEs) between the febuxostat- and allopurinol-treated groups. Conclusion: Febuxostat was effective in reducing serum urate in hyperuricemic patients with/without gout, and febuxostat (40 –120 mg/d) was more effica- cious compared with allopurinol (100 –300 mg/d). The

doses of allopurinol to which febuxostat has been com- pared, although commonly prescribed, are low in the range of approved doses of allopurinol. The tolerabil- ity of febuxostat for the treatment of hyperuricemia with/without gout is similar to that of allopurinol. ( Clin Ther. 2013;35:180–189) © 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: febuxostat, hyperuricemia, gout, meta- analysis.

INTRODUCTION

Gout is a common disease characterized by hyperuri- cemia and urate crystal deposition. 1,2 Hyperuricemia is typically defined as a serum concentration of uric acid at or above the limit of its solubility ( 6.8 mg/dL). 2,3 Individuals with hyperuricemia are usually asymptom- atic and do not always have gout symptoms. 2,4 Gout is associated with insulin resistance, diabetes, obesity, dyslipidemia, and hypertension. 2,4,5 Therefore, gout patients not only suffer potentially disabling arthritis but are also at high risk for cardiovascular diseases. 68 The management of chronic gout is aimed at main- taining serum urate (sUA) concentrations below the level of saturation ( 6.0 mg/dL). 9 11 Achieving this goal usually requires urate-lowering therapy (ULT), which, if maintained over time, may result in a reduc- tion in the frequency of acute gout flares and tophi resolution. 1214 The most commonly employed ap- proaches to ULT involve reducing urate production with a xanthine oxidase (XO) inhibitor and enhancing

Accepted for publication December 18, 2012.

http://dx.doi.org/10.1016/j.clinthera.2012.12.011

0149-2918/$ - see front matter

© 2013 Elsevier HS Journals, Inc. All rights reserved.

P. Ye et al.

urinary excretion of uric acid with a uricosuric agent. With regard to uric acid synthesis inhibitors, the pu- rinelike XO inhibitor allopurinol has been widely used. Although a maximum dosage of 800 mg/d is recom- mended by the US Food and Drug Administration (FDA) and the European League Against Rheumatism, allopurinol is commonly administered at 100 to 300 mg/d in clinical practice. 11,13,15 However, some pa - tients fail to achieve target sUA levels at the commonly utilized doses. The prolonged half-life of the primary metabolite of allopurinol, oxypurinol, in patients with decreased creatinine clearance has prompted dose re- ductions in patients with impaired renal function. 16,17 Allopurinol may occasionally induce severe or life- threatening skin reactions (eg, exfoliative dermatitis) or allopurinol-hypersensitivity syndrome. 11,18,19 Febuxostat, a non-purinelike XO inhibitor, 20 was approved by the FDA for the treatment of hyperurice- mia in patients with gout. In contrast to allopurinol, febuxostat inhibits both oxidized and reduced forms of XO and has little effect on other purine- and pyrimi- dine-metabolizing enzymes, 20,21 which indicates a po -

tential for achieving a better urate-lowering effect. Fe- buxostat is mainly metabolized in the liver, with 45% excreted in the stool, and the remaining 49%

( 3% unchanged) found in the urine, 22 which allows

febuxostat to be prescribed without dose adjustment in patients with mild to moderate renal or hepatic impair- ment. 2 Evidence on treatment outcomes and tolera - bility with febuxostat therapy have accumulated in randomized controlled trials (RCTs) over the past decade. The present meta-analysis and systematic re- view were conducted to assess the efficacy and toler- ability of febuxostat in hyperuricemic patients with/ without gout.

METHODS

Search Strategy

Literature searches of all publication years (up to February 2012) were conducted using PubMed, EMBASE, the Science Citation Index, the Cochrane library, the Chinese Biological Medical Database, the Chinese National Knowledge Infrastructure, and the VIP Database for Chinese Technical Periodicals, using the following search terms: febuxostat, Uloric, TMX- 67, and TEI-6720 in English and fei bu si ta in Chinese. The Web sites of the American College of Rheumatol- ogy, the European League Against Rheumatism, and the Chinese State Food and Drug Administration were

also searched, as was clinicaltrials.gov , for unpub- lished studies. All of the references in the articles were reviewed to identify additional studies that were not included in the electronic databases. The publication languages were restricted to English and Chinese.

