Abstract
Purpose
This network meta-analysis aimed to assess the current efficacy of decreasing the uric acid (UA) level with drugs to reduce mortality in patients with heart failure (HF).
Methods
Electronic literature searches using EMBASE and MEDLINE of studies published from 1 Jan 1950 to 26 Dec 2019 were conducted for randomized controlled trials or non-randomized cohort studies that included at least one group of patients who took UA-lowering drugs and with a study outcome of all-cause mortality. A random-effects network meta-analysis was performed within a frequentist framework. Hierarchy of treatments was expressed as the surface under the cumulative ranking curve (SUCRA) value, which is in proportion to mean rank (best is 100%).
Results
Nine studies, which included seven different types of groups, were eligible for analysis. The “untreated uricemia” group in which patients had hyperuricemia but without treatment had a significantly higher risk of mortality than the “no uricemia” group in which patients had no hyperuricemia (relative risk (RR)(95% confidence interval (CI), 1.43 (1.08–1.89)). The “start-allo” group wherein patients started to take allopurinol did not have a significantly lower risk of mortality than the “untreated uricemia” group (RR (95% CI), 0.68 (0.45–1.01)). However, in the “start-allo” group the SUCRA value was comparable to that in the “no uricemia” group (SUCRA: 65.4% for “start-allo”; 64.1% for “no uricemia”).
Conclusions
Results suggested that allopurinol therapy was not associated with a significantly improved prognosis in terms of mortality but could potentially counteract the adverse effects associated with longstanding hyperuricemia in HF patients.
Similar content being viewed by others
References
Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6):646–59.
Gotsman I, Keren A, Lotan C, Zwas DR. Changes in uric acid levels and allopurinol use in chronic heart failure: association with improved survival. J Card Fail. 2012;18(9):694–701.
Filippatos GS, Ahmed MI, Gladden JD, Mujib M, Aban IB, Love TE, et al. Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data. Eur Heart J. 2011;32(6):712–20.
Huang G, Qin J, Deng X, Luo G, Yu D, Zhang M, et al. Prognostic value of serum uric acid in patients with acute heart failure: a meta-analysis. Medicine. 2019;98(8):e14525.
Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A. Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: molecular mechanisms and clinical implications. J Cardiol. 2012;59(3):235–42.
Otaki Y, Watanabe T, Kinoshita D, Yokoyama M, Takahashi T, Toshima T, et al. Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. Int J Cardiol. 2017;228:151–7.
Sun Y. Oxidative stress and cardiac repair/remodeling following infarction. Am J Med Sci. 2007;334(3):197–205.
Prasad K, Kalra J, Chan WP, Chaudhary AK. Effect of oxygen free radicals on cardiovascular function at organ and cellular levels. Am Heart J. 1989;117(6):1196–202.
Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002;106(2):221–6.
Baldus S, Mullerleile K, Chumley P, Steven D, Rudolph V, Lund GK, et al. Inhibition of xanthine oxidase improves myocardial contractility in patients with ischemic cardiomyopathy. Free Radic Biol Med. 2006;41(8):1282–8.
Bredemeier M, Lopes LM, Eisenreich MA, Hickmann S, Bongiorno GK, d'Avila R, et al. Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2018;18(1):24.
Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.
Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.
White IR. Multivariate random-effects meta-regression: updates to mvmeta. Stata J. 2011;11(2):255–70.
White IR, Barrett JK, Jackson D, Higgins JP. Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods. 2012;3(2):111–25.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Bmj. 1997;315(7109):629–34.
Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta-analysis in STATA. PLoS One. 2013;8(10):e76654.
Harzand A, Tamariz L, Hare JM. Uric acid, heart failure survival, and the impact of xanthine oxidase inhibition. Congestive Heart Failure. 2012;18(3):179–82.
Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp AB, et al. The Seattle heart failure model: prediction of survival in heart failure. Circulation. 2006;113(11):1424–33.
Cicero AFG, Cosentino ER, Kuwabara M, Degli Esposti D, Borghi C. Effects of allopurinol and febuxostat on cardiovascular mortality in elderly heart failure patients. Intern Emerg Med. 2019;14(6):949–56.
Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med. 2010;170(15):1358–64.
Xiao J, Deng SB, She Q, Li J, Kao GY, Wang JS, et al. Allopurinol ameliorates cardiac function in non-hyperuricaemic patients with chronic heart failure. Eur Rev Med Pharmacol Sci. 2016;20(4):756–61.
Pavlusova M, Jarkovsky J, Benesova K, Vitovec J, Linhart A, Widimsky P, et al. Hyperuricemia treatment in acute heart failure patients does not improve their long-term prognosis: a propensity score matched analysis from the AHEAD registry. Clin Cardiol. 2019;42(8):720–7.
Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, et al. Effects of xanthine oxidase inhibition in Hyperuricemic heart failure patients: the xanthine oxidase inhibition for Hyperuricemic heart failure patients (EXACT-HF) study. Circulation. 2015;131(20):1763–71.
Malek F, Ostadal P, Parenica J, Jarkovsky J, Vitovec J, Widimsky P, et al. Uric acid, allopurinol therapy, and mortality in patients with acute heart failure--results of the Acute HEart FAilure Database registry. J Crit Care. 2012;27(6):737 e11–24.
Wu AH, Ghali JK, Neuberg GW, O'Connor CM, Carson PE, Levy WC. Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure. Am Heart J. 2010;160(5):928–33.
Wei L, Fahey T, Struthers AD, MacDonald TM. Association between allopurinol and mortality in heart failure patients: a long-term follow-up study. Int J Clin Pract. 2009;63(9):1327–33.
Hare JM, Mangal B, Brown J, Fisher C Jr, Freudenberger R, Colucci WS, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol. 2008;51(24):2301–9.
Struthers AD, Donnan PT, Lindsay P, McNaughton D, Broomhall J, MacDonald TM. Effect of allopurinol on mortality and hospitalisations in chronic heart failure: a retrospective cohort study. Heart. 2002;87(3):229–34.
Kanbay M, Afsar B, Siriopol D, Dincer N, Erden N, Yilmaz O, 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):315–23.
Sezai A, Soma M, Nakata K, Hata M, Yoshitake I, Wakui S, et al. Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). Circ J : Off Je Jpn Circ Soc. 2013;77(8):2043–9.
George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006;114(23):2508–16.
White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. New England J Med. 2018;378(13):1200–10.
Cameron C, Fireman B, Hutton B, Clifford T, Coyle D, Wells G, et al. Network meta-analysis incorporating randomized controlled trials and non-randomized comparative cohort studies for assessing the safety and effectiveness of medical treatments: challenges and opportunities. Syst Rev. 2015;4:147.
Ogino K, Kato M, Furuse Y, Kinugasa Y, Ishida K, Osaki S, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Failure. 2010;3(1):73–81.
Kim SC, Neogi T, Kang EH, Liu J, Desai RJ, Zhang M, et al. Cardiovascular risks of probenecid versus allopurinol in older patients with gout. J Am Coll Cardiol. 2018;71(9):994–1004.
Acknowledgments
All authors thank Ms. Haga and Ms. Chino in the Niigata University for their excellent secretarial work.
Funding
The study was funded by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (ID:19K12840). The sponsor had no influence over the design and conduct of the study; collection, management, analysis, and interpretation of the data or preparation, review; or approval of the manuscript.
Author information
Authors and Affiliations
Contributions
All authors conceived and designed the research; SK, KF, CH, MY, MK, and YY acquired the data; SK, KF, and HS analyzed the data; SK drafted the manuscript; and SK, TY, TM, YM, KW, and HS interpreted the results and made critical revision of the manuscript for important intellectual content. All authors approved the submission of the final manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
All authors declare that they have no conflict of interest.
Ethical Approval
This article does not describe any studies with human participants or animals performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOC 318 kb)
Rights and permissions
About this article
Cite this article
Kodama, S., Fujihara, K., Horikawa, C. et al. Network Meta-Analysis of Drug Therapies for Lowering Uric Acid and Mortality Risk in Patients with Heart Failure. Cardiovasc Drugs Ther 35, 1217–1225 (2021). https://doi.org/10.1007/s10557-020-07097-4
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-020-07097-4