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Ann Thorac Surg 1998;65:371-376
© 1998 The Society of Thoracic Surgeons
-Aminocaproic Acid for Primary Myocardial Revascularization
Department of Anesthesia, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada,
Department of Biostatistics, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada,
Department of Hematology, Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada
Accepted for publication July 16, 1997.
Dr Hardy, Montreal Heart Institute, 5000 Bélanger St, Montreal, PQ, Canada H1T 1C8 (e-mail: hardy@icm.umontreal.ca).
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Abstract |
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-aminocaproic acid and tranexamic acid to reduce transfusions after primary myocardial revascularization was evaluated in a teaching hospital context.
Methods. Patients (n = 134) received either -aminocaproic acid (15-g bolus + infusion of 1 g/h), high-dose tranexamic acid (10-g bolus + placebo infusion), or normal saline solution in a double-blind fashion. Anticoagulation and conduct of cardiopulmonary bypass were standardized.
Results. Tranexamic acid and -aminocaproic acid produced a significant reduction in postoperative blood loss compared with placebo (median loss, 438 mL, 538 mL, and 700 mL, respectively). Transfusion of red cells was similar in all three groups. Nonetheless, the percentage of patients receiving hemostatic blood products was significantly decreased in the -aminocaproic acid group compared with the placebo group (20% versus 43%; p = 0.03). Both tranexamic acid and -aminocaproic acid significantly decreased total exposure to allogeneic blood products compared with placebo (p = 0.01 and p = 0.05, respectively), and this reduction was clinically important (median exposure, 2, 2, and 7.5 units, respectively). Fibrinolysis was inhibited significantly in both treatment groups.
Conclusions. We conclude that either high-dose tranexamic acid or -aminocaproic acid effectively reduces transfusions in patients undergoing primary, elective myocardial revascularization.
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Introduction |
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-aminocaproic acid [EACA] and tranexamic acid [TA]) and one natural (aprotinin)—are available for clinical use. Although the efficacy of aprotinin (Trasylol; Bayer Pharmaceutical, West Haven, CT) is supported by numerous studies, the drug is expensive and can be associated with anaphylactic reactions on reexposure, thus making it unsuitable for routine clinical use in first-time procedures associated with the smallest risk of exposure to ABPs. Since 1979, several studies have reported a beneficial effect of EACA to treat or to prevent postoperative bleeding [1] [2] [3] [4]. The major advantage of EACA over the other two antifibrinolytic agents is its price. In Canada, at doses ranging from 10 to 20 g, the cost of EACA is less than $90 Canadian. Thus, introduction into everyday practice is readily feasible.
Tranexamic acid is ten times more potent than EACA, and its use in cardiac surgery is recent. Several studies [5] [6] [7] [8] [9] [10] have reported a beneficial effect of TA on postoperative bleeding with or without a reduction in transfusion of ABPs. The most effective dosage regimen to decrease the frequency of ABP transfusion remains controversial. When administered as a bolus, 10 g appears to be the optimal dose [6], but this regimen entails an expense of $280 Canadian.
Although synthetic antifibrinolytic agents have often been compared with aprotinin, there is a need for a prospective, placebo-controlled study to determine the efficacy of EACA and TA to reduce transfusions after cardiopulmonary bypass (CPB). Retrospective or noncontrolled comparative studies [5] [6] suggest that both TA and EACA reduce postoperative bleeding, but only TA reduces transfusion of ABPs. However, the amount of blood shed during and after the operation is only an intermediate outcome and does not always reflect the amount of ABPs to which patients are exposed.
It remains unclear if antifibrinolytic agents are useful in patients undergoing primary coronary artery bypass grafting (CABG), as bleeding is minimal in these patients. Nonetheless, an average of 68% of patients undergoing first-time CABG require transfusion of ABP according to the findings in a multicenter study [11] published in 1991. These patients represent an important part of the regular cardiac surgical case load, and in the present financial environment, only a relatively inexpensive regimen is likely to be implemented in routine clinical practice. The present study was conducted to evaluate the efficacy of prophylactic TA and EACA to reduce transfusion of ABPs in patients undergoing primary CABG.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Study Groups
Eligible patients older than 18 years scheduled to undergo elective CABG were randomized by the Department of Pharmacy into three groups. Each successive block of 9 patients was randomized (random allocation of 3 patients to EACA, 3 patients to TA, and 3 patients to placebo) to ensure a comparable number of patients in all groups and a similar distribution of patients over time. The EACA group received a 15-g bolus over 20 minutes, followed by an infusion of 1 g/h. The TA group received a 10-g bolus of TA over 20 minutes, followed by a placebo infusion. The control group received a bolus plus infusion of placebo solution. Placebo consisted of 0.9% normal saline solution. Infusions were discontinued on separation from CPB. All bags were coded by the Department of Pharmacy, and identical volumes (taking into account the duration of CPB) of solution were infused.
