The prevalence of hyperuricemia and gout has been increasing, but the comparative effectiveness and safety of different treatments remain uncertain. We aimed to compare the effectiveness and safety of different treatments for hyperuricemia using network meta-analysis methodology. We systematically reviewed fifteen randomized controlled trials (involving 7,246 patients through January 2016) that compared the effects of different urate-lowering drugs (allopurinol, benzbromarone, febuxostat, pegloticase and probenecid) on hyperuricemia. Drug efficacy and safety, as outcomes, were measured by whether the target level of serum urate acid was achieved and whether any adverse events occurred, respectively. We derived pooled effect sizes expressed as odds ratios (ORs) and 95% confidence intervals (CIs). The efficacy and safety of the drugs were ranked by cumulative ranking probabilities. Our findings show that febuxostat, benzbromarone, probenecid, pegloticase, and allopurinol were all highly effective at reducing the risk of hyperuricemia compared to placebo. Febuxostat had the best efficacy and safety compared to the other drugs. Furthermore, febuxostat 120 mg QD was more effective at achieving urate-lowering targets (OR: 0.17, 95% CI: 0.12–0.24) and safer (OR: 0.72, 95% CI: 0.56–0.91) than allopurinol.
Hyperuricemia (HUA), defined as a serum urate concentration exceeding the limit of solubility (approximately 6.8 mg/dl), is considered a common biochemical abnormality that reflects supersaturation of the extracellular fluid with urate1. The Global Burden of Disease (GBD) 2010 Study reported that the global prevalence of gout was 0.08%2. Recent epidemiological studies have shown evidence that hyperuricemia and gout cases have continued to grow for decades3. In view of the rapid economic development and the magnitude of populations, the prevalence rate has increased noticeably in developing countries, such as China4,5. There were 15.3 million who were diagnosed with chronic gout in major countries in 2013, and the number with gout is projected to be 17.7 million in 20216. Hyperuricemia results either from the overproduction of uric acid (10%) or the under-excretion of urate (90%)7, leading to the deposition of monosodium urate crystals in and around the joints8,9. Thus, elevated serum urate acid (sUA) levels increase the risk of gout and various comorbidities10,11,12,13,14,15.
Urate-lowering therapy (ULT) has been widely used to control hyperuricemia and prevent gout. The 2012 American College of Rheumatology (ACR) recommended that the target of ULT was to achieve a sUA level <6 mg/dl in all gout patients or a sUA <5 mg/dl for gout patients with tophi16. Anti-hyperuricemia drugs can be classified into three groups based on their pharmacologic mechanism. Uricosuric drugs are inhibitors of uric acid synthesis and the enzyme uricase. Among uricosuric agents, probenecid is commonly used16, whereas benzbromarone has been withdrawn in most European countries since 2003 due to serious hepatotoxicity17. Despite its adverse effects, benzbromarone is still applied commonly in clinics in several countries in Asia, including China18. Allopurinol, febuxostat and in particular Xanthine oxidase inhibitors (XOIs) are recommended as first-line drugs16. However, allopurinol has been reported to be associated with severe cutaneous adverse reactions19. In fact, humans lack urate oxidase, an enzyme that catalyses the oxidation of uric acid to allantoin, consequently resulting in hyperuricemia if accumulated in the blood20. Pegloticase, a recombinant polyethylene glycol conjugate of uricase (PEG-uricase), has been approved for the treatment of refractory chronic gout in the US and European Union21.
In 2014, a panel of 78 international rheumatologists raised ten key clinical questions pertinent to the diagnosis and management of gout, and one of these questions was how to determine the efficacy, cost-efficacy and safety of ULT (allopurinol, benzbromarone, febuxostat, peg-uricase and probenecid) in the treatment of gout22. Two previous pairwise meta-analyses analysed available individual studies and suggested that febuxostat may be associated with better urate lowering efficacy than allopurinol23,24. However, traditional meta-analyses can only draw interactions between comparisons among treatments with valid head-to-head trials25,26. Currently, several network-based approaches have been applied to potential drug discovery and biological information mining, e.g., drug–target interaction identification27,28, drug similarity calculation29 and genome-disease function inference30. As an extension of a pairwise meta-analysis, a network meta-analysis provides a method for assessing the relative effectiveness of two treatments when they have no direct comparison in randomized trials31. Herein, we performed a network meta-analysis to evaluate the comparative efficacy and safety of five urate-lowering drugs, focusing on their ability to achieve target serum urate acid levels and the risk of adverse events.
