Ann Thorac Surg 1999;68:2252-2256
© 1999 The Society of Thoracic Surgeons
Original Articles
Hemostatic effects of aprotinin, tranexamic acid and 
-aminocaproic acid in primary cardiac surgery
Valter Casati, MDa,
Davide Guzzon, MDa,
Michele Oppizzi, MDa,
Mariangelo Cossolini, MDa,
Giorgio Torri, MDa,
Giliola Calori, MDb,
Ottavio Alfieri, MDc
a Department of Cardiothoracic Anesthesia and Intensive Care, University of Milan, San Raffaele Hospital, Milan, Italy
b Epidemiology Unit, University of Milan, San Raffaele Hospital, Milan, Italy
c Department of Cardiac Surgery, University of Milan, San Raffaele Hospital, Milan, Italy
Address reprint requests to Dr Casati, Department of Cardiac Anesthesia, San Raffaele Hospital, Via Olgettina 60, 20132 Milan, Italy
e-mail: casati.valter{at}.hsr.it
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Abstract
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Background. The effects of 
-aminocaproic acid (EACA) and tranexamic acid (TA) on bleeding and allogeneic transfusions, and the cost of pharmacological and transfusional treatment were compared to aprotinin (AP).
Methods. We randomized 210 patients subjected to elective cardiac surgery. Of these, 68 patients received EACA (a bolus of 5 g, an infusion of 2 g/h, and 2.5 g in the priming), 72 patients received TA (a bolus of 1 g, an infusion of 400 mg/h, and 500 mg in the priming), and 70 patients received AP (a bolus of 280 mg, an infusion of 70 mg/h, and 280 mg in the priming). Postoperative blood loss and homologous transfusions were collected and the cost of pharmacological treatment and homologous transfusions were calculated.
Results. Bleeding but not allogeneic transfusions was significantly higher in the EACA group (467 ± 234 versus TA, 311 ± 231 versus AP, 283 ± 233; p < 0.001). Costs of pharmacological and transfusional treatment were significantly lower in the TA group ($58.10 ± $105.10) versus the EACA group ($100.70 ± $158.60) versus the AP group ($432.60 ± $118.70) (p < 0.0001).
Conclusions. Compared to AP, TA has the same effects on bleeding and transfusions, but with a significant reduction of costs. Patients treated with EACA showed a significantly higher postoperative bleeding with an increased trend of transfusion requirement.
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Introduction
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Excessive bleeding after cardiac surgery is still one of the main causes of postoperative morbidity [1]. Increased need for allogeneic blood derivative products exposes patients at risk of anaphylactic reactions and infective diseases as acquired immunodeficiency disease syndrome and viral hepatitis [2]. Platelet disfunction and increased fibrinolytic activity induced by the interaction of blood with foreign surfaces of the extracorporeal circuit have been identified by previous studies as important factors of postoperative bleeding [3]. For this reason, many cardiac surgery centers use intraoperative pharmacological treatment with antifibrinolytic drugs to limit coagulation impairment. Previous studies have demonstrated the efficacy of high-dose AP, a natural derivative product, in reducing blood loss and homologous blood requirements, particularly in high-risk patients [4]. Nevertheless, high-dose AP is expensive and associated with an increased risk of anaphylactic reactions to reexposure [5]. Tranexamic acid (TA) and EACA are synthetic antifibrinolytic drugs, with low cost and no immunologic reactions, recently introduced in cardiac surgery [6–7]. The aim of our study was to compare the cost-effectiveness of these drugs on postoperative bleeding and consequently on the need for homologous blood transfusions in elective adult cardiac surgery.
