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Eur J Cardiothorac Surg 2004;26:311-317
© 2004 Elsevier Science NL

Prophylactic tranexamic acid in elective, primary coronary artery bypass surgery using cardiopulmonary bypass

Department of Cardiothoracic Surgery, Aalborg University Hospital, University of Aarhus, Hobrovej, Postboks 365, DK-9100 Aalborg, Denmark

Received 14 January 2004; received in revised form 29 February 2004; accepted 15 March 2004.

^* Corresponding author. Tel.: +45-99-322964; fax: +45-99-322425
e-mail: jjandreasen{at}dadlnet.dk

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
Objective: Perioperative use of tranexamic acid (TA), a synthetic antifibrinolytic drug, decreases perioperative blood loss, and the proportion of patients receiving blood transfusion in cardiac surgery, but the results may vary in different clinical settings. The primary objective of the present study was to determine the efficacy of TA to decrease chest tube drainage and the proportion of patients requiring perioperative allogeneic transfusions following primary, elective, on-pump coronary artery bypass grafting (CABG) in patients with a low baseline risk of postoperative bleeding. Methods: In a double-blinded, prospective, placebo-controlled study, 46 patients were randomized into two groups. One group received TA 1.5 g as a bolus, followed by a constant infusion of 200 mg/h until 1.5 g. The other group received placebo (0.9% saline). Among exclusion criteria were treatment with acetylsalicylic acid, non-steroidal anti-inflammatory drugs or other platelet inhibitors within 7 days before surgery. Results: Preoperative demographics, biochemical and surgical characteristics were comparable between groups. At 6 h postoperatively, there was a trend towards a greater blood loss (median and interquartile range) in the placebo group (710 and 460–950 ml) compared to the TA group (400 and 350–550 ml), but the difference did not reach statistical significance. Neither were transfusion rates and the amount of autotransfused shed mediastinal blood different between the groups postoperatively. Postoperative D-dimer concentrations were significantly higher in the placebo group compared to the TA group (P<0.001). This difference could not be explained by differences in the amount of autotransfused shed mediastinal blood alone. Plasma concentrations of ß-thromboglobulin and platelet factor 4 were significantly increased postoperatively in both groups, but without any intergroup differences. Seven patients (15%), one in the TA group and six in the placebo group, were reoperated due to excessive bleeding. Surgical correctable bleeding was found in all except two patients from the placebo group. Conclusions: An antifibrinolytic effect following prophylactic use of TA in elective, primary CABG among patients with a low risk of postoperative bleeding, did not result in any significant decrease in postoperative bleeding compared to a placebo group.

Key Words: Coronary artery bypass grafting • Tranexamic acid • Placebo • Bleeding

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
Postoperative bleeding following coronary artery bypass surgery (CABG) using cardiopulmonary bypass (CPB) may lead to allogeneic blood transfusion and/or reoperation, which are independently associated with a number of adverse outcomes [1–3]. Various causes of bleeding have been pointed out. Most common are defective surgical hemostasis and acquired transient platelet dysfunction. More uncommonly are thrombocytopenia, vitamin K-dependent factor deficiencies, coagulopathy, fibrinolysis and heparin-rebound [4]. Perioperative use of tranexamic acid (TA), a synthetic antifibrinolytic drug, decreases perioperative blood loss and the proportion of patients receiving blood transfusions in cardiac surgery. In addition, the mortality and need for rethoracotomy are decreased [5–8]. However, use of TA may reveal different results in different clinical settings, and it has been ventilated, that the application of blood conservation strategies for primary CPB procedures must be considered on the institutional experience, and not only by type of procedure [9]. We speculated whether perioperative use of TA as a routine, would have any major significant clinical hemostatic effects in a group of patients with low risk of postoperative bleeding in our institution. The primary objective of the present study was to determine the efficacy of TA to decrease chest tube drainage and the proportion of patients requiring perioperative allogeneic transfusions in patients undergoing primary, elective CABG using CPB.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
2.1. Patients and study design
The study was approved by the local ethical committee, and written informed consent was obtained from all patients. The study was performed in a minor cardiothoracic surgical department employing senior surgeons as well as trainees. Approximately 500 CABG operations are carried out per year using on-pump as well as off-pump techniques.

