Asian Cardiovasc Thorac Ann 2007;15:285-289
© 2007 Asia Publishing EXchange Ltd
Does Tranexamic Acid Reduce Blood Loss in Off-Pump Coronary Artery Bypass?
Aflatoon Mehr-Aein, MD,
Mostafa Sadeghi, MD,
Manouchehr Madani-civi, MD1
Department of Anesthesiology, Shariati Hospital
1 Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
For reprint information contact: Aflatoon Mehr-Aein, MD Tel: 98 91 2132 4549 Fax: 98 21 8863 3039 Email: amehraein{at}yahoo.com, Madani, PO Box 16765-3156, Tehran, Iran.
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ABSTRACT
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The hemostatic effect of tranexamic acid on the bleeding tendency and transfusion requirements in patients undergoing off-pump coronary artery bypass surgery was assessed in a prospective randomized double-blind study. Of 66 patients undergoing elective operations, 33 were given tranexamic acid (15 mg·kg–1 before infusion of heparin and 15 mg·kg–1 after protamine infusion), and the other 33 received only saline. Postoperative bleeding, transfusions, complications, hematological variables, and plasma D-dimer levels were recorded. Postoperative blood loss was significantly less in the tranexamic acid group compared to the control group (320 ± 38 vs 480 ± 75 mL). Patients in the tranexamic acid group received significantly less allogeneic blood products (0.46 vs 0.94 units per patient), and they had lower postoperative D-dimer levels. No postoperative thrombotic complications were observed in either group. Although off-pump coronary artery bypass surgery is associated with reduced frequency of hemorrhagic disorders, defective hemostasis still occurs, and tranexamic acid effectively reduces postoperative blood loss and the need for allogeneic blood products.
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INTRODUCTION
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Defective hemostasis following cardiopulmonary bypass (CPB) is a serious complication in open-heart surgery, which results in increased bleeding and allogeneic blood transfusion requirements.1 The mechanisms of bleeding during and after CPB are thought to be related to hemodilution, heparin administration, impaired platelet function, and increased fibrinolytic activity.2 To reduce the morbidity associated with CPB, off-pump coronary artery bypass (OPCAB) has gained popularity. Although postoperative bleeding seems to be attenuated by the avoidance of CPB, hemorrhagic complications are not completely eliminated and there is still a need for blood transfusion after OPCAB surgery.3,4 In many centers, tranexamic acid is now used routinely for on-pump coronary artery bypass grafting (CABG).5 The aim of this study was to evaluate the hemostatic effects of tranexamic acid in OPCAB surgery.
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PATIENTS AND METHODS
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From October 2002 to November 2003, 66 consecutive patients who were scheduled for elective CABG with off-pump techniques in Shariati Hospital, Tehran University of Medical Sciences, were enrolled in this prospective double-blind randomized study. The procedures were approved by the institutional ethics committee, and informed signed consent was obtained from all patients. The patients were randomly allocated to either the tranexamic acid group (n = 33) or the control group (n = 33). In the tranexamic acid group, a loading dose of tranexamic acid (15 mg·kg–1) was administered at the beginning of surgery, with the same dose before the infusion of heparin, at the end of the surgery, and after protamine infusion. In the control group, the same volume of saline solution was infused. Staff in the operating room and the intensive care unit (ICU) were blinded to the type of treatment; the correct treatment option was assured by means of coded infusion syringes prepared by a member of staff of the hospital pharmacy, not involved otherwise in the study. Standard preoperative data are collected prospectively for every patient undergoing CABG at our institution. The dataset was filled in sequentially by the anesthetist, the surgeon, the perfusionist, and the nurses. Inclusion criteria were primary CABG, age 
70 years, left ventricular ejection fraction 
35%, body mass index 25, no administration of aspirin in the 7 days before the operation, and no preoperative heparin infusion. Exclusion criteria were redo cardiac surgery, emergency CABG, hemoglobin < 10 g·dL–1, platelet count < 100x109·L–1, known coagulopathy, and renal insufficiency.
