Abstract
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.
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.
Plain language summary
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 comparisons were supported by small, single studies only, limiting conclusions.
Summary of findings
Summary of findings for the main comparison. Allopurinol compared with placebo for chronic gout.
| 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) | Quality of the evidence (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 attacks with allopurinol: 4% (21% reduction to 12% increase) Relative change: 36% reduction with allopurinol (88% reduction to 252% increase) NNTB n/a2 This study used allopurinol 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 target serum urate with allopurinol: 96% (86% to 106% increase) Relative change: 48% increase with allopurinol (215% to 76,458% increase) 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 reported, 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 adverse 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 | Absolute risk difference in withdrawals due to adverse events with allopurinol: 2% increase (3% reduction to 6% increase) Relative change: 37% increase with allopurinol (39% reduction to 209% increase) NNT n/a2 |
| Serious adverse events Follow‐up: 0‐28 weeks | 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% increase (1% reduction to 4% increase) Relative change: 93% increase with allopurinol (52% reduction to 676% 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).
Summary of findings 2. Allopurinol 100‐300 mg daily compared with febuxostat 80 mg daily for chronic gout.
| Allopurinol 100‐300 mg daily compared with febuxostat 80 mg daily for chronic gout | ||||||
| Patient or population: people with chronic gout Settings: primary and secondary care Intervention: allopurinol 100‐300 mg daily Comparison: febuxostat 80 mg daily | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| 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 | Absolute reduction in attacks with allopurinol: 2% (7% reduction to 3% increase) Relative change: 11% reduction with allopurinol (29% reduction to 10% increase) Not statistically significant. NNT n/a6 |
| Proportion achieving target serum urate Follow‐up: 24‐52 weeks | 697 per 1000 | 383 per 1000 (335 to 439) | RR 0.56 (0.48 to 0.65) | 2618 (4 studies) | ⊕⊕⊝⊝ low3,4 | Absolute risk difference in proportion achieving target serum urate with allopurinol: 32% fewer with allopurinol (40% fewer to 25% fewer) Relative change: 45% fewer with allopurinol (52% reduction to 37% reduction). NNTH 4 (95% CI 3 to 5) |
| Pain reduction ‐ not measured | 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 febuxostat 80 mg daily (Becker 2005) |
| Withdrawal due to adverse effects Follow‐up: 24‐52 weeks | 77 per 1000 | 68 per 1000 (48 to 97) | RR 0.89 (0.62 to 1.26) | 2555 (3 studies) | ⊕⊕⊕⊝ moderate3,5 | Absolute risk difference in withdrawals due to adverse events with allopurinol: 1% reduction with allopurinol (3% reduction to 1% increase) Relative change: 11% reduction with allopurinol (38% reduction to 26% increase). Not statistically significant. NNT n/a6 |
| Serious adverse effects Follow‐up: 24‐52 weeks | 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) Relative change: 13% increase with allopurinol (29% reduction to 82% increase) Not statistically significant. NNT n/a6 |
| *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. | ||||||
| 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 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/).
Summary of findings 3. Allopurinol compared with benzbromarone for people with chronic gout.
| Allopurinol compared with benzbromarone for people with chronic gout | ||||||
| Patient or population: people with chronic gout Settings: primary and secondary care Intervention: allopurinol 100‐600 mg daily Comparison: benzbromarone 100‐200 mg daily | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect (95% CI) | No of participants (studies) | Quality of the evidence (GRADE) | Comments | |
| Assumed risk | Corresponding risk | |||||
| 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 | Absolute reduction in attacks with allopurinol: 4% (14% reduction to 6% increase) Relative change: 72% reduction with allopurinol (99% reduction to 558% increase) Not statistically significant. NNT n/a4 This study used allopurinol 100‐600 mg daily (Reinders 2009a) |
| Proportion achieving 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 | Absolute risk difference in proportion achieving target serum urate with allopurinol: 17% reduction with allopurinol (45% reduction to 10% increase) Relative change: 21% reduction with allopurinol (44% reduction to 11% increase) Not statistically significant. NNT n/a4 |
| Pain reduction ‐ not measured | 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 authors do not provide further data for analysis) (Perez‐Ruiz 1999) |
| Withdrawal due to adverse 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 | Absolute risk difference in withdrawals due to adverse events with allopurinol: 1% increase with allopurinol (10% reduction to 11% increase) Relative change: 20% reduction with allopurinol (82% reduction to 258% increase) Not statistically significant. 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 participant died of cardiac failure after entering the Perez‐Ruiz 1999 trial, and the cause of death was thought unrelated to the study medication (which was not specified) |
| *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. | ||||||
| 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 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/).