Operative Details
No attempt was made to standardize anesthesia or surgical practice except the management of anticoagulation and CPB. Pork mucosal heparin (400 IU/kg) was administered initially, and during CPB, the activated coagulation time (with the Hemochron 801 device; International Technidyne Corporation, Edison, NJ) was maintained higher than 480 seconds with additional heparin as required. A bubble oxygenator (Bentley 10 PLUS; Bentley Laboratories Inc, Irvine, CA) was primed with 1,500 to 2,000 mL of lactated Ringer’s solution containing 5,000 units of heparin. Colloids (human albumin or Pentastarch) were added to the pump prime at the discretion of the attending anesthesiologist. Flows of 2.4 L · min-1 · m-2 were obtained with a Sarns roller pump (Sarns Inc, Ann Arbor, MI). Mild systemic hypothermia (between 32° and 34°C urinary bladder temperature) was maintained during aortic cross-clamping, and the myocardium was preserved by the intermittent infusion of blood cardioplegia into the aortic root. After separation from CPB, the effects of heparin were reversed with protamine sulfate (4 mg/kg). Blood remaining in the CPB circuit after separation was collected and infused to the patient. Autologous blood transfusions, a cell-saving device, and infusion of mediastinal drainage fluid were not employed.
The protocol for transfusion of ABPs during and after CPB, prepared by the Transfusion Committee of this institution, was adhered to by anesthesiologists, surgeons, fellows, and residents involved in the care of these patients. Briefly, our usual practice is to maintain a hemoglobin concentration of approximately 70 g/L during CPB, and hemoglobin concentrations as low as 80 g/L are tolerated after CPB as long as hemodynamic stability is maintained. Human albumin (not plasma) is used when volume expansion alone is desired. Depending on the rate of bleeding and the degree of abnormality of coagulation tests, coagulopathy is treated as follows: with additional protamine if the activated coagulation time is prolonged more than 10% higher than baseline; with 2 to 4 units of fresh frozen plasma (FFP) if the international normalized ratio of the prothrombin time is greater than 1.8 or if the activated partial thromboplastin time is more than 50 seconds; with 8 units of platelet concentrates if the platelet count is less than 80 x 109/L; and finally, with 8 or 16 units of cryoprecipitates if the fibrinogen concentration is less than 1.8 or 1.0 g/L, respectively.
Data Compared
Clinical data compared between groups included basic demographic data; duration of CPB, aortic cross-clamping, and operation; dose of heparin and protamine administered during the operation; administration of protamine in the intensive care unit (ICU); surgical reexploration for excessive mediastinal bleeding; and incidence of myocardial infarction, stroke, and death. Myocardial infarction and stroke were recorded as present if described in the patient’s medical notes or on the discharge summary. Blood loss during the operation was evaluated by the attending anesthesiologist. The total volume of mediastinal blood shed after the operation and collected until removal of drains (over 12 to 18 hours) was measured hourly by the ICU nurses. Transfusions of packed red blood cells (PRBCs) and hemostatic blood products (platelets, FFP, or cryoprecipitates) during and after the operation were recorded.
Laboratory data collected for each patient included the activated coagulation time after induction of anesthesia, after sternotomy, after the administration of heparin, during CPB, and on arrival in the ICU. The hemoglobin concentration, platelet count, and routine coagulation profile (thrombin time, prothrombin time, and activated partial thromboplastin time) were measured prior to induction of anesthesia and on arrival in the ICU. Hemoglobin concentrations at the time of discharge from the hospital were compared. Serum creatinine concentrations were measured the day before operation, on arrival in the ICU, and on postoperative days 1, 2, and 6. The concentration of prothrombin fragments 1 and 2, the activity of antithrombin III, plasminogen, and 
2-antiplasmin, and the concentrations of D-dimer and fibrinogen degradation products were measured prior to induction of anesthesia, 15 minutes into CPB, and on arrival in the ICU.
Statistical Analysis
StatView (v. 4.0; Abacus Concepts Inc, Berkeley, CA) and SAS/STAT (v. 6.1; SAS Institute Inc, Cary, NC) computer programs were used to analyze the data. Analysis of categoric variables was performed using 
2 tests with Yates’ correction for continuity. Comparisons of mean values between groups were made using a t test or analysis of variance for normally distributed variables. Nonparametric Mann-Whitney tests were used to analyze intraoperative and postoperative blood losses, as these do not distribute normally. To answer the primary question, a two-step analysis was performed on the total ABP variable. First, the proportion of patients given a transfusion was compared between the treated and the control groups. Second, the total number of units of ABPs administered in those patients receiving transfusions was compared. Analysis was performed for each type of ABP separately (Mann-Whitney tests).
