Cochrane Database of Systematic Reviews (Reviews) || Allopurinol for chronic gout

Allopurinol for chronic gout (Review)

Seth R, Kydd ASR, Buchbinder R, Bombardier C, Edwards CJ

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2014, Issue 10

http://www.thecochranelibrary.com

Allopurinol for chronic gout (Review)

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

7BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

22ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

29DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

36CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Allopurinol versus placebo, Outcome 1 Acute gout attacks. . . . . . . . . . . 58

Analysis 1.2. Comparison 1 Allopurinol versus placebo, Outcome 2 Proportion achieving target serum urate. . . . 59

Analysis 1.3. Comparison 1 Allopurinol versus placebo, Outcome 3 Withdrawal due to adverse events. . . . . . 60

Analysis 1.4. Comparison 1 Allopurinol versus placebo, Outcome 4 Total adverse events. . . . . . . . . . . 60

Analysis 1.5. Comparison 1 Allopurinol versus placebo, Outcome 5 Serious adverse events. . . . . . . . . . 61

Analysis 2.1. Comparison 2 Allopurinol plus colchicine versus colchicine alone, Outcome 1 Acute gout attack frequency. 61

Analysis 3.1. Comparison 3 Allopurinol versus febuxostat, Outcome 1 Acute gout attacks. . . . . . . . . . 62

Analysis 3.2. Comparison 3 Allopurinol versus febuxostat, Outcome 2 Proportion achieving target serum urate (6-12

months). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 3.3. Comparison 3 Allopurinol versus febuxostat, Outcome 3 Withdrawals due to adverse events. . . . . 64

Analysis 3.4. Comparison 3 Allopurinol versus febuxostat, Outcome 4 Total adverse events. . . . . . . . . . 65

Analysis 3.5. Comparison 3 Allopurinol versus febuxostat, Outcome 5 Serious adverse events. . . . . . . . . 67

Analysis 4.1. Comparison 4 Allopurinol versus benzbromarone, Outcome 1 Acute gout attacks. . . . . . . . . 68

Analysis 4.2. Comparison 4 Allopurinol versus benzbromarone, Outcome 2 Proportion achieving target serum urate. 68

Analysis 4.3. Comparison 4 Allopurinol versus benzbromarone, Outcome 3 Withdrawal due to adverse events. . . 69

Analysis 4.4. Comparison 4 Allopurinol versus benzbromarone, Outcome 4 Total adverse effects. . . . . . . . 69

Analysis 5.1. Comparison 5 Allopurinol: continuous versus intermittent, Outcome 1 Acute gout attacks. . . . . 70

70APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

80HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

81DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

82NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iAllopurinol for chronic gout (Review)


[Intervention Review]

Allopurinol for chronic gout

Rakhi Seth1, Alison SR Kydd2, Rachelle Buchbinder3 , Claire Bombardier4 , Christopher J Edwards1

1Department of Rheumatology, University Hospital Southampton NHS Foundation Trust, Southampton, UK. 2Division of Rheuma-

tology, University of British Columbia, Nanaimo, Canada. 3Monash Department of Clinical Epidemiology, Cabrini Hospital, De-

partment of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Malvern,

Australia. 4Institute for Work & Health, Toronto, Canada

Contact address: Rakhi Seth, Department of Rheumatology, University Hospital Southampton NHS Foundation Trust, Southampton,

UK. [email protected].

Editorial group: Cochrane Musculoskeletal Group.

Publication status and date: New, published in Issue 10, 2014.

Review content assessed as up-to-date: 14 January 2014.

Citation: Seth R, Kydd ASR, Buchbinder R, Bombardier C, Edwards CJ. Allopurinol for chronic gout. Cochrane Database of SystematicReviews 2014, Issue 10. Art. No.: CD006077. DOI: 10.1002/14651858.CD006077.pub3.


A B S T R A C T

Background

Allopurinol, a xanthine oxidase inhibitor, is considered one of the most effective urate-lowering drugs and is frequently used in the

treatment of chronic gout.

Objectives

To assess the efficacy and safety of allopurinol compared with placebo and other urate-lowering therapies for treating chronic gout.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE on 14 January 2014. We

also handsearched the 2011 to 2012 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR)

abstracts, trial registers and regulatory agency drug safety databases.

Selection criteria

All randomised controlled trials (RCTs) or quasi-randomised controlled clinical trials (CCTs) that compared allopurinol with a placebo

or an active therapy in adults with chronic gout.

Data collection and analysis

We extracted and analysed data using standard methods for Cochrane reviews. The major outcomes of interest were frequency of acute

gout attacks, serum urate normalisation, pain, function, tophus regression, study participant withdrawal due to adverse events (AE)

and serious adverse events (SAE). We assessed the quality of the body of evidence for these outcomes using the GRADE approach.

Main results

We included 11 trials (4531 participants) that compared allopurinol (various doses) with placebo (two trials); febuxostat (four trials);

benzbromarone (two trials); colchicine (one trial); probenecid (one trial); continuous versus intermittent allopurinol (one trial) and

different doses of allopurinol (one trial). Only one trial was at low risk of bias in all domains. We deemed allopurinol versus placebo

the main comparison, and allopurinol versus febuxostat and versus benzbromarone as the most clinically relevant active comparisons

and restricted reporting to these comparisons here.

1Allopurinol for chronic gout (Review)


mailto:[email protected]

Moderate-quality evidence from one trial (57 participants) indicated allopurinol 300 mg daily probably does not reduce the rate of gout

attacks (2/26 with allopurinol versus 3/25 with placebo; risk ratio (RR) 0.64, 95% confidence interval (CI) 0.12 to 3.52) but increases

the proportion of participants achieving a target serum urate over 30 days (25/26 with allopurinol versus 0/25 with placebo, RR 49.11,

95% CI 3.15 to 765.58; number needed to treat for an additional beneficial outcome (NNTB) 1). In two studies (453 participants),

there was no significant increase in withdrawals due to AE (6% with allopurinol versus 4% with placebo, RR 1.36, 95% CI 0.61 to

3.08) or SAE (2% with allopurinol versus 1% with placebo, RR 1.93, 95% CI 0.48 to 7.80). One trial reported no difference in pain

reduction or tophus regression, but did not report outcome data or measures of variance sufficiently and we could not calculate the

differences between groups. Neither trial reported function.

Low-quality evidence from three trials (1136 participants) indicated there may be no difference in the incidence of acute gout attacks

with allopurinol up to 300 mg daily versus febuxostat 80 mg daily over eight to 24 weeks (21% with allopurinol versus 23% with

febuxostat, RR 0.89, 95% CI 0.71 to 1.1); however more participants may achieve target serum urate level (four trials; 2618 participants)

with febuxostat 80 mg daily versus allopurinol 300 mg daily (38% with allopurinol versus 70% with febuxostat, RR 0.56, 95% CI

0.48 to 0.65, NNTB with febuxostat 4). Two trials reported no difference in tophus regression between allopurinol and febuxostat

over a 28- to 52-week period; but as the trialists did not provide variance, we could not calculate the mean difference between groups.

The trials did not report pain reduction or function. Moderate-quality evidence from pooled data from three trials (2555 participants)

comparing allopurinol up to 300 mg daily versus febuxostat 80 mg daily indicated no difference in the number of withdrawals due to

AE (7% with allopurinol versus 8% with febuxostat, RR 0.89, 95% CI 0.62 to 1.26) or SAE (4% with allopurinol versus 4% with

febuxostat, RR 1.13, 95% CI 0.71 to 1.82) over a 24- to 52-week period.

Low-quality evidence from one trial (65 participants) indicated there may be no difference in the incidence of acute gout attacks with

allopurinol up to 600 mg daily compared with benzbromarone up to 200 mg daily over a four-month period (0/30 with allopurinol

versus 1/25 with benzbromarone, RR 0.28, 95% CI 0.01 to 6.58). Based on the pooled results of two trials (102 participants), there

was moderate-quality evidence of no probable difference in the proportion of participants achieving a target serum urate level with

allopurinol versus benzbromarone (58% with allopurinol versus 74% with benzbromarone, RR 0.79, 95% CI 0.56 to 1.11). Low-

quality evidence from two studies indicated there may be no difference in the number of participants who withdrew due to AE with

allopurinol versus benzbromarone over a four- to nine-month period (6% with allopurinol versus 7% with benzbromarone, pooled RR

0.80, 95% CI 0.18 to 3.58). There were no SAEs. They did not report tophi regression, pain and function.

All other comparisons were supported by small, single studies only, limiting conclusions.

Authors’ conclusions

Our review found low- to moderate-quality evidence indicating similar effects on withdrawals due to AEs and SAEs and incidence

of acute gout attacks when allopurinol (100 to 600 mg daily) was compared with placebo, benzbromarone (100 to 200 mg daily) or

febuxostat (80 mg daily). There was moderate-quality evidence of little or no difference in the proportion of participants achieving

target serum urate when allopurinol was compared with benzbromarone. However, allopurinol seemed more successful than placebo

and may be less successful than febuxostat (80 mg daily) in achieving a target serum urate level (6 mg/dL or less; 0.36 mmol/L or less)

based on moderate- to low-quality evidence. Single studies reported no difference in pain reduction when allopurinol (300 mg daily)

was compared with placebo over 10 days, and no difference in tophus regression when allopurinol (200 to 300 mg daily) was compared

with febuxostat (80 mg daily). None of the trials reported on function, health-related quality of life or participant global assessment of

treatment success, where further research would be useful.

P L A I N L A N G U A G E S U M M A R Y

Allopurinol for chronic gout

Research question

This summary of a Cochrane review presents what we know from research about the effect of allopurinol compared with placebo or

other treatments that reduce uric acid levels in treating people with chronic gout. The review is current to January 2014.

Background: what is chronic gout and what is allopurinol?

Chronic gout is a common type of inflammatory arthritis caused by high levels of uric acid in the blood leading to crystal formation

in the joints. Allopurinol is a medication that helps to lower blood uric acid levels.



Study characteristics

After searching for all relevant studies, we found 11 studies that included 4531 adults with chronic gout. Two studies compared various

doses of allopurinol (ranging from 100 to 300 mg daily) with placebo; four compared allopurinol with febuxostat; two compared

allopurinol with benzbromarone; and one study each compared allopurinol with colchicine or probenecid. Two studies compared

different treatment doses or administration methods of allopurinol. We considered allopurinol compared with placebo as the main

comparison, and present results fully below.

Key results

Allopurinol 100 to 300 mg daily versus placebo

Acute gout attacks

- 4 fewer people out of 100 had an acute gout attack with allopurinol 100 to 300 mg daily compared with placebo (4% absolute

reduction).

- 8 people out of 100 had an acute gout attack with allopurinol.

- 12 people out of 100 had an acute gout attack with placebo.

Proportion of participants achieving target serum urate

- 96 more people out of 100 achieved the target serum urate level with allopurinol (96% absolute increase).

- 96 people out of 100 achieved target serum urate with allopurinol.

- 0 people out of 100 achieved target serum urate with placebo.

Withdrawal due to adverse events

- 2 more people out of 100 had a withdrawal due to an adverse event with allopurinol (2% absolute increase).

- 6 people out of 100 had a withdrawal due to an adverse event with allopurinol.

- 4 people out of 100 had a withdrawal due to an adverse event with placebo.

Serious adverse events

- 1 more person out of 100 had a serious adverse event with allopurinol (1% absolute increase).

- 2 people out of 100 had a serious adverse event with allopurinol.

- 1 person out of 100 had a serious adverse event with placebo.

Pain, function and tophus regression were not reported in sufficient detail to present results.

Quality of the evidence

In people with chronic gout, moderate-quality evidence indicated that, compared with placebo, allopurinol (100 to 300 mg daily)

probably does not reduce the number of acute gout attacks, but does increase the proportion achieving target serum urate levels, without

increasing withdrawals due to AEs or serious adverse event rates. Further research may change the estimates. Pain and tophus regression

were not reported sufficiently to calculate group differences. Function was not measured.

In people with chronic gout, compared with febuxostat (80 mg daily), low-quality evidence indicated that allopurinol (100 to 300

mg daily) may not reduce the number of acute gout attacks, and may be less effective in achieving target serum urate levels, without

increasing withdrawals due to AEs, or serious adverse event rates. Further research is likely to change the estimates. Tophus regression

was not reported sufficiently to calculate group differences. Pain and function were not measured.

In people with chronic gout, compared with benzbromarone (up to 200 mg daily), allopurinol (up to 600 mg daily) may not reduce

the number of acute gout attacks (low-quality evidence), probably does not increase the proportion achieving target serum urate levels,

or the withdrawals due to AEs or serious adverse event rates (moderate-quality evidence). Further research may change the estimates.

Tophus regression was not reported sufficiently to calculate group differences and pain and function were not measured.

The evidence was downgraded due to limitations in study design indicating potential bias, and possible imprecision. All other com-

parisons were supported by small, single studies only, limiting conclusions.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Allopurinol compared with placebo for chronic gout

Patient or population: people with chronic gout

Settings: primary care

Intervention: allopurinol 100-300 mg daily

Comparison: placebo

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of participants

(studies)


(GRADE)

Comments

Assumed risk Corresponding risk

Placebo Allopurinol

Acute gout attacks

Follow-up: 1-30 days

120 per 1000 77 per 1000

(14 to 422)

RR 0.64

(0.12 to 3.52)

51

(1 study)

⊕⊕⊕©

moderate1,2

Absolute reduction in at-

tacks with allopurinol: 4%

(21% reduction to 12% in-

crease)

Relative change: 36% re-

duction with allopurinol

(88% reduction to 252%

increase)

NNTB n/a2

This study used allopuri-

nol 300 mg daily (Taylor

2012)

Proportion achieving

target serum urate

Follow-up: 1-30 days

960 per 1000 960 per 1000 RR 49.11

(3.15 to 765.58)

51

(1 study)

⊕⊕⊕©

moderate1,2

Absolute risk difference in

proportion achieving tar-

get serum urate with al-

lopurinol: 96% (86% to

106% increase)

Relative change: 48% in-

crease with allopurinol

(215% to 76,458% in-

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crease)

NNT 1 (95% CI 1.04 to 1.

35)

Pain reduction

Follow-up: 10 days

See comment See comment Not estimable 51

(1 study)

See comment The trial authors reported

no difference in pain: the

initial mean VAS pain

scores for the allopurinol

and placebo groups were

6.72 versus 6.28 (P value

= 0.37) decreasing to 0.

18 versus 0.27 (P value

= 0.54) at day 10. No

measures of variance re-

ported, so we could not

calculate the differences

between groups4

Function See comment See comment Not estimable - See comment Not measured

Tophus regression See comment See comment Not estimable - See comment Not measured

Withdrawal due to ad-

verse events

Follow-up: 0-28 weeks

44 per 1000 60 per 1000

(26 to 136)

RR 1.36

(0.61 to 3.08)

453

(2 studies)

⊕⊕⊕©

moderate3


withdrawals due to ad-

verse events with allop-

urinol: 2% increase (3%

reduction to 6% increase)




increase)

NNT n/a2

Serious adverse events


13 per 1000 24 per 1000

(6 to 98)

RR 1.93

(0.48 to 7.80)

453

(2 studies)

⊕⊕⊕©

moderate3

Absolute risk difference

in serious adverse events

with allopurinol: 1% in-

crease (1% reduction to

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increase)

NNT n/a2

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RR: risk ratio; VAS: visual analogue scale.

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

1 One study with a small sample size, and wide CIs, indicating imprecision (Taylor 2012).2 Number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) not applicable (n/a) when result was

not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (www.nntonline.net/visualrx/).3 Data from two studies were pooled for withdrawal due to adverse events and serious adverse events, the earlier trial is at unclear risk

of selection, performance and detection bias, and the more recent trial is at low risk of bias (Schumacher 2008; Taylor 2012).4 One study reported on pain reduction, and is at low risk of bias, and had a small sample size (Taylor 2012).

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B A C K G R O U N D

Description of the condition

Gout is the most common inflammatory arthritis in men over

the age of 40 years, and has increasing prevalence among post-

menopausal women (Chohan 2009). It results from the deposition

of monosodium urate (MSU) crystals in and around joints and

soft tissues (Schlesinger 2004). Formation of uric acid crystals re-

quires hyperuricaemia defined as serum urate concentration above

its solubility limit (6.8 mg/dL (0.41 mmol/L)) supersaturating the

body fluids (Schumacher 2004).

Gout can evolve from asymptomatic hyperuricaemia to acute gout,

which is characterised by the rapid onset of severe pain, swelling

and redness of the affected joint. The period between attacks when

the person is asymptomatic is referred to as inter-critical gout. The

final stage is chronic gout, characterised by the formation of tophi,

which are nodular masses of MSU crystals deposited in the soft

tissues of the body that can contribute to joint damage (Klippel

1994). Furthermore, hyperuricaemia can be associated with renal

damage secondary to interstitial MSU crystal deposition and the

formation of renal stones (Schlesinger 2004).

The treatment of acute gout attacks is aimed at controlling the

inflammatory response and alleviating pain, and the drugs com-

monly used for this are non-steroidal anti-inflammatory drugs

(NSAIDs), colchicine and glucocorticoids (Wortmann 2002).

Description of the intervention

As elevated serum uric acid (sUA) concentration is the most impor-

tant determinant for the risk of developing gout (Klippel 1994),

treatment is aimed at reducing hyperuricaemia. This prevents

gouty attacks and the sequelae of long-standing hyperuricaemia,

such as chronic tophaceous gout and uric acid stones (Schlesinger

2004). Maintaining the sUA level below saturating levels at a tar-

get of 6 mg/dL or less (or 0.36 mmol/L or less) is important in

the treatment of chronic gout to reduce or reverse clinical events

(Jordan 2007). The urate-lowing drugs available to treat chronic

gout are:

1. uricostatic drugs, which reduce urate production such as

xanthine oxidase (XO) inhibitors, including allopurinol and

febuxostat;

2. uricosuric drugs, which increase urate excretion, including

probenecid, benzbromarone and sulphinpyrazone;

3. recombinant uricases, which catalyse the oxidation of uric

acid to allantoin thereby lowering sUA, such as pegloticase and

rasburicase (allantoin is an inert, water-soluble purine metabolite,

which is readily eliminated, primarily by renal excretion).

Allopurinol is considered first-line therapy for prevention of gout.

The initial recommended dose of allopurinol is up to 100 mg

daily, with a lower dose of 50 mg daily suggested in stage 4 or

worse chronic kidney disease. The dose of allopurinol can be grad-

ually titrated upwards every two to five weeks to an appropriate

maximum dose in order to achieve a serum urate level target at a

minimum of 6 mg/dL or less, which is the serum saturation point

to prevent crystal formation, and may be lowered to 5 mg/dL (0.3

mmol/L) in some people with gout. The dosage of allopurinol can

be raised above 300 mg daily, even in people with renal impair-

ment, provided that the person receives adequate education and

monitoring for drug toxicity (including measurement of transam-

inase levels). The maximum dosage of allopurinol approved by

the US Food and Drug Administration (FDA) is 800 mg daily,

but the maximum dosage should be lower in people with chronic

kidney disease (Khanna 2012).

How the intervention might work

Allopurinol is a uricostatic drug that limits the production of uric

acid. It is an isomer of hypoxanthine, which inhibits XO, thereby

preventing the conversion of hypoxanthine to xanthine and xan-

thine to uric acid (Wallace 1988). This helps prevent uric acid

crystal accumulation in the joints and tissues, thereby preventing

attacks of gout and the sequelae of long-standing hyperuricaemia,

such as chronic tophaceous gout and uric acid stones.

Why it is important to do this review

Allopurinol is one of the most effective urate-lowering drugs for

gout and is frequently used. However, about 2% of people develop

hypersensitivity reactions (Dalbeth 2007), and 20% of those are

severe, including rash, toxic epidermal necrolysis, hepatitis, inter-

stitial nephritis and death (Wortmann 2002). Therefore, it is clin-

ically relevant to review the benefit and safety of allopurinol for

the treatment of chronic gout systematically.

O B J E C T I V E S

To assess the efficacy and safety of allopurinol compared with

placebo and other urate-lowering therapies for treating chronic

gout.

M E T H O D S

Criteria for considering studies for this review

Types of studies



We included all randomised controlled trials (RCTs) or quasi-ran-

domised controlled clinical trials (CCTs) comparing allopurinol

with another therapy (placebo, no treatment or other urate-low-

ering treatment) in adults with chronic gout.

We considered only trials that were published as full articles or

were available as a full trial report.

Types of participants

We considered trials that included adults (aged greater than 18

years) with a diagnosis of chronic gout. The diagnosis of gout

could have been based on the American College of Rheumatology

(ACR) criteria as outlined below or based on the diagnosis by the

trial author or the treating physician.

The ACR preliminary criteria for the classification of acute arthri-

tis of primary gout remain the most frequently used criteria for

chronic gout diagnosis in clinical trials (Wallace 1977). According

to these criteria, a person can be classified as having gout if MSU

crystals are identified in a synovial fluid sample or tophus aspirate,

or any of six out of 12 criteria are fulfilled following clinical, ra-

diographic and laboratory.

1. More than one attack of acute arthritis.

2. Maximum inflammation developed within one day.

3. Monoarthritis attack.

4. Redness observed over joints.

5. First metatarsophalangeal joint painful or swollen.

6. Unilateral first metatarsophalangeal joint attack.

7. Unilateral tarsal joint attack.

8. Tophus (proved or suspected).

9. Hyperuricaemia.

10. Asymmetric swelling within a joint on x-ray film.

11. Subcortical cysts without erosions on x-ray film.

12. Joint culture negative for organism during attack.

We excluded populations that included a mix of people with

chronic gout and asymptomatic hyperuricaemia unless we could

separate out results for the chronic gout population for analysis.

Types of interventions

We included all trials that evaluated allopurinol at any dose or

dosing interval.

Comparators could be any of the following:

1. placebo;

2. no treatment;

3. another urate-lowering therapy including febuxostat,

probenecid, benzbromarone, sulphinpyrazone, pegloticase or

rasburicase;

4. one regimen of allopurinol versus another;

5. a combination of urate-lowering therapies.

Types of outcome measures

The outcome measures were based on the 2010 Outcome Mea-

sures in Rheumatology Meeting (OMERACT 10) gout report

recommended outcome domains for chronic gout (Schumacher

2009; Singh 2011).

Major outcomes

We listed the following outcomes in the ’Summary of findings’

tables:

1. frequency of acute gout attacks and the number of

participants with an acute gout attack was the preferred

dichotomous outcome;

2. serum urate normalisation as measured by per cent change

in uric acid from baseline, absolute change in uric acid from

baseline (mmol/L or mg/dL) or proportion of participants

achieving a target serum urate (e.g. less than 6 mg/dL (less than

0.36 mmol/L)) (the preferred outcome);

3. pain (e.g. as measured on the visual analogue scale (VAS),

numerical rating scale (NRS), Likert scales or qualitative scales);

4. function (i.e. activity limitation) (e.g. as measured by the

Health Assessment Questionnaire Disability Index (HAQ-DI),

36-item Short Form (SF-36) Physical Health component or

other validated gout specific function measures);

5. tophus regression, using physical measurement techniques

(e.g. Vernier callipers) or ultrasound-guided measurements

(Dalbeth 2011);

6. proportion of participant withdrawals due to AE;

7. proportion of participants with serious adverse events

(SAEs).

Minor outcomes

1. Health-related quality of life (HRQoL) (e.g. as described by

SF-36, Gout Assessment Questionnaire (GAQ) and the Gout

Impact Scale (GIS) or other validated gout-specific HRQoL

measures (Khanna 2011);

2. participant global assessment of treatment success;

3. proportion of participants with AEs.

