Blood administration is not without risk. Antifibrinolytic agents are used to control bleeding and blood product administration. In particular, aprotinin has been shown to have adverse effects. In one study comparing aprotinin to tranexamic acid or aminocaproic acid in patients undergoing high-risk cardiac surgery, the trial was ended early because of a high death rate in patients receiving aprotinin.
MDCO-2010 is a synthetic small molecule that inhibits plasmin and plasma kallikrein action and also inhibits coagulation factors Xa, Xia, and activated Protein C. Dr. Lars Englberger, Department of Cardiovascular Surgery, University Hospital Berne, Berne, Switzerland, and colleagues evaluated pharmacokinetics with analysis of plasmatic concentrations, initial safety, and tolerance of increasing dosages of MDCO-2010 in cardiac surgical patients. The results of their study are presented in the article “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,” which was published in this month’s issue of Anesthesia & Analgesia.
Twenty-four patients received MDCO-2010, and 8 patients received placebo. MDCO-2010 plasma levels increased rapidly when boluses were given and were stable during infusion. After the infusion was stopped, plasma levels decreased approximately 40% after 30 minutes and there was a mean terminal half-life of 81 minutes. Chest tube drainage at 12 hours was significantly lower with increasing doses of MDCO-2010. Fewer MDCO-2010 patients received blood transfusions compared to patients in the control group, and patients who received MDCO-2010 also required less volume of blood products than control patients.
The story does not end here though. As Dr. David Faraoni, Department of Anesthesiology, Queen Fabiola Children’s University Hospital, Free University of Brussels, Brussels, Belgium, and Dr. Jerrold H. Levy, Department of Anesthesiology and Intensive Care, Duke University School of Medicine, Durham, North Carolina, note in their accompanying editorial titled “Development of a Novel Blood-Sparing Agent in Cardiac Surgery: Do We Need Another Agent?,” another multicenter study of the drug was stopped midway into the trial in 2012 due to unexpected patient safety issues. As the authors state in their conclusion, ”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.” The drug has been withdrawn from further development.