Background
Description of the condition
Gout is the most common inflammatory arthritis in men over the age of 40 years, and has increasing prevalence among postmenopausal 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 requires 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 commonly 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 important 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 target 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:
uricostatic drugs, which reduce urate production such as xanthine oxidase (XO) inhibitors, including allopurinol and febuxostat;
uricosuric drugs, which increase urate excretion, including probenecid, benzbromarone and sulphinpyrazone;
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 gradually 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 impairment, provided that the person receives adequate education and monitoring for drug toxicity (including measurement of transaminase 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 xanthine 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, interstitial nephritis and death (Wortmann 2002). Therefore, it is clinically relevant to review the benefit and safety of allopurinol for the treatment of chronic gout systematically.
Objectives
To assess the efficacy and safety of allopurinol compared with placebo and other urate‐lowering therapies for treating chronic gout.
Methods
Criteria for considering studies for this review
Types of studies
We included all randomised controlled trials (RCTs) or quasi‐randomised controlled clinical trials (CCTs) comparing allopurinol with another therapy (placebo, no treatment or other urate‐lowering 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 arthritis 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, radiographic and laboratory.
More than one attack of acute arthritis.
Maximum inflammation developed within one day.
Monoarthritis attack.
Redness observed over joints.
First metatarsophalangeal joint painful or swollen.
Unilateral first metatarsophalangeal joint attack.
Unilateral tarsal joint attack.
Tophus (proved or suspected).
Hyperuricaemia.
Asymmetric swelling within a joint on x‐ray film.
Subcortical cysts without erosions on x‐ray film.
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:
placebo;
no treatment;
another urate‐lowering therapy including febuxostat, probenecid, benzbromarone, sulphinpyrazone, pegloticase or rasburicase;
one regimen of allopurinol versus another;
a combination of urate‐lowering therapies.
Types of outcome measures
The outcome measures were based on the 2010 Outcome Measures 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:
frequency of acute gout attacks and the number of participants with an acute gout attack was the preferred dichotomous outcome;
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);
pain (e.g. as measured on the visual analogue scale (VAS), numerical rating scale (NRS), Likert scales or qualitative scales);
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);
tophus regression, using physical measurement techniques (e.g. Vernier callipers) or ultrasound‐guided measurements (Dalbeth 2011);
proportion of participant withdrawals due to AE;
proportion of participants with serious adverse events (SAEs).
Minor outcomes
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);
participant global assessment of treatment success;
proportion of participants with AEs.
Search methods for identification of studies
Electronic searches
We searched the following electronic databases from inception:
the Cochrane Central Register of Controlled Trials (CENTRAL) 14 January 2014 (Appendix 1);
Ovid MEDLINE 1948 to 14 January 2014 (Appendix 2);
EMBASE 1980 to 14 January 2014 (Appendix 3).
We applied no language restrictions.
Searching other resources
We searched abstracts from the two major international rheumatology 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 results of the search to identify trials that fulfilled our inclusion criteria. We reviewed titles and abstracts and, if more information was required to determine whether a trial met the inclusion criteria, we obtained the full text. We kept a record for the reasons for excluding studies and resolved any disagreements by discussion 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 relevant information from the included trials including study design, characteristics of study population, treatment regimen and duration, 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 assessing the bias in each of the following domains: random sequence generation; allocation concealment; blinding of participants, personnel and outcome assessors; completeness of outcome data; selective 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 diminished 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 sufficient 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 measure of treatment effect. SMDs larger than zero indicated a beneficial effect of allopurinol. An SMD of 0.2 indicated a small beneficial 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 multiplying the SMD by a typical among‐person SD using a familiar 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 intervention groups for trials with multiple treatment groups, or alternatively, by including only the pair with accepted drug dosages (Higgins 2011c).
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 number 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 Systematic Reviews 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 included studies were similar with respect to study participants, intervention groups, outcome measures and timing of outcome.
For studies judged as clinically similar, we assessed statistical heterogeneity using the I2 statistic (Deeks 2011). We used the following thresholds for the interpretation of the I2 statistic: 0% to 40% heterogeneity might not be important, 30% to 60% represented moderate heterogeneity, 50% to 90% represented substantial 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 attempt 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 participants 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 reporting 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 characteristics compared with gout in men (Harrold 2006).