Search strategies and selection criteria
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement for network meta-analyses of health care intervention studies32. The PubMed, Medline, Embase, Cochrane Library databases and ClinicalTrials.gov were searched from inception to Jan 16, 2016. Following the PICOS (Participants, Interventions, Comparisons, Outcomes and Study design) principle33, the key search terms included (P) hyperuricaemia, hyperuricemia, gout, (I) urate-lowering therapy, uric acid, urate, (C/O) allopurinol, benzbromarone, febuxostat, pegloticase, probenecid, and (S) random*, and randomized controlled trial.
Studies meeting the following criteria were included: (a) Patients: adults (age >18 years old) with hyperuricemia with or without chronic gout; (b) Intervention: established ULT with at least one of five agents (allopurinol, benzbromarone, febuxostat, pegloticase or probenecid); (c) Comparator: placebo or another agent of the five mentioned above; (d) the outcome of efficacy was defined as a failure to achieve the sUA treatment target level, i.e., ≤6 mg/dl (or 360 μmol/l) with ULT, and the outcome of safety was defined as any adverse events during the period of the trial, including abnormal liver function, renal impairment, hyperlipidaemia, diarrhoea, gastrointestinal disorders, joint-related signs and symptoms; and (e) Study design: randomized controlled trial (RCT). The exclusion criteria were as follows: (a) trials comparing different doses of the same medication only; (b) studies without a designated intervention/comparator arm; (c) animal experiments; and (d) studies reported in a language other than English.
Three researchers (S.L., H.X.Y. and Y.N.G.) independently screened all records according to the inclusion and exclusion criteria. Any inconsistencies were resolved by discussion among the three authors. Finally, we identified fifteen qualified RCTs that were included in the current analysis1,34,35,36,37,38,39,40,41,42,43,44,45,46,47. The complete process and the exclusion reasons are shown in Fig. 1.
Data extraction and quality assessment
Two investigators (S.L., H.Y.) reviewed the full text of the eligible studies and extracted information into an electronic database. The information included study design, patient characteristics, inclusion/exclusion criteria, treatment protocols, and outcomes (the number of patients with/without successful treatment and occurrence of adverse events, which were available as binomial counts (successes/total)). The information was double checked by referring to the original articles when an inconsistency existed.
The quality of the included studies was reviewed and assessed by two investigators (S.L., Y.G.) independently using the Cochrane Collaboration’s tool for assessing the risk of bias48. A risk of bias graph displays the grade of bias as high risk, unclear risk and low risk (see Supplementary Figure 1A,B). Five studies were considered to have a high risk of bias due to the lack of implementation of blinding37,41,42,43,47.
Data synthesis and analysis
We calculated the odds ratios (ORs) and 95% confidence intervals (95% CIs) of the drugs for their failure to achieve the sUA treatment target level and related adverse events. Head-to-head meta-analysis was used to generate direct evidence (from studies directly comparing A to B). The pairwise meta-analysis with random-effect models was performed, and statistical heterogeneity was estimated using I2 statistics, which describe the percentage of variability across studies caused by heterogeneity rather than chance49.
In addition to direct evidence, we also drew inferences between two intervention arms, such as A versus B, from indirect evidence (from combining studies through an intermediate comparator C, e.g., A vs. C and B vs. C studies)50,51. With the use of the adjusted indirect comparison method and inverse variance method, the effect estimates between treatments without direct comparisons and the combined results of direct and indirect evidence were obtained, respectively. Thus, even if there are no known comparisons for the investigated drug, a network meta-analysis still can estimate the potential effect of this drug based on existing head-to-head trials. As a result, a synthesized effect size and mean rank could be estimated for all the interventions.
