A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting

Brazilian Journal of Medical and Biological Research (2006) 39: 63-69 Tranexamic acid and bleeding after cardiopulmonary bypass ISSN 0100-879X 63 A randomized, double-blind, and placebo-controlled study with tranexamic acid of bleeding and fibrinolytic activity after primary coronary artery bypass grafting A.T.L. Santos, R.A.K. Kalil, C. Bauemann, J.B. Pereira† and I.A. Nesralla Instituto de Cardiologia do Rio Grande do Sul, Fundação Universitária de Cardiologia, Porto Alegre, RS, Brasil Abstract Correspondence A.T.L. Santos Unidade de Pesquisa Instituto de Cardiologia do Rio Grande do Sul Av. Princesa Isabel, 395 90620-001 Porto Alegre, RS, Brasil Fax: +55-51-3230-3600 E-mail: †In memoriam Research supported in part by FAPERGS and Fundo de Apoio à Pesquisa do Instituto de Cardiologia do Rio Grande do Sul - Fundação Universitária de Cardiologia. Received June 24, 2004 Accepted August 16, 2005 Cardiopulmonary bypass is frequently associated with excessive blood loss. Platelet dysfunction is the main cause of non-surgical bleeding after open-heart surgery. We randomized 65 patients in a double-blind fashion to receive tranexamic acid or placebo in order to determine whether antifibrinolytic therapy reduces chest tube drainage. The tranexamic acid group received an intravenous loading dose of 10 mg/ kg, before the skin incision, followed by a continuous infusion of 1 mg kg-1 h-1 for 5 h. The placebo group received a bolus of normal saline solution and continuous infusion of normal saline for 5 h. Postoperative bleeding and fibrinolytic activity were assessed. Hematologic data, convulsive seizures, allogeneic transfusion, occurrence of myocardial infarction, mortality, allergic reactions, postoperative renal insufficiency, and reopening rate were also evaluated. The placebo group had a greater postoperative blood loss (median (25th to 75th percentile) 12 h after surgery (540 (350-750) vs 300 (250-455) mL, P = 0.001). The placebo group also had greater blood loss 24 h after surgery (800 (520-1050) vs 500 (415-725) mL, P = 0.008). There was a significant increase in plasma D-dimer levels after coronary artery bypass grafting only in patients of the placebo group, whereas no significant changes were observed in the group treated with tranexamic acid. The D-dimer levels were 1057 (1025-1100) µg/L in the placebo group and 520 (435-837) µg/L in the tranexamic acid group (P = 0.01). We conclude that tranexamic acid effectively reduces postoperative bleeding and fibrinolysis in patients undergoing first-time coronary artery bypass grafting compared to placebo. Introduction In 1953, John Gibbon performed the first successful open-heart operation on a human patient using a heart-lung machine, starting the age of open-heart surgery. Blood require- Key words • Tranexamic acid • Coronary artery bypass • Postoperative bleeding • Clinical trial ments per cardiac case in the early 1950’s were 20 to 30 units (1). Despite continuous advances improving the safety of cardiac surgery, excessive bleeding requiring transfusion of blood components after cardiopulmonary bypass (CPB) is still one of the main causes of Braz J Med Biol Res 39(1) 2006 64 A.T.L. Santos et al. postoperative morbidity (2). Pericardial blood activates the extrinsic coagulation pathway and nonendothelialized materials in the extracorporeal circuit activate the intrinsic coagulation pathway during CPB. Despite systemic doses of heparin, thrombin generation is observed during CPB (3). Thrombin not only converts fibrinogen to fibrin, but is also the most powerful platelet activator. It activates the endothelium and fibrinolysis via the release of tissue plasminogen activator from the endothelium. Consequently, generalized fibrinolysis occurs during and immediately after CPB, as reflected by increased plasmin concentrations and fibrin degradation products, both of which have deleterious effects on platelet function (4-6). Increased fibrinolytic activity and platelet dysfunction have been identified as important factors of postoperative bleeding (7). Antifibrinolytic drugs are used to prevent platelet dysfunction and to decrease perioperative bleeding. Recently, there has been increased interest in tranexamic acid (TA) as an alternative to the more expensive drug aprotinin. TA acts by forming a reversible complex with plasminogen and plasmin through the lysine-binding sites, thus blocking interaction with the specific lysine residues of fibrin. This process retards fibrinolysis because, although plasmin is still formed, it is unable to bind to fibrin (8). TA also preserves platelet function by reducing the effect of plasmin on platelet glycoprotein 1b receptors (9). The aim of the present study was to determine the hemostatic and antifibrinolytic effect of TA in primary coronary artery bypass grafting (CABG). Material and Methods A prospective, randomized, placebo-controlled, double-blind trial was designed to determine the antifibrinolytic and hemostatic effect of TA in CABG. After approval of the Braz J Med Biol Res 39(1) 2006 study by the Hospital Ethics Committee, 65 patients undergoing primary non-emergent CABG who gave written informed consent to participate were enrolled. The groups were randomized by means of sequentially numbered sealed envelopes opened by a nurse in the operating room. This method ensured that only the nurse, who prepared the infusions, knew whether a patient received drug or placebo. Criteria for preoperative exclusion included cardiac surgery reoperation, renal insufficiency (plasma creatinine concentration higher than 2 mg/kg), and a history of hematological disorders, hepatic dysfunction or antiplatelet therapy within seven days of surgery. The enrolled patients were assigned randomly to the TA or placebo group. The TA group received an intravenous loading dose of 10 mg/kg TA (Transamin; Química e Farmacêutica Nikkho do Brasil, Rio de Janeiro, RJ, Brazil) before the skin incision, followed by a continuous infusion of 1 mg kg-1 h-1 for 5 h. The placebo group received a bolus of normal saline solution in an identical syringe and continuous infusion of normal saline for 5 h. The drugs were delivered in identical volumes. The staff in the operating room and in the intensive care unit were not aware of the treatment. The anesthetic protocol consisted of intravenous thiopental, fentanyl citrate and pancuronium bromide. Maintenance of anesthesia was obtained with fentanyl citrate and halothane or isoflurane. Exposure was provided by a median sternotomy. CPB was performed with an Oxim II-34 Ultra membrane oxygenator (Edwards Lifesciences, Irvine, CA, USA) and a Sarns CPB machine (Sarns, Ann Arbor, MI, USA) at a flow of 2.6 L min-1 m-2, under moderate systemic hypothermic conditions (28-30ºC). Systemic heparinization was performed before CPB with heparin (Liquemine, 5000 IU/mL; Produtos Roche Químicos e Farmacêuticos S/A, São Paulo, SP, Brazil) at the dose of 400 IU/kg and was reversed at (...truncated)