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Patients and methods
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After institutional review board and informed consent, 210 consecutive patients scheduled for first-time elective cardiac surgery requiring cardiopulmonary bypass (CPB) were unblinded and randomly allocated to receive: Group A (n = 68): EACA, 5 g during 20 minutes after induction of anesthesia, before sternotomy, followed by a constant infusion of 2 g/h until the end of operation and 2.5 g added to priming
Group B (n = 72): TA, 1 g over 20 minutes before sternotomy, followed by a constant infusion of 400 mg/h during operative period and 500 mg added to priming
Group C (n = 70): AP, 280 mg throughout 20 minutes before sternotomy, followed by a constant infusion of 70 mg throughout the operative period and 280 mg added to priming
Exclusion criteria were: severe left ventricular disfunction (EF < 35%); impaired renal function (serum creatinine more than 2 mg/dL); active chronic hepatitis or cirrhosis; previous hematological disorders; and need for ventricular assist device for weaning from CPB. Preoperative treatment with aspirin or heparin was not a contraindication to enrollment in the trial. No patient was preoperatively treated with erythropoietin. A standardized technique of balanced anesthesia with propofol, fentanyl, pancuronium bromide, and isoflurane, as needed, was routinely used. Arterial revascularization with both mammary arteries and/or gastroepiploic artery was employed in the majority of patients. Heparin (3 mg/kg) was administrated to maintain a kaolin-activated coagulation time (ACT) above 480 seconds. A hollow-fiber membrane oxygenator was used in each surgical procedure. Cardiopulmonary bypass was performed with moderate hypothermia (32°–34°C), with blood flow between 2.0–2.4 L/min/m2. Mean arterial pressure during CPB was maintained between 60 and 85 mm Hg. Myocardial protection was obtained according to Buckberg cardioplegia. Total heparin dose was reversed with protamine sulfate with 1:1 ratio. A cell separator was used to concentrate the remaining cellular content of the oxygenator and blood loss after the end of CPB until the end of surgical procedure. Postoperative blood loss through the drainage tubes was recorded during the first 24 hours; then, if the bleeding was less than 100 mL in the last 4 hours, drainage tubes were removed. Samples for evaluation of plasmatic levels of hemoglobin (Hb), hematocrit (Hct), platelets (PLT), prothrombin time (PT), activated thromboplastin time (aPTT), creatinine (CREA), creatine kinase (CK), and creatine kinase myocardial-band (CKmb) were measured at these following times: after the induction (basal), at the intensive care unit arrival (time 1), after 4 hours (time 2), and at 6 a.m. of the first and second postoperative day (times 3 and 4). Transfusions were evaluated intraoperatively, in the first 4 hours postoperatively, and as total amount; they were indicated in units of packed red blood cells (PRBC), fresh frozen plasma (FFP) and platelet concentrates (PLTC). Criteria for transfusion were strictly followed during the first 2 postoperative days. Criteria for transfusion of PRBC were: Hct less than 18% and Hb less than 6 g/dL during CPB, Hct less than 24% and Hb less than 8 g/dL, or clinical conditions (hypovolemia and/or tachycardia with anemia after CPB). Criteria for transfusion of FFP were PT ratio greater than 1.5 with excessive blood loss (greater than 200 mL/h for 2 consecutive hours). Criteria for transfusion of units of PLTC were PLT less than 50,000/mm3 with excessive bleeding. Surgical reexploration was performed if the bleeding in the first 2 hours was greater than 300 mL/h with normal coagulation parameters. Patients with surgical cause of bleeding were excluded from statistical analysis. Cases of perioperative acute myocardial infarction (AMI) (new Q-waves and CKmb greater than 10%), postoperative renal insufficiency (creatinine twice the baseline), thrombotic complications, and major focal neurological disfunction were recorded.
Analysis of costs
We calculated for each patient the total treatment expenditure on the basis of cost for our hospital as the sum of costs of antifibrinolytic treatment and allogenic products transfused. The costs are the following: 1 g of EACA, about $0.30; 1 g of TA, about $1.00; 70 mg of AP (1 bottle), $31.00; PRBC, $112.20 for unit; FFP, $16.80 for each unit of 200 mL; PLTC, $18.80 for a single unit product within a pooled product.
