From the *Department of Anesthesiology, Queen Fabiola Children’s University Hospital, Free University of Brussels, Brussels, Belgium; and †Department of Anesthesiology and Intensive Care, Duke University School of Medicine, Durham, North Carolina.
Accepted for publication February 8, 2014.
Funding: The work was solely supported by departmental sources.
Conflicts of Interest: See Disclosures at the end of the article.
Reprints will not be available from the authors.
Address correspondence to Jerrold H. Levy, MD, FAHA, FCCM, Department of Anesthesiology and Intensive Care, Duke University School of Medicine, DUMC 3094, Durham, NC, 27710. Address e-mail to email@example.com.
Bleeding and transfusion increase the morbidity, mortality, and costs of cardiac surgery.1 Therapeutic approaches to reducing the coagulopathy, bleeding, and transfusion requirements following cardiac surgery and cardiopulmonary bypass (CPB) are based on understanding the complex perturbations of the hemostatic system. Tissue injury, blood interfacing with nonendothelial surfaces, tissue factor production, and activation of fibrinolysis contribute to coagulopathy in cardiac surgical patients.2,3 In addition to dilutional coagulopathy, humoral activation pathways include generation of thrombin, plasmin, and inflammation-mediated processes. Although anticoagulation with unfractionated heparin followed by protamine reversal are standard practice, under- and overdosage of heparin and protamine also contribute to perioperative bleeding.4
One of the cornerstones of reducing bleeding and blood product administration is prophylactic administration of antifibrinolytic agents.5 Following publication of the Blood conservation using antifibrinolytics: A randomized trial in a cardiac surgery population (BART) study,6 aprotinin was removed from the market, although it is still available for compassionate use.7 However, Karkouti et al.8 reported a retrospective single-center cohort study of 15,365 cardiac surgical patients of which 1017 received aprotinin and 14,358 received tranexamic acid (TXA). They noted aprotinin had a better risk-benefit profile than TXA in high-risk, but not low- to moderate-risk, patients and suggested its use in high-risk cases may therefore be warranted. In 2011, Health Canada concluded that the benefits of aprotinin outweigh the risks when aprotinin is used as authorized by Health Canada. The European Medicine’s Agency made a similar recommendation.
TXA and epsilon-aminocaproic acid (EACA), 2 lysine analogs that competitively inhibit activation of plasminogen to plasmin, are current mainstays of therapy. Plasmin has a broad spectrum of adverse effects including fibrin degradation.9 TXA has been extensively compared with EACA for safety and efficacy, although the United States is likely one of the few places EACA is actually used compared with TXA. One of the increasingly recognized adverse events associated with TXA is a dose-dependent increased incidence of seizures.10 Nevertheless, the benefit-to-risk balance between lysine analogs and aprotinin is still the subject of debate. Lysine analogs have solely antifibrinolytic properties, with unproven effects on platelet function,11 and inflammatory responses.12 The multimodal effects of aprotinin, including its effect on kallikrein and other inflammatory proteases, result in the suppression of multiple pathways involved in the systemic inflammatory response induced by CPB.13
MDCO-2010 is a novel synthetic molecule that actively inhibits plasmin, plasma kallikrein, as well as coagulation factors Xa, XIa, and activated protein C. In 2009, Dietrich et al.14 reported that the main advantage of this drug, with a similar pharmacologic profile to aprotinin, comes from its potential to mitigate both excessive fibrinolysis and thrombin generation during CPB because of its anticoagulant effect. In this in vitro study, MDCO-2010 was as effective as aprotinin inhibiting fibrinolysis, was 10-fold more potent than TXA, and also inhibited plasma kallikrein, factors Xa, and XIa, and thrombin generation. In another previous study, we reported that MDCO-2010 prolonged activated clotting time values.15 In an animal study, MDCO-2010 produced a dose-dependent reduction of postoperative blood loss after CPB, comparable with aprotinin with a beneficial effect on endothelial function following cardioplegic arrest and reperfusion and improved postischemic recovery of left ventricular function.16
In this issue of Anesthesia & Analgesia, Englberger et al.17 describe the results of the first patient study of MDCO-2010. The primary end point was plasma levels, pharmacokinetics, and safety. Secondary end points were the clinical effects on coagulation, chest tube drainage, and transfusion requirements. The authors evaluated 32 patients, 8 controls and 24 randomized to receive different loading doses followed by a continuous infusion, and an additional dose in the CPB prime. They demonstrated predictable pharmacokinetics with a reduction of blood loss in the 3 highest dose groups compared with control and a lower incidence of allogeneic blood product transfusions 4/24 (17%) vs 4/8 (50%) in the control group. MDCO-2010 exhibited dose-dependent antifibrinolytic effects. One patient developed intraoperative venous graft thrombosis in the treated group, but there were no deaths. Thus, the initial evaluation reported MDCO-2010 was well tolerated and showed an acceptable initial safety profile.