Therefore, we planned the following subgroup analyses if sufficient data were available:
participant's age (65 years or greater or less than 65 years);
gender (men versus women).
We had planned to extract the outcome 'acute gout attacks' separately 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 considering the overlap of the CIs of the summary estimates in the two subgroups with non‐overlap of the CIs indicating statistical significance. 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 randomisation, 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 random‐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 evidence, the magnitude of effect of the interventions examined and the sum of available data on our seven main outcomes (participant‐reported reduction in acute gout attack frequency, proportion of participants achieving a target serum urate level, joint pain reduction, function, tophus regression, number of study participant 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 outcomes using the GRADE approach (Schünemann 2011b).
The 'Summary of findings' tables show the three most clinically relevant 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 difference using the risk difference statistic in Review Manager 5 (RevMan 2011), and expressed the result as a percentage; we calculated 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.
Results
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).
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 studies table.
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 alternative 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 "diagnosis 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 characteristic 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 delayed 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 trials compared allopurinol with benzbromarone (Perez‐Ruiz 1999; Reinders 2009a). Four trials compared allopurinol with febuxostat (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 assessed 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, double‐blind RCT (the Allopurinol and Placebo‐Controlled, Efficacy Study of Febuxostat (APEX) trial) including 1072 participants, 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‐lowering 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 investigator 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 treatment 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 assessments 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 presenting within seven days of onset of an acute attack of crystal‐confirmed gout and who met the ARA criteria and compared allopurinol 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 medications including colchicine 0.6 mg twice daily for 90 days and indomethacin 50 mg three times daily for 10 days. Outcome assessments 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 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 participants 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 primary 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 essential 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 double‐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 OMERACT. 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 of study participant withdrawals due to AEs and SAEs were also 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) including 2269 participants with gout (as per ARA criteria) that compared allopurinol 200 or 300 mg daily (depending on renal function) with febuxostat 40 or 80 mg daily, over six months and outcomes 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 prophylaxis was made by the investigator and participant, taking into account prior drug tolerance and prophylaxis experience. In addition, 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 AEs and SAEs were also reported.
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 including 100 participants with gout (as per ARA criteria) that compared 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 reported, but AEs were reported.
Allopurinol versus benzbromarone
Perez‐Ruiz 1999 performed a single‐centre open RCT in 37 participants 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 increments 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. Duration 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 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.
Reinders 2009a performed a multicentre open RCT in 65 participants with gout (confirmed by microscopic evidence of urate crystals 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 treatment was tolerated but the treatment goal of serum urate 0.30 mmol/L or less was not reached at two months, then the allopurinol dose was doubled to 300 mg twice daily and the benzbromarone 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 proposed by OMERACT. 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). Safety as assessed by the number of study participant withdrawals due to AEs and SAEs were also reported.
Allopurinol: intermittent versus continuous
Bull 1989 conducted a single‐centre, two‐armed "quasi‐randomised" CCT including 50 participants with gout (as per ARA criteria), which compared two different allopurinol regimens: continuous 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 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 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, participants 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) including 20 participants with gout defined by "recurrent paroxysms of monoarticular inflammation characteristic of acute gouty arthritis, 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 OMERACT. 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 population, 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 reasons 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.
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
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 randomisation schedule with block sizes of three to six to randomise participants (Becker 2005; Reinders 2009a); one trial used an interactive voice response system to initiate double‐blind randomisation (Becker 2010), and one trial used a random number generator (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 (detection 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 (performance 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 blinding 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 remainder were included in a modified intention‐to‐treat (ITT) analysis. Schumacher 2008 reported that all efficacy analyses were performed on an ITT population and Taylor 2012 discussed all withdrawals. 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 treatment 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 continued to be followed for three years in total. Reinders 2009a reported that 10 participants were excluded from analysis from the allopurinol group (six lost to follow‐up, three due to protocol violation and one not mentioned in results) while five participants were excluded 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%) participants 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 incomplete 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 appropriate co‐intervention (e.g. colchicine or NSAIDs) were administered and whether any pre‐administered interventions could diminish 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: Table 1; Table 2; Table 3
Allopurinol versus placebo
While the efficacy data from the two trials that compared allopurinol with placebo could not be pooled due to lack of clinical homogeneity with differences in trial design, they did report similar 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 requiring 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.
1.1. Analysis.
Comparison 1 Allopurinol versus placebo, Outcome 1 Acute gout attacks.