Statistical methods
Data were analyzed with SAS statistical software. Analysis of variance (ANOVA) and Scheffé test or Bonferroni procedure for post-hoc comparison were used for continuous variables and 
2 or Fisher’s exact test were utilized as appropriate for categorical variables. Kruskall-Wallis test and Mann-Whitney test were used to compare variables which had not a normal distribution. Because age distribution was different among the three groups of treatment, analysis of the covariance (ANCOVA) was used to investigate differences among the three groups after adjustment of the variables for age. To investigate which variables were independently associated with bleeding at each considered time, multiple regression analysis was performed.
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Results
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Of 210 patients selected for the study, 7 were excluded; reasons for withdrawal are show in Table 1. A total of 203 patients completed the study and were evaluated by statistical analyses; the population was homogeneous for baseline demographic, hematological, and coagulation parameters (Table 2) and operative data (Table 3). Only age was significantly higher in the AP than in the EACA group (p = 0.028). Of postoperative hematological and coagulation data, aPTT at time 1 and time 2 were significantly longer in the AP group when compared to both the TA group and the EACA group (aPTT time 1: EACA, 1.11 ± 0.43 versus TA, 0.92 ± 0.41 versus AP, 1.56 ± 0.64; p < 0.0001; aPTT time 2: EACA, 0.97 ± 0.41 versus TA, 1.02 ± 0.42 versus AP, 1.35 ± 0.69; p < 0.0001). Table 4 shows blood losses corrected for age; no significant differences were found between TA and AP population, whereas bleeding at any time was significantly higher in the EACA group. The same table shows PRBC transfusions. The need for transfusions was similar in the TA and AP groups, whereas patients in the EACA group required more transfusions at any time; however, significance was observed only in the first 4 postoperative hours. In the EACA group, 4 patients required a total of 18 units of FFP, versus 1 patient in the TA group (4 units) and 2 patients of AP group (6 units) (p = ns). In the EACA group, 1 patient required PLTC transfusion (8 units in intensive care unit). The cost of drug treatment and the transfusion requirement were significantly lower in the TA group when compared with the AP and EACA groups as indicated in Table 4. Reoperations for nonsurgical bleeding were similar among the three groups. The effects of the treatment on bleeding were considered in multiple regression models including the following variables: treatment, age, gender, type of intervention, preoperative therapy, basal Hct-Hb-PT-aPTT, and CPB time. Only the type of antifibrinolytic treatment was correlated with time-related bleeding and with total postoperative bleeding confirming a higher blood loss in the first 4 hours in the EACA group versus the AP group (b = 107.7; S.E.(b) = 28.6; p < 0.001) but not in the TA group versus the AP group (b = 7.1; S.E.(b) = 26.4; p = 0.8). The same results were obtained for bleeding between 4 and 24 hours (EACA versus AP: b = 79; S.E.(b) = 26.5; p < 0.001; TA versus AP: b = 15.9; S.E.(b) = 24.5; p = 0.51) and for total bleeding (EACA versus AP: b = 195.3; S.E.(b) = 45.4, p < 0.0001; TA versus AP: b = 22.3; S.E.(b) = 41.9, p = 0.59).
The incidence of total adverse events was not different among the three groups (Table 3).