Unfortunately, a subsequent multicenter study (ClinicalTrials.gov NCT01530399) was stopped in 2012, and the Medicines Company announced that it had voluntarily discontinued its Phase 2b dose-ranging study of MDCO-2010 in response to unexpected patient safety issues encountered during the trial, which had recruited 44 of a planned 90 patients in the first stage of the study.
Do we need another hemostatic agent for cardiac surgery? Our clinical practice of cardiac surgery and perioperative management has changed over the years with far more complex procedures, reoperations, use of anticoagulant and antiplatelet drugs, and many other considerations that from our view warrant additional therapeutic agents. The concerns about seizures and TXA are not inconsequential and have limited its use in some centers or allowed substitutions of EACA, another agent withdrawn from some European markets, and with limited efficacy. Aprotinin reduced bleeding associated with clopidogrel use, a finding not reproduced with other antifibrinolytics.18 The search continues for a novel hemostatic agent for cardiac surgery and other procedures associated with large blood loss and coagulopathy. The ability of MDCO-2010 to inhibit plasmin and the kallikrein system, with additional anticoagulation properties, suggested that this drug could be a promising agent (although the anticoagulant effect of Xa inhibition was problematic for bleeding).
Additional agents are needed. However, we need to define a protease inhibition profile for fibrinolysis and inflammation that yields the best balance of benefit to risk.
Name: David Faraoni, MD, FCCP.
Contribution: The author wrote the manuscript and approved the final version of the manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Jerrold H. Levy, MD, FAHA, FCCM.
Contribution: The author wrote the manuscript and approved the final version of the manuscript.
Conflicts of Interest: Jerrold H. Levy is on the steering committee of The Medicines Company (Leipzig, Germany).
This manuscript was handled by: Steven L. Shafer, MD.
1. Hein OV, Birnbaum J, Wernecke KD, Konertz W, Jain U, Spies C. Three-year survival after four major post-cardiac operative complications. Crit Care Med. 2006;34:2729–37
2. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999;91:1122–51
3. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg. 2011;113:1319–33
4. Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med. 2004;30:1873–81
5. Ortmann E, Besser MW, Klein AA. Antifibrinolytic agents in current anaesthetic practice. Br J Anesth. 2013;111:549–63
6. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius RBART Investigators. . A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358:2319–31
8. Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, Tait G, Beattie WS. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg. 2010;110:21–9
9. Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet. 2010;376:3–4
10. Koster A, Börgermann J, Zittermann A, Lueth JU, Gillis-Januszewski T, Schirmer U. Moderate dosage of tranexamic acid during cardiac surgery with cardiopulmonary bypass and convulsive seizures: incidence and clinical outcome. Br J Anesth. 2013;110:34–40
11. Weber CF, Görlinger K, Byhahn C, Moritz A, Hanke AA, Zacharowski K, Meininger D. Tranexamic acid partially improves platelet function in patients treated with dual antiplatelet therapy. Eur J Anesthesiol. 2011;28:57–62
12. Jimenez JJ, Iribarren JL, Lorente L, Rodriguez JM, Hernandez D, Nassar I, Perez R, Brouard M, Milena A, Martinez R, Mora ML. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care. 2007;11:R117
13. Mojcik CF, Levy JH. Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg. 2001;71:745–54
14. Dietrich W, Nicklisch S, Koster A, Spannagl M, Giersiefen H, van de Locht A. CU-2010–a novel small molecule protease inhibitor with antifibrinolytic and anticoagulant properties. Anesthesiology. 2009;110:123–30
15. Kim H, Szlam F, Tanaka KA, van de Locht A, Ogawa S, Levy JH. The effects of MDCO-2010, a serine protease inhibitor, on activated clotting time in blood obtained from volunteers and cardiac surgical patients. Anesth Analg. 2012;115:244–52
16. Szabó G, Veres G, Radovits T, Haider H, Krieger N, Bährle S, Niklisch S, Miesel-Gröschel C, van de Locht A, Karck M. The novel synthetic serine protease inhibitor CU-2010 dose-dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a canine model. J Thorac Cardiovasc Surg. 2010;139:732–40
17. Englberger L, Dietrich W, Eberle B, Erdoes G, Keller D, Carrel T. A novel blood sparing agent in cardiac surgery? First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: a phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg.
18. van der Linden J, Lindvall G, Sartipy U. Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double-blind, placebo-controlled, randomized clinical trial. Circulation. 2005;112:I276–80