Online first
Review Article
Published online: 2024-05-21

open access

Page views 323
Article views/downloads 205
Get Citation

Connect on Social Media

Connect on Social Media

Influence of xanthine oxidase inhibitors on all-cause mortality in adults: a systematic review and meta-analysis

Marcin M. Nowak1, Mariusz Niemczyk2, Sławomir Gołębiewski1, Leszek Pączek23
Pubmed: 38771265


Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup

Article available in PDF format

View PDF Download PDF file


  1. Chen-Xu M, Yokose C, Rai SK, et al. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019; 71(6): 991–999.
  2. Mikuls T. Gout. New England Journal of Medicine. 2022; 387(20): 1877–1887.
  3. Salem CB, Slim R, Fathallah N, et al. Drug-induced hyperuricaemia and gout. Rheumatology. 2016: kew293.
  4. Neeley WL, Essigmann JM. Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol. 2006; 19(4): 491–505.
  5. Pang Bo, McFaline JL, Burgis NE, et al. Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA. Proc Natl Acad Sci U S A. 2012; 109(7): 2319–2324.
  6. Yang HC, Nguyen PA, Islam M, et al. Gout drugs use and risk of cancer: A case-control study. Joint Bone Spine. 2018; 85(6): 747–753.
  7. Cho SK, Chang Y, Kim I, et al. U-Shaped Association Between Serum Uric Acid Level and Risk of Mortality: A Cohort Study. Arthritis Rheumatol. 2018; 70(7): 1122–1132.
  8. Lee SY, Park W, Suh YJu, et al. Association of Serum Uric Acid with Cardiovascular Disease Risk Scores in Koreans. Int J Environ Res Public Health. 2019; 16(23): 4632.
  9. Ramos GK, Goldfarb DS. Update on Uric Acid and the Kidney. Curr Rheumatol Rep. 2022; 24(5): 132–138.
  10. Moher D, Shamseer L, Clarke M, et al. PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4(1): 1.
  11. Lo CKL, Mertz D, Loeb M. Newcastle-Ottawa Scale: comparing reviewers' to authors' assessments. BMC Med Res Methodol. 2014; 14: 45.
  12. Altman DG, Bland JM. How to obtain the confidence interval from a P value. BMJ. 2011; 343: d2090.
  13. IntHout J, Ioannidis JPA, Rovers MM, et al. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open. 2016; 6(7): e010247.
  14. Baujat B, Mahé C, Pignon JP, et al. A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials. Stat Med. 2002; 21(18): 2641–2652.
  15. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315(7109): 629–634.
  16. Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 2019; 22(4): 153–160.
  17. Harrer M, Cuijpers P, Furukawa T, Ebert DD. Doing Meta-Analysis with R, A Hands-On Guide. Chapman and Hall/CRC, New York 2021.
  18. Dubreuil M, Zhu Y, Zhang Y, et al. Allopurinol initiation and all-cause mortality in the general population. Ann Rheum Dis. 2015; 74(7): 1368–1372.
  19. Hung PH, Lin CH, Hung KY, et al. Clinical burden of autosomal dominant polycystic kidney disease. Aging (Albany NY). 2020; 12(4): 3899–3910.
  20. Ju C, Lai RW, Li KaH, et al. Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users. Rheumatology (Oxford). 2020; 59(9): 2340–2349.
  21. Kuo CF, Grainge MJ, Mallen C, et al. Effect of allopurinol on all-cause mortality in adults with incident gout: propensity score-matched landmark analysis. Rheumatology (Oxford). 2015; 54(12): 2145–2150.
  22. Larsen KS, Pottegård A, Lindegaard HM, et al. Effect of Allopurinol on Cardiovascular Outcomes in Hyperuricemic Patients: A Cohort Study. Am J Med. 2016; 129(3): 299–306.e2.
  23. Luk AJ, Levin GP, Moore EE, et al. Allopurinol and mortality in hyperuricaemic patients. Rheumatology (Oxford). 2009; 48(7): 804–806.
  24. Tsuruta Y, Nitta K, Akizawa T, et al. Association between allopurinol and mortality among Japanese hemodialysis patients: results from the DOPPS. Int Urol Nephrol. 2014; 46(9): 1833–1841.
  25. Watanabe K, Nakayama M, Yamamoto T, et al. Different clinical impact of hyperuricemia according to etiologies of chronic kidney disease: Gonryo Study. PLoS One. 2021; 16(3): e0249240.
  26. Wei J, Choi HK, Neogi T, et al. Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease : A Population-Based Cohort Study. Ann Intern Med. 2022; 175(4): 461–470.
  27. Wei L, Fahey T, Struthers AD, et al. Association between allopurinol and mortality in heart failure patients: a long-term follow-up study. Int J Clin Pract. 2009; 63(9): 1327–1333.
  28. Weisman A, Tomlinson GA, Lipscombe LL, et al. Allopurinol and Renal Outcomes in Adults With and Without Type 2 Diabetes: A Retrospective, Population-Based Cohort Study and Propensity Score Analysis. Can J Diabetes. 2021; 45(7): 641–649.e4.
  29. Mackenzie I, Hawkey C, Ford I, et al. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. The Lancet. 2022; 400(10359): 1195–1205.
  30. Kanbay M, Afsar B, Siriopol D, et al. Effect of Uric Acid-Lowering Agents on Cardiovascular Outcome in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies. Angiology. 2020; 71(4): 315–323.
  31. Tamariz L, Hare JM. Xanthine oxidase inhibitors in heart failure: where do we go from here? Circulation. 2015; 131(20): 1741–1744.
  32. Mackenzie IS, Hawkey CJ, Ford I, et al. ALL-HEART Study Group. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022; 400(10359): 1195–1205.
  33. Borghi C, Domienik-Karłowicz J, Tykarski A, et al. Expert consensus for the diagnosis and treatment of patient with hyperuricemia and high cardiovascular risk: 2021 update. Cardiol J. 2021; 28(1): 1–14.
  34. Ejaz AA, Nakagawa T, Kanbay M, et al. Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage. Semin Nephrol. 2020; 40(6): 574–585.
  35. Agborbesong E, Li LX, Li Lu, et al. Molecular Mechanisms of Epigenetic Regulation, Inflammation, and Cell Death in ADPKD. Front Mol Biosci. 2022; 9: 922428.
  36. Park HC, Kang AY, Jang JY, et al. Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease. BMC Nephrol. 2013; 14: 1.