When conducting a network meta-analysis, three assumptions need to be met, including homogeneity, transitivity, and consistency. The treatment effects together with their predictive intervals (PrIs) are examined to illustrate the magnitude of heterogeneity. A predictive interval plot is drawn to make comparisons between the 95% CIs and the 95% PrIs. The transitivity (or named similarity) assumption refers to the balance between the relative treatment effects and covariates across trials that are comparing different sets of interventions52. The inconsistency accounts for disagreements between direct and indirect evidence53. It is generally recommended to evaluate the consistency assumption using both global and local approaches. To assess the assumption of consistency in the entire network, we inferred the presence of inconsistency from any source in the entire network based on a Chi-square test. To evaluate the presence of inconsistency locally, we used the loop-specific approach to evaluate the inconsistency factor (IF, the difference between the direct and indirect estimate for one of the comparisons in a particular loop). We identified inconsistency as yielding a lower 95% CI limit that does not reach the zero line.
To rank the treatments based on efficacy and safety, we calculated the probabilities of the surface under the cumulative ranking curve (SUCRA). SUCRAs can illustrate the outcome percentages of every treatment relative to an ideal treatment, which always ranks first without uncertainty. Thus, the greater the SUCRA score, the more effective or safer the drug.
We performed the network meta-analysis using a frequentist model. Stata version 13 was used to make calculations. The metan and network commands were used for the pairwise and network meta-analyses, respectively. In the network meta-analysis, zero cells were corrected with the command “network setup” in Stata.
Characteristics of eligible studies
Fifteen studies involving 7,246 adult trial subjects were included in the network meta-analysis. The characteristics of the included studies are summarized in Table 1. The earliest study was conducted in 1999, whereas the latest one was in 2016. The duration of the trials ranged from 4 to 52 weeks. Seven trials made a comparison between allopurinol and febuxostat1,35,36,37,38,46,47, two trials between allopurinol and benzbromarone41,43, one trial between benzbromarone and probenecid42, three trials between febuxostat and placebo34,39,40, and one trial between pegloticase and placebo45. A three-arm trial compared allopurinol, febuxostat and placebo44. The dosage of febuxostat among the trials ranged from 20 mg/day to 240 mg/day. In general, all of the trial patients had an average age of 30 or more years, and males accounted for more than 80% of the subjects in the included trials. At baseline, these trial subjects had sUA concentrations >8.0 mg/dl.
A network graphical structure displays the available direct comparisons of the network of trials organized from the fourteen RCTs (Fig. 2). Comparisons with febuxostat (20/40/60/80/120/240 mg once daily) or pegloticase (8 mg every two/four weeks) were classified by dosage.
Direct treatment comparisons
The pairwise meta-analysis showed that allopurinol, febuxostat 20/40/60/80/120/240 mg QD (20/40/60/80/120/240 mg once daily), and pegloticase 8 mg 2 W/4 W (8 mg every two/four weeks) were all highly effective at achieving the sUA treatment target compared to placebo (Table 2). Febuxostat was more likely to achieve the sUA treatment target than allopurinol (OR of allopurinol vs. febuxostat 40 mg QD: 1.29, 95% CI: 1.05–1.59; OR of allopurinol vs. febuxostat 80 mg QD: 3.62, 95% CI: 2.69–4.89; OR of allopurinol vs. febuxostat 120 mg QD: 6.34, 95% CI: 4.79–8.40; and OR of allopurinol vs. febuxostat 240 mg QD: 18.31, 95% CI: 9.17–36.58). Febuxostat 40/60/80 mg QD showed better efficacy than febuxostat 20 mg QD (OR of febuxostat 20 vs. 40 mg QD: 7.39, 95% CI: 3.29–16.63; OR of febuxostat 20 vs. 60 mg QD: 5.79, 95% CI: 1.99–16.63; and OR of febuxostat 20 vs. 80 mg QD: 8.28, 95% CI: 2.73–25.15). Febuxostat 80/120 mg QD showed better efficacy than febuxostat 40 mg QD (OR of febuxostat 40 vs. 80 mg QD: 2.28, 95% CI: 1.92–2.70; and OR of febuxostat 40 vs. 120 mg QD: 12.63, 95% CI: 2.60–61.38). Febuxostat 120/240 mg QD showed better efficacy than febuxostat 80 mg QD (OR of febuxostat 80 vs. 120 mg QD: 1.48, 95% CI: 1.05–2.08; and OR of febuxostat 80 vs. 240 mg QD: 4.44, 95% CI: 2.20–8.96). Febuxostat 240 mg QD showed better efficacy than febuxostat 120 mg QD (OR of febuxostat 120 vs. 240 mg QD: 3.11, 95% CI: 1.53–6.32). Regarding safety, allopurinol was more likely to cause adverse events than febuxostat 120 mg QD (OR of allopurinol vs. febuxostat 120 mg QD: 1.56, 95% CI: 1.17–2.08). There were no statistically significant differences among the other treatments identified by the direct comparisons.
