Allopurinol in Diabetes Mellitus and Multivessel Coronary Artery Disease

Summary

Atherosclerosis is a progressive disease of the arterial wall, arising from the combination of endothelial dysfunction and inflammation. This link is exacerbated in diabetic patients. Uric acid is known to generate oxidative stress and it's elevated levels has been shown to be associated with cardiac hypertrophy, inflammation, myocardial fibrosis and diastolic dysfunction. Allopurinol inhibits xanthine oxidase, an enzyme that regulates uric acid production. In observational studies it has been shown to reduce ischemia, inflammation and improve coronary flow. The aim of this study is to see whether treatment with Allopurinol in patients diagnosed with multivessel disease and undergoing treatment with either percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) , will reduce markers of inflammation and improve quality of life and major adverse cardiovascular effects (MACE).

Timeline

Start

2018-12-01

Primary completion

2019-12-31

Completion

2020-01-31

Publications

• Background Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26. doi: 10.1056/NEJM199901143400207. No abstract available.
• Background Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360(2):129-39. doi: 10.1056/NEJMoa0808431. Epub 2008 Dec 17.
• Background ACCORD Study Group; Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff DC Jr, Probstfield JL, Cushman WC, Ginsberg HN, Bigger JT, Grimm RH Jr, Byington RP, Rosenberg YD, Friedewald WT. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011 Mar 3;364(9):818-28. doi: 10.1056/NEJMoa1006524.
• Background BARI 2D Study Group; Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009 Jun 11;360(24):2503-15. doi: 10.1056/NEJMoa0805796. Epub 2009 Jun 7.
• Background Look AHEAD Research Group; Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. doi: 10.1056/NEJMoa1212914. Epub 2013 Jun 24.
• Background Arbel Y, Zlotnik M, Halkin A, Havakuk O, Berliner S, Herz I, Rabinovich I, Keren G, Bazan S, Finkelstein A, Banai S. Admission glucose, fasting glucose, HbA1c levels and the SYNTAX score in non-diabetic patients undergoing coronary angiography. Clin Res Cardiol. 2014 Mar;103(3):223-7. doi: 10.1007/s00392-013-0641-7. Epub 2013 Nov 24.
• Background de Mulder M, Umans VA, Cornel JH, van der Zant FM, Stam F, Oemrawsingh RM, Akkerhuis KM, Boersma E. Intensive glucose regulation in hyperglycemic acute coronary syndrome: results of the randomized BIOMarker study to identify the acute risk of a coronary syndrome-2 (BIOMArCS-2) glucose trial. JAMA Intern Med. 2013 Nov 11;173(20):1896-904. doi: 10.1001/jamainternmed.2013.10074.
• Background Yang SW, Zhou YJ, Tian XF, Pan GZ, Liu YY, Zhang J, Guo ZF, Chen SY, Gao ST, Du J, Jia DA, Fang Z, Hu B, Han HY, Gao F, Hu DY, Xu YY; Beijing Heart and Metabolism Survey Study Group. Association of dysglycemia and all-cause mortality across the spectrum of coronary artery disease. Mayo Clin Proc. 2013 Sep;88(9):930-41. doi: 10.1016/j.mayocp.2013.05.022.
• Background Neogi T, George J, Rekhraj S, Struthers AD, Choi H, Terkeltaub RA. Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal. Arthritis Rheum. 2012 Feb;64(2):327-38. doi: 10.1002/art.33369.
• Background Richette P, Perez-Ruiz F, Doherty M, Jansen TL, Nuki G, Pascual E, Punzi L, So AK, Bardin T. Improving cardiovascular and renal outcomes in gout: what should we target? Nat Rev Rheumatol. 2014 Nov;10(11):654-61. doi: 10.1038/nrrheum.2014.124. Epub 2014 Aug 19.