To allow a multivariate analysis of important predictors of the nonnormally distributed key outcome (transfusion of ABPs), patients were divided into moderate versus severe blood users. Moderate blood users were defined as those given only PRBC, only FFP, or both, and severe blood users were defined as those given platelets, cryoprecipitates, or both in addition to PRBCs, FFP, or both. Multiple logistic regression was used in a multivariate analysis to control for the intermediate variables suspected to affect transfusion of ABPs. Variables possibly related to the severity of transfusion by univariate analysis (with a p value 
0.2) were also included in the multivariate analysis.
All tests were two-tailed. Exact p values are reported unless the value of p is greater than 0.2, in which case p is reported as not significant.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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2-antiplasmin activities were not significantly different between groups at any time. The concentration of prothrombin fragments 1 and 2 increased significantly on arrival in the ICU, and antithrombin III activity decreased significantly during bypass and on arrival in the ICU. Plasminogen and 2-antiplasmin activities decreased significantly during bypass and on arrival in the ICU. Thirty-one percent of patients in the control group had a D-dimer concentration of greater than 0.25 mg/L in the ICU compared with 5% and 9% of patients receiving TA or EACA, respectively (p = 0.001). Similarly, fibrinogen degradation product concentrations were higher than 10 mg/L in 29% of patients in the control group compared with 10% and 14% in the TA and EACA groups, respectively (p = 0.04). Serum creatinine concentrations throughout the perioperative period remained within normal limits and were not significantly different between groups at any time during the study. The incidence of reoperation for hemostasis was similar in all three groups (Table 5) (p = not significant). Finally, the incidence of postoperative myocardial infarction, cerebrovascular accident, or death was not clinically different between groups (see Table 5). Two patients sustained more than one complication.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Intraoperatively, the estimation of blood losses is imprecise, but our results suggest that overall, bleeding was reduced somewhat by the administration of TA. Postoperatively, the volume of shed mediastinal fluid is measured accurately, and TA and EACA reduced total mediastinal drainage by about 250 mL and 150 mL, respectively. The hemoglobin concentration of shed mediastinal fluid is variable, ranging from 55 to 93 g/L [12] [13], and this concentration decreases with time [13]. Thus, despite a significant reduction in the volume of shed fluid, the mass of hemoglobin effectively lost was too small to influence transfusion of PRBCs (see Table 3), which was appropriate in all three groups, as indicated by the perioperative evolution of hemoglobin concentrations.
More important than the volume of shed mediastinal blood is the total exposure of patients to ABPs, which was decreased by the administration of synthetic antifibrinolytic agents essentially because of the decreased percentage of patients receiving ABPs in view of restoring normal hemostasis (platelets, FFP, and cryoprecipitates) in the TA and EACA groups. Table 3 shows that once transfusion is initiated, patients will receive similar numbers of individual products. This is easily explained by the quantum nature of hemostatic blood product administration, which rose from a median of 2 units in the treatment groups to 7.5 in the control group. We chose to exclude patients with "confirmed" surgical bleeding, but this is difficult to define as it depends on the surgeon’s personal opinion at the time of reoperation. However, reanalysis of our data with all patients included did not modify the results, indicating the robustness of treatment effect, as suggested also by the multivariate analysis.
It is well known that blood product use varies considerably from center to center [11]. Blood use in our center is relatively high, and therefore, it is not surprising that antifibrinolytic therapy was found effective, even in patients undergoing a primary sternotomy. Thus, each center will have to interpret these results in the light of its own blood product utilization profile to determine if TA or EACA may be of use in their patients undergoing primary myocardial revascularization. Since the trial was conducted, our criteria for administration of cryoprecipitates have become more stringent and now include only patients with a fibrinogen concentration of less than 1.0 g/L, resulting in a considerably decreased utilization of this blood component. Again, however, subsequent reanalysis of blood product utilization excluding cryoprecipitates did not negate the beneficial effects of antifibrinolytic agents on total blood product exposure (see Table 3).
In the present study, despite drug treatment, the majority of patients received PRBCs. Transfusion of PRBCs could have been eliminated altogether by the implementation of additional blood-saving strategies, especially as the median number of units administered was relatively low (2 units). It is important to realize that the objective of zero exposure to ABPs can be achieved only by the combination of different blood-saving techniques [14]. To this end, the prophylactic administration of TA or EACA in patients undergoing elective first-time CABG is recommended as part of our continued efforts to reduce total exposure to ABPs.
