Comparative Efficacy and Safety of Febuxostat and Allopurinol in the Treatment of Hyperuricemia: A Bayesian Network Meta-analysis

Gwan Gyu Song; Young Ho Lee

doi:10.4078/jrd.2015.22.6.356

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Song and Lee: Comparative Efficacy and Safety of Febuxostat and Allopurinol in the Treatment of Hyperuricemia: A Bayesian Network Meta-analysis

Original Article

J Rheum Dis 2015;22(6):356-365.

Published online: 31 October 2015

DOI: https://doi.org/10.4078/jrd.2015.22.6.356

Comparative Efficacy and Safety of Febuxostat and Allopurinol in the Treatment of Hyperuricemia: A Bayesian Network Meta-analysis

Gwan Gyu Song, Young Ho Lee

Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, Seoul, Korea

Corresponding to: Young Ho Lee, Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail: lyhcgh@korea.ac.kr

Received 8 June 2015 Revised 3 July 2015 Accepted 6 July NaN

This is a Free Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

The aim of this study was to assess the relative urate-lowering efficacy and safety of febuxostat and allopurinol in hyperuricemic patients with or without gout.

Methods

Randomized controlled trials (RCTs) examining the efficacy and safety of febuxostat compared to allopurinol or placebo in hyperuricemic patients with/without gout were included in this Bayesian network meta-analysis.

Results

Eight RCTs including 4,099 patients met the inclusion criteria. The number of subjects achieving a serum urate (sUA) level ＜6.0 mg/dL was significantly higher in the febuxostat 120 mg and 80 mg groups than in the allopurinol (100 to 300 mg) group (odds ratio [OR] 7.17, 95% credible interval [CrI] 3.86 to 14.09; OR 3.49, 95% CrI 1.97 to 5.91, respectively). However, achievement of the target sUA level was comparable between febuxostat 40 mg and allopurinol. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that febuxostat 120 mg had the highest probability of being the best treatment for achieving the target sUA (SUCRA=0.9973), followed by febuxostat 80 mg (SUCRA=0.752), febuxostat 40 mg (SUCRA=0.4289), allopurinol (SUCRA=0.3217), and placebo (SUCRA=0). In contrast, no significant difference in safety based on the number of withdrawals due to adverse events was observed among the 5 interventions.

Conclusion

Febuxostat 80 mg and 120 mg were more efficacious than allopurinol (100 to 300 mg), and febuxostat 40 mg and allopurinol were comparable in urate-lowering efficacy. The safety of febuxostat at all doses was comparable with that of allopurinol.

Keywords: Febuxostat, Allopurinol, Gout, Meta-analysis

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Figure 1.

Evidence network diagram of network meta-analysis comparisons. The width of each edge is proportional to the number of randomized controlled trials comparing each pair of treatments, and the size of each treatment node is proportional to the number of randomized participants (sample size).(A) Febuxostat 40 mg. (B) Febuxostat 80 mg. (C) Febuxostat 120 mg. (D) Allopurinol. (E) Placebo.

Figure 2.

League tables showing the results of the network metaanalyses comparing the effects of all drugs including odds ratio (OR) and 95% credible intervals. (A) Efficacy; OR ＞1 means the top-left treatment is better. (B) Safety; OR ＜1 means the top-left treatment is better.

Figure 3.

Bayesian network meta-analysis results of randomized controlled studies on the relative efficacy (A) and safety (B) of febuxostat, allopurinol, and placebo, respectively. CrI: credible interval, OR: odds ratio.

Figure 4.

Inconsistency plots for efficacy (A) and safety (B) of febuxostat, allopurinol, and placebo. Plot of the posterior mean deviance contribution of individual data points for the consistency model (horizontal axis) and the unrelated mean effects model (vertical axis), along with the line of equality.

Table 1.

Characteristics of individual studies included in the meta-analysis and systematic review

Study	Country	Patient number	Hyperuricemia (mg/dL)	Gout (%)	Daily dose (number)	Follow-up period (wk)	Jadad score
Becker et al., 2005 [8]	USA	153	＞8	100	Febuxostat 40 mg (37), febuxostat 80 mg (40), febuxostat 120 mg (38), placebo (38)	4	3
Becker et al., 2005 (FACT) [9]	USA	760	＞8	100	Febuxostat 80 mg (256), febuxostat 120 mg (251), allopurinol 300 mg (253)	52	4
Schumacher et al., 2008 (APEX) [10]	USA	804	＞8	100	Febuxostat 80 mg (267), febuxostat 120 mg (269), allopurinol 300 mg (268)	28	3
Becker et al., 2010 (CONFIRMS) [11]	USA	1,768	＞8	100	Febuxostat 40 mg (757), febuxostat 80 mg (756), allopurinol 200/300 mg (255)	26	5
Kamatani et al., 2011 [12]	Japan	244	＞8	46	Febuxostat 40 mg (122), allopurinol 100 mg (122)	8	3
Kamatani et al., 2011 [13]	Japan	121	＞7	57	Febuxostat 40 mg (41), febuxostat 80 mg (42), placebo (38)	16	3
Kamatani et al., 2011 [14]	Japan	67	＞8	49	Febuxostat 40 mg (34), placebo (33)	8	3
Park et al., 2013 [15]	Korea	182	＞8	100	Febuxostat 40 mg (36), febuxostat 80 mg (36), febuxostat 120 mg (36), allopurinol 300 mg (37), placebo (37)	4	3

