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Efficacy and Tolerability of Febuxostat in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis
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 review 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the European League Against Rheumatism, and the Chinese State Food and Drug Administration, and clinicaltrials.gov for unpublished studies. Only randomized, controlled trials (RCTs) were included. Results: Ten trials were included. A significantly greater proportion of patients achieved the target serum urate level (sUA ⱕ6.0 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 patients who achieved target sUA in the febuxostattreated 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 efficacious compared with allopurinol (100 –300 mg/d). The
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doses of allopurinol to which febuxostat has been compared, although commonly prescribed, are low in the range of approved doses of allopurinol. The tolerability 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, metaanalysis.
INTRODUCTION Gout is a common disease characterized by hyperuricemia 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 asymptomatic 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.6 – 8 The management of chronic gout is aimed at maintaining 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 reduction in the frequency of acute gout flares and tophi resolution.12–14 The most commonly employed approaches 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.
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P. Ye et al. urinary excretion of uric acid with a uricosuric agent. With regard to uric acid synthesis inhibitors, the purinelike XO inhibitor allopurinol has been widely used. Although a maximum dosage of 800 mg/d is recommended 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 patients 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 reductions in patients with impaired renal function.16,17 Allopurinol may occasionally induce severe or lifethreatening 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 hyperuricemia 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 pyrimidine-metabolizing enzymes,20,21 which indicates a potential for achieving a better urate-lowering effect. Febuxostat 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 impairment.2 Evidence on treatment outcomes and tolerability with febuxostat therapy have accumulated in randomized controlled trials (RCTs) over the past decade. The present meta-analysis and systematic review were conducted to assess the efficacy and tolerability 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, TMX67, and TEI-6720 in English and fei bu si ta in Chinese. The Web sites of the American College of Rheumatology, the European League Against Rheumatism, and the Chinese State Food and Drug Administration were
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also searched, as was clinicaltrials.gov, for unpublished 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 including studies in the present meta-analysis and review were as follows: patients were hyperuricemic (sUA ⱖ7.0 mg/dL) adults (aged ⱖ18 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 preliminary screening and full-text review. In the preliminary-screening stage, reviewers screened the titles, abstracts, and key words to exclude studies that failed to meet the criteria. The work was completed independently by 2 reviewers (P.Y. and W.Z.). When opinions differed, the differences were resolved by a third reviewer (S.Y.).
Quality Assessment and Data Extraction The methodological quality of each trial was assessed by criteria that were derived from the Cochrane Handbook23 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 levels: 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 confidence 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 intervention, proportion of subjects with sUA levels ⱕ6.0 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-extraction 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 2and I2 tests. When I2 ⬎ 50%, which
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Database search (n = 237) Manual search (n = 34) Excluded: nonclinical studies, reviews, duplication (n = 237) Potentially relevant studies identified by screening (n = 34) Excluded: non-RCTs, duplicate publication, data insufficiency (n = 24) RCTs included in meta-analysis and systematic review (n = 10)
Figure 1. Study selection flow chart.
was considered substantial heterogeneity,23 the random-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 significant. Sensitivity analyses were performed to determine the influence of each trial. We excluded individual 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 test24 and the Egger test.25
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 subjects (989 in the febuxostat group and 236 in the placebo 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 ⱕ6.0 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 (I2 ⫽ 0%; P ⫽ 0.76) (Figure 2A). Three trials21,32,33 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 indicates the superior urate-lowering effect of febuxostat compared with the placebo.
Febuxostat Versus Allopurinol 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 RCTs21,26 –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 hyperuricemic patients with/without gout, and most were obese male patients. Two trials27,29 enrolled a high proportion (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
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Seven trials21,27–31 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 ⱕ6.0 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 2B). Five trials21,27,28,30,31 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 allopurinol group (100 –300 mg/d), which had a range from ⫺32% to ⫺36.55%, which indicated a better uratelowering effect of febuxostat compared with that of allopurinol.