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 allopurinol 300 mg daily (Taylor 2012). They reported no between‐group difference in the rate of new or recurrent gout attacks between 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 participants 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 2008 reported no between‐group differences in number of tophi or tophus regression but did not provide the data. Neither trial provided data for function, participant global assessment of treatment success or quality of life.
1.2. Analysis.
Comparison 1 Allopurinol versus placebo, Outcome 2 Proportion achieving target serum urate.
Pooled analysis showed no between‐group difference in the number of participants who withdrew due to AEs (19/294 in allopurinol 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.
1.3. Analysis.
Comparison 1 Allopurinol versus placebo, Outcome 3 Withdrawal due to adverse events.
1.4. Analysis.
Comparison 1 Allopurinol versus placebo, Outcome 4 Total adverse events.
1.5. Analysis.
Comparison 1 Allopurinol versus placebo, Outcome 5 Serious adverse events.
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 receiving four doses of allopurinol) from gastroenteritis, pneumonia, 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.
2.1. Analysis.
Comparison 2 Allopurinol plus colchicine versus colchicine alone, Outcome 1 Acute gout attack frequency.
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 difference 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 analysis 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).
3.1. Analysis.
Comparison 3 Allopurinol versus febuxostat, Outcome 1 Acute gout attacks.
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).
3.2. Analysis.
Comparison 3 Allopurinol versus febuxostat, Outcome 2 Proportion achieving target serum urate (6‐12 months).
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 reduction in tophus area at final end point (12 months) with 50% for participants on allopurinol 200 or 300 mg daily, 83% for participants 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 differences 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, upper 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.
3.3. Analysis.
Comparison 3 Allopurinol versus febuxostat, Outcome 3 Withdrawals due to adverse events.
We could pool AEs for up to four trials depending on the dose of febuxostat in the control group. Becker 2010 reported no between‐group differences in AE between allopurinol (200 or 300 mg daily) and febuxostat 40 mg daily (AEs: 433/756 in allopurinol 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, allopurinol 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 versus 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 included rashes and mild hypersensitivity, abnormal liver function tests, upper respiratory tract infections, peripheral oedema, musculoskeletal and connective tissue disease features, gastrointestinal (including nausea and diarrhoea) and neurological features (including headache).
3.4. Analysis.
Comparison 3 Allopurinol versus febuxostat, Outcome 4 Total adverse events.
SAE could be pooled for up to three trials depending on the dose of febuxostat in the control group. Becker 2010 reported no between‐group differences in SAE comparing allopurinol (200 or 300 mg daily) and febuxostat 40 mg daily (SAEs: 31/756 in allopurinol 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 allopurinol 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 versus 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 included non‐specific bacterial infections, coronary artery disease, lower respiratory tract infections, prostate cancer and death.
3.5. Analysis.
Comparison 3 Allopurinol versus febuxostat, Outcome 5 Serious adverse events.
There were nine deaths (six with febuxostat and three with allopurinol), 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 included 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).
4.1. Analysis.
Comparison 4 Allopurinol versus benzbromarone, Outcome 1 Acute gout attacks.
Pooled analysis from the two studies of allopurinol and benzbromarone (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 allopurinol 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).
4.2. Analysis.
Comparison 4 Allopurinol versus benzbromarone, Outcome 2 Proportion achieving target serum urate.
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 reactions. 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 successfully re‐started and the AE was determined to be a result of colchicine (Perez‐Ruiz 1999).
4.3. Analysis.
Comparison 4 Allopurinol versus benzbromarone, Outcome 3 Withdrawal due to adverse events.
In the trial by Reinders 2009a, there was no between‐group difference 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 gastrointestinal 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).
4.4. Analysis.
Comparison 4 Allopurinol versus benzbromarone, Outcome 4 Total adverse effects.
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 allopurinol (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 reduced frequency in the continuous group compared with the intermittent 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.
5.1. Analysis.
Comparison 5 Allopurinol: continuous versus intermittent, Outcome 1 Acute gout attacks.
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 difference 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 Adverse Drug Reactions Bulletin (www.tga.gov.au/adr/aadrb.htm) (accessed 15 January 2014), found no reports of SAEs of allopurinol, 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 consequences 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), reported 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 discontinued 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‐Johnson syndrome (erythema multiforme exudativum) with or without generalised vasculitis.
An oral desensitisation regimen can be used in people with maculopapular 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 regimen using gradual dosage‐escalation of allopurinol in 32 participants (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 withdrawal of allopurinol and dosage adjustment.
