Aprotinin in adults at high risk of major blood loss during isolated CABG with cardiopulmonary bypass: a profile of its use in the EU

  • Katherine A. Lyseng-WilliamsonEmail author
Adis Drug Q&A


Prophylactic treatment with aprotinin, a haemostatic antifibrinolytic agent, is indicated to reduce blood loss and blood transfusion in adults with a high risk of major bleeding undergoing primary or repeat isolated coronary artery bypass graft (CABG) with cardiopulmonary bypass. Overall, aprotinin was consistently more effective than tranexamic acid, ε-aminocaproic acid, desmopressin and placebo in reducing massive blood loss, the need for transfusions of blood products, and the need for reoperation due to diffuse bleeding in trials in this patient population, and was generally well-tolerated. The approval of aprotinin in the EU was reinstated by the European Medicines Agency (EMA) in 2012, following subsequent analysis of the clinical data that led to its suspension in 2007. The EMA analysis concluded that the reduction in massive bleeding provided by aprotinin in patients undergoing isolated CABG is clinically relevant, as it reduces complications, the need for blood product transfusions and the length of hospital stay, without increasing mortality. The relaunch of aprotinin was accompanied by a risk management to assess the pattern of use and safety of aprotinin in clinical practice. Data from centres enrolled in the Nordic Aprotinin Patient Registry are being collected and will be assessed in the final report.



The manuscript was reviewed by: P. Meybohm, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany; M.A.N.V.P. Morgado, CICS-UBI Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; K. Zacharowski, Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany. During the peer review process, Nordic Group, the marketing-authorization holder of aprotinin, was also offered an opportunity to provide a scientific accuracy review of their data. Changes resulting from comments received were made based on their scientific and editorial merit.

Compliance with ethical standards


The preparation of this review was not supported by any external funding.

Conflict of interest

K.A. Lyseng-Williamson is an employee of Adis International Ltd/Springer Nature and the Editor of Drugs & Therapy Perspectives, and has no other conflicts of interest to declare. The Editor of D&TP was not be involved in any publishing decisions for the manuscript.