The patient population consisted of 46 consecutive patients scheduled for elective, primary isolated CABG using CPB. The patients were randomized into two groups in a double-blinded, prospective, placebo-controlled study by a random number sequence. One group received TA (Cyklokapron^®, Phizer Consumer Healthcare, Denmark) 1.5 g as an intravenously bolus via central venous catheter beginning at the induction of the anesthesia, followed by a constant infusion of 200 mg/h until additional 1.5 g was given. The other group received placebo (0.9% saline). The randomization schedule was provided in sealed envelopes, and preparation of the drug or placebo was carried out just prior to anesthesia by a staff member not involved in the treatment of the patient. Exclusion criteria: treatment with acetylsalicylic acid, non-steroidal anti-inflammatory drugs or other platelet inhibitors within 7 days before surgery, preoperative heparin administration, history of coagulopathy, thrombocytopenia (platelet count <50x10⁹/l), preoperative hemoglobin <6.0 mmol/l, serum creatinine >115 µmol/l, pregnancy and Jehovah's witnesses.

2.2. Anesthetic technique
Routine anesthetic procedures of the department were employed. All patients were premedicated with peroral diazepam 1.5 h before presenting to the operating room. An intramuscular injection of morphine/scopolamine was administered intramuscularly 0.5 h preoperatively. Anesthesia was induced with a bolus of midazolam and fentanyl. Muscle relaxation was achieved and maintained with pancuronium. Anesthesia was maintained with isoflurane 0.5–1.5%, fentanyl and midazolam. Propofol 5–20 ml/h was administered during extracorporal circulation (ECC) according to needs.

2.3. Operative procedures and cardiopulmonary bypass management
No attempt was made to select surgeons or standardize surgical practice. All patients were operated through a full median sternotomi. The left internal thoracic artery was used whenever the anterior descending artery was to be grafted. Saphenous veins were used as routine grafts for other coronary anastomoses. Standard normothermic CPB was instituted in all patients with arterial cannulation of the ascending aorta and two-stage venous cannulation via the right atrium. Anticoagulation was achieved using 300 IU/kg of heparin (Amternes lægemiddelregistreringskontor I/S, Copenhagen, Denmark) before cannulation. Anticoagulation was monitored with serial measurements of the activated clotting time (ACT) (Hemocron 801; Techodyne International Corp., Edison, NJ), which was maintained above 480 s at all time during CPB. Additional heparin was administered when needed. Standard normothermic CPB included Safe II hollow-fiber membrane oxygenators (Polystan, Denmark), arterial line filters, non-pulsatile flow using an non-occlusive roller pump with a pump flow of 2.4 l/m² per min, and a mean arterial pressure kept above 60 mmHg. The venous saturation was kept above 65%. The circuit was primed with Ringer chloride. All tubes were without any heparin-coating. Myocardial protection was obtained by intermittent antegrade or retrograde cold blood cardioplegia. Blood from the operative field was returned to the extracorporal circuit during the operation, and after weaning the patient from CPB, all blood from the circuit was returned to the patient, except for 300 ml lost in the circuit.

The heparin effect was reversed by protamine (Protaminsulfat ‘Leo’, Malmö, Sweden) administration (3 mg/kg), followed by confirmation that ACT had returned to baseline. If needed, additional protamine was given. Before closure of the chest, mediastinal and pleural tubes were positioned in the mediastinum, and pleural spaces if they have been entered. Low-grade suction was instituted.

2.4. Transfusion policies and indication for surgical re-exploration
Indications for perioperative transfusion of allogeneic red blood cells were a hematocrit below 22%, and/or a mixed venous blood saturation below 65%. If postoperatively, the hematocrit was below 25% together with a mixed venous blood saturation below 60%, packed red blood cells were given. If the ACT was at baseline and bleeding exceeded >400 ml during the first hour, or >300 ml/h during two successive hours, with no signs of clot formation in the chest tubes, transfusions of fresh frozen plasma (FFP) and/or platelets were given. Postoperatively shed mediastinal blood was returned in all patients using a closed autotransfusion system.

Quantitative chest tube drainage criteria for reoperation were >500 ml/h, >800 ml during two successive hours, >900 ml during three successive hours or total bleeding >1200 ml after 5 h, with normal coagulation parameters.

2.5. Blood sampling
Blood samples were taken the day before the operation as baseline measurements, and these included hemoglobin and serum creatinine concentrations, hematocrit, platelet number, activity of antithrombin III (AT3), activated partial thromboplastin time (APTT), international normalized ratio (INR), ACT, and plasma concentrations of ß-thromboglobulin (ß-TG), platelet factor 4 (PF4), fibrinogen and D-dimer. Blood samples were also drawn 6 and 12 h after the operation. Plasma samples for analyzes of ß-TG and PF4 were prepared and stored at –80 °C for later analyzes. Creatinine kinase MB (CK-MB) isoenzyme was measured 6 h postoperatively and next morning, with further measurements if the value exceeded 50 U/l.

