Impact of Combination of Clopidogrel With Aspirin on Postoperative Bleeding and Platelets Functions in Coronary Surgical Patients Treated Prophylactically With Tranexamic Acid: the ICARE Study.

Impact of combination of clopidogrel with aspirin on postoperative bleeding and platelets functions in coronary surgical patients treated prophylactically with tranexamic acid.

Introduction Major cardiac events are known to be reduced in patients with acute coronary syndrome by an association of aspirin with clopidogrel (1)(2). In cardiac surgery as well, aspirin treatment has been shown to reduce major cardio-vascular events and mortality in postoperative period after coronary artery bypass grafting (CABG) without any increase of postoperative bleeding (3)(4). In a recent study performed in our department, Ouattara and al. have shown in cardiac surgery that the combination of aspirin with clopidogrel does not increase postoperative bleeding, transfusion or surgical reexploration after CABG when aprotinin is used during surgery, by comparison to aspirin alone (5). In conclusion, the authors suggested no disruption of aspirin and clopidogrel when patients are treated with this association before surgery. Unfortunately, since the trials of Mangano and al. (6) and of the BART investigators (7), aprotinin, a plasmin inhibitor derived from bovine lung tissues, has been withdrawn for safety reasons. Therefore, physicians are restrained to use instead tranexamic acid, a synthetic molecule that inhibits conversion of the inactive plasminogen to plasmin, to minimize bleeding and to reduce exposure to blood products.

The aim of this study is to test the hypothesis that with tranexamic acid also, bleeding in the aspirin + clopidogrel group is not 25% more important than in the aspirin alone group after CABG surgery, according to the previous study using aprotinin. In the present study, the functionality of the platelets tested before the surgical procedure will be compared to level of the first 24 hours bleeding.

Methods Selection of patients This prospective observational study will be conducted at the Institute of Cardiology in the Pitié-Salpêtrière Hospital, Paris, France. It is planned to start in december 2009 to november 2010. Care of patients will conform to standard procedures currently used in our institute, which will not be modified by the study. Platelet function will be measured in residual blood samples, after ethical committee approval (Comité de Protection des Personnes VI - Ile de France). A written informed consent is not resquested from patients. Nevertheless, written information will be delivered for each of them. During the planned 11 months of investigation, all patients undergoing isolated first-time coronary artery by-pass grafting will be enrolled. Patients admitted for emergency procedure, following failed percutaneous transluminal coronary angioplasty and off-pump coronary surgery, will be excluded. Because antithrombotic therapy management may differ during the postoperative period, we will exclude patients in whom a mechanical support or intra-aortic balloon pump will be required for a difficult weaning from cardiopulmonary bypass. Finally, we will exclude all patients who will not have received any oral antiplatelet agents within 5 days prior surgery, those who will have been preoperatively exposed to platelet glycoprotein IIb/IIIa inhibitors, and those with history of haematological disease. Patients treated with aspirin and clopidogrel and in whom clopidogrel will be stopped more than 5 days before surgery will also be excluded.

Intraoperative management Patients will be monitored with arterial and central venous catheterizations. All patients will be considered at high risk for postoperative bleeding as they will receive at least one antiplatelet agent and therefore will be administered tranexamic acid (Exacyl®, Sanofi-Aventis, Paris, France) according to the following standardized protocol: infusion of 10 mg/kg for 20 minutes during anaesthesia induction, followed by a continuous infusion until the end of surgery, according to renal function of patients as described by Nuttall et al. (8) (See table below). The rest of intraoperative management will be the same as previously described by Ouattara and al. (5). Briefly, before aortic cannulation, an initial loading dose of heparin will be directly administered by the surgeon into the right atrium and then anticoagulation will be maintained by additional bolus during the extracorporeal circulation. Non-pulsatile cardiopulmonary bypass will be ensured at a flow of 2.4 L/min/m2. The temperature of systemic perfusion during cardiopulmonary bypass (hypothermia <32°C, mild hypothermia 32-36°C, and normothermia >36°C) will be left to the discretion of the attending surgeon. After discontinuation of the cardiopulmonary bypass, heparin will be neutralized by protamin sulfate (0.008-0.01 mg/IU of total heparin dose intraoperatively used). Intraoperative cell salvage will be systematically used (Electa, Dideco, Mirandola, Italy). The use of inotropes for difficult weaning from cardiopulmonary bypass will be left to the discretion of the attending anaesthesiologist. Discontinuation of the cardiopulmonary bypass will be done when central body temperature (estimated by vesical temperature) will be above 35°C.