Substantial heterogeneity was observed when comparing benzbromarone (I2 = 73.7%) or febuxostat 80 mg QD (I2 = 69.3%) with allopurinol for efficacy. Nevertheless, there was no evidence showing heterogeneity in the other pooled results of the direct comparisons for either efficacy or safety.
Network estimation and ranking
Network treatment comparisons
Pooled ORs and 95% CIs for the efficacy and safety of the different interventions from the network meta-analysis are shown in Fig. 3. Febuxostat, benzbromarone, probenecid, pegloticase and allopurinol were all highly effective in comparison to placebo at achieving the treatment target. Febuxostat was mostly more effective than allopurinol at achieving the treatment target of hyperuricemia (OR of allopurinol vs. febuxostat 40 mg QD: 1.52, 95% CI: 1.15–1.99; OR of allopurinol vs. febuxostat 80 mg QD: 3.54, 95% CI: 2.80–4.47; OR of allopurinol vs. febuxostat 120 mg QD: 5.95, 95% CI: 4.15–8.52; and OR of allopurinol vs. febuxostat 240 mg QD: 17.41, 95% CI: 8.22–36.89) except febuxostat 20 mg QD (OR of allopurinol vs. febuxostat 20 mg QD: 0.27, 95% CI: 0.13–0.59). Benzbromarone was found to have better efficacy than febuxostat 20 mg QD (OR of benzbromarone vs. febuxostat 20 mg QD: 0.20, 95% CI: 0.06–0.73) but was worse than febuxostat 120/240 mg QD (OR of benzbromarone vs. febuxostat 120 mg QD: 4.37, 95% CI: 1.47–12.93; and OR of benzbromarone vs. febuxostat 240 mg QD: 12.78, 95% CI: 3.58–45.60). The urate-lowering efficiency of febuxostat improved with increasing dosages. Regarding safety, the incidence of adverse events was less using febuxostat 120 mg QD than allopurinol or febuxostat 40 mg QD (OR of febuxostat 120 mg QD vs. allopurinol: 0.72, 95% CI: 0.56–0.91; and OR of febuxostat 120 mg QD vs. febuxostat 40 mg QD: 0.73, 95% CI: 0.56–0.95). Probenecid had more occurrences of adverse events than allopurinol, febuxostat 40/120/240 mg QD or placebo (OR of probenecid vs. allopurinol: 8.40, 95% CI: 1.00–70.21; OR of probenecid vs. febuxostat 40 mg QD: 8.56, 95% CI: 1.02–72.01; OR of probenecid vs. febuxostat 80 mg QD: 9.62, 95% CI: 1.15–80.86; OR of probenecid vs. febuxostat 120 mg QD: 11.71, 95% CI: 1.38–99.29; and OR of placebo vs. probenecid: 0.11, 95% CI: 0.01–0.95). Other comparison results were not significant statistically.
Heterogeneity and inconsistency
The 95% PrI and 95% CI of each pairwise comparison are displayed in Supplementary Figure 2. There was no clear evidence suggesting inconsistency between the direct and indirect network effect values in the results of the traditional pairwise meta-analysis and the network meta-analysis (see Supplementary Table 1). Specifically, no inconsistency was found in either efficacy (P = 0.054) or safety (P = 0.819) within Chi-square tests. The loop-specific approach did not present any statistically significant inconsistency.