2.6. Outcome measures
Primary outcome measures were postoperative blood loss and the proportion of patients requiring allogeneic transfusion. Bleeding was monitored as chest tube output at hourly intervals in the ICU until the next morning. The chest tube output from 0–6 and 0–12 h postoperatively were registered. The amount of autotransfused shed mediastinal blood was recorded at 6 h. The type of allogeneic transfusions (packed red blood cells, platelets and FFP) during and after the operation was registered. Secondary outcome measures were development of perioperative myocardial infarction (peak CK-MB>50 U/l and/or development of new Q waves), acute renal insufficiency (creatinine value twice the baseline or need for dialysis), transient ischemic attacks or stroke, early mortality (<30 days+hospital mortality) and mediastinal infection within 30 days. The need for surgical re-exploration within 24 h and findings were recorded. Patients requiring re-exploration were excluded from analyzes regarding postoperative bleeding, need of allogeneic transfusions as well analyzes of postoperative biochemical data.

2.7. Statistical analysis
Descriptive statistics for the groups are presented as mean±standard deviation or as a simple percentage. Differences within and between groups were analyzed using the two-tailed unpaired or paired Student's t-test or Fisher's exact test as appropriate, when continuous and dichotomized variables were compared. The Mann–Whitney U test was used to compare postoperative blood loss and transfusion requirements, which do not follow a Gaussian distribution. A P value <0.05 was considered statistically significant. The statistical software package SPSS, version 10 (SPSS, Inc., Chicago, IL) and Microsoft^® Excel 2000 were used to analyze data.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
Two patients in the TA group were excluded from the study after randomization, as it turned out that these patients had received clopidogrel or indometacin within 1 week prior to surgery.

There were no preoperative significant differences between the treatment group and the placebo group with respect to demographics, biochemical and surgical characteristics (Table 1), except that patients in the treatment group received significantly more additional heparin before CPB, than patients in the placebo group. Further, there was a tendency towards longer CPB times in the TA group, but the difference was not significant.

Fibrinogen decreased significantly 6 h postoperatively in both groups without intergroup differences, but fibrinogen concentrations were at baseline next morning. D-dimer concentrations were significantly increased postoperatively in both groups, but the increase was significantly higher in the placebo group compared to the TA group. There was still a significant difference between the groups next morning.

The APTT was significantly higher 6 h postoperatively compared to preoperative values in both groups. Next morning the APTT values remained higher than preoperatively, and the values were significantly higher in the TA group than in the placebo group.

Blood loss, autotransfusion of shed mediastinal blood and allogeneic transfusion requirements for the two groups are compared in Table 3. Blood loss at 6 and 12 h postoperatively was higher in the placebo group compared to the TA group, but the difference was not statistical significant. Neither were the amount of autotransfused shed mediastinal blood significant different between the groups.

Red blood cells were transfused to six patients in the TA group and to five patients in the placebo group. Among these patients FFP was transfused to two patients in the TA group and to three patients in the placebo group. Platelets were given to one in the TA group and to three in the placebo group. The number of patients exposed to any allogeneic blood product postoperatively was not significantly different between the groups.

Seven patients (15%), one in the TA group and six in the placebo group, were reoperated due to excessive bleeding. Surgically correctable bleeding was found in all patients except in two patients from the placebo group. In those patients diffuse microvascular bleeding was found.

There was one early sudden, unexpected, unexplained death in a patient from the treatment group. The patient was discharged from the hospital after an initial uneventful postoperative course, but died on day 29 postoperatively due to acute hypotension. Pulmonary emboli were ventilated, but autopsi was not carried out. None experienced postoperative renal insufficiency, myocardial infarction, mediastinal infection, transient ischemic attack or stroke within 30 days.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
Prophylactic use of TA has been shown to reduce perioperative blood loss following primary elective heart operations including primary myocardial revascularization in several randomized, placebo-controlled studies [10–12] and metaanalyses, but the present study is not in accordance with these findings. In a Cochrane review [8] it has been pointed out, that there is a trend towards heterogeneity in trial outcomes and the Cochrane review also found some evidence of publication bias. The present study represents a small negative trial with similar results as in another small trial [13]. These studies are suggestive, that TA is without any major effect on the amount of postoperative blood loss in a group of patients with a low risk of postoperative bleeding following primary on-pump CABG.

In contrast to our findings, TA was found to reduce postoperative bleeding in a previous study of the same size and with a similar dosing regime of TA [14]. However, these studies are not comparable because the previous study was performed in off-pump surgery. CPB is associated with various causes of bleeding [4] and this may explain the differences between the two studies.

Because the results in our study were not in accordance with most previous studies, it is important to discuss if chance and bias produced results, which depart randomly or systematically from the truth. Different patient populations may contribute to variation of the findings in different studies. In contrast to most other studies, we excluded all patients taking any platelet inhibitor within 7 day prior to surgery.

