Cardiovascular Drugs and Therapy

, Volume 27, Issue 5, pp 433–439 | Cite as

Long Term Effects of Epoetin Alfa in Patients with ST- Elevation Myocardial Infarction

  • Marieke L. Fokkema
  • Lennaert Kleijn
  • Peter van der Meer
  • Anne M. Belonje
  • Sandra K. Achterhof
  • Hans L. Hillege
  • Arnoud van ’t Hof
  • J. Wouter Jukema
  • Hans O. Peels
  • José P. Henriques
  • Jurriën M. ten Berg
  • Jeroen Vos
  • Wiek H. van Gilst
  • Dirk J. van Veldhuisen
  • Adriaan A. VoorsEmail author



The HEBE III trial showed that epoetin alfa administration in patients with a first ST-elevation myocardial infarction (STEMI) did not improve left ventricular function at 6 weeks after primary percutaneous coronary intervention (PCI). The long term effects of erythropoiesis- stimulating agents on cardiovascular morbidity and mortality are unknown, therefore we evaluated clinical events at 1 year after PCI.


A total of 529 patients with a first STEMI and successful primary PCI were randomized to standard optimal medical treatment (N = 266) or an additional bolus of 60,000 IU epoetin alfa administered intravenously (N = 263) within 3 h after PCI. Analyses were performed by intention to treat.


At 1 year after STEMI, 485 patients had complete follow-up. The rate of the composite end point of all-cause mortality, re-infarction, target vessel revascularization, stroke and/or heart failure was 6.4 % (N = 15) in the epoetin alfa group and 9.6 % (N = 24) in the control group (p = 0.18). Thromboembolic events were present in 1.3 % (N = 3) of patients in the epoetin alfa group and 2.4 % (N = 6) in the control group. There was no evidence of benefit from epoetin alfa administration in subgroups of patients.


Administration of a single bolus of epoetin alfa in patients with STEMI does not result in a reduction of cardiovascular events at 1 year after primary PCI. There was a comparable incidence of thromboembolic complications in both treatment groups, suggesting that epoetin alfa administration is safe at long term.


Erythropoietin Myocardial infarction Percutaneous coronary intervention Clinical outcome 