Cumulative ranking plots of each treatment for efficacy and safety are shown in Fig. 4. Febuxostat 80/120 mg QD provided excellent efficacy and safety with a large area under both curves. Details of the SUCRA percentages and the calculated ranks are available in Supplementary Table 2. In terms of efficacy, the SUCRAs for febuxostat 240/120/80/60/40 mg QD, benzbromarone, probenecid, pegloticase 8 mg 4 W, allopurinol, pegloticase 8 mg 2 W, febuxostat 20 mg QD and placebo were 99.5%, 88.7%, 76.7%, 61.6%, 55.0%, 50.5%, 42.4%, 39.7%, 38.6%, 29.7%, 17.5% and 0.1%, respectively. Regarding safety, the cumulative probabilities of the treatments were 91.5%, 74.9%, 67.5%, 64.2%, 57.8%, 56.1%, 52.8%, 50.0%, 42.9%, 21.6%, 13.0% and 7.8% for febuxostat 120/80 mg QD, pegloticase 8 mg 4 W, placebo, febuxostat 240/40 mg QD, allopurinol, febuxostat 20/60 mg QD, benzbromarone, pegloticase 8 mg 2 W and probenecid, respectively.
Utilizing the SUCRA values, we displayed a clustered ranking plot of these treatments in the two dimensions of the x-axis (efficacy) and the y-axis (safety) in Fig. 5. Febuxostat was superior to the other drugs in both efficacy and safety, especially febuxostat 120 mg QD. Allopurinol took a medium position in the benefits and harms ranking. Compared with pegloticase 8 mg 2 W, pegloticase 8 mg 4 W showed better efficacy and safety. Benzbromarone and probenecid were likely to have similar rankings with an overall moderate benefit. However, probenecid ranked the worst for safety.
Using a network meta-analysis approach, we found that febuxostat tended to have higher efficacy and safety than other urate-lowering drugs, especially at a dose of 120 mg once daily. There was no evidence suggesting that adverse drug events outweighed the benefits of any of the five categories of ULT other than probenecid.
Probenecid was introduced as a uricosuric drug in 1951, and it is generally applicable for patients who cannot tolerate XOIs or fail to achieve their target serum urate acid with them15,16. Allopurinol, a purine analogue, has been widely used as a hypouricemic drug since the 1960s and was approved by the US Food and Drug Administration (FDA) in 1965. However, patients taking allopurinol have a high risk of serious hypersensitivity syndromes, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, which may have a strong association with the HLA-B*5801 allele, a genetic change more commonly observed in Asian populations19,54. Benzbromarone was introduced as a uricosuric drug in the 1970s. It was widely registered in countries throughout Europe, Asia and South America before being withdrawn from the European market in 2003 due to its serious hepatotoxicity17. Febuxostat, a non-purine selective inhibitor of xanthine oxidase, has been approved by the European Medicines Agency (EMA) since 2008 and by the US-FDA since 2009. Considering that febuxostat is far more expensive than allopurinol15, it is often used when allopurinol is contraindicated or not tolerated55. Pegloticase, a new anti-hyperuricemia drug, was introduced to markets in 2010 by the FDA, and only one report including two placebo-controlled RCTs was reported in 201145. To be noted, immunogenic responses to pegloticase should be monitored because it is a recombinant porcine-like uricase.