Search methods for identification of studies

Electronic searches

We searched the following electronic databases from inception:

1. the Cochrane Central Register of Controlled Trials

(CENTRAL) 14 January 2014 (Appendix 1);

2. Ovid MEDLINE 1948 to 14 January 2014 (Appendix 2);

3. EMBASE 1980 to 14 January 2014 (Appendix 3).

We applied no language restrictions.

Searching other resources

We searched abstracts from the two major international rheuma-

tology scientific meetings - the ACR and the European League



Against Rheumatism (EULAR) - or the years 2011 and 2012,

and the reference lists of included articles for additional trials.

We searched trial registers including the ClinicalTrials.gov register

(clinicaltrials.gov) and the World Health Organization (WHO)

trial register (apps.who.int/trialsearch).

For rare SAEs, we also searched black box warnings and regulatory

agency sources:

• Medicine and Healthcare products Regulatory Agency

(MHRA), ’Drug Safety Update’ (www.mhra.gov.uk/

Publications/Safetyguidance/DrugSafetyUpdate/index.htm);

• Australian Database of Adverse Event Notifications (

www.tga.gov.au/safety/index.htm);

• MedWatch: the FDA Safety Information and Adverse Event

Reporting Program (US) - Adverse Event Reporting System (

www.fda.gov/Safety/MedWatch/default.htm);

• European Public Assessment Reports from the European

Medicines Evaluation Agency (EMEA) (www.emea.europa.eu/).

We planned to describe any data obtained from these sources.

Data collection and analysis

Selection of studies

Two review authors (RS and AK) independently reviewed the re-

sults of the search to identify trials that fulfilled our inclusion cri-

teria. We reviewed titles and abstracts and, if more information

was required to determine whether a trial met the inclusion cri-

teria, we obtained the full text. We kept a record for the reasons

for excluding studies and resolved any disagreements by discus-

sion and with a third review author (RB). We planned to translate

eligible studies to English if needed, but we identified no non-

English language studies for inclusion.

Data extraction and management

Two review authors (RS and AK) independently extracted rele-

vant information from the included trials including study design,

characteristics of study population, treatment regimen and du-

ration, outcomes and timing of outcome assessment, using pre-

determined forms. We resolved differences in data extraction by

referring back to the original articles and establishing consensus. A

third review author (RB) acted as arbiter to help resolve differences

if necessary.

We extracted the raw data (means and standard deviations (SD) for

continuous outcomes and the number of events for dichotomous

outcomes) for outcomes of interest and entered relevant data into

Review Manager 5 (RevMan 2011).

Assessment of risk of bias in included studies

Two review authors (RS and AK) independently assessed risk of

bias of all included studies using The Cochrane Collaboration’s

tool for assessing risk of bias (Higgins 2011a). This included as-

sessing the bias in each of the following domains: random sequence

generation; allocation concealment; blinding of participants, per-

sonnel and outcome assessors; completeness of outcome data; se-

lective reporting and other sources of bias (including whether there

was carry-over effect from previous therapies, whether appropriate

co-intervention (e.g. colchicine or NSAIDs) were administered

and whether any pre-administered interventions could have di-

minished the effect of the subsequent randomised intervention).

We graded each of these criteria were graded as ’high risk’ of bias,

’low risk’ of bias or ’unclear risk’ of bias. We resolved disagreements

by consensus; if we could not reach a consensus, a third review

author (RB) acted as arbiter.

Measures of treatment effect

We summarised the data in a meta-analysis only if there was suf-

ficient clinical homogeneity.

For dichotomous data, we presented the results as risk ratios (RR)

with corresponding 95% confidence intervals (CI). An RR greater

than 1.0 indicated a beneficial effect of allopurinol.

For continuous data, we presented the results as mean differences

(MD) between the intervention and comparator groups with the

corresponding 95% CIs.

When different scales were used to measure the same conceptual

domain, we planned to calculate the standardised mean differences

(SMD) with corresponding 95% CIs instead. For the calculation

of SMD, MD was divided by the SD, resulting in a unitless mea-

sure of treatment effect. SMDs larger than zero indicated a bene-

ficial effect of allopurinol. An SMD of 0.2 indicated a small bene-

ficial effect, 0.5 a medium effect and 0.8 a large effect in favour of

allopurinol. We had planned to re-express SMDs as MD by mul-

tiplying the SMD by a typical among-person SD using a famil-

iar scale in order to facilitate appraisal by clinicians (Schünemann

2011b); however, we did not need to do this.

Unit of analysis issues

We assessed whether each study evaluated the number of people

with acute flares or the number of acute flares as a unit of analysis,

and we evaluated the number of people with acute flares as the

preferred outcome.

We planned to avoid a potential unit of analysis issue by making

multiple pair-wise comparisons between all possible pairs of in-

tervention groups for trials with multiple treatment groups, or al-

ternatively, by including only the pair with accepted drug dosages

(Higgins 2011c).



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http://www.tga.gov.au/safety/index.htm



http://www.fda.gov/Safety/MedWatch/default.htm




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Dealing with missing data

If data were missing or incomplete, we planned to obtain further

information from the study authors, but this was not necessary.

We had planned that in cases where individual data were missing

from the reported results and no further information was available

from the study authors, we would assume the missing values to

have a poor outcome. For dichotomous variables that measured

AEs, we would have calculated the withdrawal rate using the num-

ber of participants who received the treatment as the denominator

(worst-case analysis). For dichotomous outcomes that measured

benefits, we would have calculated the worst-case analysis using

the number of randomised participants as the denominator. For

continuous variables, we planned to calculate the MD or the SMD

based on the number of participants analysed at each time point.

If the number of participants analysed was not available, we would

have used the number of randomised participants in each group

at baseline.

Where possible, we would have calculated missing SDs from other

statistics such as standard errors, CIs or P values, according to

methods recommended in the Cochrane Handbook for SystematicReviews of Interventions (Higgins 2011b). If we could not calculate

SDs, we would have imputed them from other studies in the meta-

analysis (Higgins 2011c).

Assessment of heterogeneity

We assessed clinical and statistical heterogeneity between studies.

For clinical homogeneity, we determined whether or not the in-

cluded studies were similar with respect to study participants, in-

tervention groups, outcome measures and timing of outcome.

For studies judged as clinically similar, we assessed statistical het-

erogeneity using the I2 statistic (Deeks 2011). We used the fol-

lowing thresholds for the interpretation of the I2 statistic: 0% to

40% heterogeneity might not be important, 30% to 60% repre-

sented moderate heterogeneity, 50% to 90% represented substan-

tial heterogeneity and greater than 75% represented considerable

heterogeneity. In cases of considerable heterogeneity, we planned

to explore the data further, including subgroup analyses, in an at-

tempt to explain heterogeneity.

Assessment of reporting biases

To assess the potential for reporting bias, we determined whether

the protocol of the trial was published before recruitment of par-

ticipants began. For trials published after 1 July 2005, we screened

the Clinical Trials Register at the International Clinical Trials

Registry Platform of the World Health Organization (WHO) (

apps.who.int/trialsearch/). We evaluated whether selective report-

ing of outcomes was present.

We planned to compare the fixed-effect model estimate against

the random-effects model estimate to assess the possible presence

of small-sample bias in the published literature (i.e. in which the

intervention effect was more beneficial in smaller studies). In the

presence of small-sample bias, the random-effects estimate of the

intervention was more beneficial than the fixed-effect estimate

(Sterne 2011).

We planned to explore the potential for small-study effects in the

main outcomes of the review using funnel plots if at least 10 studies

were included in a meta-analysis; however, this was not undertaken

due to the lack of studies.

Data synthesis

When we considered studies sufficiently homogenous in terms

of the study population and interventions delivered, we pooled

outcome data in a meta-analysis using a random-effects model,

irrespective of the I2 results (Deeks 2011).

Subgroup analysis and investigation of heterogeneity

We hypothesised that responses to treatment may differ according

to the participant’s age and gender. Elderly participants can present

with more associated conditions and possibly a greater chance of

adverse effects (Busquets 2011), while reports indicate that gout

in women may have different epidemiological and clinical charac-

teristics compared with gout in men (Harrold 2006).

Therefore, we planned the following subgroup analyses if sufficient

data were available:

1. participant’s age (65 years or greater or less than 65 years);

2. gender (men versus women).

We had planned to extract the outcome ’acute gout attacks’ sepa-

rately for men and women, and the outcome ’withdrawals due to

adverse events’ separately by age subgroups from within each trial.

We also planned to compare the magnitudes of effect informally

to assess possible differences in response to treatment by consid-

ering the overlap of the CIs of the summary estimates in the two

subgroups with non-overlap of the CIs indicating statistical sig-

nificance. However, the outcomes were not reported by subgroups

within the trials, thereby precluding the planned analyses.

Sensitivity analysis

Where sufficient studies existed, we planned sensitivity analyses to

explore the impact of any bias attributable to lack of randomisa-

tion, inadequate or unclear allocation concealment and outcome

assessor blinding.

We also planned to assess the presence of small-study bias (i.e.

intervention effect was more beneficial in smaller studies) in the

meta-analysis by comparing the fixed-effect estimate and the ran-

dom-effects estimate.

We planned to investigate the effect of any missing or imputed

data by sensitivity analysis.

Presentation of results

We presented the main results in ’Summary of findings’ tables.

These tables provide key information concerning the quality of



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evidence, the magnitude of effect of the interventions examined

and the sum of available data on our seven main outcomes (par-

ticipant-reported reduction in acute gout attack frequency, pro-

portion of participants achieving a target serum urate level, joint

pain reduction, function, tophus regression, number of study par-

ticipant withdrawals due to AEs and SAEs), as recommended by

The Cochrane Collaboration (Schünemann 2011a). It includes

an overall grading of the evidence related to each of the main out-

comes using the GRADE approach (Schünemann 2011b).

The ’Summary of findings’ tables show the three most clinically rel-

evant comparisons, as deemed by the review authors (RS, AK, RB),

including allopurinol versus placebo, allopurinol versus febuxostat

and allopurinol versus benzbromarone.

In the comments column, we calculated the absolute percentage

change and the relative percentage change; and, for outcomes with

statistically significant differences between intervention groups, we

calculated the number needed to treat for an additional beneficial

outcome (NNTB), or the number needed to treat for an additional

harmful outcome (NNTH).

For dichotomous outcomes, we calculated the absolute risk dif-

ference using the risk difference statistic in Review Manager 5

(RevMan 2011), and expressed the result as a percentage; we calcu-

lated the relative percentage change as the RR - 1 and expressed it

as a percentage; and determined the NNT from the control group

event rate and the RR using the Visual Rx NNT calculator (Cates

2008).

For continuous outcomes, we would have calculated the absolute

risk difference as the MD between intervention and control groups

in the original measurement units (divided by the scale), expressed

as a percentage; we would have calculated the relative difference

as the absolute change (or MD) divided by the baseline mean of

the control group from a representative trial; however, we did not

need to do this.

R E S U L T S

Description of studies

Results of the search

The literature search was originally performed on 17 February

2012 and updated on 6 August 2013 and 14 January 2014. It

identified 3982 abstracts (see Figure 1). After exclusion of 1266

duplicates, we screened 2716 abstracts and retrieved 46 articles

for detailed review. From this, 11 trials met the inclusion criteria

(Becker 2005; Becker 2010; Bull 1989; Gibson 1982; Perez-Ruiz

1999; Reinders 2009a; Rodnan 1975; Schumacher 2008; Scott

1966; Singal 2011; Taylor 2012).



Figure 1. Study flow diagram.



We found no additional trials from the search of abstracts from

the 2011 and 2012 annual scientific meetings of ACR or EULAR

or from the handsearch.

Included studies

We provide a full description of the 11 included trials in the

Characteristics of included studiestable.

Design

There were seven RCTs (Becker 2005; Becker 2010; Gibson 1982;

Perez-Ruiz 1999; Reinders 2009a; Schumacher 2008; Taylor

2012), and four CCTs (Bull 1989; Rodnan 1975; Scott 1966;

Singal 2011). Two trials (Becker 2005; Schumacher 2008), were

combined into a three-year open-label extension study (Becker

2009), but we have not reported these data in this review.

Participants

Five RCTs (Becker 2005; Becker 2010; Perez-Ruiz 1999;

Schumacher 2008; Taylor 2012), and two CCTs (Bull 1989; Singal

2011), defined their study population as having gout using the

ARA criteria (Wallace 1977), while the remaining four used an al-

ternative definition. Gibson 1982 defined their study population

as having “at least one attack of acute arthritis associated with a

raised blood uric acid unrelated to drugs or other diseases”; while

Reinders 2009a defined their study population as having a “diag-

nosis of gout, confirmed by microscopic evidence of urate crystals

from synovial fluid or periarticular structures or the presence of

tophi”. Rodnan 1975 defined their study population as having

“recurrent paroxysms of monoarticular inflammation characteris-

tic of acute gouty arthritis, and all had hyperuricaemia”, and Scott

1966 defined their study population as having gout which was “as

far as could be determined, primary and uncomplicated except in

some cases with minor degrees of renal functional impairment”.

Six trials specifically stated that their gout population were over

the age of 18 years (Becker 2005; Becker 2010; Rodnan 1975;

Schumacher 2008; Scott 1966; Taylor 2012), while five trials did

not (Bull 1989; Gibson 1982; Perez-Ruiz 1999; Reinders 2009a;

Singal 2011).

Three trials had an all male population (Rodnan 1975; Scott 1966;

Taylor 2012), seven RCTs had a majority male population (Becker

2005; Becker 2010; Bull 1989; Gibson 1982; Perez-Ruiz 1999;

Reinders 2009a; Schumacher 2008), and one trial did not define

the gender of their study population with gout (Singal 2011). The

duration of gout affecting the participants was reported in all 11

studies, and ranged from a few days to 25 years.

Five trials were set in the USA (Becker 2005; Becker 2010; Rodnan

1975; Schumacher 2008; Taylor 2012), three in London, UK

(Bull 1989; Gibson 1982; Scott 1966), one in the Netherlands

(Reinders 2009a), one in Spain (Perez-Ruiz 1999), and one in

Bangladesh (Singal 2011).

Interventions

Two trials compared allopurinol with placebo (Schumacher 2008;

Taylor 2012). One of these investigated immediate versus de-

layed administration of allopurinol during an acute attack of gout

and participants were randomised to allopurinol versus placebo

for the first 10 days of the trial after which time all participants

took allopurinol (Taylor 2012). One trial compared allopurinol

plus colchicine with colchicine alone (Gibson 1982). One trial

compared allopurinol with probenecid (Scott 1966), and two tri-

als compared allopurinol with benzbromarone (Perez-Ruiz 1999;

Reinders 2009a). Four trials compared allopurinol with febuxo-

stat (Becker 2005; Becker 2010; Schumacher 2008; Singal 2011).

In addition, one trial compared allopurinol 300 mg daily versus

allopurinol 100 mg three times daily (Rodnan 1975), and one trial

compared continuous versus two months per year of allopurinol

(Bull 1989).

Outcomes

All trials measured the number of acute attacks of gout, while

all except one trial (Bull 1989) measured serum urate change or

normalisation. Only one trial assessed joint pain (Taylor 2012).

Four trials included a measure of tophus regression (Becker 2005;

Perez-Ruiz 1999; Schumacher 2008; Scott 1966). Safety as as-

sessed by the number of study participant withdrawals due to AEs

and SAEs was reported in all except one trial (Gibson 1982). AEs

were reported by all except two trials (Bull 1989; Gibson 1982).

SAEs were reported in eight trials and three trials did not report

SAEs (Bull 1989; Gibson 1982; Singal 2011). None of the trials

reported on function or HRQoL measures.

Allopurinol versus placebo

Schumacher 2008 performed a multicentre, three-armed, dou-

ble-blind RCT (the Allopurinol and Placebo-Controlled, Effi-

cacy Study of Febuxostat (APEX) trial) including 1072 partici-

pants, with gout as per ARA criteria, and compared allopurinol

100 or 300 mg daily based on renal function with febuxostat 80,

120 or 240 mg daily or placebo. Additional medication included

colchicine 0.6 mg once daily or naproxen 250 mg twice daily

during the washout period for people receiving prior urate-lower-

ing therapies or on randomisation for people not on prior urate-

lowering therapy. These medications were continued for the first

eight weeks of the study as prophylaxis for gout flares. The inves-

tigator used their own judgement in selecting between naproxen



and colchicine, although colchicine was recommended for people

with a serum creatinine level greater than 1.5 mg/dL. Study treat-

ment was taken for 28 weeks and outcomes were assessed every

four weeks. The primary efficacy end point was the proportion

of participants with the last three monthly serum urate levels less

than 6.0 mg/dL (less than 0.36 mmol/L). Overall, outcome as-

sessments were made on three out of the seven essential domains

proposed by OMERACT. The study end points were acute gout

attack frequency, serum urate (both change in serum urate and

serum urate less than 6 mg/dL) and tophus regression. Safety as

assessed by the number of study participant withdrawals due to

AEs and SAEs were also reported.

Taylor 2012 performed a single-centre, parallel arm, double-

blind, placebo-controlled RCT including 57 participants present-

ing within seven days of onset of an acute attack of crystal-con-

firmed gout and who met the ARA criteria and compared allop-

urinol 300 mg daily versus placebo for 10 days. After 10 days,

participants in the placebo arm were also started on allopurinol

300 mg daily. Duration of the trial was 90 days (as colchicine

was continued for 90 days) and outcomes were assessed at day

one, three, 10 and 30 plus or minus three days to accommodate

weekends or conflicts. All participants received additional medi-

cations including colchicine 0.6 mg twice daily for 90 days and

indomethacin 50 mg three times daily for 10 days. Outcome as-

sessments were made on three out of the seven essential domains



proportion achieving a target serum urate less than 6 mg/dL) and

pain (measured using a VAS). Safety as assessed by the number

of study participant withdrawals due to AEs and SAEs were also

reported.

Allopurinol plus colchicine versus colchicine alone

Gibson 1982 performed a single-centre RCT including 59 par-

ticipants with gout that compared allopurinol 200 mg daily plus

colchicine 0.5 mg twice daily with colchicine 0.5 mg twice daily

alone. In an earlier paper, Gibson 1980 reported on the same trial

but described 57 participants. Gibson 1982 included participants

with gout defined as having at least one attack of acute arthritis

associated with a raised blood uric acid unrelated to drugs or other

diseases, while Gibson 1980 referred to participants having pri-

mary gout of at least one year’ duration. For the purpose of our

review, we used data in Gibson 1982. Duration of treatment was

at least one year and 55 participants received treatment for two

years. Outcomes were assessed every two to three months, then at

12 and 24 months and outcome assessments were made on two

out of the seven essential domains proposed by OMERACT (acute

gout attack frequency and serum urate level). Safety, as assessed

by the number of study participant withdrawals due to AEs and

SAEs, were not reported in this trial.

Allopurinol versus probenecid

Scott 1966 performed a single-centre open quasi-randomised

CCT including 40 participants with gout (investigator defined)

comparing allopurinol with a uricosuric (probenecid initially, then

5/17 on probenecid changed to sulphinpyrazone 400 mg daily due

to “minor” adverse effects). Allopurinol was commenced at 300

mg daily and increased when necessary (authors did not defined

how) up to 600 mg daily, and probenecid 1 g daily rising to 2

g/daily after two weeks. All participants also received colchicine

0.5 mg twice or three times daily and this was withdrawn “several

months after the last attack of gout”. The mean follow-up was

18.6 months for allopurinol and 19.6 months for probenecid, and

outcomes were assessed at initial assessment; two weeks; then one,

two and three months and at three-monthly intervals thereafter.

Outcome assessments were made on three out of the seven essen-

tial domains proposed by OMERACT. The study end points were

acute gout attack frequency, serum urate and tophus regression.

Safety as assessed by the number of study participant withdrawals

due to AEs were also reported, although SAEs were not reported.

Allopurinol versus febuxostat

Becker 2005 conducted a multicentre, 52-week, three-armed dou-

ble-blind RCT (the Febuxostat versus Allopurinol Controlled Trial

(FACT) trial) including 762 participants with gout (as per ARA

criteria) that compared allopurinol 300 mg daily with febuxostat

80 or 120 mg daily. All participants also received two months

of acute gout prophylaxis with either colchicine 0.6 mg daily or

naproxen 250 mg twice daily. The authors do not state how they

decided who received colchicine and who received naproxen. Any

subsequent attacks were treated according to the discretion of the

investigators. Duration of treatment was 12 months and outcomes

were assessed at two weeks, four weeks and then monthly for 12

months in total) and follow-up extended for another month to

assess AEs (13 months in total). Outcome assessments were made

on three out of the seven essential domains proposed by OMER-

ACT. The study end points included serum urate (both change in

serum urate and serum urate less than 6 mg/dL), acute gout attack

frequency and tophus regression. Safety as assessed by the number


reported.

Becker 2010 conducted a multicentre, two-armed double-blind

RCT (the urate lowering efficacy and safety of febuxostat in the

treatment of hyperuricaemia of gout (CONFIRMS) trial) includ-

ing 2269 participants with gout (as per ARA criteria) that com-

pared allopurinol 200 or 300 mg daily (depending on renal func-

tion) with febuxostat 40 or 80 mg daily, over six months and out-

comes were assessed every two months for six months in total.

Participants received acute gout prophylaxis with either colchicine

or naproxen for the duration of the trial, and choice of prophy-

laxis was made by the investigator and participant, taking into

account prior drug tolerance and prophylaxis experience. In addi-



tion, participants with an estimated creatinine clearance less than

50 mL/minute were not given naproxen. Outcome assessments

were made on two out of the seven essential domains proposed by

OMERACT. The study end points included serum urate (serum

urate less than 6 mg/dL) and acute gout attack frequency. Safety

as assessed by the number of study participant withdrawals due to


Schumacher 2008 performed a multicentre, three-armed, double-

blind RCT (the APEX trial) including 1072 participants, with

gout as per ARA criteria, and compared allopurinol 300 or 100

mg daily based on renal function with febuxostat 80, 120 or 240

mg daily or placebo. See ’Allopurinol versus placebo’.

Singal 2011 conducted a two-armed non-randomised CCT in-

cluding 100 participants with gout (as per ARA criteria) that com-

pared allopurinol 300 mg daily with febuxostat 80 mg daily, over

six months and outcomes were assessed at two weeks and then at

month four, five and six (final visit). Participants did not receive

any acute gout prophylaxis. Outcome assessments were made on

two out of the seven essential domains proposed by OMERACT.

The study end points were serum urate (less than 6 mg/dL) and

acute gout attack frequency. Safety as assessed by the number of

study participant withdrawal due to AEs or SAEs were not re-

ported, but AEs were reported.

