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08-09-2016 | Gout | Article

Comparative efficacy and safety of urate-lowering therapy for the treatment of hyperuricemia: a systematic review and network meta-analysis

Authors: Shu Li, Hongxi Yang, Yanan Guo, Fengjiang Wei, Xilin Wang, Daiqing Li, Mingzhen Li, Weili Xu, Weidong Li, Li Sun, Ying Gao, Yaogang Wang

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Abstract

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.

Sci Rep. 2016;6:33082. doi: 10.1038/srep33082.

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.

Literature
  1. Becker, M. A. et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353, 2450–2461 (2005).
  2. 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).
  3. Roddy, E. & Choi, H. K. Epidemiology of gout. Rheum Dis Clin North Am 40, 155–175 (2014).
  4. 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).
  5. 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).
  6. 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-lesinuradxanthine-oxidase-results-gout-patients-13082014.html (Accessed: 15th February 2016) (2014)
  7. Pittman, J. R. & Bross, M. H. Diagnosis and management of gout. Am Fam Physician 59, 1799–1806, 1810 (1999).
  8. 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).
  9. Retrospective analysis of a large cohort. Clin Rheumatol 33, 549–553 (2014).
  10. Luk, A. J. & Simkin, P. A. Epidemiology of hyperuricemia and gout. Am J Manag Care 11, S435–S442; quiz S465-438 (2005).
  11. Neogi, T. Clinical practice. Gout. N Engl J Med 364, 443–452 (2011).
  12. Roddy, E., Mallen, C. D. & Doherty, M. Gout. BMJ 347 (2013).
  13. 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).
  14. Edwards, N. L. The role of hyperuricemia and gout in kidney and cardiovascular disease. Cleve Clin J Med 75 Suppl 5, S13–S16 (2008).
  15. 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).
  16. 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).
  17. 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).
  18. 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).
  19. Ramasamy, S. N. et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf 36, 953–980 (2013).
  20. 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).
  21. 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).
  22. 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).
  23. Ye, P. et al. Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and metaanalysis. Clin Ther 35, 180–189 (2013).
  24. 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).
  25. 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).
  26. Caldwell, D. M., Ades, A. E. & Higgins, J. P. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331, 897–900 (2005).
  27. 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).
  28. Chen, X. et al. Drug-target interaction prediction: databases, web servers and computational models. Brief Bioinform 17, 696–712 (2016).
  29. Chen, X. et al. NLLSS: Predicting Synergistic Drug Combinations Based on Semi-supervised Learning. PLoS Comput Biol 12, e1004975 (2016).
  30. 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).
  31. Lumley, T. Network meta-analysis for indirect treatment comparisons. Stat Med 21, 2313–2324 (2002).
  32. 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).
  33. 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).
  34. 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).
  35. 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).
  36. 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).
  37. 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).
  38. 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).
  39. 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).
  40. 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).
  41. 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).
  42. 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).
  43. Reinders, M. K. et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600mg/ day versus benzbromarone 100–200mg/day in patients with gout. Ann Rheum Dis 68, 892–897 (2009).
  44. 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).
  45. 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).
  46. 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).
  47. 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).
  48. 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).
  49. Higgins, J. P., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. BMJ 327, 557–560 (2003).
  50. Salanti, G., Ades, A. E. & Ioannidis, J. P. Graphical methods and numerical summaries for presenting results from multipletreatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64, 163–171 (2011).
  51. 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).
  52. 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).
  53. 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).
  54. 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).
  55. 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).
  56. Tayar, J. H., Lopez-Olivo, M. A. & Suarez-Almazor, M. E. Febuxostat for treating chronic gout. Cochrane Database Syst Rev. 11, 202–203 (2013).
  57. 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).
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