Several meta-analyses of RCTs have attempted to address comparative effects of urate-lowering drugs. A Cochrane systematic review compared febuxostat against allopurinol in achievement of urate-lowering target levels (relative risk (RR) of febuxostat 80 mg vs. allopurinol: 1.5, 95% CI: 1.2–1.8) and (RR of febuxostat 120 mg vs. allopurinol: 2.6, 95% CI: 2.0–3.3), which outcome was measured by an opposite indicator from ours. Regarding the occurrence of adverse events, there was a lower rate when comparing febuxostat 80 mg and 120 mg against allopurinol (RR: 0.93, 95% CI: 0.87–0.99, and RR: 0.90, 95% CI: 0.84–0.96, respectively)56. Additionally, a previous meta-analysis including five trials compared febuxostat with allopurinol in urate-lowering efficacy (RR: 1.56, 95% CI: 1.22–2.00, its efficacy outcome by the proportion of patients meeting the therapeutic target for serum uric acid level) and risk of adverse events (RR: 0.94, 95% CI: 0.90–0.99)24. Using a more advanced approach, our study found that febuxostat had an advantage over allopurinol in urate-lowering efficacy and safety. According to the guidelines of ACR and the European League against Rheumatism (EULAR), XOIs such as allopurinol and febuxostat are recommended for use prior to uricosuric agents and uricase for ULT16,57. Therefore, it is also worthwhile to discuss the efficacy and safety of uricosuric agents and uricase.
According to our ranking of efficacy, benzbromarone was only second to febuxostat at achieving urate-lowering targets. Benzbromarone has performed excellently at promoting the excretion of uric acid despite life-threatening adverse events reported in the past17. Essential guidelines have been recommended to prevent benzbromarone hepatotoxicity such as regularly monitoring liver function57. Limited clinical trials have been carried out with benzbromarone and probenecid, partially owing to the impact of being withdrawn from the market, the development of new drugs, regional/ethnic differences, prescribing habits and cost. Uricase-based drugs can metabolize uric acid to allantoin, which reduces the risk of precipitate. In addition, short-term trials have shown their urate-lowering effectiveness. However, our study did not reveal any significant differences in comparisons of pegloticase against other drugs.
Our study has clinical implications. The prevalence of gout and hyperuricemia has increased around both developed and developing countries, presumably due to lifestyle changes3,10. Hyperuricemia is associated with metabolic syndromes such as hypertension, dyslipidaemia, obesity and diabetes10,11,12 and with renal and cardiovascular diseases13,14,15. More and more patients need urate-lowering treatment. It is essential to know the comparative effects and safety of urate-lowering drugs available in the market. Our study pooled and ranked the efficacy and safety of these drugs using the data from individual RCTs, and thus our findings may be useful to clinicians in their decisions on which drug to use.
Our study has strengths. We designed our network meta-analysis as standardized by the PRISMA principle and conducted it carefully to minimize errors and ensure the validity of findings from all relevant studies identified. To our knowledge, our network meta-analysis is the first to address comparative effects of different ULTs with explicit rankings of efficacy and safety of different ULTs. We look forward to using this network-based statistical method to combine findings from individual studies and provide useful information for clinical decision-making. Finally, we analysed all of the trials of ULTs being used commonly, and we came to the conclusion that febuxostat had better urate-lowering effects than other drugs.
There are some limitations to our study. Firstly, this study included a limited number of trials. On the one hand, some drugs were only used in limited countries and areas, e.g., benzbromarone. On the other hand, we set language restrictions and excluded studies not in English. Secondly, some estimated results of the network meta-analysis relied on indirect comparisons. However, our results from direct comparisons were in accordance with the indirect and mixed comparisons. No obvious evidence suggesting inconsistency was found by fitting the inconsistency model. Thirdly, medicines with specific indications and some new drugs under development were not considered. With the improvement and application of network-based approaches, we promise to implement further predictions for drug/genome-target interactions with known reachable paths in the network and provide better interpretations for decision-makers.
In conclusion, this systematic review and network meta-analysis provides clear evidence of the efficacy and safety of ULT. When comparing the ability to achieve sUA treatment targets and the occurrence of adverse events, febuxostat ranked first among the urate-lowering drugs. Benzbromarone and probenecid had moderate therapeutic effects, but they caused unpleasant side effects. Comprehensively considered, our findings support the recommendation of XOIs such as febuxostat and allopurinol. Pegloticase and similar new uricase drugs need further investigation through RCTs and meta-analyses.
How to cite this article: Li, S. et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis. Sci. Rep. 6, 33082; doi: 10.1038/srep33082 (2016).
Becker, M. A. et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353, 2450–2461 (2005).
Smith, E. et al. The global burden of gout: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis 73, 1470–1476 (2014).