Allopurinol versus benzbromarone

Perez-Ruiz 1999 performed a single-centre open RCT in 37 par-

ticipants with gout (as per ARA criteria) and renal impairment

(calculated creatinine clearance 20 to 80 mL/minute/1.73m2) and

compared allopurinol (100-150 mg daily initially and then titrated

up to 100 (according to creatinine clearance 20 to 40 mL/minute),

200 (according to creatinine clearance 40 to 60mL/minute) or

300 mg daily (according to creatinine clearance 60 to 80 mL/

minute) versus benzbromarone (100 mg daily titrated up with in-

crements of 50 to 200 mg daily). Participants in the allopurinol

group could cross-over to the benzbromarone group if they did not

achieve target sUA level (less than 6 mg/dL) at maximum doses

of allopurinol (corrected for creatinine clearance). The timing of

the titration or cross-over was not specified. Colchicine 0.5 to 1

mg daily was given for six months from the start of urate-lowering

therapy. If colchicine was not tolerated, NSAIDs were used. Du-

ration of the study was nine to 12 months if serum urate less than

6 mg/dL was achieved and 12 to 24 months for participants who

changed from allopurinol to benzbromarone or participants with

tophi. Outcomes were assessed at nine, 12 and 24 months and

assessments were made on three out of the seven essential domains



serum urate less than 6 mg/dL) and tophus regression. Safety as

assessed by the number of study participant withdrawals due to


Reinders 2009a performed a multicentre open RCT in 65 partici-

pants with gout (confirmed by microscopic evidence of urate crys-

tals from synovial fluid or peri-articular structures or the presence

of tophi) to investigate the comparative efficacy and tolerability

of dose escalation of allopurinol versus benzbromarone to attain

a target serum urate of 5 mg/dL. Participants in the allopurinol

group received a starting dose of 100 mg daily, which increased

by 100 mg each week to 300 mg daily, while participants in the

benzbromarone group initially received 100 mg daily. If the treat-

ment was tolerated but the treatment goal of serum urate 0.30

mmol/L or less was not reached at two months, then the allop-

urinol dose was doubled to 300 mg twice daily and the benzbro-

marone dose to 200 mg daily. Additional medications included

colchicine 0.5 to 1 mg daily until serum urate 0.30 mmol/L or

less was reached. If colchicine was not tolerated, then NSAIDs

were used. Duration of treatment was four months, and outcomes

were assessed at two months (before dose escalation) (stage 1) and

then at four months (after dose escalation) (stage 2). Outcome

assessments were made on two out of the seven essential domains


attack frequency and serum urate (both change in serum urate and

serum urate less than 6 mg/dL). Safety as assessed by the number


reported.

Allopurinol: intermittent versus continuous

Bull 1989 conducted a single-centre, two-armed “quasi-ran-

domised” CCT including 50 participants with gout (as per ARA

criteria), which compared two different allopurinol regimens: con-

tinuous versus intermittent. Participants in the continuous group

received allopurinol 100 mg daily for the first week, 200 mg daily

for the second week and then were maintained continuously by a

dose adequate to keep their sUA level less than 6 mg/dL for men;

this dose was usually 300 mg daily. Participants in the intermit-

tent group received allopurinol starting at 100 mg daily for the

first week, then 200 mg daily for the second week and then 300

mg daily for six weeks. This protocol could only be performed

once every 12 months. Both groups received NSAID for the first

month of starting allopurinol, and, in the continuous group, par-

ticipants with a history of duodenal ulceration were occasionally

prescribed colchicine. Duration of treatment ranged from two to

four years and outcome was assessed every three to four months.

Outcome assessments were made on two out of the seven essential

domains proposed by OMERACT. The primary study end points

were acute gout attack frequency and serum urate (although no

data on specific serum urate levels were presented). No adverse

effects were reported.

Allopurinol: split-dose allopurinol versus once-daily

allopurinol

Rodnan 1975 performed an open cross-over trial (CCT) includ-

ing 20 participants with gout defined by “recurrent paroxysms of



monoarticular inflammation characteristic of acute gouty arthri-

tis, and all had hyperuricaemia”. All participants had a two-week

washout period during which no allopurinol or other medication

known to affect sUA was given. Participants were then randomly

allocated to receive either allopurinol 300 mg daily given in three

divided doses of 100 mg (group A) or allopurinol 300 mg as a

single dose (group B) for two weeks. All participants then had a

second washout period of one week during which no allopurinol

was given and then the alternate regimen of allopurinol was given

for two weeks. Additional medications included colchicine (0.5

mg twice or three times daily) or indomethacin (25 mg twice daily

to 50 mg three times daily) or both throughout the seven-week

trial. Outcomes were assessed weekly, and assessments were made

on two out of the seven essential domains proposed by OMER-

ACT. The study end points were acute gout attack frequency and

serum urate (both change in serum urate and serum urate less than

6 mg/dL). Adverse effects were also reported.

Excluded studies

We excluded 35 studies after review of the full text of potentially

eligible articles. Of these exclusions, five were the wrong popula-

tion, seven had no or the wrong comparator, one had the wrong

outcome, 21 were the wrong study type and one study lacked hard

data for extraction.

The Characteristics of excluded studies table summarises the rea-

sons for exclusion of the 35 excluded studies.

Risk of bias in included studies

A summary assessment of the risk of bias is presented in the

Characteristics of included studies table and Figure 2 and Figure

3.

Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as

percentages across all included studies.



Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Following risk of bias assessment, we found only Taylor 2012 to

be at low risk of bias in all domains. We have summarised the risk

of bias assessments for all studies below.

Allocation

Four trials described adequate random sequence generation and

allocation concealment and we assessed them as being at low risk of

selection bias (Becker 2005; Becker 2010; Reinders 2009a; Taylor

2012). Two trials used a computer-generated central randomisa-

tion schedule with block sizes of three to six to randomise par-

ticipants (Becker 2005; Reinders 2009a); one trial used an inter-

active voice response system to initiate double-blind randomisa-

tion (Becker 2010), and one trial used a random number gener-

ator (Taylor 2012). Two trials had inadequate random sequence

generation and we assessed them as being at unclear risk of bias

(Perez-Ruiz 1999; Schumacher 2008), and both had inadequate

allocation concealment; we assessed Perez-Ruiz 1999 as being at

high risk of bias, and Schumacher 2008 at unclear risk of bias.

One trial described inadequate random sequence generation and

allocation concealment and we assessed this as being at high risk of

bias for random sequence generation and at unclear risk of bias for

allocation concealment (Rodnan 1975). The remaining four trials

were described as having inadequate random sequence generation

and allocation concealment and we assessed them as being at high

risk of selection bias (Bull 1989; Gibson 1982; Scott 1966; Singal

2011).

Blinding

Two trials described adequate blinding of both the participants and

personnel (performance bias) and of outcome assessment (detec-

tion bias) and we assessed them as being at low risk of performance

and detection bias (Bull 1989; Taylor 2012). Six trials described

inadequate blinding of both the participants and personnel (per-

formance bias) and of outcome assessment (detection bias) and we

assessed them as being at unclear risk of performance and detection

bias (Becker 2005; Becker 2010; Perez-Ruiz 1999; Rodnan 1975;

Schumacher 2008; Scott 1966). One trial described inadequate

blinding of the participants and personnel (performance bias) and

of outcome assessment (detection bias) and we assessed it as being

at high risk of performance bias and unclear risk of detection bias

(Reinders 2009a). Finally, two trials described inadequate blind-

ing of both the participants and personnel (performance bias) and

of outcome assessment (detection bias) and we assessed them as

being at high risk of both performance and detection bias (Gibson

1982; Singal 2011). Gibson 1982 did not describe the method of

blinding and Singal 2011 was a non-randomised CCT.

Incomplete outcome data

We assessed three trials as low risk for attrition bias (Becker 2010;

Schumacher 2008; Taylor 2012). Becker 2010 did not include one

participant out of 2268 in the efficacy analysis (as the sUA was

less than 8 mg/dL (less than 0.48 mmol/L)), whereas the remain-

der were included in a modified intention-to-treat (ITT) analy-

sis. Schumacher 2008 reported that all efficacy analyses were per-

formed on an ITT population and Taylor 2012 discussed all with-

drawals. We assessed four trials at unclear risk for attrition bias

(Bull 1989; Reinders 2009a; Rodnan 1975; Singal 2011). Bull

1989 reported that four participants defaulted from follow-up in

the intermittent group and six defaulted in the control group. Four

participants in the intermittent group went on to continuous treat-

ment at their own request because of recurrent attacks of gout, and

one participant in the intermittent group received an additional

prescription of allopurinol. Two participants in the continuous

group stopped taking allopurinol of their own volition but contin-

ued to be followed for three years in total. Reinders 2009a reported

that 10 participants were excluded from analysis from the allop-

urinol group (six lost to follow-up, three due to protocol violation

and one not mentioned in results) while five participants were ex-

cluded from analysis from the benzbromarone group (four lost to

follow-up and one poor adherence). There was also an unclear risk

of bias with respect to attrition given the number of participants

who withdrew from Reinders 2009a, as 15 out of 65 (23%) par-

ticipants withdrew from the study, and the number of withdrawals

were higher for allopurinol (10 participants) than benzbromarone

(five participants) (not statistically significant) and similar reasons

were given when comparing the two groups. Rodnan 1975 did

not report sufficient evidence regarding loss to follow-up. Singal

2011 did not report on loss to follow-up, treatment withdrawals

or major AEs. The remaining four trials had unexplained incom-

plete outcome data and we judged them as being at high risk of

attrition bias (Becker 2005; Gibson 1982; Perez-Ruiz 1999; Scott

1966).

Selective reporting

We assessed three trials as being at low risk for reporting bias (Perez-

Ruiz 1999; Reinders 2009a; Taylor 2012). We assessed seven trials

at unclear risk (Becker 2005; Becker 2010; Bull 1989; Rodnan

1975; Schumacher 2008; Scott 1966; Singal 2011), and one trial at

high risk for reporting bias as insufficient information was reported

(Gibson 1982).

Other potential sources of bias

We assessed other potential sources of bias including whether there

was carry-over effect from previous therapies, whether appropri-

ate co-intervention (e.g. colchicine or NSAIDs) were adminis-



tered and whether any pre-administered interventions could di-

minish the effect of the subsequent randomised intervention. We

assessed six trials as being at low risk of other potential sources

of bias (Becker 2005; Becker 2010; Bull 1989; Reinders 2009a;

Schumacher 2008; Taylor 2012), and five at unclear risk of other

sources of potential bias, such as carry-over effect from previous

therapies (Gibson 1982; Perez-Ruiz 1999; Rodnan 1975; Scott

1966; Singal 2011).

Effects of interventions

See: Summary of findings for the main comparison Allopurinol

compared with placebo for chronic gout; Summary of findings

2 Allopurinol 100-300 mg daily compared with febuxostat 80

mg daily for chronic gout; Summary of findings 3 Allopurinol

compared with benzbromarone for people with chronic gout

Allopurinol versus placebo

While the efficacy data from the two trials that compared allop-

urinol with placebo could not be pooled due to lack of clinical

homogeneity with differences in trial design, they did report sim-

ilar results, and we pooled the safety data from these two trials

(Schumacher 2008; Taylor 2012).

One trial with 1072 participants, judged to be at unclear risk of

bias, compared a dose of up to 300 mg of allopurinol (dependent

on renal function) with placebo (Schumacher 2008). There was

no between-group difference in the proportion of participants re-

quiring treatment for gout flares in the first eight weeks of the trial

(during the period of co-administration of naproxen 250 mg twice

daily or colchicine 0.6 mg daily) when allopurinol was compared

with placebo (61/268 (23%) in allopurinol group versus 27/134

(20%) in placebo group, RR 1.13, 95% CI 0.76 to 1.69) (Analysis

1.1). The authors also reported no between-group difference in

gout flares between weeks eight and 28 although these data were

not provided.

The second trial with 57 participants, judged to be at low risk

of bias, compared the initiation of allopurinol 300 mg during an

acute attack of gout versus placebo for 10 days followed by allop-

urinol 300 mg daily (Taylor 2012). They reported no between-

group difference in the rate of new or recurrent gout attacks be-

tween days one and 30 when allopurinol was compared with 10

days of placebo and then allopurinol (2/26 (7.7%) in allopurinol

group versus 3/25 (12%) in placebo group, RR 0.64, 95% CI

0.12 to 3.52) (Analysis 1.1). Both treatment groups also received

colchicine for 90 days and indomethacin for 10 days from trial

commencement.

Schumacher 2008 reported that participants in the allopurinol

group were more likely to achieve a target serum urate level less

than 6.0 mg/dL (0.36 mmol/L) with the last three monthly serum

urate measurements (103/263 in allopurinol group versus 1/127

in placebo group, RR 49.25, 95% CI 6.95 to 349.02) (Analysis

1.2). For the subgroup with impaired renal function, none of

the participants in the allopurinol 100 mg daily group (1/10) or

placebo group (0/5) achieved this target. Taylor 2012 reported that

the serum urate levels decreased rapidly in the allopurinol group,

reaching less than 6.5 mg/dL by day 10 for all but one of the par-

ticipants while none of the 25 placebo group participants achieved

this end point (25/26 in allopurinol group versus 0/25 in placebo

group, RR 49.11, 95% CI 3.15 to 765.58) (Analysis 1.2), and the

NNTB was 1 (95% CI 1.04 to 1.35). Taylor 2012 reported no

between-group differences with respect to pain reduction to day

10 (no measure of variance reported). Schumacher 2008reported

no between-group differences in number of tophi or tophus re-

gression but did not provide the data. Neither trial provided data

for function, participant global assessment of treatment success or

quality of life.

Pooled analysis showed no between-group difference in the num-

ber of participants who withdrew due to AEs (19/294 in allopuri-

nol group versus 7/159 in placebo group, RR 1.37, 95% CI 0.61

to 3.09) (Analysis 1.3), total AE (210/294 in allopurinol group

versus 110/159 in placebo group, RR 1.00, 95% CI 0.89 to 1.14)

(Analysis 1.4) or SAE (8/294 in allopurinol group versus 2/159

in placebo group, RR 1.93, 95% CI 0.48 to 7.80) (Analysis 1.5),

when allopurinol was compared with placebo.

The reasons for withdrawal in the allopurinol groups in both trials

were abnormal liver function tests, diarrhoea and a gout attack less

than 24 hours after starting allopurinol. An elevation in creatinine

greater than 1.5 mg/dL occurred in one participant in each study

arm in Taylor 2012. One participant died unexpectedly (after re-

ceiving four doses of allopurinol) from gastroenteritis, pneumo-

nia, fever, dehydration and acute renal failure. The authors did

not state whether or not they considered it related to the study

medication (Schumacher 2008). One participant initially in the

placebo group had a hypersensitivity reaction with rash, fever and

mild transaminitis leading to discontinuation of allopurinol at day

30 (Taylor 2012), and we have excluded from the data analysis as

both placebo and allopurinol were given to this participant.

Allopurinol plus colchicine versus colchicine alone

One trial including 59 participants, judged to be at high risk of

bias, compared allopurinol 200 mg daily plus colchicine 0.5 mg

twice daily with colchicine 0.5 mg twice daily alone (Gibson

1982). There was no between-group difference in the number of

gout attacks in the first year of treatment (recurrent attacks: 5/26 in

allopurinol plus colchicine group versus 10/33 in colchicine alone

group, RR 0.63, 95% CI 0.25 to 1.63) (Analysis 2.1). The mean

serum urate level after two years was reported to be significantly

lower in the allopurinol plus colchicine group (mean ± SD: 0.28

± 0.07 in allopurinol plus colchicine group versus 0.37 ± 0.1 in

colchicine only group, between-group difference and variance not

provided). Three participants in the allopurinol plus colchicine

group were analysed in the colchicine group because they were

non-compliant with medication. No data for joint pain, function,



quality of life, participant global assessment of treatment success,

tophus regression or safety were provided.

Allopurinol versus probenecid

One trial including 40 participants, judged to be at high risk of

bias, compared allopurinol 300 to 600 mg daily with probenecid

(1 g daily increasing to 2 g daily after two weeks) (Scott 1966).

The trial authors did not provide any statistical analyses. From

the data presented, there did not appear to be a between-group

difference in the number of gout attacks reported over the duration

of the study (11/20 in allopurinol group versus 9/17 in probenecid

group). Mean (range) serum urate was reported to decrease from

9.3 (7.5 to 10.6) mg/dL at baseline to 4.7 (2.6 to 5.5) mg/dL at

the final end point in the allopurinol group and 8.5 (7.5 to 11.7)

mg/dL at baseline to 5.2 (3.8 to 7.3) mg/dL at final end point

in the probenecid group (no measures of variance were reported).

Of those participants with tophi (five overall), disappearance of

tophi occurred in two of three participants in the allopurinol group

and one of two in the probenecid group. None of our other pre-

specified efficacy outcomes were reported, therefore we extracted

no other outcomes. There did not appear to be any between-group

difference in number of adverse effects and no SAEs were reported

in either group.

Allopurinol versus febuxostat

Data from four trials, of which we considered three to be at unclear

risk of bias (Becker 2005; Becker 2010; Schumacher 2008), and

one at high risk of bias (Singal 2011), were considered sufficiently

clinically homogeneous to be pooled (number of participants: 762

with Becker 2005, 2269 with Becker 2010, 1072 with Schumacher

2008, 100 with Singal 2011). The allopurinol dose varied between

300 mg daily (Becker 2005; Singal 2011) and either 100 to 300 mg

(Schumacher 2008), or 200 to 300 mg daily depending on renal

function (Becker 2010). Febuxostat doses varied between 40 or 80

mg daily (Becker 2010); 80 or 120 mg daily (Becker 2005); 80,

120 or 240 mg daily (Schumacher 2008); or 80 mg daily (Singal

2011). All participants in the three larger trials received acute

gout prophylaxis during the first two months of treatment (Becker

2005; Becker 2010; Schumacher 2008), whereas participants in

the smaller trial did not receive any flare prophylaxis (Singal 2011).

Pooled analyses showed that there was no between-group differ-

ence in the frequency of acute gout attacks when allopurinol up to

300 mg daily was compared with febuxostat 80 mg daily (118/569

in allopurinol group versus 132/567 in febuxostat 80 mg group,

RR 0.89, 95% CI 0.71 to 1.10) (Analysis 3.1) based on three trials

(Becker 2005; Schumacher 2008; Singal 2011). A sensitivity anal-

ysis excluding the non-randomised CCT (Singal 2011) did not

alter the results (113/519 in allopurinol group versus 128/517 in

febuxostat 80 mg group, RR 0.88, 95% CI 0.70 to 1.09) (analysis

not shown). Participants taking allopurinol had significantly fewer

acute gout attacks compared with participants taking higher doses

of febuxostat based on two trials (116/519 in allopurinol group

versus 187/519 in febuxostat 120 mg group, RR 0.62, 95% CI

0.51 to 0.76) (Becker 2005; Schumacher 2008), and based on one

trial (61/268 in allopurinol group versus 69/134 in febuxostat 240

mg group, RR 0.44 95% CI 0.34 to 0.58) (Schumacher 2008).

Achievement of a target serum urate less than 6 mg/dL at final

end point (six to 12 months) could be pooled for up to four trials

depending on dose of febuxostat in the control group. One trial

reported no difference between allopurinol 200 or 300 mg daily

and febuxostat 40 mg daily at final end point (six months) (number

achieving target serum urate: 318/755 in allopurinol group versus

342/757 in febuxostat 40 mg daily group, RR 0.93, 95% CI 0.83

to 1.05) (Analysis 3.2) (Becker 2010). Allopurinol was less likely

to achieve the target serum urate when compared with higher

doses of febuxostat: febuxostat 80 mg daily based on four trials

(526/1310 in allopurinol group versus 912/1308 in febuxostat

group, RR 0.55, 95% CI 0.48 to 0.63) (Becker 2005; Becker

2010; Schumacher 2008; Singal 2011); febuxostat 120 mg daily

based on two trials (190/505 in allopurinol group versus 402/

507 in febuxostat group, RR 0.48, 95% CI 0.42 to 0.54) (Becker

2005; Schumacher 2008); or febuxostat 240 mg daily based on one

trial (102/263 in allopurinol group versus 116/126 in febuxostat

group, RR 0.42, 95% CI 0.36 to 0.49) (Schumacher 2008).

A sensitivity analysis of achievement of target serum urate less than

6 mg/dL at final end point (six to 12 months) of allopurinol up

to 300 mg daily versus febuxostat 80 mg daily excluding the non-

randomised CCT (Singal 2011) did not alter the results (508/

1260 in allopurinol group versus 875/1258 in febuxostat group,

RR 0.56, 95% CI 0.48 to 0.65) (data not shown).

There were no between-group difference in the percentage reduc-

tion in tophus area at final end point (12 months) with 50% for

participants on allopurinol 200 or 300 mg daily, 83% for par-

ticipants on febuxostat 80 mg daily and 66% for participants on

febuxostat 120 mg daily (Becker 2005). There was no between-

group differences in the number of tophi, with the exception of

a mean percentage reduction in the number of tophi occurring

in participants on febuxostat 120 mg daily (-1.2) compared with

placebo (-0.3) at the final end point (Becker 2010).

Withdrawals due to adverse effects could be pooled for up to three

trials depending on the dose of febuxostat in the control group.

One trial reported no between-group differences in withdrawals

between allopurinol (200 or 300 mg daily) and febuxostat 40 mg

daily (64/755 withdrawals in allopurinol group versus 49/757 in

febuxostat 40 mg daily group, RR 1.31, 95% CI 0.92to 1.87)

(Analysis 3.3) (Becker 2010). Based on three trials, there were no

between-group differences in withdrawals comparing allopurinol

and febuxostat 80 mg daily (withdrawals: 90/1276 in allopurinol

group versus 98/1279 in febuxostat 80 mg daily group, RR 0.89,

95% CI 0.62 to 1.26) (Analysis 3.3). Based on two trials, there

were also no between-group differences in withdrawals comparing

allopurinol and febuxostat 120 mg daily (withdrawals: 36/521 in



allopurinol group versus 42/520 in febuxostat 120 mg daily group,

RR 0.85, 95% CI 0.56 to 1.31) (Analysis 3.3) (Becker 2005;

Schumacher 2008), and based on one trial, no between-group dif-

ferences in withdrawals comparing allopurinol and febuxostat 240

mg daily (withdrawals: 18/268 in allopurinol group versus 13/134

in febuxostat 240 mg daily group, RR 0.69, 95% CI 0.35 to 1.37)

(Analysis 3.3) (Schumacher 2008). Reasons for withdrawals due to

AEs included abnormal liver function tests, diarrhoea, rashes, up-

per respiratory tract infections and musculoskeletal and connective

tissue disease features (Becker 2005; Becker 2010; Schumacher

2008). Singal 2011 did not report any withdrawals due to AE or

SAE in either group.

We could pool AEs for up to four trials depending on the dose

of febuxostat in the control group. Becker 2010 reported no be-

tween-group differences in AE between allopurinol (200 or 300

mg daily) and febuxostat 40 mg daily (AEs: 433/756 in allopuri-

nol group versus 429/757 in febuxostat 40 mg daily group, RR

1.01, 95% CI 0.93 to 1.10) (Analysis 3.4). Based on four trials, al-

lopurinol resulted in more AEs than febuxostat 80 mg daily (AEs:

850/1327 in allopurinol group versus 802/1329 in febuxostat 80

mg daily group, RR 1.06, 95% CI 1.01 to 1.12) (Analysis 3.4)

(Becker 2005; Becker 2010; Schumacher 2008; Singal 2011), and

based on two trials, allopurinol also resulted in more AEs than

febuxostat 120 mg daily (AEs: 415/516 in allopurinol group ver-

sus 372/520 in febuxostat 120 mg daily group, RR 1.12, 95%

CI 1.05 to 1.20) (Analysis 3.4) (Becker 2005; Schumacher 2008).

Schumacher 2008 reported no between-group differences in AE

between allopurinol and febuxostat 240 mg daily (AEs: 200/268

in allopurinol group versus 98/134 in febuxostat 240 mg daily

group, RR 1.02, 95% CI 0.90 to 1.15) (Analysis 3.4). AEs in-

cluded rashes and mild hypersensitivity, abnormal liver function

tests, upper respiratory tract infections, peripheral oedema, mus-

culoskeletal and connective tissue disease features, gastrointestinal

(including nausea and diarrhoea) and neurological features (in-

cluding headache).