Anesthesia was standardized for all patients. Anesthetic induction consisted of fentanyl 3 µg·kg–1 followed by diazepam 0.1 mg·kg–1 and sodium thiopental 2 mg·kg–1. Intubation was performed after injection of succinylcholine 3 mg·kg–1. In patients with systolic hypertension > 140 mm Hg, lidocaine 1 mg·kg–1 was tried before intubation. During surgery, halothane 0.5% with fentanyl 1–3 µg·kg–1·min–1 was used. Maintenance of muscle relaxation was accomplished with pancuronium 2 mg·hr–1. All patients were operated on according to a standardized surgical protocol. After a full midline sternotomy, the left internal mammary artery was harvested as well as a saphenous vein. An Octopus tissue stabilizer (Octopus 4.3; Medtronic Inc., Minneapolis, MN, USA) was used to stabilize the target site on the beating heart. Patients were heparinized fully according to body weight at a dose of 150 U·kg–1. Heparin was reversed with protamine, 130 units for every 100 units of heparin used during the operation. A cell separator was not used. Intraoperatively, no blood was retransfused. Before chest closure, mediastinal drains were inserted. On arrival in the ICU, patients were kept on mechanical ventilation. All patients were evaluated for extubation every hour. All hemodynamically stable patients without excessive drainage and with good arterial blood gases were extubated.
Blood loss was recorded on arrival in the ICU and at 1, 4, 8, 12, and 24 hr after surgery. If drainage was more than 500 mL in the first hour or 800 mL in the 2 hours after the operation, the patient underwent re-operation. The indications for whole blood transfusion were hematocrit < 20% and/or hemoglobin < 7 g·dL–1 during the operation; and hematocrit < 28% and/or hemoglobin < 9 g·dL–1 postoperatively. The protocols for fresh frozen plasma were prolonged prothrombin time (> 1.5 times the normal range) and bleeding > 200 mL·hr–1. The protocol for platelet transfusion was platelet count < 75x109·L–1, and bleeding > 200 mL for longer than 2 hr. Prophylactic measures were started on the first postoperative day with oral aspirin (80 mg·day–1) and subcutaneous injection of low-molecular-weight heparin.
Perioperatively, routine hematologic and blood chemistry parameters were evaluated in all patients. In the ICU, glucose, hemoglobin, hematocrit, platelets, prothrombin time, electrolyte levels, and serum creatinine were measured routinely. Oxygen saturation, respiratory rate, and serial electrocardiograms were continuously monitored for 48 hr. If there was suspicion of myocardial infarction (clinical symptoms or electrocardiographic changes), creatine kinase-MB and troponin I levels were measured. Neurologic and pulmonary embolic events were checked for by specialists every day. In all patients, arterial blood samples were collected at 4 time points to determine D-dimer: preoperatively, at the end of surgery, 4 and 24 hr postoperatively. D-dimer, which reflects the fibrinolytic status, was measured using an enzyme-linked fluorescent assay (MiniVidas; bioMérieux, Marcy L’Etoile, France).
Statistical analyses were performed with SPSS version 11.0 software for Windows (SPSS, Inc., Chicago, IL, USA). All values are expressed as mean ± standard deviation. Comparisons of results between the two groups were carried out by the two-tailed unpaired t test for each normally distributed variable. Nonparametric evaluation was performed for variables not normally distributed (Mann-Whitney U test). A p value of less than 0.05 was considered statistically significant.
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RESULTS
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The patients’ clinical characteristics are shown in Table 1
. No statistically significant differences were noted between the groups with respect to mean age, sex, body mass index, left ventricular function, mean duration of operation, or number of grafts per patient. Routine hematological and blood chemistry data compared preoperatively and on the first postoperative day showed no significant differences between the two groups (Table 2). The increase in D-dimer levels after surgery was significantly inhibited in the tranexamic acid group compared to the control group (p < 0.05; Figure 1). Blood loss and transfusion requirements are compared in Table 3. There were significantly less postoperative bleeding and transfusion requirements in the tranexamic acid group. Intraoperative and postoperative data (Table 4) were similar in both groups. There was no difference between the groups in terms of pulmonary dysfunction and neurological deficits. There was no hospital mortality (up to 7 days after operation and before discharge) in either group.