Study Selection

Only RCTs were considered. The criteria for includ- ing studies in the present meta-analysis and review were as follows: patients were hyperuricemic (sUA 7.0 mg/dL) adults (aged 18 years) with/without gout, and febuxostat treatment was compared with either an allopurinol or placebo treatment for 4 weeks or longer. The study-selection process included prelim- inary screening and full-text review. In the prelimi- nary-screening stage, reviewers screened the titles, ab- stracts, and key words to exclude studies that failed to meet the criteria. The work was completed indepen- dently by 2 reviewers (P.Y. and W.Z.). When opinions differed, the differences were resolved by a third re- viewer (S.Y.).

Quality Assessment and Data Extraction

The methodological quality of each trial was as- sessed by criteria that were derived from the Cochrane Handbook 23 and was mainly based on randomization, blinding, allocation concealment, incomplete outcome data, selective outcome reporting, and other sources of bias. The trials were classified using the following lev- els: A (plausible bias was unlikely to obviously alter the results); B (plausible bias raised some doubt about the results); or C (plausible bias seriously weakened confi- dence in the results). The following information was extracted: first author, year of publication, country in which the study was conducted, inclusion/exclusion criteria, participant characteristics, duration of inter- vention, proportion of subjects with sUA levels 6.0 mg/dL at the final visit, percentage change in sUA level on comparing the baseline and final visits, and the prevalences of AEs. The data were extracted by the 2 independent reviewers using a structured data-extrac- tion form. When there was a lack of information, the investigator was contacted for supplemental data.

Statistical Analysis

Statistical analyses were performed using RevMan 5 software provided by the Cochrane Collaboration. The degree of heterogeneity among the studies was assessed using 2 and I 2 tests. When I 2 50%, which

Clinical Therapeutics

Database search (n = 237) Manual search (n = 34)

Database search (n = 237) Manual search (n = 34) Potentially relevant studies identified by screening

Potentially relevant studies identified by screening (n = 34)

relevant studies identified by screening (n = 34) RCTs included in meta-analysis and systematic review (n

RCTs included in meta-analysis and systematic review (n = 10)

included in meta-analysis and systematic review (n = 10) Excluded: nonclinical studies, reviews, duplication (n =

Excluded:

nonclinical studies, reviews,

duplication (n = 237)

nonclinical studies, reviews, duplication (n = 237) Excluded: non-RCTs, duplicate publication, data

Excluded:

non-RCTs, duplicate publication,

data insufficiency (n = 24)

Figure 1. Study selection flow chart.

was considered substantial heterogeneity, 23 the ran - dom-effects model was used for the meta-analysis, and if not, the fixed-effects model was used. The analysis results of dichotomous data were expressed as odds ratios (ORs) (95% CI), which were combined for meta-analysis. P 0.05 and 95% CIs of OR that did not include 1.00 were considered to be statistically sig- nificant. Sensitivity analyses were performed to deter- mine the influence of each trial. We excluded individ- ual study estimates one at a time and aggregated the remaining studies to examine the influence of each study on the overall OR. To assess the potential for publication bias, we performed the Begg test 24 and the Egger test. 25

RESULTS Studies Included in the Meta-analysis and Systematic Review

We identified 271 citations, from which 237 were excluded based on the title and abstract. Therefore, 34

studies were selected for a full-text review, of which 6 were excluded for not meeting the inclusion criteria,

16 for containing duplicate data, 1 for letters, and 1

for data insufficiency for meta-analysis. In summary,

10 RCTs 21,26 33 were included in the meta-analysis

( Figure 1 ). The characteristics of these studies are summarized in Table I. 21,26 33 All of the studies enrolled hyperuri- cemic patients with/without gout, and most were obese male patients. Two trials 27,29 enrolled a high propor - tion (35% and 65.4%) of patients with impaired renal function. Febuxostat was given at a dosage of 20 to 240 mg/d and allopurinol at 100 to 300 mg/d. The

number of patients in these studies ranged from 40 to 2268, and the duration ranged from 4 to 172 weeks. The methodological quality of 8 studies was classified as A level, whereas the other 2 studies were of B-level

quality.