SAE could be pooled for up to three trials depending on the dose

of febuxostat in the control group. Becker 2010 reported no be-

tween-group differences in SAE comparing allopurinol (200 or

300 mg daily) and febuxostat 40 mg daily (SAEs: 31/756 in al-

lopurinol group versus 19/757 in febuxostat 40 mg daily group,

RR 1.63, 95% CI 0.93 to 2.87) (Analysis 3.5). Based on three

trials, there were no between-group differences in SAE comparing

allopurinol and febuxostat 80 mg daily (SAEs: 57/1277 in allop-

urinol group versus 50/1279 in febuxostat 80 mg daily group, RR

1.13, 95% CI 0.71 to 1.82) (Analysis 3.5) (Becker 2005; Becker

2010; Schumacher 2008), and based on two trials, there were

no between-group differences in SAE comparing allopurinol with

febuxostat 120 mg daily (SEAs: 26/521 in allopurinol group ver-

sus 30/520 in febuxostat 120 mg daily group, RR 0.86, 95% CI

0.52 to 1.44) (Analysis 3.5) (Becker 2005; Schumacher 2008).

Schumacher 2008 reported no between-group differences in SAE

comparing allopurinol with febuxostat 240 mg daily (SAEs: 7/

268 in allopurinol group versus 5/134 in febuxostat 240 mg daily

group, RR 0.70, 95% CI 0.23 to 2.16) (Analysis 3.5). SAEs in-

cluded non-specific bacterial infections, coronary artery disease,

lower respiratory tract infections, prostate cancer and death.

There were nine deaths (six with febuxostat and three with allop-

urinol), all reported to be unrelated to the study drugs, in two

trials (Becker 2005; Becker 2010).

Allopurinol versus benzbromarone

We considered data from two trials that compared allopurinol

with benzbromarone to be sufficiently clinically homogeneous to

be pooled (Perez-Ruiz 1999; Reinders 2009a). One trial that in-

cluded 37 participants, judged to be at high risk of bias, compared

allopurinol (100-150 mg daily initially, titrated to 100, 200 or 300

mg daily according to creatinine clearance) with benzbromarone

(100 mg daily titrated with increments of 50 mg daily to 200

mg daily) (Perez-Ruiz 1999). The trialists reported no between-

group difference in the number of acute gout attacks but did not

provide data by treatment group. The second trial that included

65 participants, judged to be at unclear risk of bias, reported no

between-group difference in the frequency of acute gout attacks

at four months (attacks: 0/30 in allopurinol group versus 1/25 in

benzbromarone group, RR 0.28, 95% CI 0.01 to 6.58) (Analysis

4.1) (Reinders 2009a).

Pooled analysis from the two studies of allopurinol and benzbro-

marone (Perez-Ruiz 1999: target 6 mg/dL or less, nine months;

Reinders 2009a: target 5 mg/dL or less, four months) showed there

was no between-group difference with respect to the percentage

of participants achieving the target serum urate (33/55 in allop-

urinol group versus 34/46 in benzbromarone group; pooled RR

0.79, 95% CI 0.56 to 1.11) (Analysis 4.2). No data for our other

pre-specified efficacy outcomes were reported in either trial (and

tophi regression was not reported by treatment group in Perez-Ruiz

1999).

Pooled analysis of withdrawal due to AEs showed no between-

group difference between allopurinol and benzbromarone (3/49

in allopurinol group versus 3/42 in benzbromarone group, RR

0.85, 95% CI 0.21 to 3.52) (Analysis 4.3). Three participants

in the allopurinol group withdrew due to skin rashes, while one

participant in the benzbromarone group withdrew with dizziness

and flushing and another two withdrew after gastrointestinal re-

actions. One additional person treated with benzbromarone was

temporarily taken off of treatment when he developed diarrhoea

and was not included in this analysis as benzbromarone was suc-

cessfully re-started and the AE was determined to be a result of

colchicine (Perez-Ruiz 1999).

In the trial by Reinders 2009a, there was no between-group differ-

ence in the number of participants with AEs (2/30 in allopurinol

group versus 5/25 in benzbromarone group, RR 0.33, 95% CI

0.07 to 1.57) (Analysis 4.4). Two participants in the allopurinol

group experienced rash/skin reactions and five participants in the



benzbromarone group experienced adverse effects (two with gas-

trointestinal symptoms, one with an acute gout attack, one with

dizziness and flushing, and one with an increase in international

normalised ratio) and none was considered serious. In the trial

by Perez-Ruiz 1999, one participant died of cardiac failure three

months after entering study, and the cause of death was considered

to be unrelated to the study medication (and the medication was

not specified).

Allopurinol: intermittent versus continuous

One trial by Bull 1989 including 50 participants, judged to be

at high risk of bias, compared two different allopurinol regimens.

They reported no between-group difference in the number of acute

gout attacks between participants who received continuous allop-

urinol (allopurinol 100 mg daily for the first week, 200 mg daily

for the second week and then maintained continuously by a dose

adequate to keep their sUA level less than 6 mg/dL; this dose was

usually 300 mg daily) and participants who received intermittent

allopurinol (allopurinol starting at 100 mg daily for the first week,

then 200 mg daily for the second week and then 300 mg daily for

six weeks; this protocol could only be performed once every 12

months) during the first year. Thereafter, attacks occurred with re-

duced frequency in the continuous group compared with the inter-

mittent group (attacks: 0/166 in continuous group versus 10/140

in intermittent group, RR 0.04, 95% CI 0.00 to 0.68) (Analysis

5.1). No data for joint pain, function, quality of life, participant

global assessment of treatment success, tophus regression or harms

were provided.

Allopurinol: split-dose versus once-daily allopurinol

One cross-over trial by Rodnan 1975 including 20 participants,

judged to be at high risk of bias, found no between-group differ-

ence in number of participants who achieved a serum urate less

than 6 mg/dL after two weeks of either allopurinol 300 mg daily

or 100 mg three times daily (data not shown).

Further safety assessment of allopurinol

From the UK MHRA pharmacovigilance and drug safety updates

(www.mhra.gov.uk) (accessed 15 January 2014), there were no

new drug safety updates with allopurinol.

A search of the EMEA (www.emea.europa.eu) and Australian Ad-

verse Drug Reactions Bulletin (www.tga.gov.au/adr/aadrb.htm)

(accessed 15 January 2014), found no reports of SAEs of allop-

urinol, but did note the potential drug interactions of allopurinol

with azathioprine, suggesting avoidance of their use together. The

Adverse Drug Reactions Advisory Committee (ADRAC) received

10 reports (since 1980) attributing adverse haematological conse-

quences to this interaction, including one report of a person who

died.

Reports from a search of the US FDA MedWatch (www.fda.gov/

Safety/MedWatch/default.htm) (accessed 15 January 2014), re-

ported the incidence of adverse reactions with allopurinol is less

than 1%. They reported the most common adverse reaction to

allopurinol was skin rash, and recommended treatment be discon-

tinued immediately if a rash develops. In some cases, a skin rash

may be followed by more severe hypersensitivity reactions such as

exfoliative, urticarial and purpuric lesions as well as Stevens-John-

son syndrome (erythema multiforme exudativum) with or with-

out generalised vasculitis.

An oral desensitisation regimen can be used in people with macu-

lopapular rashes, particularly in people with gout who cannot be

treated with uricosurics or other urate-lowering drugs. Fam 2001

performed a retrospective evaluation of an oral desensitisation reg-

imen using gradual dosage-escalation of allopurinol in 32 partici-

pants (30 with gout and two with chronic lymphocytic leukaemia)

whose treatment was interrupted because of a pruritic cutaneous

reaction to the drug. They reported that although pruritic skin

eruptions may recur both during and after desensitisation, most of

these cutaneous reactions could be managed by temporary with-

drawal of allopurinol and dosage adjustment.

The FDA reported on a few cases of reversible clinical hepato-

toxicity in people taking allopurinol, and in some people, asymp-

tomatic rises in serum alkaline phosphatase or transaminase have

been observed. In people with pre-existing liver disease, periodic

liver function tests are recommended during the early stages of

treatment with allopurinol.

In cases where allopurinol (300 to 600 mg daily) is administered

with mercaptopurine or azathioprine, a reduction in dose to ap-

proximately one-third to one-quarter of the usual dose of mercap-

topurine or azathioprine should be made, and subsequent dose

adjustment made on the basis of therapeutic response and the ap-

pearance of toxic effects. The FDA also reported that allopurinol

can cause rare irreversible hepatotoxicity and, on occasions, death.



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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Allopurinol 100-300 mg daily compared with febuxostat 80 mg daily for chronic gout


Settings: primary and secondary care


Comparison: febuxostat 80 mg daily


(95% CI)

No of participants

(studies)


(GRADE)

Comments


Febuxostat 80 mg daily Allopurinol 100-300 mg

daily

Acute gout attacks

Follow-up: up to 24

weeks

233 per 1000 207 per 1000

(165 to 256)

RR 0.89

(0.71 to 1.1)

1136

(3 studies)

⊕⊕©©

low1,2




crease)




crease)

Not statistically signifi-

cant. NNT n/a6


target serum urate


697 per 1000 383 per 1000

(335 to 439)

RR 0.56

(0.48 to 0.65)

2618

(4 studies)

⊕⊕©©

low3,4




lopurinol: 32% fewer with

allopurinol (40% fewer to

25% fewer)

Relative change: 45%

fewer with allopurinol


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http://www.thecochranelibrary.com/view/0/SummaryFindings.html

reduction)

NNTH 4 (95% CI 3 to 5)

Pain reduction - notmea-

sured

See comment See comment Not estimable - See comment Not measured

Function - not measured See comment See comment Not estimable - See comment Not measured

Tophus regression

Follow-up: 52 weeks

See comment See comment Not estimable - See comment There were no between-

group difference in the

percentage reduction in

tophus area at 52 weeks

with 50% for participants

taking allopurinol 200 or

300 mg daily and 83% for

participants taking febux-

ostat 80 mg daily (Becker

2005)


verse effects


77 per 1000 68 per 1000

(48 to 97)

RR 0.89

(0.62 to 1.26)

2555

(3 studies)

⊕⊕⊕©

moderate3,5




urinol: 1% reduction with

allopurinol (3% reduction

to 1% increase)




crease)


cant. NNT n/a6

Serious adverse effects


39 per 1000 44 per 1000

(28 to 71)

RR 1.13

(0.71 to 1.82)

2556

(3 studies)

⊕⊕⊕©

moderate3,5

Absolute risk difference

in serious adverse events

with allopurinol: 0% (2%

reduction to 3% increase)


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crease)


cant. NNT n/a6



CI: confidence interval; RR: risk ratio.






1 Two studies were at unclear risk (Becker 2005; Schumacher 2008), and one study was at high risk (Singal 2011), of performance and

detection bias.2 One study was at high risk of attrition bias (Becker 2005), one at unclear risk of attrition bias (Singal 2011), and one at low risk of

attrition bias (Schumacher 2008).3 Three studies were at unclear risk (Becker 2005; Becker 2010; Schumacher 2008), and one study at high risk of performance and

detection bias (Singal 2011), and one trial at high risk of attrition bias (Becker 2005), whereas one was at unclear risk of attrition bias

(Singal 2011), and the other two studies were at low risk of attrition bias (Becker 2010, Schumacher 2008).4 Three studies used low-dose allopurinol (100 to 300 mg daily depending on renal function) (Becker 2005; Becker 2010; Schumacher

2008).5 Three studies were at unclear risk of reporting bias (Becker 2005; Becker 2010; Schumacher 2008).6 Number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) not applicable (n/a) when result was

not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (www.nntonline.net/visualrx/).

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Allopurinol compared with benzbromarone for people with chronic gout


Settings: primary and secondary care


Comparison: benzbromarone 100-200 mg daily


(95% CI)

No of participants

(studies)


(GRADE)

Comments


Benzbromarone Allopurinol

Acute gout attacks

Follow-up: mean 4

months

40 per 1000 11 per 1000

(0 to 263)

RR 0.28

(0.01 to 6.58)

55

(1 study)

⊕⊕©©

low1,2




crease)




increase)


cant. NNT n/a4

This study used allop-

urinol 100-600 mg daily

(Reinders 2009a)


target serum urate

Follow-up: 4-9 months

739 per 1000 584 per 1000

(414 to 820)

RR 0.79

(0.56 to 1.11)

101

(2 studies)

⊕⊕⊕©

moderate3




lopurinol: 17% reduction

with allopurinol (45% re-

duction to 10% increase)



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crease)


cant. NNT n/a4

Pain reduction - notmea-

sured

See comment See comment Not estimable - See comment Not measured

Function - not measured See comment See comment Not estimable - See comment Not measured

Tophus regression - not

reported

See comment See comment Not estimable - See comment Not reported in 1 study

(Reinders 2009a), while

the other study reported

that 18/20 participants

were cleared of tophi at

24 months but the au-

thors do not provide fur-

ther data for analysis)

(Perez-Ruiz 1999)


verse events

Follow-up: median 4-9

months

71 per 1000 57 per 1000

(13 to 256)

RR 0.80

(0.18 to 3.58)

91

(2 studies)

⊕⊕©©

low1,3




urinol: 1% increase with

allopurinol (10% reduc-

tion to 11% increase)




increase)


cant. NNT n/a4

Serious adverse effects

Follow-up: 4-9 months

See comment See comment Not estimable - See comment ‘ ‘ No adverse effects

were considered serious’’

in the trial by Reinders

2009a and 1 partici-

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pant died of cardiac fail-

ure after entering the

Perez-Ruiz 1999 trial, and

the cause of death was

thought unrelated to the

study medication (which

was not specified)



CI: confidence interval; RR: risk ratio.






1 Small study (65 participants) (Reinders 2009a). Few events resulting in wide confidence interval.2 Open-label study with possible performance and detection bias and unclear risk related to possible attrition bias (Reinders 2009a).3 Open-label studies with possible performance bias and unclear risk related to possible attrition bias (Perez-Ruiz 1999; Reinders 2009a).4 Number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) not applicable (n/a) when result is

not statistically significant. NNT for dichotomous outcomes calculated using Cates NNT calculator (www.nntonline.net/visualrx/).

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D I S C U S S I O N

Summary of main results

This systematic review analysed the evidence from all published

RCT and CCTs of allopurinol in the treatment of chronic gout.

We retrieved 11 trials including 4531 participants with chronic

gout receiving allopurinol. There were seven RCTs (Becker 2005;

Becker 2010; Gibson 1982; Perez-Ruiz 1999; Reinders 2009a;

Schumacher 2008; Taylor 2012), and four CCTs (Bull 1989;

Rodnan 1975; Scott 1966; Singal 2011). Only one trial was at

low risk of bias (Taylor 2012), four at unclear risk of bias (Becker

2005; Becker 2010; Reinders 2009a; Schumacher 2008), and six

trials at high risk of bias (Bull 1989; Gibson 1982; Perez-Ruiz

1999; Rodnan 1975; Scott 1966; Singal 2011).

There was moderate-quality evidence based on one trial (57 par-

ticipants) of no between-group difference in the rate of new or

recurrent gout attacks when allopurinol 300 mg daily was com-

pared with placebo, over a 30-day period, and no between-group

difference in reduction of pain when allopurinol was compared

with placebo over a 10-day period (Taylor 2012). The trial was the

first RCT to our knowledge, that compared allopurinol initiation

during an acute attack of gout to delayed initiation (day 11) and

has shown no difference in the rate of gout attacks or reduction in

pain. There was moderate-quality evidence based on this trial of

a significant difference in the proportion of participants achiev-

ing a target serum urate level, favouring allopurinol 300 mg daily

when compared with placebo over a 30-day period. The NNTB

was 1 (95% CI 1.04 to 1.35). There was moderate-quality evi-

dence based on the pooled data of two trials (453 participants) of

no between-group difference in the number of participants who

withdrew due to AEs or in the number of participants who had

SAEs, when allopurinol was compared with placebo over a 28-

week period (Summary of findings for the main comparison).

There was low-quality evidence based on one small trial (65 par-

ticipants) of no between-group difference in the incidence of acute

gout attacks, when allopurinol up to 300 mg twice daily was com-

pared with benzbromarone up to 200 mg daily over a four-month

period. Based on the pooled results of two small trials (102 par-

ticipants), there was moderate-quality evidence of no between-

group difference in the proportion of participants achieving a tar-

get serum urate level and low-quality evidence of no between-

group difference in the number of participants who withdrew due

to AEs when allopurinol was compared with benzbromarone, over

a four- to nine-month period (Summary of findings 3). In view

of the small number of participants in these trials, they may have

failed to detect a significant difference in these outcomes if one

was truly present.

There was low-quality evidence based on pooled data from three

trials (1136 participants) of no between-group difference in the

incidence of acute gout attacks when allopurinol up to 300 mg

daily was compared with febuxostat 80 mg daily over an eight-

week period, during which co-administration of flare prophylaxis

with naproxen or colchicine was given in two trials (Becker 2005;

Schumacher 2008), and up to a 24-week period (six months) in

the third trial (Singal 2011), which did not provide flare prophy-

laxis. There was low-quality evidence based on pooled data of four

trials (2618 participants) of a significant difference in the propor-

tion of participants achieving target serum urate level favouring

febuxostat 80 mg daily (RR 0.56, 95% CI 0.48 to 0.65; NNTH

4, 95% CI 3 to 5) as the intervention (allopurinol) was less ef-

fective at achieving target sUA than the comparator (febuxostat).

There was moderate-quality evidence based on the pooled data

from three trials (2555 participants) of no between-group differ-

ence in the number of participants who withdrew due to AEs

of allopurinol up to 300 mg daily versus febuxostat 80 mg daily

(Becker 2005; Becker 2010; Schumacher 2008). There was also

moderate-quality evidence based on pooled data from these three

trials (2556 participants) of no between-group difference in the

number of participants with SAEs when allopurinol up to 300

mg daily was compared with febuxostat 80 mg daily over a 24-

to 52-week period (Summary of findings 2). One trial at unclear

risk of bias showed no between-group difference in the percentage

reduction in tophus area at 52 weeks with 50% for participants

on allopurinol 200 or 300 mg daily and 83% for participants on

febuxostat 80 mg daily (Becker 2005).

A further safety assessment on allopurinol was performed by

searching the safety registries including the UK MHRA pharma-

covigilance and drug safety updates (www.mhra.gov.uk), EMEA

(www.emea.europa.eu), Australian Adverse Drug Reactions Bul-

letin (www.tga.gov.au/adr/aadrb.htm) and the US FDA - Med-

Watch (www.fda.gov/Safety/MedWatch/default.htm). The FDA

reported the incidence of adverse reactions was less than 1%, and

that the most common adverse reaction to allopurinol is skin rash,

recommending treatment be discontinued immediately if a rash

develops. In some cases, a skin rash may be followed by more se-

vere hypersensitivity reactions such as exfoliative, urticarial and

purpuric lesions as well as Stevens-Johnson syndrome (erythema

multiforme exudativum) or generalised vasculitis or both.

Overall completeness and applicability ofevidence

We have included 11 published trials (seven RCTs and four CCTs)

examining the efficacy and safety of allopurinol in the treatment

of chronic gout. Two studies assessed allopurinol versus placebo

(Schumacher 2008; Taylor 2012), two studies assessed allopurinol

versus benzbromarone (Perez-Ruiz 1999; Reinders 2009a), while

three RCTs and one CCT examined allopurinol versus febuxostat

(Becker 2005; Becker 2010; Schumacher 2008; Singal 2011). We

summarised these studies in the ’Summary of findings’ tables as

the most clinically relevant comparisons.

The remaining four trials compared allopurinol with other treat-

ments. One RCT compared allopurinol 200 mg daily plus



http://www.mhra.gov.uk

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colchicine 0.5 mg twice daily with colchicine 0.5 mg twice daily

alone (Gibson 1982). One open quasi-randomised CCT com-

pared allopurinol 300 to 600 mg daily to probenecid 1 g daily

increasing to 2 g daily after two weeks (Scott 1966). One quasi-

randomised CCT compared two different allopurinol regimens

(continuous versus intermittent) (Bull 1989). One open cross-over

CCT compared allopurinol 300 mg daily with allopurinol 100

mg three times daily (Rodnan 1975).

Based on the inclusion criteria of these 11 trials (Characteristics

of included studies), the results are most relevant to males, aged

50 to 60 years without any significant renal or liver disease. As

benzbromarone is not currently available in many countries, there

is also a limitation to the applicability of the allopurinol versus

benzbromarone data to current practice. However, allopurinol and

febuxostat are widely available for use in clinical practice.


There was a paucity of high-quality RCTs comparing allopurinol

versus placebo, with only two trials assessing this comparison. As

there was significant clinical heterogeneity between these trials, we

could not pool their efficacy data. One trial judged to be at low risk

of bias and of small size (57 participants) was designed to test the

hypothesis that there is no difference in pain or the frequency of

gout attacks with early versus delayed initiation of allopurinol for

an acute attack of gout (Taylor 2012). In doing this, the partici-

pants received allopurinol versus placebo for a short 10-day period

only (and the total trial duration was 90 days, as colchicine was

continued for 90 days). It was the only trial that assessed pain as an

outcome, and confirmed the hypothesis relating to pain and acute

gout attack frequency over a short period of 10 days. In compari-

son, another trial was judged to be at unclear risk of bias; however,

it was much larger (1072 participants) and had a longer (28 week)

duration of follow-up (Schumacher 2008). There was moderate-

quality evidence based on these two trials that allopurinol 100 to

300 mg daily probably does not reduce the number of acute gout

attacks or pain, but does increase the proportion achieving tar-

get serum urate levels compared with placebo, without increasing

withdrawals due to AEs or SAE rates. Further research may change

the estimates. There was low-quality evidence that there may be

no difference in pain reduction when allopurinol was compared

with placebo over a 10-day period (Taylor 2012), and no differ-

ence in tophus regression (Schumacher 2008). However, limited

data were reported so further research is likely to change the esti-

mates. Neither trial included an assessment of function or partic-

ipant global assessment of treatment success.

There was also a paucity of high-quality RCTs comparing allop-

urinol versus benzbromarone, and we only identified two trials as-

sessing this comparison (Perez-Ruiz 1999; Reinders 2009a). These

trials were limited by their small size (Reinders 2009a: 65 partici-

pants; Perez-Ruiz 1999: 36 participants). In addition, the study by

Reinders 2009a was limited by the short duration (four months)

while the Perez-Ruiz 1999 trial had limitations related to the vari-

able duration of follow-up. Neither trial included a placebo arm

and both trials were open-label rendering them at risk of per-

formance and detection bias. As both of the allopurinol versus

benzbromarone trials were small, there was a risk that they lacked

power to detect differences in the outcomes discussed. There was

low-quality evidence based on these two trials that allopurinol up

to 600 mg daily may not reduce the number of acute gout attacks,

and moderate-quality evidence that allopurinol up to 600 mg daily

may not increase the proportion of participants achieving target

serum urate levels compared with benzbromarone up to 200 mg

daily. There may be no difference in the number of withdrawals

due to AEs or SAE rates. Further research may change the esti-

mates. Tophus regression was not fully reported and pain, func-

tion and participant global assessment of treatment success were

not measured.