  1. 1.
    Ott I, Schulz S, Mehilli J, et al. Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomized, double-blind trial. Circ Cardiovasc Interv. 2010;3:408–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Voors AA, Belonje AM, Zijlstra F, et al. A single dose of erythropoietin in ST-elevation myocardial infarction. Eur Heart J. 2010;31:2593–600.PubMedCrossRefGoogle Scholar
  3. 3.
    Taniguchi N, Nakamura T, Sawada T, et al. Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study. Circ J. 2010;74:2365–71.PubMedCrossRefGoogle Scholar
  4. 4.
    Ozawa T, Toba K, Suzuki H, et al. Single-dose intravenous administration of recombinant human erythropoietin is a promising treatment for patients with acute myocardial infarction—randomized controlled pilot trial of EPO/AMI-1 study. Circ J. 2010;74:1415–23.PubMedCrossRefGoogle Scholar
  5. 5.
    Suh JW, Chung WY, Kim YS, et al. The effect of intravenous administration of erythropoietin on the infarct size in primary percutaneous coronary intervention. Int J Cardiol. 2011;149:216–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Ferrario M, Arbustini E, Massa M, et al. High-dose erythropoietin in patients with acute myocardial infarction: a pilot, randomised, placebo-controlled study. Int J Cardiol. 2011;147:124–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA. 2011;305:1863–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Ludman AJ, Yellon DM, Hasleton J, et al. Effect of erythropoietin as an adjunct to primary percutaneous coronary intervention: a randomised controlled clinical trial. Heart. 2011;97:1560–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Prunier F, Biere L, Gilard M, et al. Single high-dose erythropoietin administration immediately after reperfusion in patients with ST-segment elevation myocardial infarction: results of the erythropoietin in myocardial infarction trial. Am Heart J. 2012;163:200–7.e1.PubMedCrossRefGoogle Scholar
  10. 10.
    Belonje AM, Voors AA, van Gilst WH, et al. Effects of erythropoietin after an acute myocardial infarction: rationale and study design of a prospective, randomized, clinical trial (HEBE III). Am Heart J. 2008;155:817–22.PubMedCrossRefGoogle Scholar
  11. 11.
    van Veldhuisen DJ, Anker SD, Ponikowski P, et al. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Cardiol. 2011;8:485–93.PubMedCrossRefGoogle Scholar
  12. 12.
    Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol. 2005;23:5960–72.PubMedCrossRefGoogle Scholar
  13. 13.
    Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117:526–35.PubMedCrossRefGoogle Scholar
  16. 16.
    van Veldhuisen DJ, Dickstein K, Cohen-Solal A, et al. Randomized, double-blind, placebo-controlled study to evaluate the effect of two dosing regimens of darbepoetin alfa in patients with heart failure and anaemia. Eur Heart J. 2007;28:2208–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368:1210–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.PubMedGoogle Scholar
  19. 19.
    Ehrenreich H, Weissenborn K, Prange H, et al. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647–56.PubMedCrossRefGoogle Scholar
  20. 20.
    Lipsic E, Schoemaker RG, van der Meer P, et al. Protective effects of erythropoietin in cardiac ischemia: from bench to bedside. J Am Coll Cardiol. 2006;48:2161–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Lipsic E, van der Meer P, Henning RH, et al. Timing of erythropoietin treatment for cardioprotection in ischemia/reperfusion. J Cardiovasc Pharmacol. 2004;44:473–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Parsa CJ, Matsumoto A, Kim J, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Invest. 2003;112:999–1007.PubMedGoogle Scholar
  23. 23.
    Tramontano AF, Muniyappa R, Black AD, et al. Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an akt-dependent pathway. Biochem Biophys Res Commun. 2003;308:990–4.PubMedCrossRefGoogle Scholar
  24. 24.
    Calvillo L, Latini R, Kajstura J, et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003;100:4802–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Hirata A, Minamino T, Asanuma H, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48:176–84.PubMedCrossRefGoogle Scholar
  26. 26.
    van der Meer P, Lipsic E, Henning RH, et al. Erythropoietin induces neovascularization and improves cardiac function in rats with heart failure after myocardial infarction. J Am Coll Cardiol. 2005;46:125–33.PubMedCrossRefGoogle Scholar
  27. 27.
    van der Meer P, van Veldhuisen DJ. Acute coronary syndromes: the unfulfilled promise of erythropoietin in patients with MI. Nat Rev Cardiol. 2011;8:425–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Talan MI, Ahmet I, Lakatta EG. Did clinical trials in which erythropoietin failed to reduce acute myocardial infarct size miss a narrow therapeutic window? PLoS One. 2012;7:e34819.PubMedCrossRefGoogle Scholar
  29. 29.
    Lipsic E, van der Meer P, Voors AA, et al. A single bolus of a long-acting erythropoietin analogue darbepoetin alfa in patients with acute myocardial infarction: a randomized feasibility and safety study. Cardiovasc Drugs Ther. 2006;20:135–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Kleijn L, de Boer RA, Voors AA. Should erythropoietin treatment in chronic heart failure be haemoglobin targeted? Eur J Heart Fail. 2010;12:215–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Gao D, Ning N, Niu X, et al. Erythropoietin treatment in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials. Am Heart J. 2012;164:715–27.e1.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Marieke L. Fokkema
    • 1
  • Lennaert Kleijn
    • 1
  • Peter van der Meer
    • 1
  • Anne M. Belonje
    • 2
  • Sandra K. Achterhof
    • 1
  • Hans L. Hillege
    • 1
  • Arnoud van ’t Hof
    • 3
  • J. Wouter Jukema
    • 4
  • Hans O. Peels
    • 5
  • José P. Henriques
    • 6
  • Jurriën M. ten Berg
    • 7
  • Jeroen Vos
    • 8
  • Wiek H. van Gilst
    • 1
  • Dirk J. van Veldhuisen
    • 1
  • Adriaan A. Voors
    • 1
    Email author
  1. 1.Department of CardiologyUniversity Medical Center GroningenGroningenThe Netherlands
  2. 2.Athena InstituteVU UniversityAmsterdamThe Netherlands
  3. 3.Department of CardiologyIsala ClinicsZwolleThe Netherlands
  4. 4.Department of CardiologyLeiden University Medical CenterLeidenThe Netherlands
  5. 5.Department of CardiologyMedical Center AlkmaarAlkmaarThe Netherlands
  6. 6.Department of CardiologyAcademic Medical CenterAmsterdamThe Netherlands
  7. 7.Department of CardiologySt Antonius HospitalNieuwegeinThe Netherlands
  8. 8.Department of CardiologyAmphia HospitalBredaThe Netherlands

Personalised recommendations