APEX: allopurinol- and placebo-controlled, efficacy study of febuxostat trial, COMFIRMS: the urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial, FACT: febuxostat versus allopurinol controlled trial, NA: not available.

Table 2.

Characteristics of direct comparison

Comparison	Study number	Patient number
Febuxostat 40 mg vs. febuxostat 80 mg	4	1,449
Febuxostat 40 mg vs. febuxostat 120 mg	2	143
Febuxostat 40 mg vs. placebo	4	284
Febuxostat 80 mg vs. febuxostat 120 mg	4	998
Febuxostat 80 mg vs. placebo	4	479
Febuxostat 120 mg vs. placebo	3	432
Febuxostat 80 mg vs. allopurinol	4	2,164
Febuxostat 120 mg vs. allopurinol	3	969
Allopurinol vs. placebo	2	380
Febuxostat 40 mg vs. allopurinol	3	1,559

Table 3.

Rank probability of febuxostat, allopurinol, and placebo^*

Treatment	SUCRA
Treatment	Efficacy	Safety
Febuxostat 120 mg	0.9973	0.1819
Febuxostat 80 mg	0.7520	0.3342
Febuxostat 40 mg	0.4289	0.8484
Allopurinol	0.3217	0.4352
Placebo	0	0.7002
SUCRA, surface under	r the cumulativ	e ranking curve.

^* Efficacy based on the number of patients achieving a serum urate level of less than 6.0 mg/dL and safety based on the number of withdrawals due to adverse events.

Table 4.

Sensitivity analysis of the network meta-analysis comparing the random- and fixed-effects models

Comparison	Random-effects model		Fixed-effects model
Comparison	OR	95% CrI	OR	95% CrI
Efficacy
Febuxostat 40 mg vs. allopurinol	1.16	0.62∼2.06	1.22	1.00∼1.47
Febuxostat 120 mg vs. febuxostat 80 mg	2.06	1.16∼4.12	1.89	1.46∼2.45
Febuxostat 80 mg vs. febuxostat 40 mg	3.01	1.66∼5.52	2.78	2.26∼3.41
Febuxostat 80 mg vs. allopurinol	3.49	1.97∼5.91	3.37	2.83∼4.03
Febuxostat 120 mg vs. febuxostat 40 mg	6.22	3.16∼13.62	5.24	3.91∼7.10
Febuxostat 120 mg vs. allopurinol	7.17	3.86∼14.09	6.37	4.92∼8.29
Allopurinol vs. placebo	319.39	76.45∼2,501.25	313.87	82.99∼2,304.15
Febuxostat 40 mg vs. placebo	367.65	90.66∼2,806.62	381.24	101.31∼2,794.08
Febuxostat 80 mg vs. placebo	1,109.63	268.89∼8,382.23	1,054.30	281.45∼7,800.31
Febuxostat 120 mg vs. placebo	2,327.75	539.96∼18,986.14	2,000.80	525.76∼14,947.68
Safety
Placebo vs. febuxostat 120 mg	0.50	0.14∼1.17	0.54	0.23∼1.15
Febuxostat 40 mg vs. febuxostat 120 mg	0.57	0.20∼1.75	0.56	0.34∼0.95
Placebo vs. febuxostat 80 mg	0.59	0.17∼1.17	0.68	0.29∼1.42
Placebo vs. allopurinol	0.65	0.17∼1.27	0.71	0.30∼1.50
Febuxostat 40 mg vs. febuxostat 80 mg	0.66	0.23∼1.83	0.71	0.49∼1.01
Febuxostat 40 mg vs. allopurinol	0.72	0.24∼2.03	0.74	0.51∼1.06
Allopurinol vs. febuxostat 120 mg	0.78	0.37∼1.96	0.76	0.50∼1.18
Febuxostat 80 mg vs. febuxostat 120 mg	0.85	0.42∼1.98	0.80	0.52∼1.23
Allopurinol vs. febuxostat 80 mg	0.86	0.21∼2.54	0.96	0.71∼1.28
Febuxostat 40 mg vs. placebo	0.92	0.46∼1.90	1.05	0.47∼2.52

CrI: credible interval, OR: odds ratio.

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