There was low-quality evidence from three RCTs (Becker 2005;

Becker 2010; Schumacher 2008), and one CCT (Singal 2011),

comparing allopurinol up to 300 mg daily versus febuxostat 80

mg daily, that allopurinol 100 to 300 mg daily may not reduce

the number of acute gout attacks, and may be less effective in

achieving target serum urate levels compared with febuxostat 80

mg daily, without increasing withdrawals due to AEs or SAE rates.

Three studies were at unclear risk (Becker 2005; Becker 2010;

Schumacher 2008) and one study at high risk (Singal 2011) of

performance and detection bias. One trial was at high risk of at-

trition bias (Becker 2005), whereas one trial was at unclear risk of

attrition bias (Singal 2011), and the other two studies were at low

risk of attrition bias (Becker 2010; Schumacher 2008), therefore

reducing the overall quality of the evidence. Furthermore, three

studies used low dose allopurinol 100 to 300 mg daily (depending

on renal function) compared with a reasonable dose of febuxo-

stat 80 mg daily (Becker 2005; Becker 2010; Schumacher 2008).

There was low-quality evidence that there may be no difference

in tophus regression between allopurinol up to 300 mg daily and

febuxostat 80 mg daily. Further research is likely to change the

estimates. None of these trials included an assessment of pain,

function or participant global assessment of treatment success.

None of the trials appeared to be limited by indirectness or incon-

sistency of results. In addition, there did not appear to be a high

risk of publication bias.

All other comparisons were supported by small, single studies only,

limiting conclusions.

Potential biases in the review process

We are confident that the broad literature search used in this re-

view has captured all relevant studies. Two review author indepen-

dently performed a review of all abstracts and titles as well as data

extraction and risk of bias assessment. Consensus was reached after

discussing any discrepancies thus minimising bias. We performed

a sensitivity analysis where there was concern about risk of bias



of an included non-randomised CCT, and this showed no overall

difference. The biggest limitation of the review process was the

heterogeneity between the trials and the lack of data in a form that

could be extracted for meta-analysis. To address more SAEs, we

also searched regulatory agency reports.

Agreements and disagreements with otherstudies or reviews

Current guidelines by the British Society for Rheumatology

(Jordan 2007), ACR (Khanna 2012), and EULAR (Zhang 2006),

recommendations by Hamburger 2011, and the FDA all recom-

mend starting allopurinol at a low dose of 100 mg daily and in-

creasing the dose slowly, every two to five weeks. Our review iden-

tified trials where allopurinol doses ranged from 100 to 600 mg

daily and highlighted one moderate-quality RCT where a dose

of 300 mg daily of allopurinol was compared with placebo and

is the first to our knowledge that compared allopurinol initiation

during an acute attack of gout to delayed initiation (day 11) and

demonstrated no difference in the rate of gout attacks or reduc-

tion in pain (Taylor 2012). These findings may begin to change

our current clinical practice from delaying the initiation of urate-

lowering therapy until after the acute attack has settled, to start-

ing urate-lowering treatment during an acute attack of gout. The

ACR gout guidelines suggest that urate-lowering therapy could

be started during an acute gout attack, providing that effective

acute management is instituted, and these recommendations are

based on “consensus opinion of experts, case studies, or standard

of care”, rather than RCT evidence, as we have shown (Khanna

2012). While the Taylor 2012 trial was published in November

2012, after the ACR guidelines were published, it does support

ACR recommendations although it may be underpowered (as it

is a small trial with 57 participants) and was of short duration.

Therefore, further high-quality RCT evidence assessing early ver-

sus delayed initiation of urate lowering therapy would be useful.

The ACR recommends gradual upwards titration of the allopuri-

nol dose every two to five weeks to an appropriate maximum dose

for gout, in order to treat to the serum urate target appropriate for

the individual participant. The FDA dosing guide lists 200 to 300

mg daily as typical doses for people with mild gout and doses of

400 to 600 mg daily for people with moderately severe tophaceous

gout. Allopurinol can be used at doses as high as 800 mg daily

to achieve target serum urate level less than 6.0 mg/dL (less than

0.36 mmol/L), although limited safety data were available at these

high doses (Chao 2009 Hamburger 2011). Our review did not

identify any RCTs or CCTs that used allopurinol in doses as high

as 800 mg daily, although one trial titrated the dose to 600 mg

daily, which enabled achievement of the target serum urate target

level (Reinders 2009a).

Our review did not identify any RCTs that compared allopurinol

with probenecid in chronic gout, although did retrieve one CCT

at high risk of bias where limited data were presented (Scott 1966).

The EULAR guidelines (Zhang 2006) and gout recommenda-

tions by Hamburger 2011 suggest a role for probenecid, a urico-

suric agent, as an alternative to allopurinol, based on data from

uncontrolled trials (e.g. Reinders 2007; Stocker 2011), which we

excluded.

In contrast to our review that separately compared allopurinol 100

to 300 mg daily with different doses of febuxostat (40, 80, 120

and 240 mg daily), one systematic review pooled data compar-

ing allopurinol 100 to 300 mg daily with different daily doses of

febuxostat (40, 80, 120 and 240 mg daily) into a single meta-anal-

ysis (Faruque 2013). They reported that participants on febuxo-

stat (all doses combined) were more likely to have a gout attack

when compared with allopurinol 100 to 300 mg daily (RR 1.16,

95% CI 1.02 to 1.31), and more likely to achieve target serum

urate level (RR 1.56, 95% CI 1.22 to 2.0). This is consistent with

our results comparing allopurinol with febuxostat 120 and 240

mg for acute gout attacks and our results comparing allopurinol

with febuxostat 80, 120 and 240 mg for achieving the target serum

urate. However, we found no between-group differences between

allopurinol up to 300 mg daily and febuxostat 80 mg daily with

respect to acute gout attacks and no between-group differences

between allopurinol 200 or 300 mg daily and febuxostat 40 mg

daily with respect to serum urate normalisation. Both reviews re-

ported similar safety data.

In contrast to our review, Faruque 2013 included two trials with

mixed populations of people with hyperuricaemia and chronic

gout (Kamatani 2011a (S13-18); Kamatani 2011b (S44-S49); and

excluded Singal 2011 from their review due to methodological

limitations. While we recognised that Singal 2011 was at high risk

of bias, a sensitivity analysis excluding this trial did not alter our

results for acute gout attack frequency, proportion of participants

achieving target serum urate and total AEs.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Allopurinol is widely considered a safe and effective urate-lower-

ing therapy used to treat chronic gout. However, our review high-

lights the relatively limited availability of high-quality randomised

controlled trial (RCT) evidence to support this view.

Chronic gout results from the deposition of monosodium urate

(uric acid crystals) from supersaturated body fluids and its manifes-

tations include arthritis, tophi, uric acid urolithiasis and nephropa-

thy. Urate-lowering therapy reduces serum urate concentrations

to subsaturating levels preventing the formation and deposition

of urate crystals and consequently reduces the long-term manifes-

tations of chronic gout. However, the initiation of urate-lowering

therapy has been associated with an increased incidence of acute

gout attacks and, therefore, flare prophylaxis (with non-steroidal



anti-inflammatory drugs or colchicine) during this period is rec-

ommended.

Allopurinol 300 mg daily probably does not reduce the incidence

of acute gout attacks when compared with placebo over 30 days,

and allopurinol 100 to 600 mg daily may not reduce acute gout

attacks compared with benzbromarone 100 to 200 mg daily or

febuxostat 80 mg daily over 16 to 24 weeks. While this review

shows there may be similar effects when allopurinol was compared

with benzbromarone for serum urate normalisation (moderate-

quality evidence), it does provide moderate-quality evidence from

one trial (57 participants) that allopurinol is probably more effec-

tive than placebo, and low-quality evidence based on four stud-

ies (2618 participants) that allopurinol 100 to 300 mg daily may

be less effective than febuxostat 80 mg daily in achieving a target

serum urate level at 24 to 52 weeks. Single studies reported no

difference in pain reduction when allopurinol 300 mg daily was

compared with placebo over 10 days, and no difference in tophus

regression when allopurinol 200 to 300 mg daily was compared

with febuxostat 80 mg daily. None of the trials reported on other

outcomes of interest including function, health-related quality of

life or participant global assessment of treatment success, where

further research would be useful for clinical practice.

Our review found low- to moderate-quality evidence indicating

similar effects on withdrawals due to adverse events or serious

adverse events when allopurinol 100 to 600 mg daily was compared

with placebo, benzbromarone 100 to 200 mg daily or febuxostat

80 mg daily. We did not identify any major new concerns regarding

safety of allopurinol based on alerts from regulatory bodies. The

most common adverse reaction with allopurinol was reported to

be skin rash.

We downgraded the evidence due to limitations in study design

indicating potential bias, and possible imprecision.

All other comparisons (allopurinol versus colchicine, allopurinol

versus probenecid, continuous versus intermittent allopurinol and

different doses of allopurinol) were supported by small, single stud-

ies only, limiting conclusions.

Implications for research

Due to the paucity of high-quality RCT evidence comparing al-

lopurinol initiation during an acute attack of gout with delayed

initiation and potentially significant cost implications in changing

our current practice, future trials assessing this would be beneficial

for clinical practice. Future trials of allopurinol versus other urate-

lowering drugs should report on the method of randomisation

and treatment allocation concealment, blinding of study partici-

pants, study personnel and outcome assessment, follow-up of all

participants who entered the trial and complete reporting of out-

comes. To enable comparison and pooling of the results of RCTs,

we suggest that future trials report means with SDs for continu-

ous measures and number of events and total numbers analysed

for dichotomous measures, and assess outcomes recommended by

OMERACT (Outcome Measures in Rheumatology) for studies

of acute gout, including pain, joint swelling, joint tenderness, par-

ticipant global assessment and activity limitations (Schumacher

2009).

A C K N O W L E D G E M E N T S

The authors would like to thank Louise Falzon from Columbia

University Medical Centre for her assistance and valuable com-

ments in the search strategy development.

R E F E R E N C E S

References to studies included in this review

Becker 2005 {published data only}

Becker MA, Schumacher HR Jr, Wortmann RL,

MacDonald PA, Eustace D, Palo WA, et al.Febuxostat

compared with allopurinol in patients with hyperuricemia

and gout. New England Journal of Medicine 2005;353(23):

2450–61.

Becker 2010 {published data only}

Becker MA, Schumacher HR, Espinoza LR, Wells AF,

MacDonald P, Lloyd E, et al.The urate-lowering efficacy and

safety of febuxostat in the treatment of the hyperuricemia

of gout: the CONFIRMS trial. Arthritis Research Therapy

2010;12(2):R63.

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Bull PW, Scott JT. Intermittent control of hyperuricemia in

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Gibson 1982 {published data only}

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(1):59–65.

Perez-Ruiz 1999 {published data only}

Perez-Ruiz F, Calabozo M, Fernandez-Lopez MJ, Herrero-

Beites A, Ruiz-Lucea E, Garcia-Erauskin G, et al.Treatment

of chronic gout in patients with renal function impairment:

an open, randomized, actively controlled study. Journal of

Clinical Rheumatology 1999;5(2):49–55.

Reinders 2009a {published data only}

Reinders MK, Haagsma C, Jansen TL, van Roon EN,

Delsing J, van de Laar MA, et al.A randomised controlled

trial on the efficacy and tolerability with dose escalation of



allopurinol 300-600 mg/day versus benzbromarone 100-

200 mg/day in patients with gout. Annals of the Rheumatic

Diseases 2009;68(6):892–7.

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Rodnan GP, Robin JA, Tolchin SF, Elion GB. Allopurinol

and gouty hyperuricemia. Efficacy of a single daily dose.

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Schumacher 2008 {published data only}

Schumacher HR, Becker MA, Wortmann RL, Macdonald

PA, Hunt B, Streit J, et al.Effects of febuxostat versus

allopurinol and placebo in reducing serum urate in subjects

with hyperuricemia and gout: a 28-week, phase III,

randomized, double-blind, parallel-group trial. Arthritis

and Rheumatism 2008;59(11):1540–8.

Scott 1966 {published data only}

Scott JT. Comparison of allopurinol and probenecid.

Annals of the Rheumatic Diseases 1966;25(6 Suppl):623–6.

Singal 2011 {published data only}

Singal KK, Goyal S, Gupta P, Aggawal BK. Comparison

between allopurinol and febuxostat in management of gout

patients - a prospective study. Bangladesh Journal of Medical

Science 2011;10:257–9.

Taylor 2012 {published data only}

Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie

TA. Initiation of allopurinol at first medical contact for

acute attacks of gout: a randomized clinical trial. American

Journal of Medicine 2012;125(11):1126–34.

References to studies excluded from this review

Akkasilpa 2004 {published data only}

Akkasilpa S, Osiri M, Deesomchok U, Avihingsanon Y.

The efficacy of combined low dose of allopurinol and

benzbromarone compared to standard dose of allopurinol

in hyperuricemia. Journal of the Medical Association of

Thailand 2004;87(9):1087–91.

Akram 2010 {published data only}

Akram M, Mohiuddin E, Hannan A, Usmanghani K.

Comparative study of herbal medicine with allopathic

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Auscher C, Amor B, Brouilhet H, Pasquier C, Delbarre

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Berg 1990 {published data only}

Berg H. Effectiveness and tolerance of long-term uricosuric

treatment [in German]. Zeitschrift fur die Gesamte Innere

Medizin und Ihre Grenzgebiete 1990;45(23):719–20.

Bowie 1967 {published data only}

Bowie EA, Simmonds HA, North JD. Allopurinol in

treatment of patients with gout and chronic renal failure.

New Zealand Medical Journal 1967;66(421):606–11.

Bresnik 1975 {published data only}

Bresnik W, Heiter H, Mertz DP, Holler HD, Lang PD,

Vollmar J. Uric acid lowering effect of allopurinol (300

mg) in single or in fractionated dosage [Vergleich der

harnsauresenkenden wirkung von 300 mg allopurinol bei

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25(36):4862–4.

Brewis 1975 {published data only}

Brewis I, Ellis RM, Scott JT. Single daily dose of allopurinol.

Annals of the Rheumatic Diseases 1975;34(3):256–9.

Chou 1995 {published data only}

Chou CT, Kuo SC. The anti-inflammatory and anti-

hyperuricemic effects of Chinese herbal formula danggui-

nian-tong-tang on acute gouty arthritis: a comparative

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of Chinese Medicine 1995;23(3-4):261–71.

Emmerson 1987 {published data only}

Emmerson BT, Hazelton RA, Whyte IM. Comparison

of the urate lowering effects of allopurinol and diflunisal.

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Fraser 1987 {published data only}

Fraser RC, Davis RH, Walker FS. Comparative trial of

azapropazone and indomethacin plus allopurinol in acute

gout and hyperuricaemia. Journal of the Royal College of

General Practitioners 1987;37(302):409–11.

Goldfarb 1966 {published data only}

Goldfarb E, Smyth CJ. Effects of allopurinol, a xanthine

oxidase inhibitor, and sulfinpyrazone upon the urinary

and serum urate concentrations in eight patients with

tophaceous gout. Arthritis and Rheumatism 1966;9(3):

414–23.

Hanvivadhanakul 2002 {published data only}

Hanvivadhanakul P, Akkasilpa S, Deesomchok U. Efficacy

of benzbromarone compared to allopurinol in lowering

serum uric acid level in hyperuricemic patients. Journal of

the Medical Association of Thailand 2002;85(Suppl 1):40–7.

Kamatani 2011a {published data only}

Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K,

Toshitaka N, et al.An allopurinol-controlled, multicenter,

randomized, open-label, parallel 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. Journal of Clinical Rheumatology

2011;17(4 Suppl 2):S44–9.

Kamatani 2011b {published data only}

Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K,

Nakamura T, et al.An allopurinol-controlled, randomized,

double-dummy, double-blind, parallel 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 3

clinical study. Journal of Clinical Rheumatology 2011;17(4

Suppl 2):S13–8.

Kawenoki-Minc 1970 {published data only}

Kawenoki-Minc E, Eyman E, Sopata I, Werynska-

Przybylska J. The influence of allopurinol on the course of

gout. A study of 28 cases. Reumatologia 1970;8(3):177–92.



Kersley 1966 {published data only}

Kersley GD. Allopurinol in primary gout with and after the

administration of uricosuric agents. Annals of the Rheumatic

Diseases 1966;25(6 Suppl):643–4.

Kuzell 1966 {published data only}

Kuzell WC, Seebach LM, Glover RP, Jackman AE.

Treatment of gout with allopurinol and sulphinpyrazone

in combination and with allopurinol alone. Annals of the

Rheumatic Diseases 1966;25(6 Suppl):634–42.

Matzkies 1992 {published data only}

Matzkies F. Long lasting normalization of uric acid after

combination therapy with 300 mg allopurinol and 60 mg

benzbromarone in patients with gout and hyperuricemia

[Lang anhaltende Normalisierung der Harnsaure nach

einer Kombinations–therapie mit 300mg Allopurinol

and 60mg Benzbromaron bei Patienten mit Gicht und

Hyperurikamie]. Medizinische Klinik 1992;87(9):460–2.

Mituszova 1973 {published data only}

Mituszova L, Erdely E, Benyai B. Use of milurit in the

treatment of gout. Therapia Hungarica 1973;21(3-4):

111–3.

Muller 1993 {published data only}

Muller FO, Schall R, Groenewoud G, Hundt HKL, Van

der Merwe JC, Van Dyk M. The effect of benzbromarone

on allopurinol/oxypurinol kinetics in patients with gout.

European Journal of Clinical Pharmacology 1993;44(1):

69–72.

O’Duffy 1968 {published data only}

O’Duffy JD, Scherbel AL. Treatment of gout and urate

calculi with allopurinol. Cleveland Clinic Quarterly 193;35

(3):145–54.

Panomvana 2008 {published data only}

Panomvana D, Sripradit S, Angthararak S. Higher

therapeutic plasma oxypurinol concentrations might be

required for gouty patients with chronic kidney disease.

Journal of Clinical Rheumatology 2008;14(1):6–11.


Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites

A, Garcia-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol

and benzbromarone for the control of hyperuricaemia. A

pathogenic approach to the treatment of primary chronic

gout. Annals of the Rheumatic Diseases 1998;57(9):545–9.


Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM,

Ruibal A. Effect of urate-lowering therapy on the velocity

of size reduction of tophi in chronic gout. Arthritis and

Rheumatism 2002;47(4):356–60.

Qiu 2008 {published data only}

Qiu R, Shen R, Lin D, Chen Y, Ye H. Treatment of 60 cases

of gouty arthritis with modified Simiao Tang. Journal of

Traditional Chinese Medicine 2008;28(2):94–7.

Radak-Perovic 2013 {published data only}

Radak-Perovic M, Zlatkovic-Svenda M. The efficacy and

tolerability of allopurinol dose escalation in patients with

gout [in Serbian]. Srpski Arhiv za Celokupno Lekarstvo 2013;

141(5-6):333–6.

Reinders 2007 {published data only}

Reinders M, van Roon E, Houtman P, Brouwers J, Jansen

T. Biochemical effectiveness of allopurinol and allopurinol-

probenecid in previously benzbromarone-treated gout

patients. Clinical Rheumatology 2007;26(9):1459–65.

Reinders 2009b {published data only}

Reinders MK, van Roon EN, Jansen TL, Delsing J,

Griep EN, Hoekstra M, et al.Efficacy and tolerability of

urate-lowering drugs in gout: a randomised controlled

trial of benzbromarone versus probenecid after failure of

allopurinol. Annals of the Rheumatic Diseases 2009;68(1):

51–6.

Stamp 2011a {published data only}

Stamp LK, Barclay ML, O’Donnell JL, Zhang M,

Drake J, Frampton C, et al.Relationship between serum

urate and plasma oxypurinol in the management of

gout: determination of minimum plasma oxypurinol

concentration to achieve a target serum urate level. Clinical

Pharmacology & Therapeutics 2011;90(3):392–8.

Stamp 2011b {published data only}

Stamp LK, O’Donnell JL, Zhang MJ, Frampton C, Barclay

ML, Chapman PT. Using allopurinol above the dose based

on creatinine clearance is effective and safe in patients

with chronic gout, including those with renal impairment.

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GG, Day RO. Pharmacokinetic and pharmacodynamic

interaction between allopurinol and probenecid in healthy

subjects. Clinical Pharmacokinetics 2008;47(2):111–8.

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KM, Day RO. Pharmacokinetic and pharmacodynamic

interaction between allopurinol and probenecid in patients

with gout. Journal of Rheumatology 2011;38(5):904–10.

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uric acid metabolism. Annals of the Rheumatic Disease 2003;

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Templeton 1982 {published data only}

Templeton JS. Azapropazone or allopurinol in the treatment

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report. British Journal of Clinical Practice 1982;36(10):

353–8.

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Zöllner N, Schattenkirchner M. Allopurinol in the

treatment of gout and uric acid nephrolithiasis. Deutsche

Medizinische Wochenschrift 1967;92(14):654–60.

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of Pharma Medicine and Biological Sciences 2013;2(4):52–6.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Becker 2005

Methods Study design: phase 3, multicentre, randomised, double-blind, allopurinol-controlled

trial

Study duration: 52 weeks

Participants Number of participants randomised: 762

Number of participants analysed: 756 (2 withdrew without receiving study drug, 4

excluded because baseline sUA was < 8.0 mg/dL (< 0.48 mmol/dL))

Age (mean ± SD): 51.8 ± 12.1 years

Gender: 96% male

Country: USA and Canada

Duration of gout symptoms (mean ± SD): 11.9 ± 9.6 years

Inclusion criteria: preliminary criteria of the ACR for gout and sUA ≥ 8.0 mg/dL

Exclusion criteria: serum creatinine > 1.5 mg/dL or eCLcr rate < 50 mL/minute; preg-

nancy or lactation; use of uric acid-lowering agents, azathioprine, 6-mercaptopurine,

thiazide diuretics or medications containing aspirin (> 325 mg daily) or other salicylates;

BMI > 50; history of xanthinuria, active liver disease or hepatic dysfunction; use of pred-

nisone at > 10 mg daily; change in hormone replacement therapy or oral contraceptive

therapy within the previous 3 months and history of alcohol abuse or alcohol intake of

more than 14 drinks/week

Interventions Group 1: febuxostat 80 mg daily (n = 257; 256 received ≥ 1 dose)

Group 2: febuxostat 120 mg daily (n = 2513)

Group 3: allopurinol 300 mg daily (n = 254; 253 received ≥ 1 dose)

2 weeks’ washout period before randomisation for people already on uric acid-lowering

therapy. Prophylaxis with naproxen (250 mg twice daily) or colchicine (0.6 mg daily)

given to all participants during the washout period and the first 8 weeks of the trial.