• Background Jia G, Habibi J, Bostick BP, Ma L, DeMarco VG, Aroor AR, Hayden MR, Whaley-Connell AT, Sowers JR. Uric acid promotes left ventricular diastolic dysfunction in mice fed a Western diet. Hypertension. 2015 Mar;65(3):531-9. doi: 10.1161/HYPERTENSIONAHA.114.04737. Epub 2014 Dec 8.
• Background Baena CP, Lotufo PA, Mill JG, Cunha Rde S, Bensenor IJ. Serum Uric Acid and Pulse Wave Velocity Among Healthy Adults: Baseline Data From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Am J Hypertens. 2015 Aug;28(8):966-70. doi: 10.1093/ajh/hpu298. Epub 2015 Jan 21.
• Background 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 May;59(3):235-42. doi: 10.1016/j.jjcc.2012.01.013. Epub 2012 Mar 6.
• Background 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 Sep;18(9):694-701. doi: 10.1016/j.cardfail.2012.06.528. Epub 2012 Aug 3.
• Background Miyaoka T, Mochizuki T, Takei T, Tsuchiya K, Nitta K. Serum uric acid levels and long-term outcomes in chronic kidney disease. Heart Vessels. 2014 Jul;29(4):504-12. doi: 10.1007/s00380-013-0396-0. Epub 2013 Aug 9.
• Background 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 Nov;160(5):928-33. doi: 10.1016/j.ahj.2010.08.006.
• Background Ito H, Abe M, Mifune M, Oshikiri K, Antoku S, Takeuchi Y, Togane M. Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS One. 2011;6(11):e27817. doi: 10.1371/journal.pone.0027817. Epub 2011 Nov 18.
• Background Takagi H, Umemoto T. Atorvastatin therapy reduces serum uric acid levels: a meta-analysis of randomized controlled trials. Int J Cardiol. 2012 May 31;157(2):255-7. doi: 10.1016/j.ijcard.2012.01.092. Epub 2012 Feb 21. No abstract available.
• Background Kanbay M, Segal M, Afsar B, Kang DH, Rodriguez-Iturbe B, Johnson RJ. The role of uric acid in the pathogenesis of human cardiovascular disease. Heart. 2013 Jun;99(11):759-66. doi: 10.1136/heartjnl-2012-302535. Epub 2013 Jan 23.
• Background Fan Y, Wei F, Lang Y, Wang S. Losartan treatment for hypertensive patients with hyperuricaemia in Chinese population: a meta-analysis. J Hypertens. 2015 Apr;33(4):681-8; discussion 689. doi: 10.1097/HJH.0000000000000478.
• Background El-Bassossy HM, Watson ML. Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: effect on low grade inflammation and the angiotensin system. J Transl Med. 2015 Mar 6;13:82. doi: 10.1186/s12967-015-0445-9.
• Background Erdogan D, Tayyar S, Uysal BA, Icli A, Karabacak M, Ozaydin M, Dogan A. Effects of allopurinol on coronary microvascular and left ventricular function in patients with idiopathic dilated cardiomyopathy. Can J Cardiol. 2012 Nov-Dec;28(6):721-7. doi: 10.1016/j.cjca.2012.04.005. Epub 2012 Jun 19.
• Background Rekhraj S, Gandy SJ, Szwejkowski BR, Nadir MA, Noman A, Houston JG, Lang CC, George J, Struthers AD. High-dose allopurinol reduces left ventricular mass in patients with ischemic heart disease. J Am Coll Cardiol. 2013 Mar 5;61(9):926-32. doi: 10.1016/j.jacc.2012.09.066.
• Background Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med. 2010 Aug 9;170(15):1358-64. doi: 10.1001/archinternmed.2010.198.
• Background de Abajo FJ, Gil MJ, Rodriguez A, Garcia-Poza P, Alvarez A, Bryant V, Garcia-Rodriguez LA. Allopurinol use and risk of non-fatal acute myocardial infarction. Heart. 2015 May;101(9):679-85. doi: 10.1136/heartjnl-2014-306670. Epub 2015 Jan 5.
• Background Grimaldi-Bensouda L, Alperovitch A, Aubrun E, Danchin N, Rossignol M, Abenhaim L, Richette P; PGRx MI Group. Impact of allopurinol on risk of myocardial infarction. Ann Rheum Dis. 2015 May;74(5):836-42. doi: 10.1136/annrheumdis-2012-202972. Epub 2014 Jan 6.