The FDA reported on a few cases of reversible clinical hepatotoxicity in people taking allopurinol, and in some people, asymptomatic 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 approximately one‐third to one‐quarter of the usual dose of mercaptopurine or azathioprine should be made, and subsequent dose adjustment made on the basis of therapeutic response and the appearance of toxic effects. The FDA also reported that allopurinol can cause rare irreversible hepatotoxicity and, on occasions, death.
Discussion
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 participants) of no between‐group difference in the rate of new or recurrent gout attacks when allopurinol 300 mg daily was compared 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 achieving 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 evidence 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 (Table 1).
There was low‐quality evidence based on one small trial (65 participants) of no between‐group difference in the incidence of acute gout attacks, when allopurinol up to 300 mg twice daily was compared with benzbromarone up to 200 mg daily over a four‐month period. Based on the pooled results of two small trials (102 participants), there was moderate‐quality evidence of no between‐group difference in the proportion of participants achieving a target 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 (Table 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 prophylaxis. There was low‐quality evidence based on pooled data of four trials (2618 participants) of a significant difference in the proportion 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 effective 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 difference 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 (Table 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 pharmacovigilance and drug safety updates (www.mhra.gov.uk), EMEA (www.emea.europa.eu), Australian Adverse Drug Reactions Bulletin (www.tga.gov.au/adr/aadrb.htm) and the US FDA ‐ MedWatch (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 severe 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 of evidence
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 treatments. One RCT compared allopurinol 200 mg daily plus colchicine 0.5 mg twice daily with colchicine 0.5 mg twice daily alone (Gibson 1982). One open quasi‐randomised CCT compared 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.
Quality of the evidence
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 participants 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 comparison, 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 target 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 difference in tophus regression (Schumacher 2008). However, limited data were reported so further research is likely to change the estimates. Neither trial included an assessment of function or participant global assessment of treatment success.
There was also a paucity of high‐quality RCTs comparing allopurinol versus benzbromarone, and we only identified two trials assessing this comparison (Perez‐Ruiz 1999;Reinders 2009a). These trials were limited by their small size (Reinders 2009a: 65 participants; 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 variable duration of follow‐up. Neither trial included a placebo arm and both trials were open‐label rendering them at risk of performance 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 estimates. Tophus regression was not fully reported and pain, function 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 attrition 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 febuxostat 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 inconsistency 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 review has captured all relevant studies. Two review author independently 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 other studies 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 recommend starting allopurinol at a low dose of 100 mg daily and increasing the dose slowly, every two to five weeks. Our review identified 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 reduction 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 starting 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 versus delayed initiation of urate lowering therapy would be useful.
The ACR recommends gradual upwards titration of the allopurinol 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 2009Hamburger 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 recommendations by Hamburger 2011 suggest a role for probenecid, a uricosuric 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 comparing allopurinol 100 to 300 mg daily with different daily doses of febuxostat (40, 80, 120 and 240 mg daily) into a single meta‐analysis (Faruque 2013). They reported that participants on febuxostat (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 reported 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.
Authors' conclusions
Implications for practice.
Allopurinol is widely considered a safe and effective urate‐lowering therapy used to treat chronic gout. However, our review highlights 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 manifestations include arthritis, tophi, uric acid urolithiasis and nephropathy. Urate‐lowering therapy reduces serum urate concentrations to subsaturating levels preventing the formation and deposition of urate crystals and consequently reduces the long‐term manifestations 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 recommended.
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 effective than placebo, and low‐quality evidence based on four studies (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 studies only, limiting conclusions.
Implications for research.
Due to the paucity of high‐quality RCT evidence comparing allopurinol 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 participants, study personnel and outcome assessment, follow‐up of all participants who entered the trial and complete reporting of outcomes. To enable comparison and pooling of the results of RCTs, we suggest that future trials report means with SDs for continuous 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, participant global assessment and activity limitations (Schumacher 2009).