Subsequent gout flares treated at the investigators discretion

Outcomes Outcome assessments were made on 3 out of the 7 essential domains proposed by

OMERACT

Outcomes: serum urate (both change in serum urate and serum urate < 6 mg/dL at each

of the last 3-monthly measurements), acute gout attack frequency, tophus regression,

safety as assessed by the number of study participant withdrawals due to AEs and SAEs

Notes Source of funding: TAP Pharmaceutical Products, Inc

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk A computer-generated central randomisa-

tion schedule with a block size of 3 was

used to assign each participant to 1 of the

3 groups



Becker 2005 (Continued)

Allocation concealment (selection bias) Low risk Not described, but considered probable

due to central randomisation

Blinding of participants and personnel

(performance bias)

All outcomes

Unclear risk No details provided other than stating that

this is a double-blind trial

Blinding of outcome assessment (detection

bias)

All outcomes


this is a double-blind trial

Incomplete outcome data (attrition bias)

All outcomes

High risk Some study participants were not ac-

counted for in the efficacy analysis: 4 par-

ticipants excluded because they had sUA <

8 mg/dL at baseline and 3 because they did

not receive the study treatment

Selective reporting (reporting bias) Unclear risk The study protocol was not available, but

the authors only reported on 2 out of the

7 essential OMERACT domains (OMER-

ACT 9)

Other bias Low risk Representatives of TAP Pharmaceutical

Products collected the data and statisticians

at TAP conducted all statistical analysis

Becker 2010

Methods Study design: multicentre, 2-armed double-blind RCT (known as the urate lowering ef-

ficacy and safety of febuxostat in the treatment of hyperuricaemia of gout (CONFIRMS)

trial)

Study duration: 6 months (outcomes were assessed at every 2 months for 6 months in

total)

Stratification by renal function (normal, mildly impaired = eCLcr 60-89 mL/minute, or

moderately impaired = eCLcr 30-59 mL/minute) and prior completion of either of 2

open-label febuxostat or febuxostat/allopurinol extension trials

Participants Number of participants randomised: 2269 with gout (as per ARA criteria)

Number of participants analysed (modified ITT cohort): 2268 (1 participant randomised

to allopurinol was excluded from the efficacy analysis because baseline sUA was < 8.0

mg/dL (< 0.48 mmol/L))

Age (mean): 52.8 years

Gender: 94% male

Country: USA (324 sites)

Duration of gout symptoms (mean): 11.6 years

Inclusion criteria: preliminary criteria of the ACR for gout, sUA of ≥ 8.0 mg/dL, aged

18-85 years. Participant successfully completing either of 2 prior open-label extension

studies were eligible (participants from FACT, FOCUS, APEX were eligible for 1 of




these 2 open-label studies)

Exclusion criteria: secondary hyperuricaemia; xanthinuria; severe renal dysfunction

(eCLcr < 30 mL/minute); hepatic dysfunction (ALT and AST > 1.5 times upper limit of

normal); consumption of > 14 alcoholic drinks/week or a history of alcoholism or drug

abuse within 5 years; or a medical condition that, in the investigator’s opinion, would

interfere with treatment, harms or adherence to the protocol

Interventions Group 1: febuxostat 40 mg daily (n = 757)


Group 3: allopurinol 200 mg daily for moderately impaired renal function or 300 mg

daily for normal to mildly impaired renal function (n = 755; n = 145 for 200 mg

daily; n = 610 for 300 mg daily (modified ITT cohort). 30-day washout period before

randomisation for participants already on uric acid-lowering therapy

Participants received acute gout prophylaxis with either colchicine (0.6 mg daily) or

naproxen (250 mg twice daily) for the duration of the trial, and choice of prophylaxis

was made by the investigator and participant, taking into account prior drug tolerance

and prophylaxis experience. In addition, participants with an eCLcr < 50 mL/minute

were not given naproxen. All participants receiving naproxen prophylaxis also received

lansoprazole 15 mg daily


OMERACT

Outcomes: serum urate (serum urate < 6 mg/dL), acute gout attack frequency, safety as

assessed by the number of study participant withdrawals due to AEs and SAEs

Notes Source of funding: TAP Pharmaceutical Products, Inc

Risk of bias



bias)

Low risk Authors stated that “an interactive voice re-

sponse system was utilized by site person-

nel during screening visits to initiate dou-

ble blind randomisation. Subjects were ran-

domised 1:1:1 on day 1 to receive daily

febuxostat 40 mg, febuxostat 80 mg, or al-

lopurinol”

Allocation concealment (selection bias) Low risk No details provided, but considered prob-

able due to randomisation type


(performance bias)

All outcomes


this was a double-blind trial


bias)

All outcomes


this was a double-blind trial





All outcomes

Low risk Only 1 participant out of 2268 was not in-

cluded in the efficacy analysis because sUA

was < 8 mg/dL; the remainder were in-

cluded in a modified ITT analysis


the authors only reported on 2 out of the

7 essential OMERACT domains (OMER-

ACT 9)

Other bias Low risk Source of funding: TAP Pharmaceutical

Products, Inc

Bull 1989

Methods Study design: single-centre, 2-armed ’quasi-randomised’ CCT

Study duration: 2-4 years and outcome assessed every 3-4 months

Participants Number of participants randomised: 50 participants with gout (as per ARA criteria)

Number of participants analysed: 40

Age (mean): 56 years (continuous group); 53 years (intermittent group)

Gender: 49 were male and 1 female

Country: Charing Cross Hospital Gout Clinic, London, UK

Duration of gout symptoms: 4.5 years (continuous group); 5 years (intermittent group)

Inclusion criteria: all participants satisfied the ARA criteria for gout, had ≥ 3 attacks

of classical gouty arthritis associated with hyperuricaemia and had entered a quiescent

phase. No participant had received allopurinol before the trial

Exclusion criteria: renal failure, renal stones, extensive tophaceous deposits

Interventions Participants were randomly allocated to 1 of 2 groups depending on the last digit in their

hospital file numbers; odd numbers received continuous allopurinol and even numbers

received intermittent allopurinol

Group 1: continuous group received allopurinol 100 mg daily for the first week, 200 mg

daily for the second week and then were maintained continuously by a dose adequate to

keep sUA level < 6 mg/dL (0.36 mmol/L) for men; this dose was usually 300 mg daily

(n = 26; 6 defaulted from follow-up; 20 analysed)

Group 2: intermittent group received allopurinol starting at 100 mg daily for the first

week, then 200 mg daily for the second week and then 300 mg daily for 6 weeks. This

protocol could only be performed once every 12 months (n = 24; 4 defaulted from

follow-up; 20 analysed)

Both groups received NSAID for the first month of starting allopurinol, and in the con-

tinuous group, people with a history of duodenal ulceration were occasionally prescribed

colchicine


OMERACT

Outcomes: acute gout attack frequency and sUA (although no data on specific sUA levels

were presented). No adverse effects were reported



Bull 1989 (Continued)

Notes Outcome assessments were made on 2 out of the 7 essential domains proposed by

OMERACT

Risk of bias



bias)

High risk Quote: “Patients were randomly allocated

to one of 2 study groups depending on the

last digit in their hospital file number; odd

numbers received continuous allopurinol

and even numbers received allopurinol for

2 months of the year only”

Allocation concealment (selection bias) High risk Allocation concealment was not discussed


(performance bias)

All outcomes

Low risk It is unlikely that the outcome (acute gout

attacks) would be altered by blinding


bias)

All outcomes

Low risk It is unlikely that the outcome (acute gout

attacks) would be altered by blinding


All outcomes

Unclear risk 4 participants “defaulted from follow-up”

in intermittent group and 6 “defaulted” in

control group. “4 patients in the intermit-

tent group went onto continuous treatment

at their own request because of recurrent

attacks of gout.” 1 participants in intermit-

tent group received an additional prescrip-

tion of allopurinol from his family doc-

tor. Two participants in continuous group

stopped taking allopurinol of their own vo-

lition but continued to be followed for 3

years in total

Selective reporting (reporting bias) Unclear risk The serum urate outcome was not dis-

cussed in detail; just a sentence: “urate lev-

els fell during treatment periods and rose

after stopping the drug in the intermittent

group”

Other bias Low risk None



Gibson 1982

Methods Study design: single centre RCT

Study duration: ≥ 1 year and 55 participants received treatment for 2 years

Participants Number of participants randomised: 59 participants (stratified for age (< 50 years or >

50 years) and the presence or absence of hypertension)

1 participant was withdrawn from the randomisation schedule and given allopurinol as

he had large tophi

Age (mean ± SD): 49 ± 12 years

Gender: 98% male

Country: Guy’s Hospital, London, UK

Duration of gout symptoms (mean ± SD): 6.4 ± 6.0 years in allopurinol + colchicine

group; 5.4 ± 5.9 years in colchicine alone

Inclusion criteria: all had ≥ 1 attack of acute arthritis associated with a raised blood uric

acid unrelated to drugs or other diseases

Exclusion criteria: none were described specifically, but no participants had renal insuf-

ficiency

No participants were receiving regular hypouricaemic treatment, though many had un-

dergone sporadic treatment in the past. Percentage with tophi: 11% in allopurinol +

colchicine group and 21% in colchicine alone group

Interventions Group 1: allopurinol 200 mg daily + colchicine 0.5 mg twice daily (n = 26)

Group 2: colchicine 0.5 mg twice daily alone (n = 33)

Duration of treatment: ≥ 1 year and 55/59 for 2 years

Outcomes Outcomes were assessed every 2-3 months, then at 12 and 24 months and outcome

assessments were made on 2 out of the 7 essential domains proposed by OMERACT

Outcomes: acute gout attack frequency, serum urate level

Safety as assessed by the number of study participant withdrawals due to AEs and SAEs

were not reported in this trial

Notes An earlier paper reported on the same trial but described 57 participants (Gibson 1980)

. Gibson 1982 included participants with gout defined as having ≥ 1 attack of acute

arthritis associated with a raised blood uric acid unrelated to drugs or other diseases,

while Gibson 1980 referred to participants having primary gout of ≥ 1 year’s duration.

For the purpose of our review we used data in Gibson 1982

Risk of bias



bias)

High risk Quote: “randomly allocated to 2 treatment

groups which were stratified for age (<or

> 50years) and the presence or absence of

hypertension”

Allocation concealment (selection bias) High risk Process of randomisation not described,

other than age-stratification



Gibson 1982 (Continued)


(performance bias)

All outcomes

High risk No blinding


bias)

All outcomes

High risk No blinding


All outcomes

High risk Quotes: “One patient was withdrawn from

the randomisation schedule and given al-

lopurinol because he had large tophi”; “For

various reasons it was not possible to per-

form all investigations for every patient

at each annual assessment. It was there-

fore considered appropriate to analyse only

those results which could be paired with

a previous or subsequent investigation for

analysis by Student’s t-test”; “Allopurinol

compliance was monitored by following se-

rial blood uric acid levels. 3 patients failed

to take allopurinol regularly and were re-

allocated to the colchicine treatment group

for the purposes of analysis”

Selective reporting (reporting bias) High risk Insufficient evidence presented to prove

otherwise

Other bias Unclear risk Unclear

Perez-Ruiz 1999

Methods Study design: single-centre open RCT (open and actively controlled)

Study duration: 9-12 months if serum urate < 6 mg/dL (0.36 mmol/L) was achieved

and 12-24 months for participants who changed from allopurinol to benzbromarone or

participants with tophi


Age (mean ± SD): 64.6 ± 11.3 years

Gender: 86% male

Country: gout clinic in a Rheumatology division, Spain

Duration of gout symptoms (mean ± SD): 8.8 ± 1.2 years

Inclusion criteria: gout as per ARA preliminary criteria; persistent creatinine clearance

20-80 mL/minute, acceptance of urate-lowering therapy

Exclusion criteria: none described

Interventions Group 1: allopurinol 100-150 mg daily initially and then titrated up to 100 mg daily

with creatinine clearance 20-40 mL/minute; 200 mg daily with creatinine clearance 40-

60 mL/minute or 300 mg daily with creatinine clearance 60-80 mL/minute

Group 2: benzbromarone 100 mg daily titrated up with increments of 50-200 mg daily



Perez-Ruiz 1999 (Continued)

Participants in allopurinol group could cross-over to the benzbromarone group if they

did not achieve a target sUA level < 6 mg/dL at maximum doses of allopurinol (corrected

for creatinine clearance). Timing of the titration or cross-over was not specified

Colchicine 0.5-1 mg daily was given for 6 months from the start of urate-lowering

therapy. If colchicine was not tolerated, NSAIDs were used

Outcomes Outcomes were assessed at 9, 12 and 24 months and assessments were made on 3 out

of the 7 essential domains proposed by OMERACT

Outcomes: acute gout attack frequency, serum urate (both change in serum urate and

serum urate < 6 mg/dL), tophus regression, safety as assessed by the number of study

participant withdrawals due to AEs and SAEs

Notes

Risk of bias



bias)

Unclear risk RCT, open and actively controlled

Allocation concealment (selection bias) High risk RCT, open and actively controlled


(performance bias)

All outcomes

Unclear risk RCT, open and actively controlled


bias)

All outcomes

Unclear risk The study outcomes may be influenced by

lack of blinding in this case


All outcomes

High risk Quotes: “One patient died of cardiac fail-

ure 3 months after entering study, so ef-

ficacy could not be evaluated and results

were available for 36 patients”. “One pa-

tient taking allopurinol showed a pruritic

erythematous rash that was attributed to al-

lopurinol, and this drug was withdrawn”

Selective reporting (reporting bias) Low risk Comment: the outcome variables were the

following: reduction of serum urate, the

percentage of reduction from basal serum

urate and proper control of sUA (< 6 mg/

dL). The number of gouty bouts during

follow-up and the reduction of the size of

tophi were also recorded. The efficacy of

urate-lowering drugs on sUA was evaluated

when 2 consecutive determinations of sUA

did not differ in more than 1 mg/dL



Perez-Ruiz 1999 (Continued)

Other bias Unclear risk No comment on washout period and vari-

able follow-up times

Reinders 2009a

Methods Study design: multicentre open-label, RCT

Study duration: 4 months


Number of participants analysed: 65 (3 participants did not meet inclusion criteria)

Age (mean ± SD): 58.6 ± 12.3 years in allopurinol group; 59.6 ± 11.3 years in benzbro-

marone group

Gender: 81% males in allopurinol group; 83% males in benzbromarone group

Country: the Netherlands

Inclusion criteria: diagnosis of gout (with either confirmation of synovial/peri-articular

urate crystals or presence of tophi), creatinine clearance ≥ 50 mL/minute, indication for

serum urate-lowering therapy (presence of tophi or frequent attacks: 2 per year)

Exclusion criteria: history of having used 1 of the study drugs, relevant liver disease

Interventions Group 1: allopurinol starting dose 100 mg daily that increased by 100 mg each week to

300 mg daily. If the treatment was tolerated but the treatment goal of serum urate ≤ 5

mg/dL (≤ 0.30 mmol/L) was not reached at 2 months, then dose was doubled to 300

mg twice daily

Group 2: benzbromarone 100 mg daily. If the treatment was tolerated but the treatment

goal of serum urate ≤ 5 mg/dL was not reached at 2 months, then dose to 200 mg daily

Additional medications included colchicine 0.5-1 mg daily until serum urate ≤ 0.30

mmol/L. If colchicine was not tolerated, then NSAIDs were used

Duration of treatment: 4 months; outcomes assessed at 2 months (before dose escalation)

(stage 1) and then at 4 months (after dose escalation) (stage 2)


OMERACT


serum urate < 6 mg/dL), safety as assessed by the number of study participant withdrawals

due to AEs and SAEs

Notes

Risk of bias



bias)

Low risk Quote: “a computer generated central ran-

domisation schedule with a block size of six

was used”



Reinders 2009a (Continued)

Allocation concealment (selection bias) Low risk It was an open-label study

Quote: “at the time of inclusion in the

study, patients were assigned an inclusion

number by the rheumatologist (blinded)

and subsequently randomised to allopuri-

nol or benzbromarone treatment”


(performance bias)

All outcomes

High risk It was an open-label study


bias)

All outcomes

Unclear risk It was an open-label study. The primary

outcome (serum urate) was unlikely to be

influenced by lack of blinding, whereas the

secondary outcomes including AEs may be

influenced


All outcomes

Unclear risk Quote: “2 patients stopped receiving allop-

urinol and 3 stopped receiving benzbro-

marone because of adverse drug reactions.

10 excluded from analysis from Allopuri-

nol: 6 lost to follow up, 3 protocol vi-

olation. 5 excluded from analysis from

Benzbromarone: 4 loss to follow up; 1 poor

adherence”

Selective reporting (reporting bias) Low risk All planned outcomes as defined in the trial

registration of both trials were reported in

the results

Other bias Low risk None identified

Rodnan 1975

Methods Study design: non-randomised open cross-over CCT including 20 participants with gout

defined by “recurrent paroxysms of monoarticular inflammation characteristic of acute

gouty arthritis, and all had hyperuricaemia”

Study duration: 7 weeks

Participants Number of participants: 20

Country: Pittsburgh rheumatology clinic, USA

Inclusion criteria: “recurrent paroxysms of monoarticular inflammation characteristic of

acute gouty arthritis, and all had hyperuricaemia”

Exclusion criteria: not described

Interventions All participants had a 2-week washout period during which no allopurinol or other

medication known to affect sUA was given

Group 1: allopurinol 300 mg daily given in 3 divided doses of 100 mg for 2 weeks

Group 2: allopurinol 300 mg as a single dose for 2 weeks



Rodnan 1975 (Continued)

All participants then had a second washout period of 1 week during where no allopurinol

was given and then the alternate regimen of allopurinol was given for 2 weeks

Additional medications included colchicine (0.5 mg twice daily or 3 times daily) or

indomethacin (25 mg twice daily to 50 mg 3 times daily) or both throughout the 7-

week trial

Outcomes Outcomes were assessed weekly during the 7-week trial, and assessments were made on

2 out of the 7 essential domains proposed by OMERACT


serum urate < 6 mg/dL (< 0.36 mmol/L)), adverse effects

Notes Outcome assessments were made on 2 out of the 7 essential domains proposed by

OMERACT 9

Risk of bias



bias)

High risk Open-labelled cross-over trial

Allocation concealment (selection bias) Unclear risk Open-labelled cross-over trial


(performance bias)

All outcomes

Unclear risk The outcome is unlikely to be influenced

by lack of blinding


bias)

All outcomes

Unclear risk The outcome is unlikely to be influenced

by lack of blinding


All outcomes

Unclear risk No mention of loss to follow-up (i.e. insuf-

ficient evidence)

Selective reporting (reporting bias) Unclear risk Insufficient evidence. In addition, outcome

assessments were made on 2 out of the 7 es-

sential domains proposed by OMERACT


Schumacher 2008

Methods Study design: multicentre, 3-armed, double-blind RCT (known as the APEX trial)

Study duration: 28 weeks and outcomes were assessed every 4 weeks


Number of participants analysed: 1072

Age: 51-54 years

Gender: 93.6% male (overall)



Schumacher 2008 (Continued)

Country: USA

Inclusion criteria: preliminary criteria of the ACR for gout, sUA concentrations of ≥ 8.

0 mg/dL (≥ 0.48 mmol/L), aged 18-85 year, serum creatinine ≤ 2 mg/dL

Exclusion criteria: intolerance to allopurinol, naproxen, or colchicine; history of renal

calculi; alcohol intake of ≥ 14 drinks/week; hepatic dysfunction (ALT and AST > 1.5

times upper limit of normal); any other significant medical conditions

Interventions Group 1: allopurinol 100 or 300 mg daily based on renal function

Group 2: febuxostat 80, 120 or 240 mg daily based on renal function

Group 3: placebo

Additional medication included colchicine 0.6 mg once daily or naproxen 250 mg twice

daily during the washout period for participants receiving prior urate-lowering therapies

or on randomisation for participants not on prior urate-lowering therapy. These medica-

tions were continued for the first 8 weeks of the study as prophylaxis for gout flares. The

investigators used their own judgement in selecting between naproxen and colchicine,

although colchicine was recommended for participants with a serum creatinine level >

1.5 mg/dL

Study treatment was taken for 28 weeks and outcomes were assessed every 4 weeks

Outcomes The primary efficacy end point was the proportion of participants with the last 3 monthly

serum urate levels < 6.0 mg/dL. Overall, outcome assessments were made on 3 out of

the 7 essential domains proposed by OMERACT


serum urate < 6 mg/dL), tophus regression, safety as assessed by the number of study

participant withdrawals due to AEs and SAEs

Notes Study supported by Takeda Global Research & Development Centre, Inc (of which TAP

Pharmaceutical Products, Inc is a subsidiary). Outcome assessments were made on 3 out

of the 7 essential domains proposed by OMERACT

Risk of bias



bias)

Unclear risk Authors stated that “subjects were ran-

domised in a 2:2:1:2:1 ratio to once daily

febuxostat 80 mg, febuxostat 120 mg,

febuxostat 240 mg, allopurinol, or placebo”

The randomisation was stratified by renal

function, but not further details about the

sequence generation were given

Allocation concealment (selection bias) Unclear risk No details were provided


(performance bias)

All outcomes

Unclear risk No details were provided



Schumacher 2008 (Continued)


bias)

All outcomes

Unclear risk No details were provided


All outcomes

Low risk All efficacy analyses were performed on the

ITT population. If a participant discontin-

ued the study before ≥ 3 sUA levels were

obtained, the participant was considered a

non-responder


the authors did not report on 5 of the 9

outcomes recommended by OMERACT

(OMERACT 9)

Other bias Low risk Study supported by a pharmaceutical com-

pany. Representatives of Takeda Global Re-

search & Development Centre, Inc, col-

lected the data and statisticians at Takeda

Global Research & Development Centre,

Inc, conducted all statistical analysis

Scott 1966

Methods Study design: single-centre open quasi-randomised CCT

Study duration: mean follow-up 18.6 months in allopurinol group; 19.6 months in

probenecid group, and outcomes were assessed at initial assessment, 2 weeks, then 1, 2

and 3 months, and at 3-monthly intervals thereafter

Participants Number of participants randomised: 40 (21 in allopurinol group (1 defaulted); 19 in

uricosuric group (2 defaulted))

Age (mean): 54 years

Gender: 100% male

Country: outpatient clinics at Charing Cross and West London Hospitals, UK

Inclusion criteria: investigator-defined gout (“Gout was, as far as could be determined,

primary and uncomplicated except in some cases with minor degrees of renal functional

impairment”)

Exclusion criteria: none described

Interventions Group 1: allopurinol 300 mg daily and increased when necessary (they did not defined

how) up to 600 mg daily

Group 2: uricosuric (probenecid initially, then 5/17 on probenecid changed to sulphin-

pyrazone 400 mg daily due to ’minor’ adverse effects) and probenecid 1 g daily increasing

to 2 g daily after 2 weeks

All participants also received colchicine 0.5mg twice or 3 times daily and this was with-

drawn “several months after the last attack of gout”

Mean follow-up 18.6 months in allopurinol group and 19.6 months in probenecid

group. Outcomes were assessed at initial assessment, 2 weeks, then 1, 2 and 3 months,



Scott 1966 (Continued)

and at 3-monthly intervals thereafter


OMERACT

Outcomes: acute gout attack frequency, serum urate, tophus regression, safety as assessed

by the number of study participant withdrawals due to AEs

SAEs were not reported

Notes

Risk of bias



bias)

High risk Open trial

Quote: “patients were allocated to treat-

ment with either allopurinol or uricosuric

drugs by reference to the last digit of their

hospital number; those with an even digit

received allopurinol and those with an odd

digit uricosuric therapy”

Allocation concealment (selection bias) High risk Open trial


(performance bias)

All outcomes

Unclear risk -


bias)

All outcomes

Unclear risk It is unlikely that the primary outcome

(serum urate level) would be altered by

blinding


All outcomes

High risk Quote: “one patient taking allopurinol de-

faulted from follow-up. One patient tak-

ing uricosuric therapy defaulted from fol-

low-up and one left the district so that ad-

equate follow-up was impossible. The re-

sults therefore apply to the 20 patients tak-

ing allopurinol and the 17 patients taking

uricosuric therapy”

It is unclear when participants were lost to

follow-up. The losses are balanced between

groups

Selective reporting (reporting bias) Unclear risk Insufficient evidence




Singal 2011

Methods Study design: non-randomised CCT

Study duration: 6 months


Age: not provided - but authors report: “the mean age, sex ratio and mean baseline serum

urate concentration were similar in both groups”