The ideal dosage of synthetic antifibrinolytic agents remains controversial. "Low-dose" TA (10 mg/kg followed by 1 mg · kg-1 · h-1) has been shown convincingly to decrease bleeding, but not transfusions, after CPB [8] [10]. A retrospective review [6] of prophylactic synthetic antifibrinolytic use supports the concept that increased doses of TA (10-g infusion before sternotomy) may decrease transfusions more effectively. Compared with historical controls, patients receiving 10 g of TA (2-g bolus before CPB and 8 g by infusion during CPB) bled less postoperatively and required fewer ABPs [9]. Increasing the dose of TA to 20 g did not reduce transfusions any farther [7]. Of note, in the latter prospective, double-blind, randomized trial [7], there was no significant difference in transfusion of PRBCs, platelets, and FFP between treatment (TA 10 g and TA 20 g) and control groups.
The doses recommended for EACA range from a 5-g bolus administered just before CPB [2] to a total of 30 g administered as 10 g before skin incision, 10 g in the CPB priming solution, and 10 g after administration of protamine [3]. Contrary to most reports on TA, a majority of trials with EACA have shown a decreased use of any ABPs [1] [3] [4] or, as in the present study, a decreased transfusion of hemostatic blood products [2].
Few pharmacokinetic data are available to determine a rational dosage regimen of TA or EACA in cardiac operations. We elected to administer the 10-g dose of TA recommended by Karski and associates [6], as our principal objective was to decrease exposure to ABPs. The dose of EACA was also chosen arbitrarily, but we postulated that relatively high doses would be required to allow valid comparisons because EACA is six to ten times less potent than TA [15]. The highest reported dose at the time the study was conducted was 15 g administered as an infusion prior to CPB [6]. It was thought that the addition of an infusion of EACA, 1 g/h, until the end of CPB would be important to maintain effective blood concentrations because a dose of EACA equivalent to the high-dose TA regimen was not administered at the beginning of the operation, EACA undergoes rapid renal excretion, and the antifibrinolytic activity of TA in tissues is considerably higher and more sustained than that of EACA [15].
Although this study was not designed to explore in depth the mechanism or mechanisms by which TA or EACA decreases bleeding and transfusions after cardiac operations, the results of coagulation testing performed before, during, and after CPB allow a few conclusions. First, as expected, but in contrast to aprotinin [16], hemostatic activation was not decreased by TA or EACA, as demonstrated by similar increases in prothrombin fragments 1 and 2 in all three groups. Second, TA and EACA inhibited fibrinolysis, as measured by the production of fibrinogen degradation products and D-dimers, but the generation of plasmin was not decreased, as shown by similarly reduced plasminogen and 2-antiplasmin activities in all three groups. Patients have a hypofibrinolytic period lasting 48 hours after CPB, probably to conserve stable hemostatic plugs in injured tissues [17], but the risk of exaggerating this normal postoperative prothrombotic state with synthetic antifibrinolytic drugs remains unknown.
In the doses evaluated in this study, TA is three times more expensive than EACA ($280 versus $90 Canadian, respectively). The cost of TA is still notably less than that of high-dose aprotinin (6 million units) but similar to that of a low-dose aprotinin regimen (2 million units in the CPB priming solution). The health care system is not capable of affording prophylactic high-dose aprotinin for all patients undergoing cardiac operations, and this explains why numerous studies have examined less expensive alternatives. Inasmuch as efficacy is similar, the risk of complications must be taken into consideration when deciding to adopt one form of therapy rather than another. In the present study, the small number of patients could not support a meaningful statistical analysis, but the incidence of myocardial infarction, cerebrovascular accident, or death was not clinically different between groups. Data reporting in the individual studies reviewed by Fremes and colleagues [18] prevented the authors from studying prothrombotic events in their metaanalysis of prophylactic drug treatment in the prevention of bleeding after CPB, but presumably they were not increased, as drug treatment produced a favorable effect on perioperative death.
In summary, both TA and EACA effectively reduce transfusion of ABPs in patients undergoing primary elective CABG. The prophylactic use of either drug as part of a multifaceted strategy to decrease exposure to ABPs after myocardial revascularization is recommended. Considering only the initial costs incurred, routine use of EACA is the least expensive antifibrinolytic therapy available at present.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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We thank our colleagues from the Department of Surgery for their support and the members of the Department of Pharmacy for their help in the blinding and randomization procedure.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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-aminocaproic acid before cardiopulmonary bypass. Ann Thorac Surg 1994;57:1108-1113.[Abstract]
-aminocaproic acid (EACA) administration minimizes blood replacement therapy during cardiac surgery. Anesth Analg 1995;80:827-829.[Medline]
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