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Figure 1. Plasma D-dimer levels. There were significant differences between the groups at 4 and 24 hr postoperatively.
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DISCUSSION
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Cardiopulmonary bypass has long been recognized as one of the major causes of the systemic inflammatory response syndrome that may contribute to postoperative complications and multiple organ dysfunction, such as heart, brain, lung, and kidney dysfunction.6 The most important factors in hemostatic defects after CABG are inadequate surgical hemostasis, inadequate heparin reversal, complement activation, platelet dysfunction, and hyperfibrinolysis. Surgical incisions and cardiac surgery increase the levels of tissue plasminogen activator that converts plasminogen to plasmin, which inactivates fibrin. However, platelet defects have been shown to be another important factor. Contact with a synthetic surface results in release of 
-granules with subsequent reduced aggregation and adhesiveness of platelets.7 Off-pump coronary artery bypass might offer hemostatic advantages compared to CABG with CPB. Eliminating exposure of blood to the extracorporeal circuit could reduce hemostatic defects, but significant bleeding and use of allogeneic blood in OPCAB surgery was reported in some studies. Cartier and colleagues3 reported mean postoperative bleeding of 525 mL, with 31% of patients transfused with allogeneic blood products. Ascione and colleagues8 described a mean total blood loss of 770 mL, with not inconsiderable use of allogeneic products.
It is well recognized that tranexamic acid reduces both blood loss and the need for blood product transfusion following CABG with CPB.9,10 It exerts its antifibrinolytic effect by suppressing tissue plasminogen activator activity and thereby inhibiting secondary fibrinolysis. Tranexamic acid showed no effects on plasmin neutralization and the most important plasminogen activator inhibitor: PAI-1. However, tranexamic acid stabilizes adenosine diphosphate granules in platelets and inhibits platelet dysfunction. The effect of tranexamic acid on blood loss during and after CPB agrees with other studies.11,12 However, beneficial effects of tranexamic acid have not yet been established in OPCAB. We found significantly higher levels of D-dimer in the control group, whereas no significant changes were evident in the tranexamic acid group. An inter-group difference was seen at the end of surgery and it became more marked in the postoperative hours. This illustrates that improved hemostasis is achieved at least partly by the antifibrinolytic action of tranexamic acid.
In OPCAB, there is great surgical trauma (sternotomy, graft harvesting, pericardiotomy), manipulation of the heart, and exposure to heparin and protamine. These factors determine the activation of coagulation during OPCAB by release of tissue factor and activation of the extrinsic pathway.13 Recently, Casati and colleagues14 demonstrated the effectiveness of tranexamic acid in OPCAB surgery.
The potential for hypercoagulability to occur with the use of antifibrinolytic agents was taken into account in this study.15,16 The possibility of thromboembolic complications, especially graft occlusion with myocardial infarction caused by tranexamic acid, must be considered when giving this drug to patients. In recent studies, a Canadian group of investigators assessed saphenous vein graft patency with magnetic resonance imaging 5 to 30 days after surgery; they showed that administration of tranexamic acid before CPB did not seem to compromise early venous graft patency rates.17 We found no evidence of hypercoagulability, such as an increased incidence of cerebrovascular accidents, deep venous thrombosis, or pulmonary emboli. A long-term study with more patients may be necessary to clarify the issue of hypercoagulability. Mortality and other clinical outcomes were similar in the two groups, except for bleeding and transfusion requirements.
It was concluded that tranexamic acid effectively reduces postoperative bleeding and thus decreases the need for allogeneic blood products after OPCAB. Defective hemostasis occurs even in the absence of CPB, and the use of antifibrinolytic agents decreases postoperative bleeding.
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ACKNOWLEDGMENTS
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We thank Dr. Alipasha Meysamie, Assistant Professor, Community Preventive Medicine, TUMS, for his advice on the statistical analysis.
Presented at the 7th Annual Scientific Meeting of the International Society for Minimally Invasive Cardiac Surgery, London, England, June 23–26, 2004.
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ABSTRACT
INTRODUCTION