Feedback
New or recurrent gout attacks, 17 November 2014
Summary
Comment: As a chronic gout sufferer who swears by allopurinol which I have taken on a long term basis I found the study on allopurinol fascinating in its conclusions... The evidence: "‐ 8 people out of 100 had an acute gout attack with allopurinol. ‐ 12 people out of 100 had an acute gout attack with placebo." The conclusion: "moderate‐quality evidence indicated that, compared with placebo, allopurinol (100 to 300 mg daily) probably does not reduce the number of acute gout attacks, " My verdict harking back to being a statistician in my youth is that they werent asking the right questions! Instead of asking whether you had an attack of gout during the study period, it should have been "HOW MANY attacks did you have over the study period?" I suspect people taking allopurinol get far fewer attacks. That is certainly the case with me. I am not sure the duration of the study was sufficient either. With the group who took the allopurinol, I would also ask whether they were likely to continue with the allopurinol after the end of the study! In other words, the conclusion drawn by the study is I believe misleading, as in my opinion Allopurinol SIGNIFICANTLY reduces the frequency and severity of attacks. Remember that the other conclusion is that the blood serum level targets were reached in 25/26 partiicpants, with 0 in placebo, which is a pretty compelling statistic I would have thought.
Arthur Galletly
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.
Reply
Thank you for your feedback.
The trial from which we calculated the outcome, new or recurrent gout attacks, is a measure of the how many new or recurrent gout attacks the participants reported over the study treatment period (of 30 days). The frequency of new or recurrent gout attacks that we calculated from this study was: 2/26 (7.7%, or 8/100) in allopurinol group versus 3/25 (12%, or 12/100) in the placebo group. It is interesting that the large difference in people achieving an ideal serum urate concentration with allopurinol treatment compared to placebo did not necessarily translate to a difference in gout attacks following treatment. We suggest that blood urate level is not the most relevant outcome measure, it is really an interim measure, and we are not sure if it is predictive of the number of gout attacks. We are not sure if the outcome (or question asked of participants) was the incorrect one, or if the study was just too small to give us a result we could have more confidence in.
A second trial also reported no between‐group difference in the proportion of participants requiring treatment for gout flares in the first eight weeks of the trial: 61/268 (23%) in allopurinol group versus 27/134 (20%) in placebo group. It is possible these results were influenced by the co‐administration of naproxen or colchicine.
R Seth, on behalf of the authors.
Contributors
Arthur Galletly
What's new
| Date | Event | Description |
|---|---|---|
| 31 December 2014 | Feedback has been incorporated | Feedback and response added |
History
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 Collaboration guidance. |
| 3 September 2008 | Amended | Converted to new review format |
Notes
None.
Acknowledgements
The authors would like to thank Louise Falzon from Columbia University Medical Centre for her assistance and valuable comments in the search strategy development.
Appendices
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
Data and analyses
Comparison 1. Allopurinol versus placebo.
| Outcome or subgroup title | No. 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.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 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.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 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] |
| 1.2 Febuxostat 120 mg daily | 2 | 1038 | Risk Ratio (M‐H, Random, 95% CI) | 0.62 [0.51, 0.76] |
| 1.3 Febuxostat 240 mg daily | 1 | 402 | Risk Ratio (M‐H, Random, 95% CI) | 0.44 [0.34, 0.58] |
| 2 Proportion achieving target serum urate (6‐12 months) | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 2.1 Febuxostat 40 mg daily | 1 | 1512 | Risk Ratio (M‐H, Random, 95% CI) | 0.93 [0.83, 1.05] |
| 2.2 Febuxostat 80 mg daily | 4 | 2618 | Risk Ratio (M‐H, Random, 95% CI) | 0.55 [0.48, 0.63] |
| 2.3 Febuxostat 120 mg daily | 2 | 1012 | Risk Ratio (M‐H, Random, 95% CI) | 0.48 [0.42, 0.54] |
| 2.4 Febuxostat 240 mg daily | 1 | 389 | Risk Ratio (M‐H, Random, 95% CI) | 0.42 [0.36, 0.49] |
| 3 Withdrawals due to adverse events | 3 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 3.1 Febuxostat 40 mg daily | 1 | 1512 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [0.92, 1.87] |
| 3.2 Febuxostat 80 mg daily | 3 | 2555 | Risk Ratio (M‐H, Random, 95% CI) | 0.89 [0.62, 1.26] |
| 3.3 Febuxostat 120 mg daily | 2 | 1041 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.56, 1.31] |
| 3.4 Febuxostat 240 mg daily | 1 | 402 | Risk Ratio (M‐H, Random, 95% CI) | 0.69 [0.35, 1.37] |
| 4 Total adverse events | 4 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 4.1 Febuxostat 40 mg daily | 1 | 1513 | Risk Ratio (M‐H, Random, 95% CI) | 1.01 [0.93, 1.10] |
| 4.2 Febuxostat 80 mg daily | 4 | 2656 | Risk Ratio (M‐H, Random, 95% CI) | 1.06 [1.01, 1.12] |
| 4.3 Febuxostat 120 mg daily | 2 | 1036 | Risk Ratio (M‐H, Random, 95% CI) | 1.12 [1.05, 1.20] |
| 4.4 Febuxostat 240 mg daily | 1 | 804 | Risk Ratio (M‐H, Random, 95% CI) | 1.02 [0.90, 1.15] |
| 5 Serious adverse events | 3 | 5512 | Risk Ratio (M‐H, Random, 95% CI) | 1.11 [0.85, 1.46] |
| 5.1 Febuxostat 40 mg daily | 1 | 1513 | Risk Ratio (M‐H, Random, 95% CI) | 1.63 [0.93, 2.87] |
| 5.2 Febuxostat 80 mg daily | 3 | 2556 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.71, 1.82] |