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Table I. Characteristics of included randomized controlled trials of febuxostat.* Baseline sUA, Mean (SD), mg/dL Study Becker et al (2005)26 Becker et al (2005)27
Schumacher et al (2008)21
Becker et al (2009)28 Becker et al (2010)29 Naoyuki et al (2011)30
Design
Patient Characteristics
Febuxostat
4-Wk, multicenter, Phase II, randomized, double-blind, parallel-group 52-Wk, multicenter, Phase III, randomized, double-blind, parallelgroup 28-Wk, multicenter, Phase III, randomized, double-blind, parallelgroup 172-Wk, multicenter, randomized, openlabel, parallel-group 26-Wk, multicenter, randomized, double-blind, parallel-group 16-Wk, multicenter, Phase II, randomized, open-label, parallel-group
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 54.0 (24.6) y Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.8 (12.1) y
9.72 (1.17) (n ⫽ 115) 9.82 (1.25) (n ⫽ 508)
9.87 (1.33) (Placebo; n ⫽ 38) 9.90 (1.23) (Allopurinol; n ⫽ 254)
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.6 (12.5) y
9.85 (1.26)† (n ⫽ 670)
9.85 (1.26)† (Allopurinol/placebo; n ⫽ 402)
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.2 (11.8) y Gout and sUA ⱖ8 mg/dL; mean (SD) age, 52.8 (11.7) y sUA ⱖ7 mg/dL with gout, ⱖ8 mg/dL with medication therapy for complications, or ⱖ9 mg/dL without complications; mean (SD) age, 52.3 (10.8) y sUA ⱖ8 mg/dL (including gout); mean (SD) age, 52.1 (13.5) y sUA ⱖ7 mg/dL with gout, ⱖ8 mg/dL with medication therapy for complications, or ⱖ9 mg/dL without complications; mean (SD) age, 52.7 (12.9) y sUA ⱖ8 mg/dL (including gout); mean (SD) age, 47.5 (13.9) y Gout with sUA ⱖ8 mg/dL; mean (SD) age, 47.4 (11.1) y
9.80 (1.26) (n ⫽ 941) 9.60 (1.18) (n ⫽ 1513) 8.56 (0.94) (n ⫽ 20)
9.82 (1.16) (Allopurinol; n ⫽ 145) 9.50 (1.19) (Allopurinol; n ⫽ 755) 8.34 (1.16) (Allopurinol; n ⫽ 20)
8.94 (1.06) (n ⫽ 122)
8.92 (0.87) (Allopurinol; n ⫽ 122)
8.79 (0.98) (n ⫽ 164)
8.84 (1.02) (Placebo; n ⫽ 38)
8.83 (0.72) (n ⫽ 69)
8.95 (0.99) (Placebo; n ⫽ 33)
9.37 (1.21) (n ⫽ 342)
9.50 (1.42) (Allopurinol; n ⫽ 171)
Kamatani et al (2011)31
8-Wk, Phase III, randomized, doubleblind, parallel-group
Naoyuki et al (2011)32
16-Wk, Phase II, multicenter, randomized, double-blind, parallelgroup
Naoyuki et al (2011)33
8-Wk, Phase III, multicenter, randomized, double-blind, parallelgroup 28-Wk, multicenter, randomized, double-blind, parallel-group
Fengchun Zhang et al (data on file, http:// www.sfda.gov.cn/WS01/ CL0001/)
Control
*All studies were quality rating A, except Becker et al (2009)28 and Naoyuki et al (2011)30 (both rating B). † Mean value in the overall study group; separate values by treatment group were not reported.
For further study, we performed a subgroup analysis of the efficacy between different dosages of febuxostat (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 (I2 ⫽ 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 ⱕ6.0 mg/dL at the final visit (OR ⫽ 1.25; 95% CI, 1.05–1.49; P ⫽ 0.01) (Figure 3A). 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 3C). Five trials reported the percentage change in sUA levels, which
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demonstrated that with increasing febuxostat dosages (40 mg/d,30,31 80 mg/d,21,27,28, and 120 mg/d21,27,28), 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 compared the prevalences of adverse events (AEs), including 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
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Clinical Therapeutics
A Study or Subgroup Becker (2005)26 Schumacher (2008)21 Kamatani (2011)32 Kamatani (2011)33 Total (95% CI)
Febuxostat Events Total 82 508 120 47
115 644 161 69 989
Placebo Events Total 0 1 1 0
Weight (%)
Odds Ratio M-H, Fixed, (95% CI)
18.1 189.63 (11.32–3176.57) 29.5 470.65 (65.19–3397.90) 24.4 108.29 (14.40–814.44) 18.1 141.44 (8.29–2413.94) 100.0 235.73 (75.39–737.08)
38 127 38 33 236
757 2 Total events Heterogeneity: χ2 = 1.19, df = 3 (P = 0.76); I2 = 0% Test for overall effect: z = 9.39 (P < 0.00001)
0.001 0.1 Favors placebo
B Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Becker (2010)29 Kamatani (2011)30 Kamatani (2011)31 Fengchun Zhang
Febuxostat Events Total 378 508 742 849 16 100 155
491 644 897 1513 20 122 307
Allopurinol Events Total
Weight (%)
Odds Ratio M-H, Fixed (95% CI)
242 263 139 755 20 120 157
15.6 15.7 15.4 16.3 7.9 13.8 15.3
5.85 (4.18–38.19) 5.90 (4.32–8.05) 5.61 (3.85–8.17) 1.76 (1.47–2.10) 3.27 (0.80–13.35) 1.95 (1.06–3.57) 1.37 (0.93–2.02)
1696
100.0
3.14 (1.82–5.44)
88 102 64 318 11 84 67
Odds Ratio M-H, Fixed (95% CI)
1
10 1000 Favors febuxostat
Odds Ratio M-H, Random (95% CI)
(data on file)
Total (95% CI) Total events
3994 2748
734
Heterogeneity: t2 = 0.47,χ2 = 94.79, df = 6 (P < 0.00001); I2 = 94% Test for overall effect: z = 4.09 (P < 0.0001)
0.01 0.1 1 10 100 Favors allopurinol Favors febuxostat
Figure 2. Forest plot-analysis of the efficacy of febuxostat versus (A) placebo and (B) allopurinol. Compared with the allopurinol and placebo groups, the proportion of patients who achieved sUA ⱕ6.0 mg/dL at the final visit was significantly higher in the febuxostat-treated group. *Data was extracted from the first month treatment before treatment was switched. Fixed ⫽ fixed-effects model; M.H. ⫽ MantelHaenszel method; Random ⫽ random-effects model.
trials (Table II) (data on file, http://www.sfda.gov.cn/ WS01/CL0001/).21,27–31 The results demonstrated no significant differences between the 2 groups, and heterogeneity was not apparent in any of the analyses.