Roddy, E. & Choi, H. K. Epidemiology of gout. Rheum Dis Clin North Am 40, 155–175 (2014).
Conen, D. et al. Prevalence of hyperuricemia and relation of serum uric acid with cardiovascular risk factors in a developing country. BMC Public Health 4, 9 (2004).
Qiu, L. et al. Prevalence of hyperuricemia and its related risk factors in healthy adults from Northern and Northeastern Chinese provinces. BMC Public Health 13, 664 (2013).
AstraZeneca announces top-line results from the Phase III programme of lesinurad in combination with xanthine oxidase inhibitors in gout patients. Available at: https://www.astrazeneca.com/our-company/media-centre/press-releases/2014/astrazeneca-lesinurad-xanthine-oxidase-results-gout-patients-13082014.html (Accessed: 15th February 2016) (2014)
Pittman, J. R. & Bross, M. H. Diagnosis and management of gout. Am Fam Physician 59, 1799–1806, 1810 (1999).
Lin, K. C., Lin, H. Y. & Chou, P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 27, 1501–1505 (2000).
Retrospective analysis of a large cohort. Clin Rheumatol 33, 549–553 (2014).
Luk, A. J. & Simkin, P. A. Epidemiology of hyperuricemia and gout. Am J Manag Care 11, S435–S442; quiz S465-438 (2005).
Neogi, T. Clinical practice. Gout. N Engl J Med 364, 443–452 (2011).
Roddy, E., Mallen, C. D. & Doherty, M. Gout. BMJ 347 (2013).
Johnson, R. J., Kivlighn, S. D., Kim, Y. G., Suga, S. & Fogo, A. B. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis 33, 225–234 (1999).
Edwards, N. L. The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 75 Suppl 5, S13–S16 (2008).
Stamp, L. K. & Chapman, P. T. Urate-lowering therapy: current options and future prospects for elderly patients with gout. Drugs Aging 31, 777–786 (2014).
Khanna, D. et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res 64, 1431–1446 (2012).
Jansen, T. L., Reinders, M. K., van Roon, E. N. & Brouwers, J. R. Benzbromarone withdrawn from the European market: another case of “absence of evidence is evidence of absence”? Clin Exp Rheumatol 22, 651 (2004).
Lee, M. H., Graham, G. G., Williams, K. M. & Day, R. O. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf 31, 643–665 (2008).
Ramasamy, S. N. et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf 36, 953–980 (2013).
Wu, X. W., Muzny, D. M., Lee, C. C. & Caskey, C. T. Two independent mutational events in the loss of urate oxidase during hominoid evolution. J Mol Evol 34, 78–84 (1992).
Diaz-Torne, C., Perez-Herrero, N. & Perez-Ruiz, F. New medications in development for the treatment of hyperuricemia of gout. Curr Opin Rheumatol 27, 164–169 (2015).
Sivera, F. et al. Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Ann Rheum Dis 73, 328–335 (2014).
Ye, P. et al. Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and meta-analysis. Clin Ther 35, 180–189 (2013).
Faruque, L. I. et al. A systematic review and meta-analysis on the safety and efficacy of febuxostat versus allopurinol in chronic gout. Semin Arthritis Rheum 43, 367–375 (2013).
Bucher, H. C., Guyatt, G. H., Griffith, L. E. & Walter, S. D. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol 50, 683–691 (1997).
Caldwell, D. M., Ades, A. E. & Higgins, J. P. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331, 897–900 (2005).
Chen, X., Liu, M. X. & Yan, G. Y. Drug-target interaction prediction by random walk on the heterogeneous network. Mol Biosyst 8, 1970–1978 (2012).
Chen, X. et al. Drug-target interaction prediction: databases, web servers and computational models. Brief Bioinform 17, 696–712 (2016).
Chen, X. et al. NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning. PLoS Comput Biol 12, e1004975 (2016).
Wang, E. et al. Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data. Semin Cancer Biol 30, 4–12 (2015).
Lumley, T. Network meta-analysis for indirect treatment comparisons. Stat Med 21, 2313–2324 (2002).