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Comment
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To the best of our knowledge, few reports comparing the three drugs head-to-head are present in the literature [8–9] and the main finding of our study is that TA, but not EACA, is more cost saving than and equally effective to high-dose AP in reducing blood loss and transfusion requirements in first-time cardiac surgery. High-dose AP costs about $370.00, whereas the cost of TA is about $3.70 and the cost of EACA is about $3.80. The cost of high-dose AP restricts its use to high-risk patients, so, most patients are denied the potential benefits of the drug. Reduction of the costs obtained by lowering the dose of AP is not advisable, because of some concerns about the safety of low-dose AP [10]. Even if the cost of pharmacological treatment with EACA or TA is similar, the increased need for allogeneic transfusion in the EACA group, due to the significant increase of postoperative bleeding, causes a doubling of total costs compared to TA. The lack of statistical significance in the difference of the amount of homologous transfusions among the three groups, despite the presence of a favorable trend for EACA, is probably due to the inadequate number of patients enrolled. Fibrinolysis is a common cause of excessive bleeding after cardiac surgery. Secondary fibrinolysis initiated by contact-activation-related and surgery-related (cellular disruption) release of tPA, thrombin generation, or retransfusion of tPA from pericardial cardiotomy is an important mechanism with respect to consumption of coagulation factors (factors V and VIII) and platelets (eg, internalization or destruction of glycoprotein Ib receptors). Increased plasmin activity and elevation of the levels of D-dimers and of fibrin degradation products induced by CPB are evidenced by previous studies and related with an increased risk of perioperative bleeding [11–12]. So, in an effort to decrease the morbidity associated with bleeding and transfusions, the use of antifibrinolytic drugs is receiving widespread attention. TA and EACA derive their antifibrinolytic effect from formation of a complex with plasminogen through lysine-binding sites, thus blocking their adhesion to fibrin [13]. The action of AP is more complex: it is a serine protease inhibitor, with an antifibrinolytic effect carried by the inhibition of plasmin and kallikrein, demonstrated by reduction of fibrin degradation products. Moreover, studies have demonstrated the protection of platelet GpIb by AP, thus reducing thrombin-mediated consumption of the platelets [14]. A metaanalysis of prophylactic treatment with EACA and TA to prevent postoperative bleeding in primary and redo cardiac surgery, reviewing 32 studies published from 1980 to 1993, has showed a reduction of about 30% of chest-tube loss for each treatment versus placebo and a greater reduction in blood loss and transfusion requirements in groups treated with AP or EACA/TA compared to desmopressin [15]. Drug delivery protocols were fairly uniform for desmopressin and AP (high-dose) but not for EACA and TA (low doses and high doses). Moreover, both synthetic antifibrinolytic drugs were considered together in the same group, so the differences between EACA and TA cannot be highlighted. Several authors have reported the efficacy of EACA, compared to that of a placebo, in reducing perioperative blood loss and transfusions. High doses of EACA (20–30 g) in recent studies limited to primary coronary revascularization have been shown as effective on bleeding and blood products requirements as high-dose AP [16] and TA [17]. Unfortunately, we were not able to reproduce these previous good results. Accordingly, a metaanalysis of only randomized studies of EACA reports no statistically significant effect of EACA in reducing transfusion requirement [18]. One explanation of the ineffectiveness of EACA could be its weaker effect compared to TA: EACA is six to ten times less potent and has a shorter half-life and a minor affinity for plasminogen binding sites [13]. Comparative studies between TA and AP have different results. In one study, TA failed to be as effective as AP on blood loss and transfusion requirements, but the number of patients enrolled was too small [19]. Two of the more recent studies demonstrated the same efficacy between the two drugs in reducing blood loss and transfusions, both in primary and in redo cardiac surgery [20–21]. Our trial confirms and extends these previous favorable results of TA. Our trial confirms these previous favorable results of TA also in high-risk patients for bleeding; in fact, about a third of the patients enrolled did not suspend preoperatively this treatment with aspirin. Although the risk of hypersensitivity phenomena during first exposure to AP is low (< 1%), it increases to 5% to 6% on readministration. This is an area of concern, considering that redo surgery is increasing and this population of patients at high risk of bleeding could realize the major benefit of AP administration. Unlike AP, TA does not interfere with ACT measurement, whereas ACT measurement is inaccurate with AP and kaolin-activated tube are required. The prolongation of postoperative aPTT in our study in the AP group is confirmed by previous studies [22]. In the present study, no differences were found regarding the incidence of AMI or renal failure among the three groups. Although no apparent increases in the rate of thrombotic complications were observed in our study or in estimates addressed by other metaanalyses [19], no clear conclusions can be made regarding safety of these agents based on lack of enrollment of an appropriate number of patients. The conclusion of our trial is that in our population of patients undergoing first-time cardiac surgery, TA, but not EACA, has been shown to be more cost-effective than high dose AP.
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Accepted for publication June 9, 1999.
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Top
Abstract
Introduction