Publication Bias Assessment Evidence of publication bias for studies that compared 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 function, fail to achieve target sUA levels with allopurinol because of the dose reduction in these patients. Moreover, 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-
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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 febuxostat and placebo treatments. Meta-analysis demonstrated 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. Febuxostat was further compared with allopurinol. In those included RCTs, 7 trials compared febuxostat with allopurinol. The pooled data from the 7 trials suggested that more patients achieved target sUA levels in the febuxostat-treated group compared with the allopurinol-treated group. Subgroup analysis demonstrated that, compared with the allopurinol 100 –300-mg/d group, the febuxostat 40-mg/d group had a higher proportion of patients who achieved target sUA. With the febuxostat dosage increased to 80 and 120 mg/d, both
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A Study or Subgroup Becker (2005)29 Kamatani (2011)30 Kamatani (2011)31 Fengchun Zhang
Febuxostat 40 mg Events Total 342 8 100 81
757 10 122 154
Odds Ratio M-H, Fixed (95% CI)
Allopurinol Events Total
Weight (%)
755 20 120 157
78.4 0.7 6.9 14.1
1.13 (0.92–1.39) 3.27 (0.55–19.45) 1.95 (1.06–3.57) 1.49 (0.95–2.33)
1052
100.0
1.25 (1.05–1.49)
318 11 84 67
Odds Ratio M-H, Fixed (95% CI)
(data on file)
1043
Total (95% CI)
531 480 Total events Heterogeneity: χ2 = 4.69, df = 3 (P = 0.20); I2 = 36% Test for overall effect: z = 2.52 (P = 0.01)
B Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Becker (2010)29 Fengchun Zhang
Febuxostat 80 mg Events Total 185 183 501 507 74
249 253 620 756 153
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
Allopurinol Events Total 88 102 64 318 67
Odds Ratio Weight (%) M-H, Random (95% CI)
242 263 139 755 157
19.7 19.9 19.6 22.2 18.6
5.06 (3.44–7.45) 4.13 (2.85–5.98) 4.93 (3.34–7.28) 2.80 (2.27–3.45) 1.26 (0.80–1.97)
1556
100.0
3.27 (2.14–5.00)
Odds Ratio M-H, Random (95% CI)
(data on file)
2031
Total (95% CI) Total events
1450
639
Heterogeneity: t2 = 0.20,χ2 = 30.24, df = 4 (P < 0.00001); I2 = 87% Test for overall effect: z = 5.47 (P < 0.00001)
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
C Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Total (95% CI)
Febuxostat 120 mg Events Total 193 209 241
242 265 277 784
Allopurinol Events Total
Weight (%)
242 263 139 644
35.3 42.8 21.9 100.0
88 102 64
643 254 Total events Heterogeneity: χ2 = 0.86, df = 2 (P = 0.65); I2 = 0% Test for overall effect: z = 15.33 (P < 0.00001)
Odds Ratio M-H, Fixed (95% CI)
Odds Ratio M-H, Fixed (95% CI)
6.89 (4.58–10.37) 5.89 (4.01–8.66) 7.85 (4.84–12.72) 6.67 (5.23–8.51)
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
Figure 3. Forest plot-analysis of the efficacy of febuxostat 40, 80, 120 mg/d versus allopurinol. (A) Compared with the allopurinol-treated group, patients treated with febuxostat 40mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. (B) Patients treated with febuxostat 80 mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. (C) Patients treated with febuxostat 40 mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. *Data was extracted from the first month treatment before treatment was switched. Fixed ⫽ fixed-effects model; M.H. ⫽ Mantel-Haenszel method; Random ⫽ random-effects model.
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 studies30 –33 (n ⫽ 588) included patients with hyperuricemia but not gout. Asymptomatic hyperuricemia does not typically require clinical treatment, and evidence of febuxostat in patients with simple hyperuricemia is insufficient. According to results mentioned earlier, the authors recommend an initial febuxostat dosage of 40 mg/d in gout patients with hyperuricemia,
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and if they fail to achieve target sUA levels, the febuxostat 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 tolerability of febuxostat in hyperuricemic women with/without gout. Finally, the authors could not perform a sexstratified subgroup analysis due to data limitations. Chohan et al34 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
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Table II. Tolerability of febuxostat versus allopurinol. No. (%) of AEs Parameter
No. of Included Studies
Total AEs
6
Serious AEs
4
Diarrhea
4
Headache
2
Elevated liver enzymes
6
Cardiovascular AE
3
Musculoskeletal and connective tissue AE Gastrointestinal AE
4
Joint-related AE
2
4
Heterogeneity
Overall Effect
Febuxostat
Allopurinol
P=
I2, %
OR (95% CI)
P
1672 (52.7) (n ⫽ 3174) 105 (3.5) (n ⫽ 3032) 164 (5.4) (n ⫽ 3032) 47 (4.0) (n ⫽ 1177) 193 (6.1) (n ⫽ 3174) 36 (1.4) (n ⫽ 2525) 168 (6.0) (n ⫽ 2812) 157 (9.6) (n ⫽ 1641) 55 (4.7) (n ⫽ 1177)
862 (54.2) (n ⫽ 1589) 58 (4.0) (n ⫽ 1448) 82 (5.7) (n ⫽ 1448) 27 (5.2) (n ⫽ 521) 97 (6.1) (n ⫽ 1589) 14 (1.2) (n ⫽ 1195) 72 (5.2) (n ⫽ 1398) 57 (7.0) (n ⫽ 813) 26 (5.0) (n ⫽ 521)
0.45
0
0.27
0.59
0
0.37
4
0.45
19
0.38
6
0.33
11
0.65
0
0.20
36
0.57
0
0.93 (0.82–1.06) 0.90 (0.62–1.20) 0.93 (0.71–1.23) 0.71 (0.44–1.17) 0.99 (0.77–1.27) 1.23 (0.66–2.29) 1.14 (0.86–1.52) 1.30 (0.94–1.80) 0.87 (0.54–1.41)
0.37 0.62 0.18 0.93 0.52 0.36 0.11 0.58
AE ⫽ adverse event; OR ⫽ odds ratio.