Efficacy Evaluation Febuxostat Versus Placebo

Four trials were eligible, which included 1225 sub- jects (989 in the febuxostat group and 236 in the pla- cebo group); the duration ranged from 4 to 28 weeks. 21,26,32,33 Compared with the placebo-treated group, the proportion of subjects who achieved an sUA level 6.0 mg/dL at the final visit was higher (0.8% vs 76.5%) in the febuxostat-treated group (OR 235.73; 95% CI, 75.39 –737.08; P 0.01), and there was no statistical heterogeneity among the included trials (I 2 0%; P 0.76) ( Figure 2 A ). Three tri- als 21,32,33 reported the percentage change from the baseline to the final visit of sUA levels. However, we could not conduct a meta-analysis for lack of data. Nonetheless, all of the febuxostat doses that ranged from 20 to 240 mg in these trials produced significantly greater percent changes in sUA levels from the baseline to the final visit ( 28.9% to 66%) compared with the placebo treatments ( 0.6% to 3%), which indi- cates the superior urate-lowering effect of febuxostat compared with the placebo.

Febuxostat Versus Allopurinol

Seven trials 21,2731 were eligible, which included 5690 subjects (3994 in the febuxostat group and 1696 in the allopurinol group); the duration ranged from 8 to 172 weeks. The random effect model was used for the meta-analysis due to the significant heterogeneity among these trials. Compared with the allopurinol group, the proportion of patients who achieved an sUA level 6.0 mg/dL at the final visit was higher (43.3% vs 68.8%) in the febuxostat-treated group (OR 3.14; 95% CI, 1.82–5.44; P 0.01) ( Figure 2 B ). Five trials 21,27,28,30,31 reported the percentage change from the baseline to the final visit of sUA levels in the febuxostat group (40 –240 mg/d) as ranging from 40.75% to 66% compared with the allopuri- nol group (100 –300 mg/d), which had a range from 32% to 36.55%, which indicated a better urate- lowering effect of febuxostat compared with that of allopurinol.

P. Ye et al.

For further study, we performed a subgroup analy- sis of the efficacy between different dosages of febuxo- stat (40/80/120 mg/d) and allopurinol (100 –300 mg/d). The pooled data from the 4 trials compared the efficacy of febuxostat 40 mg/d and allopurinol (100 – 300 mg/d) with acceptable heterogeneity (I 2 36%; P 0.20) (data on file, http://www.sfda.gov.cn/WS01/ CL0001/ ). 29 31 Compared with the allopurinol 100 – 300-mg/d group, the febuxostat 40-mg/d group had a higher proportion (45.6% vs 50.9%) of patients who achieved sUA 6.0 mg/dL at the final visit (OR 1.25; 95% CI, 1.05–1.49; P 0.01) ( Figure 3 A ). With the febuxostat dosage increased to 80 and 120 mg/d, the proportions of achieving the target sUA level rose to 71.4% and 82.0% ( Figures 3B and 3 C ). Five trials reported the percentage change in sUA levels, which

demonstrated that with increasing febuxostat dosages

(40 mg/d, 30,31 80 mg/d, 21,27,28 , and 120 mg/d 21,27,28 ), the percentage change in sUA level also increased

( 40.75% to 42.96%; 44.73% to 47%; and

51.52% to 53%), whereas in the allopurinol 100 – 300-mg/d group, the percentage change in sUA level ranged from 32% to 36.55%.

Tolerability

The assessment of tolerability of febuxostat com- pared the prevalences of adverse events (AEs), includ- ing the total number of AEs and serious AEs, as well as those of diarrhea, headache, elevated liver enzymes, cardiovascular AEs, musculoskeletal and connective tissue AEs, gastrointestinal AEs, and joint-related AEs between the febuxostat and allopurinol groups in 7

Clinical Therapeutics

Clinical Therapeutics tr ials ( Table II ) (d ata on file, http: // www.s fd

trials (Table II ) (data on file, http://www.sfda.gov.cn/ WS01/CL0001/ ). 21,2731 The results demonstrated no significant differences between the 2 groups, and het- erogeneity was not apparent in any of the analyses.

Publication Bias Assessment

Evidence of publication bias for studies that com- pared the efficacy of febuxostat and allopurinol was not noted in using the Egger test ( P 0.537) or the Begg test ( P 0.746).