• Background Struthers A, Shearer F. Allopurinol: novel indications in cardiovascular disease. Heart. 2012 Nov;98(21):1543-5. doi: 10.1136/heartjnl-2012-302249. Epub 2012 Jul 16. No abstract available.
• Background Rentoukas E, Tsarouhas K, Tsitsimpikou C, Lazaros G, Deftereos S, Vavetsi S. The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Int J Cardiol. 2010 Nov 19;145(2):257-258. doi: 10.1016/j.ijcard.2009.08.037. Epub 2009 Sep 22.
• Background Givertz MM, Anstrom KJ, Redfield MM, Deswal A, Haddad H, Butler J, Tang WH, Dunlap ME, LeWinter MM, Mann DL, Felker GM, O'Connor CM, Goldsmith SR, Ofili EO, Saltzberg MT, Margulies KB, Cappola TP, Konstam MA, Semigran MJ, McNulty SE, Lee KL, Shah MR, Hernandez AF; NHLBI Heart Failure Clinical Research Network. Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (EXACT-HF) Study. Circulation. 2015 May 19;131(20):1763-71. doi: 10.1161/CIRCULATIONAHA.114.014536. Epub 2015 Apr 14.
• Background Higgins P, Walters MR, Murray HM, McArthur K, McConnachie A, Lees KR, Dawson J. Allopurinol reduces brachial and central blood pressure, and carotid intima-media thickness progression after ischaemic stroke and transient ischaemic attack: a randomised controlled trial. Heart. 2014 Jul;100(14):1085-92. doi: 10.1136/heartjnl-2014-305683. Epub 2014 May 1.
• Background Kao MP, Ang DS, Gandy SJ, Nadir MA, Houston JG, Lang CC, Struthers AD. Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2011 Jul;22(7):1382-9. doi: 10.1681/ASN.2010111185. Epub 2011 Jun 30.
• Background Erol T, Tekin A, Katircibasi MT, Sezgin N, Bilgi M, Tekin G, Zumrutdal A, Sezgin AT, Muderrisoglu H. Efficacy of allopurinol pretreatment for prevention of contrast-induced nephropathy: a randomized controlled trial. Int J Cardiol. 2013 Aug 20;167(4):1396-9. doi: 10.1016/j.ijcard.2012.04.068. Epub 2012 May 8.
• Background Goicoechea M, Garcia de Vinuesa S, Verdalles U, Verde E, Macias N, Santos A, Perez de Jose A, Cedeno S, Linares T, Luno J. Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial. Am J Kidney Dis. 2015 Apr;65(4):543-9. doi: 10.1053/j.ajkd.2014.11.016. Epub 2015 Jan 13.
• Background Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010 Jun 19;375(9732):2161-7. doi: 10.1016/S0140-6736(10)60391-1. Epub 2010 Jun 9.
• Background Guedes M, Esperanca A, Pereira AC, Rego C. What is the effect on cardiovascular events of reducing hyperuricemia with allopurinol? An evidence-based review. Rev Port Cardiol. 2014 Nov;33(11):727-32. doi: 10.1016/j.repc.2014.06.002. Epub 2014 Nov 20. English, Portuguese.
• Background Castrejon I, Toledano E, Rosario MP, Loza E, Perez-Ruiz F, Carmona L. Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis. Rheumatol Int. 2015 Jul;35(7):1127-37. doi: 10.1007/s00296-014-3189-6. Epub 2014 Dec 18.
• Background Kydd AS, Seth R, Buchbinder R, Falzon L, Edwards CJ, van der Heijde DM, Bombardier C. Urate-lowering therapy for the management of gout: a summary of 2 Cochrane reviews. J Rheumatol Suppl. 2014 Sep;92:33-41. doi: 10.3899/jrheum.140460.
• Background Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ. Allopurinol for chronic gout. Cochrane Database Syst Rev. 2014 Oct 14;2014(10):CD006077. doi: 10.1002/14651858.CD006077.pub3.
• Background Spina M, Nagy Z, Ribera JM, Federico M, Aurer I, Jordan K, Borsaru G, Pristupa AS, Bosi A, Grosicki S, Glushko NL, Ristic D, Jakucs J, Montesinos P, Mayer J, Rego EM, Baldini S, Scartoni S, Capriati A, Maggi CA, Simonelli C; FLORENCE Study Group. FLORENCE: a randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk. Ann Oncol. 2015 Oct;26(10):2155-61. doi: 10.1093/annonc/mdv317. Epub 2015 Jul 27.

Drugs

Indications