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-analysis enrolled some patients with impaired renal function (data on file, http://www.sfda.gov.cn/WS01/ CL0001/).21,27–29,31–33 However, only 1 trial performed a subgroup analysis of urate-lowering efficacy based on renal function. In this subgroup analysis, Becker et al29 found that 60.9% patients with mild or moderate renal impairment in the 40/80 mg/d febuxostat-treated group achieved the target sUA level compared with 42.3% in the 200/300mg/d allopurinoltreated 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-
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grees of renal impairment, an 80-mg/d dosage of febuxostat 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. However, 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 demonstrated that febuxostat and allopurinol shared similar prevalences of AEs, most of which were mild to moderate. 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 observed in the febuxostat-treated group were cardiovas-
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P. Ye et al. cular AEs,21,28,29 suggesting particular attention should be paid to the signs and symptoms of cardiovascular 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 trials27–29; these deaths were not considered to have been related to the study drug. These findings suggest that urate-lowering therapy with febuxostat and allopurinol 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 appreciably change the pooled OR, and the estimates in each case were within the confidence limits of the overall estimate. The present meta-analysis had several limitations. First, when the data were pooled, the 7 trials exhibited significant heterogeneity, which may have been associated with the differences in the characteristics of the included patients, drug dosages and time for intervention; therefore, the random-effects model was used for the meta-analysis. However, the random-effects model analysis also provided a reliable result, and the reasons are as follows: (1) 5 of the 7 studies included in this meta-analysis were A level in terms of methodological quality; (2) compared with the fixedeffect models, the random-effects model would increase 95% CIs (nonetheless, the results demonstrated a significant difference between febuxostat and allopurinol); and (3) further subgroup analysis, which reduced the heterogeneity, achieved similar results. Second, 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 commonly 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
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were granted by the pharmaceutical company of febuxostat, which may have caused potential publication 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 omitted 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 febuxostat for treatment of hyperuricemia with/without gout was similar to that of allopurinol. However, febuxostat has been used clinically for a relatively short time and clinical uses of febuxostat need further study, including: (1) whether febuxostat is superior to allopurinol at a dose ⬎300 mg/d; (2) the efficacy and tolerability of febuxostat in patients with renal insufficiency; 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, assessed the methodological quality of each trial and extracted 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 indicated that they have no other conflicts of interest with regard to the content of this article.
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International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65:1312–1324. Perez-Ruiz F, Calabozo M, Pijoan JI, et al. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum. 2002;47:356 –360. Sarawate CA, Patel PA, Schumacher HR, et al. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol. 2006;12: 61– 65. Shoji A, Yamanaka H, Kamatani N. A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy. Arthritis Rheum. 2004;51:321–325. Dalbeth N, Stamp L. Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events. Semin Dial. 2007;20:391–395. Terkeltaub R, Bushinsky DA, Becker MA. Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics. Arthritis Res Ther. 2006;8(Suppl 1):S4. Elion GB, Yu TF, Gutman AB, et al. Renal clearance of oxipurinol, the chief metabolite of allopurinol. Am J Med. 1968;45:69 –77. Arellano F, Sacristan JA. Allopurinol hypersensitivity syndrome: a review. Ann Pharmacother. 1993;27:337–343. Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984;76:47–56. Takano Y, Hase-Aoki K, Horiuchi H, et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 2005;76:1835–1847. Schumacher HR, Jr., Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with
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hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008;59:1540 –1548. (FDA) FaDA. ULORIC (febuxostat) tablet for oral use. http://www. accessdata.fda.gov/drugsatfda_docs/ label/2009/021856lbl.pdf. Accessed 2009. Higgins JPT, Green S. (The Cochrane Collaboration). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. www.cochranehandbook.org. Accessed March 2011. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088 –1101. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629 – 634. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eightday, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum. 2005;52:916 –923. Becker MA, Schumacher HR, Jr., Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:2450 –2461. Becker MA, Schumacher HR, MacDonald PA, et al. Clinical efficacy and safety of successful longterm urate lowering with febuxostat or allopurinol in subjects with gout. J Rheumatol. 2009;36:1273– 1282. Becker MA, Schumacher HR, Espinoza LR, et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther. 2010;12:R63. Naoyuki K, Shin F, Toshikazu H, et al. An allopurinol-controlled, multicenter, randomized, open-label, par-
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allel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. J Clin Rheumatol. 2011;17(4 Suppl 2):S44 –S49. Kamatani N, Fujimori S, Hada T, et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a nonpurine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011;17(Suppl 2):S13– S18. Naoyuki K, Shin F, Toshikazu H, et al. Placebo-controlled double-blind dose-response study of the nonpurine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol. 2011; 17(Suppl 2):S35–S43. Naoyuki K, Shin F, Toshikazu H, et al. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011; 17(Suppl 2):S19–S26. Chohan S, Becker MA, MacDonald PA, et al. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken). 2012;64:256 –261. Mayer MD, Khosravan R, Vernillet L, et al. Pharmacokinetics and pharmacodynamics of febuxostat, a new nonpurine selective inhibitor of xanthine oxidase in subjects with renal impairment. Am J Ther. 2005;12:22–34. Sarawate CA, Brewer KK, Yang W, et al. Gout medication treatment patterns and adherence to standards of care from a managed care perspective. Mayo ClinProc.2006;81:925–934.