DISCUSSION

Allopurinol is a widely used urate-lowering agent in the treatment of chronic gout. However, some patients with gout, especially those with impaired renal func- tion, fail to achieve target sUA levels with allopurinol because of the dose reduction in these patients. More- over, allopurinol can occasionally induce exfoliative dermatitis or allopurinol hypersensitivity syndrome, which also limits the usage of allopurinol. As a novel urate-lowering agent, febuxostat may offer gout pa-

tients another option. A number of RCTs of febuxostat have been conducted over the past decade, and the present meta-analysis systematically evaluated those RCTs to provide useful information for the clinical treatment of gout. First, 4 trials were identified that compared febuxo- stat and placebo treatments. Meta-analysis demon- strated that the proportion of patients who had achieved target sUA levels was significantly higher in the febuxostat-treated group, which provided evidence of the urate-lowering efficacy of febuxostat. Febuxo- stat was further compared with allopurinol. In those included RCTs, 7 trials compared febuxostat with al- lopurinol. The pooled data from the 7 trials suggested that more patients achieved target sUA levels in the febuxostat-treated group compared with the allopuri- nol-treated group. Subgroup analysis demonstrated that, compared with the allopurinol 100 –300-mg/d group, the febuxostat 40-mg/d group had a higher pro- portion of patients who achieved target sUA. With the febuxostat dosage increased to 80 and 120 mg/d, both

P. Ye et al.

P. Ye et al. the proportions of patients who had achieved target sUA levels and the

the proportions of patients who had achieved target sUA levels and the percentage changes in sUA level from baseline increased, all of which were lower in the allopurinol-treated group. Most patients in the pooled studies (n 5854) were hyperuricemic with gout, and 4 studies 30 33 (n 588) included patients with hyper - uricemia but not gout. Asymptomatic hyperuricemia does not typically require clinical treatment, and evi- dence of febuxostat in patients with simple hyperuri- cemia is insufficient. According to results mentioned earlier, the authors recommend an initial febuxostat dosage of 40 mg/d in gout patients with hyperuricemia,

and if they fail to achieve target sUA levels, the febuxo- stat dosage could be increased to 80 or 120 mg/d. Most subjects in the pooled studies were male, and no trial specifically evaluated the efficacy and tolerabil- ity of febuxostat in hyperuricemic women with/with- out gout. Finally, the authors could not perform a sex- stratified subgroup analysis due to data limitations. Chohan et al 34 reported that 80 mg/d of febuxostat may be more efficacious than allopurinol (100 –300 mg/d) in female gout patients. However, the major study limitations were the post hoc nature and that only 226 female subjects were included; these factors

Clinical Therapeutics

might weaken the reliability of the conclusion. Further studies should be performed for the optimal usage of febuxostat in female gout patients. Eight studies included in the present meta-analy- sis enrolled some patients with impaired renal func- tion (data on file, http://www.sfda.gov.cn/WS01/ CL0001/ ). 21,2729,3133 However, only 1 trial per - formed a subgroup analysis of urate-lowering efficacy based on renal function. In this subgroup analysis, Becker et al 29 found that 60.9% patients with mild or moderate renal impairment in the 40/80 mg/d febuxo- stat-treated group achieved the target sUA level com- pared with 42.3% in the 200/300mg/d allopurinol- treated group. In another study by Mayer et al, 35 febuxostat 80 mg/d was orally administered for 7 days to patients with normal renal function or to patients with mild, moderate, or severe renal impairment. Mayer et al found that the percentage changes in sUA levels by day 7 were comparable regardless of renal function. Although plasma levels of febuxostat and its metabolites were generally greater with increasing de-

grees of renal impairment, an 80-mg/d dosage of fe- buxostat appeared to be well tolerated with differing renal functions. According to the study results reported by Becker et al and Mayer et al, febuxostat without a dosage adjustment might be used for gout patients with mild to moderate renal function impairment. How- ever, the study by Mayer et al was a non-RCT with a small sample (31 patients), and febuxostat has not been studied in patients with a creatinine clearance 30 mL/min and in a limited number in patients with creatinine clearance 30 to 60 mL/min. Therefore, the actual tolerability in patients with renal insufficiency is not known. The pooled data from this meta-analysis demon- strated that febuxostat and allopurinol shared similar prevalences of AEs, most of which were mild to mod- erate. Elevated liver enzymes was the most common AE that led to withdrawal in the febuxostat-treated group (data on file, http://www.sfda.gov.cn/WS01/ CL0001/ ). 21,27,29 The most frequent serious AEs ob - served in the febuxostat-treated group were cardiovas-