| 5.3 Febuxostat 120 mg daily | 2 | 1041 | Risk Ratio (M‐H, Random, 95% CI) | 0.86 [0.52, 1.44] |
| 5.4 Febuxostat 240 mg daily | 1 | 402 | Risk Ratio (M‐H, Random, 95% CI) | 0.7 [0.23, 2.16] |
Comparison 4. Allopurinol versus benzbromarone.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Acute gout attacks | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Proportion achieving target 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.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Acute gout attacks | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected |
Characteristics of studies
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; pregnancy 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 prednisone 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 randomisation schedule with a block size of 3 was used to assign each participant to 1 of the 3 groups |
| 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 | Unclear risk | No details provided other than stating that this is a double‐blind trial |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Some study participants were not accounted for in the efficacy analysis: 4 participants 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 (OMERACT 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 efficacy 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 2: febuxostat 80 mg daily (n = 756) 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 |
|
| Outcomes | Outcome assessments were made on 2 out of the 7 essential domains proposed by 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Authors stated that "an interactive voice response system was utilized by site personnel during screening visits to initiate double blind randomisation. Subjects were randomised 1:1:1 on day 1 to receive daily febuxostat 40 mg, febuxostat 80 mg, or allopurinol" |
| Allocation concealment (selection bias) | Low risk | No details provided, but considered probable due to randomisation type |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details provided other than stating that this was a double‐blind trial |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details provided other than stating that this was a double‐blind trial |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Only 1 participant out of 2268 was not included in the efficacy analysis because sUA was < 8 mg/dL; the remainder were included in a modified ITT analysis |
| 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 (OMERACT 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 continuous group, people with a history of duodenal ulceration were occasionally prescribed colchicine |
|
| Outcomes | Outcome assessments were made on 2 out of the 7 essential domains proposed by OMERACT Outcomes: acute gout attack frequency and sUA (although no data on specific sUA levels were presented). No adverse effects were reported |
|
| Notes | Outcome assessments were made on 2 out of the 7 essential domains proposed by OMERACT | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection 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 |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | It is unlikely that the outcome (acute gout attacks) would be altered by blinding |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | It is unlikely that the outcome (acute gout attacks) would be altered by blinding |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 4 participants "defaulted from follow‐up" in intermittent group and 6 "defaulted" in control group. "4 patients in the intermittent group went onto continuous treatment at their own request because of recurrent attacks of gout." 1 participants in intermittent group received an additional prescription of allopurinol from his family doctor. Two participants in continuous group stopped taking allopurinol of their own volition but continued to be followed for 3 years in total |
| Selective reporting (reporting bias) | Unclear risk | The serum urate outcome was not discussed in detail; just a sentence: "urate levels 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 insufficiency No participants were receiving regular hypouricaemic treatment, though many had undergone 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection 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 |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Quotes: "One patient was withdrawn from the randomisation schedule and given allopurinol because he had large tophi"; "For various reasons it was not possible to perform all investigations for every patient at each annual assessment. It was therefore 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 serial 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 |
|
| Participants | Number of participants randomised: 37 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 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | RCT, open and actively controlled |
| Allocation concealment (selection bias) | High risk | RCT, open and actively controlled |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | RCT, open and actively controlled |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | The study outcomes may be influenced by lack of blinding in this case |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Quotes: "One patient died of cardiac failure 3 months after entering study, so efficacy could not be evaluated and results were available for 36 patients". "One patient taking allopurinol showed a pruritic erythematous rash that was attributed to allopurinol, 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 |
| Other bias | Unclear risk | No comment on washout period and variable follow‐up times |
Reinders 2009a.