As the postoperative bleeding exceeded our expectations, a new power analysis based on the observed postoperative bleeding was performed in order to evaluate, whether this study was sufficiently powered to show any major differences. The analysis showed, that we have a 70% chance of observing an approximately 30% difference in postoperative bleeding at a significance level of 0.05. Minor positive effects might have been elucidated, if more patients were included in the study.

The re-exploration rates due to postoperative bleeding following cardiac surgery are reported to be <4% [15], but the re-exploration rate was considerable higher among patients included in the present study. Inadequate surgical hemostasis may confound a possible association between prophylactic use of TA and reduced postoperative bleeding, although we excluded patients who were re-explored from the analysis of postoperative blood loss. One patient in the TA group and six in the placebo group, were reoperated due to excessive bleeding, and surgical correctable bleeding was found in all patients except in two from the placebo group. These results points towards inadequate surgical hemostasis as a risk factor for increased bleeding in both groups, thus overshadowing any bleeding related to fibrinolysis.

Significant elevated values of APTT in the treatment group next morning may be explained by a possible heparin-rebound effect, as this group received more additional heparin during ECC, compared to the control group. Heparin-rebound has been shown to be associated with a small but significant increase in postoperative bleeding following CPB [16], and this may have contributed to bleeding in the TA group.

High levels of D-dimer has been found in shed mediastinal blood compared with plasma concentrations [17–19], and there is a linearity between D-dimer levels in plasma and the amount of autotransfused shed mediastinal blood [17]. Autotransfusion of shed mediastinal blood is a possible confounding factor, which might have been able compromised our results systematically with respect to the differences of postoperatively measured D-dimers. However, we found no statistical differences between the groups regarding the amount of autotransfused shed mediastinal blood, and we therefore believe, that the much higher plasma levels of D-dimer in the placebo group reflect increased fibrinolysis in this groups compared to the treatment group. However, this did not result in clinical differences in the amount of postoperative bleeding.

TA may also affect postoperative bleeding by preventing platelet activation [20], but we did not find any intergroup differences in elevated plasma concentrations of ß-TG and PF4. These plasma concentrations may reflect equally sequestered intraplatelet substances from activated platelets in both groups, but increased plasma levels of ß-TG has also been described following postoperative autotransfusion of shed mediastinal blood [21].

Transfusion rates during CABG vary between 0 and 100% [1,2,6,22]. Major benefit of prophylactic TA may not be found in institutions with low transfusion rates. Although the transfusion rate was 29% in the placebo group, we did not find any clinical significant differences in transfusion rates between the groups in the present study. If more patients were included in the study, we would perhaps be able to show a minor benefit of TA, but simple changes in transfusion policy may decrease the use of allogeneic blood as much as any pharmacological strategy among low-risk patients. During the present study, we employed strict transfusion criteria, and it is very likely that transfusion rates may be reduced, if indications for postoperative allogeneic transfusion become more individualized. Decisions to transfuse red blood cells should be based on differentiated data as hematocrit, blood loss, age, presence or absence of symptoms, underlying cardiopulmonary status and presence or absence of perioperative complications.

Different dosing regimens of TA have been used in cardiac surgery. We did not use a weight-based dosing regimen. For simplicity, we used a standard loading dose followed by a standard maintenance infusion. Our dosing regimen exceeded minimum recommended doses for prophylactic administration of TA [23]. Looking into pharmacokinetic studies on TA [23–25], our dosing regimen seems to result in plasma concentrations of TA preventing fibrinolysis during CPB and in the immediate postoperative period.

Potential benefits of TA must be weighed against the risk of complications, as there is a potential thrombotic risk using antifibrinolytic drugs. Metaanalyses, however, have not found evidence of increased rates of myocardial infarction, stroke, or venous thromboembolism following prophylactic use of TA [5–8]. No patients in the present study suffered from thromboembolic events within 30 days, but as in most series, this study was not powered to evaluate such complications.

Our results are limited by the small number of patients included, but the results indicate, that meticulous efforts to achieve surgical hemostasis may be more rewarding than using TA in low-risk patients undergoing on-pump CABG.

	5. Conclusions

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 
An antifibrinolytic effect following prophylactic use of TA in elective, primary CABG among patients with a low risk of postoperative bleeding did not result in any significant decrease in postoperative bleeding compared to a placebo group.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusions References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jan J. Andreasen Conny Nielsen Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Andreasen, J. J. Articles by Nielsen, C. Search for Related Content PubMed PubMed Citation Articles by Andreasen, J. J. Articles by Nielsen, C. Related Collections Cardiac - other Coronary disease