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,
Peoples 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the European League Against Rheumatism, and the Chinese State Food and Drug Administration, and clinicaltrials.gov for unpublished studies.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 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, 1.051.49; 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

180

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;35:180189) 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.1214 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.

Volume 35 Number 2

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

February 2013

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
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 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 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-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 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 (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

182

Seven trials21,2731 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, 1.825.44; 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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P. Ye et al.

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 8 mg/dL;

mean (SD) age, 54.0 (24.6) y
Gout and sUA 8 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 8 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 8 mg/dL;

mean (SD) age, 51.2 (11.8) y
Gout and sUA 8 mg/dL;
mean (SD) age, 52.8 (11.7) y
sUA 7 mg/dL with gout,
8 mg/dL with medication
therapy for complications, or
9 mg/dL without
complications;
mean (SD) age, 52.3 (10.8) y
sUA 8 mg/dL (including
gout);
mean (SD) age, 52.1 (13.5) y
sUA 7 mg/dL with gout,
8 mg/dL with medication
therapy for complications, or
9 mg/dL without
complications;
mean (SD) age, 52.7 (12.9) y
sUA 8 mg/dL (including
gout);
mean (SD) age, 47.5 (13.9) y
Gout with sUA 8 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 6.0 mg/dL at the final visit (OR 1.25;
95% CI, 1.051.49; 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

February 2013

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 (11.323176.57)

29.5 470.65 (65.193397.90)
24.4 108.29 (14.40814.44)
18.1 141.44 (8.292413.94)
100.0 235.73 (75.39737.08)

38
127
38
33
236

757
2
Total events
Heterogeneity: 2 = 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 (4.1838.19)
5.90 (4.328.05)
5.61 (3.858.17)
1.76 (1.472.10)
3.27 (0.8013.35)
1.95 (1.063.57)
1.37 (0.932.02)

1696

100.0

3.14 (1.825.44)

88
102
64
318
11
84
67

Odds Ratio
M-H, Fixed (95% CI)

10
1000
Favors febuxostat

Odds Ratio
M-H, Random (95% CI)

(data on file)

Total (95% CI)

Total events

3994
2748

734

Heterogeneity: t2 = 0.47,2 = 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 6.0 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/).21,2731 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-

184

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

Volume 35 Number 2

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 (0.921.39)
3.27 (0.5519.45)
1.95 (1.063.57)
1.49 (0.952.33)

1052

100.0

1.25 (1.051.49)

318
11
84
67

Odds Ratio
M-H, Fixed (95% CI)

(data on file)

1043

Total (95% CI)

531
480
Total events
Heterogeneity: 2 = 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 (3.447.45)
4.13 (2.855.98)
4.93 (3.347.28)
2.80 (2.273.45)
1.26 (0.801.97)

1556

100.0

3.27 (2.145.00)

Odds Ratio
M-H, Random (95% CI)

(data on file)

2031

Total (95% CI)

Total events

1450

639

Heterogeneity: t2 = 0.20,2 = 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: 2 = 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 (4.5810.37)
5.89 (4.018.66)
7.85 (4.8412.72)
6.67 (5.238.51)

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 6.0 mg/dL. (B) Patients treated with febuxostat 80 mg/d had a
greater proportion of achieving targeted sUA level 6.0 mg/dL. (C) Patients treated with febuxostat
40 mg/d had a greater proportion of achieving targeted sUA level 6.0 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,

February 2013

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

Serious AEs

Diarrhea

Headache

Elevated liver enzymes

Cardiovascular AE

Musculoskeletal and
connective tissue AE
Gastrointestinal AE

Joint-related AE

Heterogeneity

Overall Effect

Febuxostat

Allopurinol

P=

I2, %

OR (95% CI)

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

0.27

0.59

0.37

0.45

19

0.38

0.33

11

0.65

0.20

36

0.57

0.93
(0.821.06)
0.90
(0.621.20)
0.93
(0.711.23)
0.71
(0.441.17)
0.99
(0.771.27)
1.23
(0.662.29)
1.14
(0.861.52)
1.30
(0.941.80)
0.87
(0.541.41)

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/).21,2729,3133 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-

186

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
trials2729; 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

February 2013

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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February 2013

Address correspondence to: Qifu Li, MD, PhD, Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, No.1
Youyi Street, Chongqing 400016, Peoples Republic of China. E-mail:
liqifu@yeah.net

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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.