| Methods | Study design: multicentre open‐label, RCT Study duration: 4 months |
|
| Participants | Number of participants randomised: 68 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 benzbromarone 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) |
|
| Outcomes | Outcome assessments were made on 2 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), safety as assessed by the number of study participant withdrawals due to AEs and SAEs |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "a computer generated central randomisation schedule with a block size of six was used" |
| 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 allopurinol or benzbromarone treatment" |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | It was an open‐label study |
| Blinding of outcome assessment (detection 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 |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Quote: "2 patients stopped receiving allopurinol and 3 stopped receiving benzbromarone because of adverse drug reactions. 10 excluded from analysis from Allopurinol: 6 lost to follow up, 3 protocol violation. 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 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 Outcomes: acute gout attack frequency, serum urate (both change in serum urate and 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Open‐labelled cross‐over trial |
| Allocation concealment (selection bias) | Unclear risk | Open‐labelled cross‐over trial |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | The outcome is unlikely to be influenced by lack of blinding |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | The outcome is unlikely to be influenced by lack of blinding |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | No mention of loss to follow‐up (i.e. insufficient evidence) |
| Selective reporting (reporting bias) | Unclear risk | Insufficient evidence. In addition, outcome assessments were made on 2 out of the 7 essential domains proposed by OMERACT |
| Other bias | Unclear risk | Unclear |
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 |
|
| Participants | Number of participants randomised: 1072 Number of participants analysed: 1072 Age: 51‐54 years Gender: 93.6% male (overall) 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 medications 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 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 | 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Authors stated that "subjects were randomised 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 |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | No details were provided |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | No details were provided |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | All efficacy analyses were performed on the ITT population. If a participant discontinued the study before ≥ 3 sUA levels were obtained, the participant was considered a non‐responder |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available, but 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 company. Representatives of Takeda Global Research & Development Centre, Inc, collected 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 sulphinpyrazone 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 withdrawn "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, and at 3‐monthly intervals thereafter |
|
| Outcomes | Outcome assessments were made on 3 out of the 7 essential domains proposed by 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | High risk | Open trial Quote: "patients were allocated to treatment 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 |
| Blinding of participants and personnel (performance bias) All outcomes | Unclear risk | ‐ |
| Blinding of outcome assessment (detection bias) All outcomes | Unclear risk | It is unlikely that the primary outcome (serum urate level) would be altered by blinding |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Quote: "one patient taking allopurinol defaulted from follow‐up. One patient taking uricosuric therapy defaulted from follow‐up and one left the district so that adequate follow‐up was impossible. The results therefore apply to the 20 patients taking 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 |
| Other bias | Unclear risk | Unclear |
Singal 2011.
| Methods | Study design: non‐randomised CCT Study duration: 6 months |
|
| Participants | Number of participants randomised: 100 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) Group 2: febuxostat 80 mg daily (n = 50) No additional medications (flare prophylaxis) were given |
|
| Outcomes | Outcome assessments were made on 2 out of the 7 essential domains proposed by 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 | Authors' judgement | Support for judgement |
| Random sequence generation (selection 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 |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No details provided other than stating that this was a non‐randomised CCT |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No details provided other than stating that this was a non‐randomised CCT |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | 100 participants were enrolled in the trial and there are no reported losses to follow‐up, no treatment withdrawals, no trial group changes and no major AEs |
| Selective reporting (reporting bias) | Unclear risk | The study protocol was not available, but the authors did not report on 7 of the 9 outcomes recommended by OMERACT (OMERACT 9) |
| Other bias | Unclear risk | Unclear |
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 |
|
| Participants | Number of participants randomised: 57 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 participants 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 |
|
| Outcomes | Outcome 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 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 withdrawals due to AEs and SAEs, erythrocyte sedimentation rate and C‐reactive protein levels |
|
| Notes | ||
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection 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 |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Double‐blind RCT for the first 10 days of study |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | After 10 days, all participants received allopurinol |
| Incomplete outcome data (attrition bias) 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‐Controlled, 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 Allopurinol 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 |
| 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 |
| 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 hyperuricaemia 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 allopurinol 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 |
| 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 |
Differences between protocol and review
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.
Contributions of authors
RS drafted the review and all authors contributed to the final version.
Sources of support
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
Declarations of interest
None.
Edited (no change to conclusions), comment added to review
References
References to studies included in this review
Becker 2005 {published data only}
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Akkasilpa 2004 {published data only}
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