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Address correspondence to: Qifu Li, MD, PhD, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Street, Chongqing 400016, People’s Republic of China. E-mail: [email protected]
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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 review 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 Rheumatism, and the Chinese State Food and Drug Administration, and clinicaltrials.gov for unpublished studies. Only randomized, controlled trials (RCTs) were included. Results: Ten trials were included. A significantly greater proportion of patients achieved the target serum urate level (sUA ⱕ6.0 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 patients who achieved target sUA in the febuxostattreated 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 efficacious compared with allopurinol (100 –300 mg/d). The
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doses of allopurinol to which febuxostat has been compared, although commonly prescribed, are low in the range of approved doses of allopurinol. The tolerability 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, metaanalysis.
INTRODUCTION Gout is a common disease characterized by hyperuricemia 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 asymptomatic 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.6 – 8 The management of chronic gout is aimed at maintaining 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 reduction in the frequency of acute gout flares and tophi resolution.12–14 The most commonly employed approaches 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.
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P. Ye et al. urinary excretion of uric acid with a uricosuric agent. With regard to uric acid synthesis inhibitors, the purinelike XO inhibitor allopurinol has been widely used. Although a maximum dosage of 800 mg/d is recommended 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 patients 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 reductions in patients with impaired renal function.16,17 Allopurinol may occasionally induce severe or lifethreatening 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 hyperuricemia 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 pyrimidine-metabolizing enzymes,20,21 which indicates a potential for achieving a better urate-lowering effect. Febuxostat 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 impairment.2 Evidence on treatment outcomes and tolerability with febuxostat therapy have accumulated in randomized controlled trials (RCTs) over the past decade. The present meta-analysis and systematic review were conducted to assess the efficacy and tolerability 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, TMX67, and TEI-6720 in English and fei bu si ta in Chinese. The Web sites of the American College of Rheumatology, the European League Against Rheumatism, and the Chinese State Food and Drug Administration were
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also searched, as was clinicaltrials.gov, for unpublished 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 including studies in the present meta-analysis and review were as follows: patients were hyperuricemic (sUA ⱖ7.0 mg/dL) adults (aged ⱖ18 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 preliminary screening and full-text review. In the preliminary-screening stage, reviewers screened the titles, abstracts, and key words to exclude studies that failed to meet the criteria. The work was completed independently by 2 reviewers (P.Y. and W.Z.). When opinions differed, the differences were resolved by a third reviewer (S.Y.).
Quality Assessment and Data Extraction The methodological quality of each trial was assessed by criteria that were derived from the Cochrane Handbook23 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 levels: 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 confidence 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 intervention, proportion of subjects with sUA levels ⱕ6.0 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-extraction 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 2and I2 tests. When I2 ⬎ 50%, which
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Clinical Therapeutics
Database search (n = 237) Manual search (n = 34) Excluded: nonclinical studies, reviews, duplication (n = 237) Potentially relevant studies identified by screening (n = 34) Excluded: non-RCTs, duplicate publication, data insufficiency (n = 24) RCTs included in meta-analysis and systematic review (n = 10)
Figure 1. Study selection flow chart.
was considered substantial heterogeneity,23 the random-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 significant. Sensitivity analyses were performed to determine the influence of each trial. We excluded individual 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 test24 and the Egger test.25
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 subjects (989 in the febuxostat group and 236 in the placebo 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 ⱕ6.0 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 (I2 ⫽ 0%; P ⫽ 0.76) (Figure 2A). Three trials21,32,33 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 indicates the superior urate-lowering effect of febuxostat compared with the placebo.
Febuxostat Versus Allopurinol 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 RCTs21,26 –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 hyperuricemic patients with/without gout, and most were obese male patients. Two trials27,29 enrolled a high proportion (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
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Seven trials21,27–31 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 ⱕ6.0 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 2B). Five trials21,27,28,30,31 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 allopurinol group (100 –300 mg/d), which had a range from ⫺32% to ⫺36.55%, which indicated a better uratelowering effect of febuxostat compared with that of allopurinol.