Gender: not provided - but authors report: “the mean age, sex ratio and mean baseline

serum urate concentration were similar in both groups”

Country: Bangladesh

Exclusion criteria: people with renal or hepatic insufficiency; pregnant or lactating

women; people taking azathioprine, 6-mercaptopurine, thiazide diuretics, prednisolone

> 10 mg, oral contraceptive therapy, aspirin or other salicylates and excessive alcohol

Interventions Group 1: allopurinol 300 mg daily (n = 50)


No additional medications (flare prophylaxis) were given


OMERACT

Outcomes: acute gout attack frequency, serum urate (< 6 mg/dL (< 0.36 mmol/L)),

adverse effects

Withdrawals due to AE and SAE were not reported

Notes The trial by Singal 2011 showed no between-group difference in the incidence of acute

gout attacks on allopurinol 300 mg daily; however, the data in this trial were presented

as percentages, which suggested 4.5/50 participants had acute gout attacks in allopurinol

group, which we have rounded up to 5/50 in order to allow for data analysis, compared

with febuxostat 80 mg daily (4/50) (RR 1.25, 95% CI 0.36 to 4.38) (Analysis 3.1). (A

similar need for ’rounding up’ occurred when analysing the AE data for this particular

trial)

Risk of bias



bias)

High risk Non-randomised CCT

Allocation concealment (selection bias) High risk No details provided other than stating that

this was a non-randomised CCT


(performance bias)

All outcomes

High risk No details provided other than stating that



bias)

All outcomes

High risk No details provided other than stating that




Singal 2011 (Continued)


All outcomes

Unclear risk 100 participants were enrolled in the trial

and there are no reported losses to fol-

low-up, no treatment withdrawals, no trial

group changes and no major AEs


the authors did not report on 7 of the 9

outcomes recommended by OMERACT

(OMERACT 9)


Taylor 2012

Methods Study design: single-centre, parallel arm, double-blind, placebo controlled RCT

Study duration: 90 days (as colchicine was continued for 90 days); outcomes assessed at

days 1, 3, 10 and 30 ± 3 days to accommodate weekends or conflicts


Age (mean): 57 years in allopurinol group; 61 years in placebo group

Gender: 100% male

Country: Veteran’s Affairs Medical Centre in White River Junction, Vermont, USA

Inclusion criteria: all met ARA criteria and MSU crystals present. “Patients with acute

gout” (not ’chronic’). “Patients presenting within 7 days of an attack were evaluated”

Exclusion criteria: secondary gout; presence of tophaceous gout; history of congestive

cardiac failure; anticoagulant use; recent creatinine > 1.3 mg/dL (because these partici-

pants should not receive indomethacin); or the use of steroids, colchicine, allopurinol,

uricosurics, chemotherapy or immunosuppressive therapy in the last 6 months

Interventions Group 1: allopurinol 300 mg daily for 10 days

Group 2: placebo for 10 days. After 10 days participants were also commenced on

allopurinol 300 mg daily

All participants received additional medications including colchicine 0.6 mg twice daily

for 90 days and indomethacin 50 mg 3 times daily for 10 days


OMERACT


proportion achieving a target serum urate < 6 mg/dL (< 0.36 mmol/L)), pain (measured

on visual analogue scale), safety as assessed by the number of study participant with-

drawals due to AEs and SAEs, erythrocyte sedimentation rate and C-reactive protein

levels

Notes

Risk of bias




Taylor 2012 (Continued)


bias)

Low risk Participants and evaluators had no access

to the randomisation sequence, which was

determined by the study pharmacist using

a random number generator and kept in

the pharmacy vault

Allocation concealment (selection bias) Low risk As above


(performance bias)

All outcomes

Low risk Double-blind RCT for the first 10 days of

study


bias)

All outcomes

Low risk After 10 days, all participants received al-

lopurinol


All outcomes

Low risk Withdrawals discussed

Selective reporting (reporting bias) Low risk Outcomes stated and reported on

Other bias Low risk None

ACR: American College of Rheumatology; AE: adverse event; ALT: alanine aminotransferase; APEX: Allopurinol and Placebo-Con-

trolled, Efficacy Study of Febuxostat; ARA: American Rheumatism Association; AST: aspartate aminotransferase; BMI: body mass

index; CCT: controlled clinical trial; CI: confidence interval; eCLcr: estimated creatinine clearance; FACT: Febuxostat versus Allop-

urinol Controlled Trial; FOCUS: Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety; ITT: intention to treat;

MSU: monosodium urate; NSAID: non-steroidal anti-inflammatory drug; OMERACT: Outcome Measures in Rheumatology;

RCT: randomised controlled trial; RR: risk ratio; SAE: serious adverse event; SD: standard deviation; sUA: serum uric acid.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Akkasilpa 2004 Incorrect population: the participants did not all have chronic gout. This was an RCT of 94 hyperuricaemic

participants of whom 88 (94%) were symptomatic, and data for just symptomatic participants (assuming

symptomatic means having gout) was not extractable. We have requested clarification from the authors

but no response has been received. They compared allopurinol 300 mg daily with allopurinol 100 mg +

benzbromarone 20 mg daily. All participants received colchicine 0.6 mg daily. Timing of follow-up and

duration of treatment was 1 month. Outcome assessments were made on 2 out of the 7 essential outcome

domains proposed by OMERACT. These study end points included serum urate (change in serum urate

specifically) and acute gout attack frequency. In addition, adverse effects were reported



(Continued)

Akram 2010 Incorrect population: 100 participants with hyperuricaemia were randomly assigned into 2 groups, 50 in

each group. Test group was treated with herbal medicine and control group was treated with allopathic

medicine; allopurinol. The hypouricaemic effect was observed and the level of serum uric acid was measured

before and after treatment. Comparison of data recorded by participants relating to these variables showed

significant differences between test and control groups (P value < 0.05). The efficacy of the test treated

medication (Gouticin) was superior as P value = 0.03. Gouticin was more effective than the allopurinol in

the treatment of hyperuricaemia

Auscher 1974 Incorrect study type: not RCT or quasi-randomised CCT

Berg 1990 Incorrect population: in an open-controlled, randomised trial over 24 weeks, the serum uric acid lowering

effect of a daily dose of allopurinol 100 mg in combination with benzbromarone 20 mg compared with

allopurinol 300 mg alone was investigated on 60 participants with hyperuricaemia. Both preparations

decreased serum uric acid value to normal. In the participants who had received the combination, the

reduction of the serum uric acid level was more pronounced. Tolerance was generally good. Adverse events

were not reported

Bowie 1967 Incorrect study type: not an RCT or quasi-randomised CCT

Bresnik 1975 Incorrect outcome: 28 participants with gout, previously adjusted to allopurinol, were subjected to 4-week

courses of allopurinol 100 mg 3 times daily (Urosin) or 300 mg once daily (Urosin) in random sequences.

No significant differences between serum uric acid levels after fractionated and single-dose administration,

neither were there differences in the aspartate aminotransferase, alanine aminotransferase, gamma glutamyl

transpeptidase, leukocyte and thrombocyte figures. It was concluded that administration of allopurinol in

a single dose daily has no adverse effects

Brewis 1975 Incorrect study type: not an RCT or quasi-randomised CCT

Chou 1995 Incorrect comparator: the traditional Chinese anti-rheumatic herb Danggui-Nian-Tong-Tang (DGNTT)

was studied comparatively with indomethacin and allopurinol to evaluate its anti-inflammatory and anti-

hyperuricaemic effects in people with gout

Emmerson 1987 Incorrect comparator and study type: cross-over study compared the urate-lowering effect of diflunisal, a

fluorinated salicylate with an anti-inflammatory action, to that of allopurinol

Fraser 1987 Incorrect comparator: compared the effects of azapropazone (no longer licensed for gout) and indomethacin

plus allopurinol in the management of acute gout and hyperuricaemia. 93 participants were randomly

allocated to azapropazone (days 1-225) or indomethacin (days 1-28) followed by allopurinol (days 29-

225) on a double-blind double-dummy basis

Goldfarb 1966 Incorrect study type: case series of 8 participants with gout comparing the effects of allopurinol with

sulphinpyrazone on the urinary and serum urate concentrations

Hanvivadhanakul 2002 Incorrect study type: not an RCT or quasi-randomised CCT

Kamatani 2011a Incorrect population: participants did not all have chronic gout



(Continued)

Kamatani 2011b Incorrect population: participants did not all have chronic gout. They were a mixed population of gout

and hyperuricaemia and data for people with gout was not extractable

Kawenoki-Minc 1970 Incorrect study type: study assessed the influence of allopurinol on the course of gout in 28 participants

Kersley 1966 Incorrect study type: allopurinol in primary gout with and after the administration of uricosuric agents in

4 participants

Kuzell 1966 Incorrect study type: 48 cases of gout comparing allopurinol alone versus allopurinol + sulphinpyrazone

Matzkies 1992 Incorrect study type/population (mixed): 210 participants (163 men, 47 women) with gout and hyper-

uricaemia were treated for 3 months with daily doses of allopurinol 300 mg and benzbromarone 60 mg.

During the course of treatment, the uric acid levels decreased to 4.3 ± 1.3 mg/dL in men, and 4.4 ± 1.3

mg/dL in women. Both of these levels differ significantly from the initial levels (P value < 0.001). 3 months

after discontinuation of treatment, uric acid levels were 5.9 ± 1.4 mg/dL in men and 5.7 ± 1.2 mg/dL in

women, levels that again differed significantly from the initial levels (P value < 0.001); however, both levels

were within the therapeutic range of < 6.4 mg/dL

Mituszova 1973 Incorrect study type: not an RCT or quasi-randomised CCT

Muller 1993 No comparator drug in this trial. This was an RCT (open randomised cross-over design) compared allop-

urinol 200 mg once daily versus allopurinol 200 mg once daily + benzbromarone 40 mg once daily

O’Duffy 1968 Incorrect study type: case series of 15 people with gout

Panomvana 2008 Incorrect study type: not an RCT or quasi-randomised CCT

Perez-Ruiz 1998 Incorrect study type: prospective parallel open study

Perez-Ruiz 2002 Incorrect study type: prospective observational study

Qiu 2008 Incorrect comparator: 120 cases of gout were randomly divided into the treatment and control groups

with 60 cases in each group. Modified Simiao Tang (MST) was orally administered to the participants

in the treatment group and allopurinol was orally administered to the participants in the control group.

The clinical effects of 2 groups were evaluated after 1-week treatment and uric acid and C-reactive protein

levels in blood were determined after 1-month treatment

Radak-Perovic 2013 Incorrect study type: not an RCT or quasi-randomised CCT. Allopurinol was increased in step-up dose

scheme (beginning at 100 mg daily then increased for 100 mg every 4 weeks) until therapeutic goal reached

of < 6 mg/dL (< 0.36 mmol/L). So allopurinol 300 mg daily (n = 19) and allopurinol 400-600 mg daily

(n=8) (English abstract, full-paper in Serbian)

Reinders 2007 Incorrect study type: prospective open cohort study

Reinders 2009b No comparator arm in stage 1 for allopurinol

Stamp 2011a Incorrect study type: prospective observational study



(Continued)

Stamp 2011b Incorrect study type

Stocker 2008 Incorrect study type: prospective observational study

Stocker 2011 Incorrect study type: prospective observational study

Takahashi 2003 Incorrect study type

Templeton 1982 Incorrect comparator/population: azapropazone (no longer licensed) was compared with allopurinol in the

treatment of chronic gout or hyperuricaemia or both

Zöllner 1967 Lack of hard data: study compared allopurinol 400 mg daily vs. allopurinol 800 mg daily in people with

gout, many of whom also had kidney stones. There were numerous graphs in the paper but no numbers

extractable or otherwise reported. So excluded for lack of raw data

CCT: controlled clinical trial; OMERACT: Outcome Measures in Rheumatology; RCT: randomised controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

Kumar 2013

Methods Selected participants were randomly assigned to allopurinol 100 mg or febuxostat 40 mg. 2 increments of 100 mg

each were made in allopurinol group at day 10 and day 20 (i.e. at the end of 3 weeks all participants in this group

were taking allopurinol 300 mg (100 mg 3 times daily))

Participants Adults with hyperuricaemia > 8 mg/dL (> 0.48 mmol/L) or gout or both, aged 35-55 years

Interventions Allopurinol 100 mg daily (titrated up to 300 mg daily) versus febuxostat 40 mg daily

Outcomes % change in serum uric acid level and adverse events were recorded

Notes Authors have been contacted to obtain further information about the trial, specifically whether the population all

had chronic gout



D A T A A N D A N A L Y S E S

Comparison 1. Allopurinol versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Acute gout attacks 2 Risk Ratio (M-H, Random, 95% CI) Totals not selected

2 Proportion achieving target

serum urate

2 Risk Ratio (M-H, Random, 95% CI) Totals not selected

3 Withdrawal due to adverse

events

2 453 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.61, 3.09]

4 Total adverse events 2 453 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.89, 1.14]

5 Serious adverse events 2 453 Risk Ratio (M-H, Fixed, 95% CI) 1.93 [0.48, 7.76]

Comparison 2. Allopurinol plus colchicine versus colchicine alone


studies

No. of


1 Acute gout attack frequency 1 59 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.25, 1.63]

Comparison 3. Allopurinol versus febuxostat


studies

No. of


1 Acute gout attacks 3 Risk Ratio (M-H, Random, 95% CI) Subtotals only

1.1 Febuxostat 80 mg daily 3 1136 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.71, 1.10]




serum urate (6-12 months)

4 Risk Ratio (M-H, Random, 95% CI) Subtotals only





3 Withdrawals due to adverse

events

3 Risk Ratio (M-H, Random, 95% CI) Subtotals only





4 Total adverse events 4 Risk Ratio (M-H, Random, 95% CI) Subtotals only







5 Serious adverse events 3 5512 Risk Ratio (M-H, Random, 95% CI) 1.11 [0.85, 1.46]





Comparison 4. Allopurinol versus benzbromarone


studies

No. of




serum urate

2 101 Risk Ratio (M-H, Random, 95% CI) 0.79 [0.56, 1.11]

3 Withdrawal due to adverse

events

2 91 Risk Ratio (M-H, Random, 95% CI) 0.80 [0.18, 3.58]

4 Total adverse effects 1 55 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.07, 1.57]

Comparison 5. Allopurinol: continuous versus intermittent


studies

No. of



Analysis 1.1. Comparison 1 Allopurinol versus placebo, Outcome 1 Acute gout attacks.

Review: Allopurinol for chronic gout

Comparison: 1 Allopurinol versus placebo

Outcome: 1 Acute gout attacks

Study or subgroup Allopurinol Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Taylor 2012 2/26 3/25 0.64 [ 0.12, 3.52 ]

Schumacher 2008 61/268 27/134 1.13 [ 0.76, 1.69 ]

0.05 0.2 1 5 20

Favours Allopurinol Favours Placebo



Analysis 1.2. Comparison 1 Allopurinol versus placebo, Outcome 2 Proportion achieving target serum

urate.



Outcome: 2 Proportion achieving target serum urate

Study or subgroup Allopurinol Placebo Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Schumacher 2008 (1) 102/263 1/127 49.25 [ 6.95, 349.02 ]

Taylor 2012 (2) 25/26 0/25 49.11 [ 3.15, 765.58 ]

0.002 0.1 1 10 500

Favours Placebo Favours Allopurinol

(1) Target serum urate was defined as < 6mg/dl (<0.36 mol/L) for the last 3 serum urate estimations.

(2) Proportion who had achieved serum urate of <6.5 mg/dl.



Analysis 1.3. Comparison 1 Allopurinol versus placebo, Outcome 3 Withdrawal due to adverse events.



Outcome: 3 Withdrawal due to adverse events

Study or subgroup Allopurinol Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Schumacher 2008 18/268 7/134 94.8 % 1.29 [ 0.55, 3.00 ]

Taylor 2012 1/26 0/25 5.2 % 2.89 [ 0.12, 67.75 ]

Total (95% CI) 294 159 100.0 % 1.37 [ 0.61, 3.09 ]

Total events: 19 (Allopurinol), 7 (Placebo)

Heterogeneity: Chi2 = 0.24, df = 1 (P = 0.63); I2 =0.0%

Test for overall effect: Z = 0.76 (P = 0.45)

Test for subgroup differences: Not applicable

0.01 0.1 1 10 100


Analysis 1.4. Comparison 1 Allopurinol versus placebo, Outcome 4 Total adverse events.



Outcome: 4 Total adverse events



Schumacher 2008 200/268 97/134 90.7 % 1.03 [ 0.91, 1.17 ]

Taylor 2012 10/26 13/25 9.3 % 0.74 [ 0.40, 1.37 ]

Total (95% CI) 294 159 100.0 % 1.00 [ 0.89, 1.14 ]


Heterogeneity: Chi2 = 1.12, df = 1 (P = 0.29); I2 =11%



0.01 0.1 1 10 100




Analysis 1.5. Comparison 1 Allopurinol versus placebo, Outcome 5 Serious adverse events.



Outcome: 5 Serious adverse events



Schumacher 2008 7/268 2/134 84.0 % 1.75 [ 0.37, 8.31 ]

Taylor 2012 1/26 0/25 16.0 % 2.89 [ 0.12, 67.75 ]

Total (95% CI) 294 159 100.0 % 1.93 [ 0.48, 7.76 ]


Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%



0.01 0.1 1 10 100


Analysis 2.1. Comparison 2 Allopurinol plus colchicine versus colchicine alone, Outcome 1 Acute gout

attack frequency.


Comparison: 2 Allopurinol plus colchicine versus colchicine alone

Outcome: 1 Acute gout attack frequency

Study or subgroup Allopurinol No allopurinol Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Gibson 1982 5/26 10/33 100.0 % 0.63 [ 0.25, 1.63 ]

Total (95% CI) 26 33 100.0 % 0.63 [ 0.25, 1.63 ]

Total events: 5 (Allopurinol), 10 (No allopurinol)

Heterogeneity: not applicable



0.01 0.1 1 10 100

Favours no allopurinol Favours allopurinol



Analysis 3.1. Comparison 3 Allopurinol versus febuxostat, Outcome 1 Acute gout attacks.


Comparison: 3 Allopurinol versus febuxostat


Study or subgroup Allopurinol Febuxostat Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

1 Febuxostat 80 mg daily

Becker 2005 52/251 55/255 42.0 % 0.96 [ 0.69, 1.35 ]

Schumacher 2008 61/268 73/262 55.0 % 0.82 [ 0.61, 1.10 ]

Singal 2011 5/50 4/50 3.0 % 1.25 [ 0.36, 4.38 ]

Subtotal (95% CI) 569 567 100.0 % 0.89 [ 0.71, 1.10 ]

Total events: 118 (Allopurinol), 132 (Febuxostat)

Heterogeneity: Tau2 = 0.0; Chi2 = 0.80, df = 2 (P = 0.67); I2 =0.0%



Becker 2005 55/251 90/250 47.5 % 0.61 [ 0.46, 0.81 ]

Schumacher 2008 61/268 97/269 52.5 % 0.63 [ 0.48, 0.83 ]

Subtotal (95% CI) 519 519 100.0 % 0.62 [ 0.51, 0.76 ]



Test for overall effect: Z = 4.75 (P < 0.00001)


Schumacher 2008 61/268 69/134 100.0 % 0.44 [ 0.34, 0.58 ]

Subtotal (95% CI) 268 134 100.0 % 0.44 [ 0.34, 0.58 ]




Test for subgroup differences: Chi2 = 15.49, df = 2 (P = 0.00), I2 =87%

0.2 0.5 1 2 5

Favours febuxostat Favours allopurinol



Analysis 3.2. Comparison 3 Allopurinol versus febuxostat, Outcome 2 Proportion achieving target serum

urate (6-12 months).



Outcome: 2 Proportion achieving target serum urate (6-12 months)


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Becker 2010 (1) 318/755 342/757 100.0 % 0.93 [ 0.83, 1.05 ]

Subtotal (95% CI) 755 757 100.0 % 0.93 [ 0.83, 1.05 ]





Becker 2005 (2) 88/242 185/249 25.8 % 0.49 [ 0.41, 0.59 ]

Becker 2010 (3) 318/755 507/756 37.2 % 0.63 [ 0.57, 0.69 ]

Schumacher 2008 (4) 102/263 183/253 27.3 % 0.54 [ 0.45, 0.64 ]

Singal 2011 18/50 37/50 9.6 % 0.49 [ 0.32, 0.73 ]

Subtotal (95% CI) 1310 1308 100.0 % 0.55 [ 0.48, 0.63 ]


Heterogeneity: Tau2 = 0.01; Chi2 = 7.46, df = 3 (P = 0.06); I2 =60%



Becker 2005 (5) 88/242 193/242 45.9 % 0.46 [ 0.38, 0.54 ]

Schumacher 2008 102/263 209/265 54.1 % 0.49 [ 0.42, 0.58 ]

Subtotal (95% CI) 505 507 100.0 % 0.48 [ 0.42, 0.54 ]





Schumacher 2008 102/263 116/126 100.0 % 0.42 [ 0.36, 0.49 ]

Subtotal (95% CI) 263 126 100.0 % 0.42 [ 0.36, 0.49 ]





0.2 0.5 1 2 5




(1) Target serum urate was defined as < 6mg/dl (<0.36 mol/L) at final endpoint (6 months)





Analysis 3.3. Comparison 3 Allopurinol versus febuxostat, Outcome 3 Withdrawals due to adverse events.



Outcome: 3 Withdrawals due to adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Becker 2010 64/755 49/757 100.0 % 1.31 [ 0.92, 1.87 ]

Subtotal (95% CI) 755 757 100.0 % 1.31 [ 0.92, 1.87 ]





Becker 2005 8/253 16/256 15.7 % 0.51 [ 0.22, 1.16 ]

Becker 2010 64/755 61/756 57.8 % 1.05 [ 0.75, 1.47 ]

Schumacher 2008 18/268 21/267 26.5 % 0.85 [ 0.47, 1.57 ]

Subtotal (95% CI) 1276 1279 100.0 % 0.89 [ 0.62, 1.26 ]





Becker 2005 18/253 23/251 52.5 % 0.78 [ 0.43, 1.40 ]

Schumacher 2008 18/268 19/269 47.5 % 0.95 [ 0.51, 1.77 ]

Subtotal (95% CI) 521 520 100.0 % 0.85 [ 0.56, 1.31 ]


0.2 0.5 1 2 5


(Continued . . . )



(. . . Continued)Study or subgroup Allopurinol Febuxostat Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI




Schumacher 2008 18/268 13/134 100.0 % 0.69 [ 0.35, 1.37 ]

Subtotal (95% CI) 268 134 100.0 % 0.69 [ 0.35, 1.37 ]





0.2 0.5 1 2 5


Analysis 3.4. Comparison 3 Allopurinol versus febuxostat, Outcome 4 Total adverse events.