P. Ye et al.

cular AEs, 21,28,29 suggesting particular attention should be paid to the signs and symptoms of cardio- vascular events in patients treated with febuxostat. In total, 16 of 2962 febuxostat-treated patients (0.54%) and 3 of 1154 allopurinol-treated patients (0.26%) were reported to have died during 3 of the clinical trials 2729 ; these deaths were not considered to have been related to the study drug. These findings suggest that urate-lowering therapy with febuxostat and allo- purinol is generally well tolerated. To avoid selection bias, a highly sensitive searching strategy was used, and unpublished articles were also searched using manual search techniques. Meanwhile,

a sensitivity analysis was conducted in the included

studies. Individual study estimates were excluded one

at a time to examine the influence of each study on the

overall OR. The omission of any 1 study did not ap- preciably change the pooled OR, and the estimates in each case were within the confidence limits of the over- all estimate. The present meta-analysis had several lim- itations. First, when the data were pooled, the 7 trials exhibited significant heterogeneity, which may have been associated with the differences in the characteris- tics of the included patients, drug dosages and time for intervention; therefore, the random-effects model was used for the meta-analysis. However, the random-ef- fects model analysis also provided a reliable result, and the reasons are as follows: (1) 5 of the 7 studies in- cluded in this meta-analysis were A level in terms of methodological quality; (2) compared with the fixed- effect models, the random-effects model would in- crease 95% CIs (nonetheless, the results demonstrated

a significant difference between febuxostat and allo-

purinol); and (3) further subgroup analysis, which re- duced the heterogeneity, achieved similar results. Sec- ond, allopurinol was used at the dose of 100 to 300 mg/d in these studies, which might be associated with the low proportion of achieving target sUA levels. Whether febuxostat is superior to allopurinol with a higher dose is still unknown. However, according to the study conducted by Sarawate et al, 36 in the United

States, 64.9% patients took the dosage of 300 mg/d, 32.3% took the dosage 300 mg/d, only 2.9% were treated with the dose 300 mg/d in clinical practice. Therefore 100 to 300 mg/d represented the most com- monly used dose in clinical practice. Third, although evidence of publication bias for studies comparing the efficacy of febuxostat and allopurinol was not noted using the Egger test or the Begg test, 6 of 10 studies

were granted by the pharmaceutical company of fe- buxostat, which may have caused potential publica- tion bias. In addition, most of the trials reported the number of subjects who had AEs instead of the number of events; therefore, the number of patients was used to calculate the incidence of AEs, which may have omit- ted some valuable information.

CONCLUSIONS

Febuxostat was effective in reducing serum urate in hyperuricemic patients with/without gout. The efficacy of 40 mg/d was superior to that of allopurinol 100 to 300 mg/d, and with dosage increases, the efficacy of febuxostat 80 and 120 mg/d was enhanced. The doses of allopurinol to which febuxostat has been compared, though commonly prescribed, are low in the range of approved doses of allopurinol. The tolerability of fe- buxostat for treatment of hyperuricemia with/without gout was similar to that of allopurinol. However, fe- buxostat has been used clinically for a relatively short time and clinical uses of febuxostat need further study, including: (1) whether febuxostat is superior to allo- purinol at a dose 300 mg/d; (2) the efficacy and tol- erability of febuxostat in patients with renal insuffi- ciency; and (3) the tolerability of long-term febuxostat (eg, cardiovascular events).

ACKNOWLEDGMENTS

Drs. Ye and Yang are co-first authors. Drs. Lv, Cheng and Mei made the search strategy and searched major electronic databases. Drs. Luo and Liu searched the websites and reviewed the references for unpublished studies. Drs. Ye, Yang and Zhang selected studies, as- sessed the methodological quality of each trial and ex- tracted data. Drs. Li and Chen reviewed/edited the manuscript.

CONFLICTS OF INTEREST

This research and its publication were supported by National Natural Science Foundation of China grant nos. 81170751 and 81200589. The authors have indi- cated that they have no other conflicts of interest with regard to the content of this article.

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Address correspondence to: Qifu Li, MD, PhD, Department of Endocrinol- ogy, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Street, Chongqing 400016, People’s Republic of China. E-mail:

liqifu@yeah.net

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