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Table I. Characteristics of included randomized controlled trials of febuxostat.* Baseline sUA, Mean (SD), mg/dL Study Becker et al (2005)26 Becker et al (2005)27
Schumacher et al (2008)21
Becker et al (2009)28 Becker et al (2010)29 Naoyuki et al (2011)30
Design
Patient Characteristics
Febuxostat
4-Wk, multicenter, Phase II, randomized, double-blind, parallel-group 52-Wk, multicenter, Phase III, randomized, double-blind, parallelgroup 28-Wk, multicenter, Phase III, randomized, double-blind, parallelgroup 172-Wk, multicenter, randomized, openlabel, parallel-group 26-Wk, multicenter, randomized, double-blind, parallel-group 16-Wk, multicenter, Phase II, randomized, open-label, parallel-group
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 54.0 (24.6) y Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.8 (12.1) y
9.72 (1.17) (n ⫽ 115) 9.82 (1.25) (n ⫽ 508)
9.87 (1.33) (Placebo; n ⫽ 38) 9.90 (1.23) (Allopurinol; n ⫽ 254)
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.6 (12.5) y
9.85 (1.26)† (n ⫽ 670)
9.85 (1.26)† (Allopurinol/placebo; n ⫽ 402)
Gout and sUA ⱖ8 mg/dL; mean (SD) age, 51.2 (11.8) y Gout and sUA ⱖ8 mg/dL; mean (SD) age, 52.8 (11.7) y sUA ⱖ7 mg/dL with gout, ⱖ8 mg/dL with medication therapy for complications, or ⱖ9 mg/dL without complications; mean (SD) age, 52.3 (10.8) y sUA ⱖ8 mg/dL (including gout); mean (SD) age, 52.1 (13.5) y sUA ⱖ7 mg/dL with gout, ⱖ8 mg/dL with medication therapy for complications, or ⱖ9 mg/dL without complications; mean (SD) age, 52.7 (12.9) y sUA ⱖ8 mg/dL (including gout); mean (SD) age, 47.5 (13.9) y Gout with sUA ⱖ8 mg/dL; mean (SD) age, 47.4 (11.1) y
9.80 (1.26) (n ⫽ 941) 9.60 (1.18) (n ⫽ 1513) 8.56 (0.94) (n ⫽ 20)
9.82 (1.16) (Allopurinol; n ⫽ 145) 9.50 (1.19) (Allopurinol; n ⫽ 755) 8.34 (1.16) (Allopurinol; n ⫽ 20)
8.94 (1.06) (n ⫽ 122)
8.92 (0.87) (Allopurinol; n ⫽ 122)
8.79 (0.98) (n ⫽ 164)
8.84 (1.02) (Placebo; n ⫽ 38)
8.83 (0.72) (n ⫽ 69)
8.95 (0.99) (Placebo; n ⫽ 33)
9.37 (1.21) (n ⫽ 342)
9.50 (1.42) (Allopurinol; n ⫽ 171)
Kamatani et al (2011)31
8-Wk, Phase III, randomized, doubleblind, parallel-group
Naoyuki et al (2011)32
16-Wk, Phase II, multicenter, randomized, double-blind, parallelgroup
Naoyuki et al (2011)33
8-Wk, Phase III, multicenter, randomized, double-blind, parallelgroup 28-Wk, multicenter, randomized, double-blind, parallel-group
Fengchun Zhang et al (data on file, http:// www.sfda.gov.cn/WS01/ CL0001/)
Control
*All studies were quality rating A, except Becker et al (2009)28 and Naoyuki et al (2011)30 (both rating B). † Mean value in the overall study group; separate values by treatment group were not reported.
For further study, we performed a subgroup analysis of the efficacy between different dosages of febuxostat (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 (I2 ⫽ 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 ⱕ6.0 mg/dL at the final visit (OR ⫽ 1.25; 95% CI, 1.05–1.49; P ⫽ 0.01) (Figure 3A). 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 3C). Five trials reported the percentage change in sUA levels, which
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demonstrated that with increasing febuxostat dosages (40 mg/d,30,31 80 mg/d,21,27,28, and 120 mg/d21,27,28), 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 compared the prevalences of adverse events (AEs), including 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
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Clinical Therapeutics
A Study or Subgroup Becker (2005)26 Schumacher (2008)21 Kamatani (2011)32 Kamatani (2011)33 Total (95% CI)
Febuxostat Events Total 82 508 120 47
115 644 161 69 989
Placebo Events Total 0 1 1 0
Weight (%)
Odds Ratio M-H, Fixed, (95% CI)
18.1 189.63 (11.32–3176.57) 29.5 470.65 (65.19–3397.90) 24.4 108.29 (14.40–814.44) 18.1 141.44 (8.29–2413.94) 100.0 235.73 (75.39–737.08)
38 127 38 33 236
757 2 Total events Heterogeneity: χ2 = 1.19, df = 3 (P = 0.76); I2 = 0% Test for overall effect: z = 9.39 (P < 0.00001)
0.001 0.1 Favors placebo
B Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Becker (2010)29 Kamatani (2011)30 Kamatani (2011)31 Fengchun Zhang
Febuxostat Events Total 378 508 742 849 16 100 155
491 644 897 1513 20 122 307
Allopurinol Events Total
Weight (%)
Odds Ratio M-H, Fixed (95% CI)
242 263 139 755 20 120 157
15.6 15.7 15.4 16.3 7.9 13.8 15.3
5.85 (4.18–38.19) 5.90 (4.32–8.05) 5.61 (3.85–8.17) 1.76 (1.47–2.10) 3.27 (0.80–13.35) 1.95 (1.06–3.57) 1.37 (0.93–2.02)
1696
100.0
3.14 (1.82–5.44)
88 102 64 318 11 84 67
Odds Ratio M-H, Fixed (95% CI)
1
10 1000 Favors febuxostat
Odds Ratio M-H, Random (95% CI)
(data on file)
Total (95% CI) Total events
3994 2748
734
Heterogeneity: t2 = 0.47,χ2 = 94.79, df = 6 (P < 0.00001); I2 = 94% Test for overall effect: z = 4.09 (P < 0.0001)
0.01 0.1 1 10 100 Favors allopurinol Favors febuxostat
Figure 2. Forest plot-analysis of the efficacy of febuxostat versus (A) placebo and (B) allopurinol. Compared with the allopurinol and placebo groups, the proportion of patients who achieved sUA ⱕ6.0 mg/dL at the final visit was significantly higher in the febuxostat-treated group. *Data was extracted from the first month treatment before treatment was switched. Fixed ⫽ fixed-effects model; M.H. ⫽ MantelHaenszel method; Random ⫽ random-effects model.