Outcome: 4 Total adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Becker 2010 433/756 429/757 100.0 % 1.01 [ 0.93, 1.10 ]

Subtotal (95% CI) 756 757 100.0 % 1.01 [ 0.93, 1.10 ]





Becker 2005 213/253 205/256 42.0 % 1.05 [ 0.97, 1.14 ]

Becker 2010 433/756 410/756 34.2 % 1.06 [ 0.97, 1.16 ]

Schumacher 2008 200/268 181/267 23.6 % 1.10 [ 0.99, 1.23 ]

0.5 0.7 1 1.5 2


(Continued . . . )



(. . . Continued)Study or subgroup Allopurinol Febuxostat Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Singal 2011 4/50 6/50 0.2 % 0.67 [ 0.20, 2.22 ]

Subtotal (95% CI) 1327 1329 100.0 % 1.06 [ 1.01, 1.12 ]





Becker 2005 215/253 189/251 59.5 % 1.13 [ 1.03, 1.23 ]

Schumacher 2008 200/263 183/269 40.5 % 1.12 [ 1.01, 1.24 ]

Subtotal (95% CI) 516 520 100.0 % 1.12 [ 1.05, 1.20 ]





Schumacher 2008 7/268 5/134 1.2 % 0.70 [ 0.23, 2.16 ]

Schumacher 2008 200/268 98/134 98.8 % 1.02 [ 0.90, 1.16 ]

Subtotal (95% CI) 536 268 100.0 % 1.02 [ 0.90, 1.15 ]





0.5 0.7 1 1.5 2




Analysis 3.5. Comparison 3 Allopurinol versus febuxostat, Outcome 5 Serious adverse events.



Outcome: 5 Serious adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI


Becker 2010 31/756 19/757 21.0 % 1.63 [ 0.93, 2.87 ]

Subtotal (95% CI) 756 757 21.0 % 1.63 [ 0.93, 2.87 ]





Becker 2005 19/253 11/256 13.2 % 1.75 [ 0.85, 3.60 ]

Becker 2010 31/756 28/756 25.9 % 1.11 [ 0.67, 1.83 ]

Schumacher 2008 7/268 11/267 8.1 % 0.63 [ 0.25, 1.61 ]

Subtotal (95% CI) 1277 1279 47.1 % 1.13 [ 0.71, 1.82 ]





Becker 2005 19/253 21/251 18.9 % 0.90 [ 0.49, 1.63 ]

Schumacher 2008 7/268 9/269 7.4 % 0.78 [ 0.30, 2.07 ]

Subtotal (95% CI) 521 520 26.3 % 0.86 [ 0.52, 1.44 ]





Schumacher 2008 7/268 5/134 5.6 % 0.70 [ 0.23, 2.16 ]

Subtotal (95% CI) 268 134 5.6 % 0.70 [ 0.23, 2.16 ]




Total (95% CI) 2822 2690 100.0 % 1.11 [ 0.85, 1.46 ]





0.01 0.1 1 10 100




Analysis 4.1. Comparison 4 Allopurinol versus benzbromarone, Outcome 1 Acute gout attacks.


Comparison: 4 Allopurinol versus benzbromarone


Study or subgroup Allopurinol Benzbromarone Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Reinders 2009a 0/30 1/25 0.28 [ 0.01, 6.58 ]

0.01 0.1 1 10 100

Favours Benzbromarone Favours Allopurinol

Analysis 4.2. Comparison 4 Allopurinol versus benzbromarone, Outcome 2 Proportion achieving target

serum urate.



Outcome: 2 Proportion achieving target serum urate

Study or subgroup Allopurinol Benzbromarone Risk Ratio Weight Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Perez-Ruiz 1999 (1) 12/19 16/17 52.7 % 0.67 [ 0.47, 0.97 ]

Reinders 2009a (2) 21/36 18/29 47.3 % 0.94 [ 0.63, 1.40 ]

Total (95% CI) 55 46 100.0 % 0.79 [ 0.56, 1.11 ]

Total events: 33 (Allopurinol), 34 (Benzbromarone)




0.01 0.1 1 10 100


(1) Target serum urate defined as achieving a level <6mg/dl (3mmol/L)

(2) Target uric acid was defined as achieving a level <0.3mmol/L (5mg/dl)



Analysis 4.3. Comparison 4 Allopurinol versus benzbromarone, Outcome 3 Withdrawal due to adverse

events.



Outcome: 3 Withdrawal due to adverse events


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Perez-Ruiz 1999 1/19 0/17 22.9 % 2.70 [ 0.12, 62.17 ]

Reinders 2009a 2/30 3/25 77.1 % 0.56 [ 0.10, 3.07 ]

Total (95% CI) 49 42 100.0 % 0.80 [ 0.18, 3.58 ]





0.01 0.1 1 10 100

Favours [Benzbromarone] Favours [Allopurinol]

Analysis 4.4. Comparison 4 Allopurinol versus benzbromarone, Outcome 4 Total adverse effects.



Outcome: 4 Total adverse effects


n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Reinders 2009a 2/30 5/25 100.0 % 0.33 [ 0.07, 1.57 ]

Total (95% CI) 30 25 100.0 % 0.33 [ 0.07, 1.57 ]





0.01 0.1 1 10 100




Analysis 5.1. Comparison 5 Allopurinol: continuous versus intermittent, Outcome 1 Acute gout attacks.


Comparison: 5 Allopurinol: continuous versus intermittent


Study or subgroupContinuousAllopurinol

IntermittentAllopurinol Risk Ratio Risk Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Bull 1989 0/166 10/140 0.04 [ 0.00, 0.68 ]

0.01 0.1 1 10 100

Favours Intermittent Favours Continuous

A P P E N D I C E S

Appendix 1. The Cochrane Library

#1 MeSH descriptor Gout explode all trees

#2 gout*:ti,ab

#3 tophus“ti,ab

#4 tophi:ti,ab

#5 tophaceous:ti,ab

#6 #1 or #2 or #3 or #4 or #5

#7 MeSH descriptor Allopurinol, this term only

#8 Abburic:ti,ab

#9 Abopur:ti,ab

#10 Acepurin:ti,ab

#11 Acifugan:ti,ab

#12 Acyprin:ti,ab

#13 Alfadiman:ti,ab

#14 Algut:ti,ab

#15 Alinol:ti,ab

#16 allo*:ti,ab

#17 Allpargin:ti,ab

#18 Allupol:ti,ab



#19 Allura*:ti,ab

#20 Alluri*:ti,ab

#21 Aloprim:ti,ab

#22 Alopur:ti,ab

#23 Aloral:ti,ab

#24 Alosfar:ti,ab

#25 Alpur*:ti,ab

#26 Aluline:ti,ab

#27 Aluprol:ti,ab

#28 Aluron:ti,ab

#29 Alzoprim:ti,ab

#30 Anurate:ti,ab

#31 Apnol:ti,ab

#32 Apo-Tinole:ti,ab

#33 Apronol:ti,ab

#34 Apulonga:ti,ab

#35 Apurin:ti,ab

#36 Apurol:ti,ab

#37 Arnol:ti,ab

#38 Arsol:ti,ab

#39 Artrex:ti,ab

#40 Arturic:ti,ab

#41 Atisuril:ti,ab

#42 Aurigen:ti,ab

#43 Benoxuric:ti,ab

#44 Be-Uric:ti,ab

#45 Bionol:ti,ab

#46 Biuricowas:ti,ab

#47 Bleminol:ti,ab

#48 Caplenal:ti,ab

#49 Capurate:ti,ab

#50 Cellidrin*:ti,ab

#51 Chinnol:ti,ab

#52 Ciploric:ti,ab

#53 Colpuril:ti,ab

#54 Comburic:ti,ab

#55 Cosuric:ti,ab

#56 Dabroson:ti,ab

#57 Darzune:ti,ab

#58 Desatura:ti,ab

#59 Docallopu:it,ab

#60 Duovitan:ti,ab

#61 “dura AL”:ti,ab

#62 Elavil:ti,ab

#63 Embarin:ti,ab

#64 Epidropal:ti,ab

#65 Erloric:ti,ab

#66 Ethipurinol:ti,ab

#67 Etindrax:ti,ab

#68 Facilit:ti,ab

#69 Foligan:ti,ab

#70 Gealgica:ti,ab

#71 Gewapurol:ti,ab



#72 Gichtex:ti,ab

#73 Gotir:ti,ab

#74 Hamarin:ti,ab

#75 Harpagin:ti,ab

#76 Hexanurat:it,ab

#77 Hycemia:ti,ab

#78 Isoric:ti,ab

#79 Jenapurinol:ti,ab

#80 Labopurinol:ti,ab

#81 Labypurol:ti,ab

#82 Lanolone:ti,ab

#83 Licoric:ti,ab

#84 Llanol:ti,ab

#85 Lonol:ti,ab

#86 Lop?ric:ti,ab

#87 Lopur*:ti,ab

#88 Loricid:ti,ab

#89 Lo-Uric:ti,ab

#90 Lysuron:ti,ab

#91 Marinol:ti,ab

#92 Medoric:ti,ab

#93 Mephanol:ti,ab

#94 Milurit:ti,ab

#95 Nilapur:ti,ab

#96 Novo-Purol:ti,ab

#97 Oloprim:ti,ab

#98 Petrazyc:ti,ab

#99 Ponuric:ti,ab

#100 Prinol:ti,ab

#101 Pritanol:ti,ab

#102 Progout:ti,ab

#103 Pureduct:ti,ab

#104 Puricemia:ti,ab

#105 Puricin:ti,ab

#106 Puricos:ti,ab

#107 Puride:ti,ab

#108 Purigan:ti,ab

#109 Purinase:ti,ab

#110 Purinol:ti,ab

#111 Purispec:ti,ab

#112 Puristen:ti,ab

#113 Puritenk:ti,ab

#114 Pyrazol:ti,ab

#115 Ranpuric:ti,ab

#116 Redurate:ti,ab

#117 Remid:ti,ab

#118 Reucid:ti,ab

#119 Rimapurinol:ti,ab

#120 Rinolic:ti,ab

#121 Sigapurol:ti,ab

#122 Sinoric:ti,ab

#123 Soluric:ti,ab

#124 Stradumel:ti,ab



#125 Suspendol:ti,ab

#126 Synol:ti,ab

#127 Synpurinol:ti,ab

#128 Talol:ti,ab

#129 Tipuric:ti,ab

#130 Trianol:ti,ab

#131 Tylonic:ti,ab

#132 Unizuric:ti,ab

#133 Uredimin:ti,ab

#134 Uribenz:ti,ab

#135 Urica*:ti,ab

#136 Uricemil:ti,ab

#137 Uricina:ti,ab

#138 Uricnol:ti,ab

#139 Urico*:ti,ab

#140 Urifugan:ti,ab

#141 Urikoliz:ti,ab

#142 Urinol:ti,ab

#143 Uriprim:ti,ab

#144 Uripurinol:ti,ab

#145 Uritab:ti,ab

#146 Urobenyl:ti,ab

#147 Urogotan:ti,ab

#148 Uroplus:ti,ab

#149 Urosi:ti,ab

#150 Urozyl-SR:ti,ab

#151 Urtias:ti,ab

#152 Valeric:ti,ab

#153 Xandase:ti,ab

#154 Xanol:ti,ab

#155 Xanthomax:ti,ab

#156 Xanturic:ti,ab

#157 Xanurace:ti,ab

#158 Xuric-A:ti,ab

#159 “Z 300”:ti,ab

#160 Zilopur:ti,ab

#161 Zurim:ti,ab

#162 Zygout:ti,ab

#163 Zylapour:ti,ab

#164 Zylic:ti,ab

#165 Zylo*:ti,ab

#166 #7 OR #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or

#25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #

43 or #44 or #45 or #46 or #47 or #48 or #49 or #50 or #51 or #52 or #53 or #54 or #55 or #56 or #57 or #58 or #59 or #60 or #61

or #62 or #63 or #64 or #65 or #66 or #67 or #68 or #69 or #70 or #71 or #72 or #73 or #74 or #75 or #76 or #77 or #78 or #79 or

#80 or #81 or #82 or #83 or #84 or #85 or #86 or #87 or #88 or #89 or #90 or #91 or #92 or #93 or #94 or #95 or #96 or #97 or #

98 or #99 or #100 or #101 or #102 or #103or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111 or #112 or #113 or

#114 or #115 or #116 or #117 or #118 or #119 or #120 or #121 or #122 or #123 or #124 or #125 or #126 or #127 OR #128 OR

#129 OR #130 OR #131 OR #132 OR #133 OR #134 OR #135 OR #136 OR #137 OR #138 or #139 OR #140 OR #141 OR #

142 OR #143 OR #144 OR #145 OR #146 OR #147 OR #148 OR #149 OR #150 OR #151 OR #152 OR #153 OR #154 OR #

155 OR #156 OR #157 OR #158 OR #159 OR #160 OR #161 OR #162 OR #163 OR #164 OR #165

#167 #6 AND #166



Appendix 2. MEDLINE search strategy

1. exp Gout/

2. gout$.tw.

3. tophus.tw.

4. tophi.tw.

5. tophaceous.tw.

6. or/1-5

7. Allopurinol/

8. Abburic.tw.

9. Abopur.tw.

10. Acepurin.tw.

11. Acifugan.tw.

12. Acyprin.tw.

13. Alfadiman.tw.

14. Algut.tw.

15. Alinol.tw.

16. allo$.tw.

17. Allpargin.tw.

18. Allupol.tw.

19. Allura$.tw.

20. Alluri$.tw.

21. Aloprim.tw.

22. Alopur.tw.

23. Aloral.tw.

24. Alosfar.tw.

25. Alpur$.tw.

26. Aluline.tw.

27. Aluprol.tw.

28. Aluron.tw.

29. Alzoprim.tw.

30. Anurate.tw.

31. Apnol.tw.

32. Apo-Tinole.tw.

33. Apronol.tw.

34. Apulonga.tw.

35. Apurin.tw.

36. Apurol.tw.

37. Arnol.tw.

38. Arsol.tw.

39. Artrex.tw.

40. Arturic.tw.

41. Atisuril.tw.

42. Aurigen.tw.

43. Benoxuric.tw.

44. Be-Uric.tw.

45. Bionol.tw.

46. Biuricowas.tw.

47. Bleminol.tw.

48. Caplenal.tw.

49. Capurate.tw.

50. Cellidrin$.tw.

51. Chinnol.tw.



52. Ciploric.tw.

53. Colpuril.tw.

54. Comburic.tw.

55. Cosuric.tw.

56. Dabroson.tw.

57. Darzune.tw.

58. Desatura.tw.

59. Docallopu.tw.

60. Duovitan.tw.

61. dura AL.tw.

62. Elavil.tw.

63. Embarin.tw.

64. Epidropal.tw.

65. Erloric.tw.

66. Ethipurinol.tw.

67. Etindrax.tw.

68. Facilit.tw.

69. Foligan.tw.

70. Gealgica.tw.

71. Gewapurol.tw.

72. Gichtex.tw.

73. Gotir.tw.

74. Hamarin.tw.

75. Harpagin.tw.

76. Hexanurat.tw.

77. Hycemia.tw.

78. Isoric.tw.

79. Jenapurinol.tw.

80. Labopurinol.tw.

81. Labypurol.tw.

82. Lanolone.tw.

83. Licoric.tw.

84. Llanol.tw.

85. Lonol.tw.

86. Lop?ric.tw.

87. Lopur$.tw.

88. Loricid.tw.

89. Lo-Uric.tw.

90. Lysuron.tw.

91. Marinol.tw.

92. Medoric.tw.

93. Mephanol.tw.

94. Milurit.tw.

95. Nilapur.tw.

96. Novo-Purol.tw.

97. Oloprim.tw.

98. Petrazyc.tw.

99. Ponuric.tw.

100. Prinol.tw.

101. Pritanol.tw.

102. Progout.tw.

103. Pureduct.tw.

104. Puricemia.tw.



105. Puricin.tw.

106. Puricos.tw.

107. Puride.tw.

108. Purigan.tw.

109. Purinase.tw.

110. Purinol.tw.

111. Purispec.tw.

112. Puristen.tw.

113. Puritenk.tw.

114. Pyrazol.tw.

115. Ranpuric.tw.

116. Redurate.tw.

117. Remid.tw.

118. Reucid.tw.

119. Rimapurinol.tw.

120. Rinolic.tw.

121. Sigapurol.tw.

122. Sinoric.tw.

123. Soluric.tw.

124. Stradumel.tw.

125. Suspendol.tw.

126. Synol.tw.

127. Synpurinol.tw.

128. Talol.tw.

129. Tipuric.tw.

130. Trianol.tw.

131. Tylonic.tw.

132. Unizuric.tw.

133. Uredimin.tw.

134. Uribenz.tw.

135. Urica$.tw.

136. Uricemil.tw.

137. Uricina.tw.

138. Uricnol.tw.

139. Urico$.tw.

140. Urifugan.tw.

141. Urikoliz.tw.

142. Urinol.tw.

143. Uriprim.tw.

144. Uripurinol.tw.

145. Uritab.tw.

146. Urobenyl.tw.

147. Urogotan.tw.

148. Uroplus.tw.

149. Urosin.tw.

150. Urozyl-SR.tw.

151. Urtias.tw.

152. Valeric.tw.

153. Xandase.tw.

154. Xanol.tw.

155. Xanthomax.tw.

156. Xanturic.tw.

157. Xanurace.tw.



158. Xuric-A.tw.

159. Z 300.tw.

160. Zilopur.tw.

161. Zurim.tw.

162. Zygout.tw.

163. Zylapour.tw.

164. Zylic.tw.

165. Zylo$.tw.

166. or/7-165

167. 6 and 166

168. randomized controlled trial.pt.

169. controlled clinical trial.pt.

170. randomized.ab.

171. placebo.ab.

172. drug therapy.fs.

173. randomly.ab.

174. trial.ab.

175. groups.ab.

176. or/168-175

177. (animals not (humans and animals)).sh.

178. 176 not 177

179. 167 and 178

Appendix 3. EMBASE search strategy

1. exp gout/

2. gout$.tw.

3. tophus.tw.

4. tophi.tw.

5. tophaceous.tw.

6. or/1-5

7. allopurinol/

8. Abburic.tw.

9. Abopur.tw.

10. Acepurin.tw.

11. Acifugan.tw.

12. Acyprin.tw.

13. Alfadiman.tw.

14. Algut.tw.

15. Alinol.tw.

16. allo$.tw.

17. Allpargin.tw.

18. Allupol.tw.

19. Allura$.tw.

20. Alluri$.tw.

21. Aloprim.tw.

22. Alopur.tw.

23. Aloral.tw.

24. Alosfar.tw.

25. Alpur$.tw.

26. Aluline.tw.

27. Aluprol.tw.



28. Aluron.tw.

29. Alzoprim.tw.

30. Anurate.tw.

31. Apnol.tw.

32. Apo-Tinole.tw.

33. Apronol.tw.

34. Apulonga.tw.

35. Apurin.tw.

36. Apurol.tw.

37. Arnol.tw.

38. Arsol.tw.

39. Artrex.tw.

40. Arturic.tw.

41. Atisuril.tw.

42. Aurigen.tw.

43. Benoxuric.tw.

44. Be-Uric.tw.

45. Bionol.tw.

46. Biuricowas.tw.

47. Bleminol.tw.

48. Caplenal.tw.

49. Capurate.tw.

50. Cellidrin$.tw.

51. Chinnol.tw.

52. Ciploric.tw.

53. Colpuril.tw.

54. Comburic.tw.

55. Cosuric.tw.

56. Dabroson.tw.

57. Darzune.tw.

58. Desatura.tw.

59. Docallopu.tw.

60. Duovitan.tw.

61. dura AL.tw.

62. Elavil.tw.

63. Embarin.tw.

64. Epidropal.tw.

65. Erloric.tw.

66. Ethipurinol.tw.

67. Etindrax.tw.

68. Facilit.tw.

69. Foligan.tw.

70. Gealgica.tw.

71. Gewapurol.tw.

72. Gichtex.tw.

73. Gotir.tw.

74. Hamarin.tw.

75. Harpagin.tw.

76. Hexanurat.tw.

77. Hycemia.tw.

78. Isoric.tw.

79. Jenapurinol.tw.

80. Labopurinol.tw.



81. Labypurol.tw.

82. Lanolone.tw.

83. Licoric.tw.

84. Llanol.tw.

85. Lonol.tw.

86. Lop?ric.tw.

87. Lopur$.tw.

88. Loricid.tw.

89. Lo-Uric.tw.

90. Lysuron.tw.

91. Marinol.tw.

92. Medoric.tw.

93. Mephanol.tw.

94. Milurit.tw.

95. Nilapur.tw.

96. Novo-Purol.tw.

97. Oloprim.tw.

98. Petrazyc.tw.

99. Ponuric.tw.

100. Prinol.tw.

101. Pritanol.tw.

102. Progout.tw.

103. Pureduct.tw.

104. Puricemia.tw.

105. Puricin.tw.

106. Puricos.tw.

107. Puride.tw.

108. Purigan.tw.

109. Purinase.tw.

110. Purinol.tw.

111. Purispec.tw.

112. Puristen.tw.

113. Puritenk.tw.

114. Pyrazol.tw.

115. Ranpuric.tw.

116. Redurate.tw.

117. Remid.tw.

118. Reucid.tw.

119. Rimapurinol.tw.

120. Rinolic.tw.

121. Sigapurol.tw.

122. Sinoric.tw.

123. Soluric.tw.

124. Stradumel.tw.

125. Suspendol.tw.

126. Synol.tw.

127. Synpurinol.tw.

128. Talol.tw.

129. Tipuric.tw.

130. Trianol.tw.

131. Tylonic.tw.

132. Unizuric.tw.

133. Uredimin.tw.



134. Uribenz.tw.

135. Urica$.tw.

136. Uricemil.tw.

137. Uricina.tw.

138. Uricnol.tw.

139. Urico$.tw.

140. Urifugan.tw.

141. Urikoliz.tw.

142. Urinol.tw.

143. Uriprim.tw.

144. Uripurinol.tw.

145. Uritab.tw.

146. Urobenyl.tw.

147. Urogotan.tw.

148. Uroplus.tw.

149. Urosin.tw.

150. Urozyl-SR.tw.

151. Urtias.tw.

152. Valeric.tw.

153. Xandase.tw.

154. Xanol.tw.

155. Xanthomax.tw.

156. Xanturic.tw.

157. Xanurace.tw.

158. Xuric-A.tw.

159. Z 300.tw.

160. Zilopur.tw.

161. Zurim.tw.

162. Zygout.tw.

163. Zylapour.tw.

164. Zylic.tw.

165. Zylo$.tw.

166. or/7-165

167. 6 and 166

168. (random$ or placebo$).ti,ab.

169. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab.

170. controlled clinical trial$.ti,ab.

171. RETRACTED ARTICLE/

172. or/168-171

173. (animal$ not human$).sh,hw.

174. 172 not 173

175. 167 and 174



H I S T O R Y

Protocol first published: Issue 3, 2006

Review first published: Issue 10, 2014

Date Event Description

14 November 2012 Amended New authors took over the protocol, and updated methods in line with current Cochrane Col-

laboration guidance

3 September 2008 Amended Converted to new review format

C O N T R I B U T I O N S O F A U T H O R S

RS drafted the review and all authors contributed to the final version.

D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

Internal sources

• University Hospital Southampton NHS Foundation Trust, UK.

In-kind support

• Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University,

Australia.

In-kind support

• Division of Rheumatology, University of British Columbia, Vancouver, Canada.

In-kind support

• Institute for Work & Health, Toronto, Canada.

In-kind support

External sources

• No sources of support supplied



D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

We clarified that we excluded mixed populations in the review; included search of registries for serious adverse effects and specified the

other sources of bias we looked for: whether there was a carry-over effect from previous therapies, whether appropriate co-intervention

(e.g. colchicine or non-steroidal anti-inflammatory drugs) were administered and whether any pre-administered interventions could

diminish the effect of the subsequent randomised intervention.

We replaced the primary and secondary outcomes by a list of major outcomes (i.e. those presented in the ’Summary of findings’ tables)

in the review. This was done to implement GRADE and the use of ’Summary of findings’ tables.

N O T E S

None.



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