Erythropoietin

Erythropoietin is a 30.4-kDa glycoprotein best known for its action on erythroid progenitor cells and regulation of circulating red cell mass. It is currently used clinically for the treatment if anemia. However, several studies within the past two decades have shown that erythropoietin also activates potent cell protective mechanisms, which among other effects provide mitochondrial protection, resulting in protection from ischemia and reperfusion injury in a broad array of organs including the heart,1,2 brain,3,4 and kidneys.5

Preclinical studies in rat6,7 and pig models8,9 of cardiac arrest at the Resuscitation Institute and at other institutions,10-13 and a small clinical study in Maribor, Slovenia14 showed that erythropoietin given during cardiac resuscitation reduces the injury to the myocardium resulting in more effective CPR, better cardiac function post-resuscitation, and higher survival.

– ERYCA TRIAL –

We have designed a phase 3 clinical trial named the ERYCA Trial (ERYthropoietin for Cardiac Arrest). The study will assess the effects of administering a 90,000 IU of erythropoietin or vehicle control during CPR in adult victims of out-of-hospital cardiac arrest using a group sequential trial design with interim analyses for futility and for efficacy. The primary outcome will be 72-hour survival. Secondary outcomes will include effects on the resuscitation efforts (e.g., duration of CPR, end-tidal PCO2, and doses of epinephrine), return of spontaneous circulation rate, ICU admission rate, use of vasoactive and/or inotropic drugs post-resuscitation, and survival with good neurological outcome at the time of hospital discharge and at 30 and 90 days. The study will also assess whether the plasma levels of cytochrome c – used as a marker of mitochondrial injury15 – would be lower in patients treated with erythropoietin. A positive result of the ERYCA Trial will pave the way for FDA approval for clinical use and subsequent commercialization, facilitated by the 505(b)(2) pathway designed for repurposing drugs.

Related Publications:

  1. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, Koch WJ. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest 2003;112:999-1007.
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  1. Lipsic E, van der MP, Henning RH, Suurmeijer AJ, Boddeus KM, van Veldhuisen DJ, van Gilst WH, Schoemaker RG. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol 2004;44:473-9.
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  1. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 2000;97:10526-31.
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  1. Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P. Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 2001;98:4044-9.
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  1. Vesey DA, Cheung C, Pat B, Endre Z, Gobe G, Johnson DW. Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant 2004;19:348-55.
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  1. Singh D, Kolarova JD, Wang S, Ayoub IM, Gazmuri RJ. Myocardial protection by erythropoietin during resuscitation from ventricular fibrillation. Am J Ther 2007;14:361-8.
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  1. Radhakrishnan J, Upadhyaya MP, Ng M, Edelheit A, Moy HM, Ayoub IM, Gazmuri RJ. Erythropoietin facilitates resuscitation from ventricular fibrillation by signaling protection of mitochondrial bioenergetic function in rats. Am J Transl Res 2013;5:316-26.
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  1. Borovnik-Lesjak V, Whitehouse K, Baetiong A, Artin B, Radhakrishnan J, Gazmuri RJ. High-dose erythropoietin during cardiac resuscitation lessens postresuscitation myocardial stunning in swine. Transl Res 2013;162:110-21.
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  1. Gazmuri RJ, Whitehouse K, Borovnik-Lesjak V, Shah K, Baetiong A, Radhakrishnan J. High-dose erythropoietin improves survival in a swine model of ventricular fibrillation. Crit Care Med 42(Suppl.):110 (Abstract)
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  1. Huang CH, Hsu CY, Chen HW, Tsai MS, Cheng HJ, Chang CH, Lee YT, Chen WJ. Erythropoietin improves postresuscitation myocardial dysfunction and survival in the asphyxia-induced cardiac arrest model. Shock 2007;28:53-8.
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  1. Incagnoli P, Ramond A, Joyeux-Faure M, Pepin JL, Levy P, Ribuot C. Erythropoietin improved initial resuscitation and increased survival after cardiac arrest in rats. Resuscitation 2009;80:696-700.
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  1. Jiang HL, Zhu YC, Chen XH, Lin PY, Wang HJ. [The myocardium protective effects of erythropoietin (EPO) in a rat model of asphyxia-induced cardiac arrest/cardiopulmonary resuscitation (CPR)]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2011;23:608-12.
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  1. Vasileiou PV, Xanthos T, Barouxis D, Pantazopoulos C, Papalois AE, Lelovas P, Kotsilianou O, Pliatsika P, Kouskouni E, Iacovidou N. Erythropoietin administration facilitates return of spontaneous circulation and improves survival in a pig model of cardiac arrest. Am J Emerg Med 2014.
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  1. Grmec S, Strnad M, Kupnik D, Sinkovic A, Gazmuri RJ. Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest. Resuscitation 2009;80:631-7.
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  1. Radhakrishnan J, Origenes R, Littlejohn G, Nikolich S, Choi E, Smite S, Lamoureux L, Baetiong A, Shah M, Gazmuri RJ. Plasma Cytochrome c Detection Using a Highly Sensitive Electrochemiluminescence Enzyme-Linked Immunosorbent Assay. Biomark Insights 2017;12:1177271917746972.
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