trials (Table II) (data on file, http://www.sfda.gov.cn/ WS01/CL0001/).21,27–31 The results demonstrated no significant differences between the 2 groups, and heterogeneity was not apparent in any of the analyses.
Publication Bias Assessment Evidence of publication bias for studies that compared 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 function, fail to achieve target sUA levels with allopurinol because of the dose reduction in these patients. Moreover, 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-
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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 febuxostat and placebo treatments. Meta-analysis demonstrated 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. Febuxostat was further compared with allopurinol. In those included RCTs, 7 trials compared febuxostat with allopurinol. The pooled data from the 7 trials suggested that more patients achieved target sUA levels in the febuxostat-treated group compared with the allopurinol-treated group. Subgroup analysis demonstrated that, compared with the allopurinol 100 –300-mg/d group, the febuxostat 40-mg/d group had a higher proportion of patients who achieved target sUA. With the febuxostat dosage increased to 80 and 120 mg/d, both
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P. Ye et al.
A Study or Subgroup Becker (2005)29 Kamatani (2011)30 Kamatani (2011)31 Fengchun Zhang
Febuxostat 40 mg Events Total 342 8 100 81
757 10 122 154
Odds Ratio M-H, Fixed (95% CI)
Allopurinol Events Total
Weight (%)
755 20 120 157
78.4 0.7 6.9 14.1
1.13 (0.92–1.39) 3.27 (0.55–19.45) 1.95 (1.06–3.57) 1.49 (0.95–2.33)
1052
100.0
1.25 (1.05–1.49)
318 11 84 67
Odds Ratio M-H, Fixed (95% CI)
(data on file)
1043
Total (95% CI)
531 480 Total events Heterogeneity: χ2 = 4.69, df = 3 (P = 0.20); I2 = 36% Test for overall effect: z = 2.52 (P = 0.01)
B Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Becker (2010)29 Fengchun Zhang
Febuxostat 80 mg Events Total 185 183 501 507 74
249 253 620 756 153
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
Allopurinol Events Total 88 102 64 318 67
Odds Ratio Weight (%) M-H, Random (95% CI)
242 263 139 755 157
19.7 19.9 19.6 22.2 18.6
5.06 (3.44–7.45) 4.13 (2.85–5.98) 4.93 (3.34–7.28) 2.80 (2.27–3.45) 1.26 (0.80–1.97)
1556
100.0
3.27 (2.14–5.00)
Odds Ratio M-H, Random (95% CI)
(data on file)
2031
Total (95% CI) Total events
1450
639
Heterogeneity: t2 = 0.20,χ2 = 30.24, df = 4 (P < 0.00001); I2 = 87% Test for overall effect: z = 5.47 (P < 0.00001)
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
C Study or Subgroup Becker (2005)27 Schumacher (2008)21 Becker (2009)*28 Total (95% CI)
Febuxostat 120 mg Events Total 193 209 241
242 265 277 784
Allopurinol Events Total
Weight (%)
242 263 139 644
35.3 42.8 21.9 100.0
88 102 64
643 254 Total events Heterogeneity: χ2 = 0.86, df = 2 (P = 0.65); I2 = 0% Test for overall effect: z = 15.33 (P < 0.00001)
Odds Ratio M-H, Fixed (95% CI)
Odds Ratio M-H, Fixed (95% CI)
6.89 (4.58–10.37) 5.89 (4.01–8.66) 7.85 (4.84–12.72) 6.67 (5.23–8.51)
0.05 0.2 1 5 20 Favors allopurinol Favors febuxostat
Figure 3. Forest plot-analysis of the efficacy of febuxostat 40, 80, 120 mg/d versus allopurinol. (A) Compared with the allopurinol-treated group, patients treated with febuxostat 40mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. (B) Patients treated with febuxostat 80 mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. (C) Patients treated with febuxostat 40 mg/d had a greater proportion of achieving targeted sUA level ⱕ6.0 mg/dL. *Data was extracted from the first month treatment before treatment was switched. Fixed ⫽ fixed-effects model; M.H. ⫽ Mantel-Haenszel method; Random ⫽ random-effects model.