Hutton, B. et al. The PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions: Checklist and ExplanationsPRISMA Extension for Network Meta-analysis. Ann Intern Med 162, 777–784 (2015).
O’Connor, D., Green, S. & Higgins, J. P. In Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series (eds Higgins, J. P. & Green, S. ) Ch. 5, 81–94 (John Wiley & Sons, Ltd, 2008).
Becker, M. A. et al. Febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase: a twenty-eight-day, multicenter, phase II, randomized, double-blind, placebo-controlled, dose-response clinical trial examining safety and efficacy in patients with gout. Arthritis Rheum 52, 916–923 (2005).
Becker, M. A. et al. The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 12, R63 (2010).
Huang, X. et al. An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. Int J Rheum Dis 17, 679–686 (2014).
Kamatani, N. et al. An allopurinol-controlled, multicenter, randomized, open-label, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 2 exploratory clinical study. J Clin Rheumatol 17, S44–S49 (2011).
Kamatani, N. et al. An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol 17, S13–S18 (2011).
Kamatani, N. et al. Placebo-controlled double-blind dose-response study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia (including gout patients) in japan: late phase 2 clinical study. J Clin Rheumatol 17, S35–S43 (2011).
Kamatani, N. et al. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor Febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol 17, S19–S26 (2011).
Perez-Ruiz, F. et al. Treatment of chronic gout in patients with renal function impairment: an open, randomized, actively controlled study. J Clin Rheumatol 5, 49–55 (1999).
Reinders, M. K. et al. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 68, 51–56 (2009).
Reinders, M. K. et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis 68, 892–897 (2009).
Schumacher, H. R. et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum 59, 1540–1548 (2008).
Sundy, J. S. et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA 306, 711–720 (2011).
Xu, S. et al. A phase 3, multicenter, randomized, allopurinol-controlled study assessing the safety and efficacy of oral febuxostat in Chinese gout patients with hyperuricemia. Int J Rheum Dis 18, 669–678 (2015).
Yu, K. H. et al. Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study. Scand J Rheumatol 45, 304–311 (2016).
Higgins, J. P. & Altman, D. G. In Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series (eds Higgins, J. P. & Green, S. ) Ch. 8, 187–241 (John Wiley & Sons, Ltd, 2008).
Higgins, J. P., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. BMJ 327, 557–560 (2003).
Salanti, G., Ades, A. E. & Ioannidis, J. P. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64, 163–171 (2011).
Li, T., Puhan, M. A., Vedula, S. S., Singh, S. & Dickersin, K. Network meta-analysis-highly attractive but more methodological research is needed. BMC Med. 9, 79 (2011).
Jansen, J. P. et al. Interpreting indirect treatment comparisons and network meta-analysis for health-care decision making: report of the ISPOR Task Force on Indirect Treatment Comparisons Good Research Practices: part 1. Value Health 14, 417–428 (2011).
Jansen, J. P. & Naci, H. Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers. BMC Med. 11, 159 (2013).
Ko, T. M. et al. Use of HLA-B*58:01 genotyping to prevent allopurinol induced severe cutaneous adverse reactions in Taiwan: national prospective cohort study. BMJ 351, h4848 (2015).
Beard, S. M., von Scheele, B. G., Nuki, G. & Pearson, I. V. Cost-effectiveness of febuxostat in chronic gout. Eur J Health Econ. 15, 453–463 (2014).
Tayar, J. H., Lopez-Olivo, M. A. & Suarez-Almazor, M. E. Febuxostat for treating chronic gout. Cochrane Database Syst Rev. 11, 202–203 (2013).
Zhang, W. et al. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 65, 1312–1324 (2006).
We are very grateful for the information provided by the authors of fifteen studies included in this report. We appreciate the efforts of all authors who contributed to this present work. This work was supported by grants from the National Natural Science Foundation of China (71473175) and the Tianjin Science and Technology Commission (15ZCZDSY00500).
The authors declare no competing financial interests.
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Li, S., Yang, H., Guo, Y. et al. Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis. Sci Rep 6, 33082 (2016). https://doi.org/10.1038/srep33082
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