  1. 1.
    Aprotinin 10,000 KIU/ml injection BP: UK summary of product characteristics. Reading: Nordic Pharma Limited; 2017.Google Scholar
  2. 2.
    Committee for Medicinal Products for Human Use (CHMP). Assessment report: antifibrinolytics containing aprotinin, aminocaproic acid and tranexamic acid. London: European Medicines Agency; 2013.Google Scholar
  3. 3.
    Mangano DT, Tudor IC, Dietzel C, et al. The risk associated with aprotinin in cardiac surgery. N Eng J Med. 2006;354(4):353–65.CrossRefGoogle Scholar
  4. 4.
    Karkouti K, Beattie W, Dattilo K, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion (Paris). 2006;46(3):327–38.CrossRefGoogle Scholar
  5. 5.
    Fergusson DA, Hébert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358(22):2319–31.CrossRefGoogle Scholar
  6. 6.
    European Medicines Agency. European Medicines Agency recommends lifting suspension of aprotinin. Media release; 17 Feb 2012.Google Scholar
  7. 7.
    Engles L. Review and application of serine protease inhibition in coronary artery bypass graft surgery. Am J Health Syst Pharm. 2005;62(18 Suppl 4):S9–14.CrossRefGoogle Scholar
  8. 8.
    McEvoy MD, Reeves ST, Reves JG, et al. Aprotinin in cardiac surgery: a review of conventional and novel mechanisms of action. Anesth Analg. 2007;105(4):949–62.CrossRefGoogle Scholar
  9. 9.
    Michalets E, Harris L. Chapter 44. Antifibrolytics: pharmacologic profile and clinical utilization. In: Topaz, O, editor. Cardiovascular thrombus: from pathology and clinical presentations to imaging, pharmacotherapy and interventions. Cambridge (MA): Academic Press; 2018. p. 615–49.Google Scholar
  10. 10.
    Royston D. Serine protease inhibition prevents both cellular and humoral responses to cardiopulmonary bypass. J Cardiovasc Pharmacol. 1996;27(Suppl 1):S42–9.CrossRefGoogle Scholar
  11. 11.
    Peters DC, Noble S. Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery. Drugs. 1999;57(2):233–60.CrossRefGoogle Scholar
  12. 12.
    Szczeklik W, Morawski W, Sanak M, et al. A single dose of aprotinin prevents platelet hyporeactivity after coronary artery bypass graft surgery. Pol Arch Med Wewn. 2010;120(9):321–7.PubMedGoogle Scholar
  13. 13.
    Lindvall G, Sartipy U, Bjessmo S, et al. Aprotinin reduces the antiplatelet effect of clopidogrel. Interact Cardiovasc Thorac Surg. 2009;9(2):178–81.CrossRefGoogle Scholar
  14. 14.
    Karaca P, Konuralp C, Enҁ Y, et al. Cardioprotective effect of aprotinin on myocardial ischemia/reperfusion injury during cardiopulmonary bypass. Circ J. 2006;70(11):1432–6.CrossRefGoogle Scholar
  15. 15.
    Greilich PE, Okada K, Latham P, et al. Aprotinin but not ε-aminocaproic acid decreases interleukin-10 after cardiac surgery with extracorporeal circulation: randomized, double-blind, placebo-controlled study in patients receiving aprotinin and ε-aminocaproic acid. Circulation. 2001;104(Suppl 1):I265–9.CrossRefGoogle Scholar
  16. 16.
    Schmartz D, Tabardel Y, Preiser JC, et al. Does aprotinin influence the inflammatory response to cardiopulmonary bypass in patients? J Thorac Cardiovasc Surg. 2003;125(1):184–90.CrossRefGoogle Scholar
  17. 17.
    Koster A, Buz S, Krabatsch T, et al. High-dose aprotinin effectively reduces blood loss during on-pump coronary artery bypass grafting with bivalirudin anticoagulation. J Thorac Cardiovasc Surg. 2008;135(3):685–7.CrossRefGoogle Scholar
  18. 18.
    Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency after aprotinin use: results from the international multicenter aprotinin graft patency experience (IMAGE) trial. J Thorac Cardiovasc Surg. 1998;116(5):716–30.CrossRefGoogle Scholar
  19. 19.
    Bidstrup B, Royston D, Sapsford R, et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg. 1989;97(3):364–72.PubMedGoogle Scholar
  20. 20.
    Bidstrup BP, Underwood SR, Sapsford RN, et al. Effect of aprotinin (Trasylol) on aorta-coronary bypass graft patency. J Thorac Cardiovasc Surg. 1993;105(1):147–52.PubMedGoogle Scholar
  21. 21.
    Harder MP, Eijsman L, Roosendall KJ, et al. Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass. Ann Thorac Surg. 1991;51(6):936–41.CrossRefGoogle Scholar
  22. 22.
    Lemmer JH Jr, Dilling EW, Morton JR, et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg. 1996;62(6):1659–68.CrossRefGoogle Scholar
  23. 23.
    Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary bypass operations: efficacy, safety, and influence on early saphenous vein graft patency. J Thorac Cardiovasc Surg. 1994;107(2):543–53.PubMedGoogle Scholar
  24. 24.
    Cosgrove DM III, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebo-controlled study. Ann Thorac Surg. 1992;54(6):1031–8.CrossRefGoogle Scholar
  25. 25.
    Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind, placebo-controlled trial of aprotinin for reducing blood loss and the requirement for donor blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation. 1995;92(8):2236–44.CrossRefGoogle Scholar
  26. 26.
    Dietrich W, Spannagl M, Boehm J, et al. Tranexamic acid and aprotinin in primary cardiac operations: an analysis of 220 cardiac surgical patients treated with tranexamic acid or aprotinin. Anesth Analg. 2008;107(5):1469–78.CrossRefGoogle Scholar
  27. 27.
    Hekmat K, Zimmermann T, Kampe S, et al. Impact of tranexamic acid vs. aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: a prospective, randomised, double-blind trial. Curr Med Res Opin. 2004;20(1):121–6.CrossRefGoogle Scholar
  28. 28.
    Mongan PD, Brown RS, Thwaites BK. Tranexamic acid and aprotinin reduce postoperative bleeding and transfusions during primary coronary revascularisation. Anesth Analg. 1998;87(2):258–65.PubMedGoogle Scholar
  29. 29.
    Menichetti A, Tritapepe L, Ruvolo G, et al. Changes in coagulation patterns, blood loss and blood use after cardiopulmonary bypass: aprotinin vs tranexamic acid vs epsilon aminocaproic acid. J Cardiovasc Surg. 1996;37(4):401–7.Google Scholar
  30. 30.
    Eberle B, Mayer E, Hafner G, et al. High-dose ε-aminocaproic acid versus aprotinin: antifibrinolytic efficacy in first-time coronary operations. Ann Thorac Surg. 1998;65:667–73.CrossRefGoogle Scholar
  31. 31.
    Brown JR, Birkmeyer NJ, O’Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007;115(22):2801–13.CrossRefGoogle Scholar
  32. 32.
    Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg. 1997;85(6):1258–67.CrossRefGoogle Scholar
  33. 33.
    Brown RS, Thwaites BK, Mongan PD. Tranexamic acid is effective in decreasing postoperative bleeding and transfusion in primary coronary artery bypass operations: a double-blind randomized, placebo-controlled trial. Anesth Analg. 1997;85:963–70.CrossRefGoogle Scholar
  34. 34.
    Carless PA, Moxey AJ, Stokes BJ, et al. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials. BMC Cardiovasc Disord. 2005;5:19.CrossRefGoogle Scholar
  35. 35.
    Fremes SE, Wong BI, Lee E, et al. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg. 1994;58(6):1580–8.CrossRefGoogle Scholar
  36. 36.
    Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999;354(9194):1940–7.CrossRefGoogle Scholar
  37. 37.
    Meybohm P, Herrmann E, Nierhoff J, et al. Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and ε-aminocaproic acid: a meta-analysis of randomised and observational trials of over 30.000 patients. PLoS One. 2013;8(3):e58009.CrossRefGoogle Scholar
  38. 38.
    Royston D, Levy JH, Fitch J, et al. Full-dose aprotinin use in coronary artery bypass graft surgery: an analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg. 2006;103(5):1082–8.CrossRefGoogle Scholar
  39. 39.
    Henry D, Carless P, Fergusson D, et al. The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ. 2009;180(2):183–93.CrossRefGoogle Scholar
  40. 40.
    Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary artery bypass grafting: effect on postoperative renal function. Ann Thorac Surg. 1995;59(1):132–6.CrossRefGoogle Scholar
  41. 41.
    Wademan BH, Galvin SD. Desmopressin for reducing postoperative blood loss and transfusion requirements following cardiac surgery in adults. Interact Cardiovasc Thorac Surg. 2014;18(3):360–70.CrossRefGoogle Scholar
  42. 42.
    European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP). Non-interventional post-authorisation safety study of pattern of use of Nordic Aprotinin: Nordic Aprotinin Patient Registry (EUPAS11384). Accessed 2019 Sep 30.

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Springer NatureAucklandNew Zealand

Personalised recommendations