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 studies30 –33 (n ⫽ 588) included patients with hyperuricemia but not gout. Asymptomatic hyperuricemia does not typically require clinical treatment, and evidence of febuxostat in patients with simple hyperuricemia is insufficient. According to results mentioned earlier, the authors recommend an initial febuxostat dosage of 40 mg/d in gout patients with hyperuricemia,
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and if they fail to achieve target sUA levels, the febuxostat 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 tolerability of febuxostat in hyperuricemic women with/without gout. Finally, the authors could not perform a sexstratified subgroup analysis due to data limitations. Chohan et al34 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
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Clinical Therapeutics
Table II. Tolerability of febuxostat versus allopurinol. No. (%) of AEs Parameter
No. of Included Studies
Total AEs
6
Serious AEs
4
Diarrhea
4
Headache
2
Elevated liver enzymes
6
Cardiovascular AE
3
Musculoskeletal and connective tissue AE Gastrointestinal AE
4
Joint-related AE
2
4
Heterogeneity
Overall Effect
Febuxostat
Allopurinol
P=
I2, %
OR (95% CI)
P
1672 (52.7) (n ⫽ 3174) 105 (3.5) (n ⫽ 3032) 164 (5.4) (n ⫽ 3032) 47 (4.0) (n ⫽ 1177) 193 (6.1) (n ⫽ 3174) 36 (1.4) (n ⫽ 2525) 168 (6.0) (n ⫽ 2812) 157 (9.6) (n ⫽ 1641) 55 (4.7) (n ⫽ 1177)
862 (54.2) (n ⫽ 1589) 58 (4.0) (n ⫽ 1448) 82 (5.7) (n ⫽ 1448) 27 (5.2) (n ⫽ 521) 97 (6.1) (n ⫽ 1589) 14 (1.2) (n ⫽ 1195) 72 (5.2) (n ⫽ 1398) 57 (7.0) (n ⫽ 813) 26 (5.0) (n ⫽ 521)
0.45
0
0.27
0.59
0
0.37
4
0.45
19
0.38
6
0.33
11
0.65
0
0.20
36
0.57
0
0.93 (0.82–1.06) 0.90 (0.62–1.20) 0.93 (0.71–1.23) 0.71 (0.44–1.17) 0.99 (0.77–1.27) 1.23 (0.66–2.29) 1.14 (0.86–1.52) 1.30 (0.94–1.80) 0.87 (0.54–1.41)
0.37 0.62 0.18 0.93 0.52 0.36 0.11 0.58
AE ⫽ adverse event; OR ⫽ odds ratio.
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-analysis enrolled some patients with impaired renal function (data on file, http://www.sfda.gov.cn/WS01/ CL0001/).21,27–29,31–33 However, only 1 trial performed a subgroup analysis of urate-lowering efficacy based on renal function. In this subgroup analysis, Becker et al29 found that 60.9% patients with mild or moderate renal impairment in the 40/80 mg/d febuxostat-treated group achieved the target sUA level compared with 42.3% in the 200/300mg/d allopurinoltreated 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-
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grees of renal impairment, an 80-mg/d dosage of febuxostat 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. However, 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 demonstrated that febuxostat and allopurinol shared similar prevalences of AEs, most of which were mild to moderate. 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 observed in the febuxostat-treated group were cardiovas-
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P. Ye et al. cular AEs,21,28,29 suggesting particular attention should be paid to the signs and symptoms of cardiovascular 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 trials27–29; these deaths were not considered to have been related to the study drug. These findings suggest that urate-lowering therapy with febuxostat and allopurinol 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 appreciably change the pooled OR, and the estimates in each case were within the confidence limits of the overall estimate. The present meta-analysis had several limitations. First, when the data were pooled, the 7 trials exhibited significant heterogeneity, which may have been associated with the differences in the characteristics of the included patients, drug dosages and time for intervention; therefore, the random-effects model was used for the meta-analysis. However, the random-effects model analysis also provided a reliable result, and the reasons are as follows: (1) 5 of the 7 studies included in this meta-analysis were A level in terms of methodological quality; (2) compared with the fixedeffect models, the random-effects model would increase 95% CIs (nonetheless, the results demonstrated a significant difference between febuxostat and allopurinol); and (3) further subgroup analysis, which reduced the heterogeneity, achieved similar results. Second, 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 commonly 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
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were granted by the pharmaceutical company of febuxostat, which may have caused potential publication 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 omitted 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 febuxostat for treatment of hyperuricemia with/without gout was similar to that of allopurinol. However, febuxostat has been used clinically for a relatively short time and clinical uses of febuxostat need further study, including: (1) whether febuxostat is superior to allopurinol at a dose ⬎300 mg/d; (2) the efficacy and tolerability of febuxostat in patients with renal insufficiency; 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, assessed the methodological quality of each trial and extracted 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 indicated 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 Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No.1 Youyi Street, Chongqing 400016, People’s Republic of China. E-mail: [email protected]
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