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Anesth Analg 2003;96:923-928 © 2003 International Anesthesia Research Society
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Abstract |
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Tranexamic acid reduces postoperative bleeding after coronary artery bypass grafting. We evaluated the effects of a single dose of tranexamic acid given immediately before cardiopulmonary bypass (CPB) in patients treated with aspirin until the day before surgery. The study was a prospective, randomized, double-blinded, placebo-controlled, parallel-group trial. Eighty patients were included and divided into two groups: one group received tranexamic acid 30 mg/kg, and one group received placebo (0.9% NaCl) as a bolus injection before CPB. Postoperative blood loss was recorded for 16 h. Transfusions of blood products were recorded for the whole hospital stay. Transfusions of packed red cells were given when the hematocrit value was less than 20% during CPB and less than 25% after surgery. The patients in the tranexamic acid group had significantly less postoperative bleeding compared with the patients in the placebo group (mean [SD]) (475 [274] mL versus 713 [243] mL; P < 0.001). An effective inhibition of fibrinolysis was found in patients receiving tranexamic acid. Tranexamic acid reduces postoperative bleeding in coronary artery bypass grafting patients treated with aspirin until the day before surgery.
IMPLICATIONS: Continuation of aspirin medication until the day before coronary artery bypass grafting may increase postoperative bleeding. The administration of a single dose of tranexamic acid (30 mg/kg) immediately before cardiopulmonary bypass significantly reduced postoperative bleeding and inhibited fibrinolysis in these patients.
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Introduction |
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Most patients with ischemic heart disease are treated with antiplatelet medication, usually aspirin. Because platelet-active medication may increase postoperative bleeding (1–3) , aspirin therapy is often routinely terminated 1 wk before cardiac surgery. However, in many centers, aspirin is continued until surgery not only in patients with unstable angina, but increasingly also in patients with stable angina. Cardiopulmonary bypass (CPB) causes platelet dysfunction and increased fibrinolytic activity (1,4,5) . The additional effect of aspirin may cause excessive postoperative bleeding (1). Excessive bleeding and reexploration remains a major source of postoperative morbidity and mortality in cardiac surgery (6,7) . The risks of transfusion-related infections and immunological transfusion reactions, as well as the increased costs, also justify efforts to minimize blood loss after operations.
The release of plasmin during CPB (8) activates fibrinolysis and may contribute to platelet dysfunction (9). Pharmacological inhibition of the fibrinolytic system may therefore ameliorate platelet dysfunction and fibrinolysis after CPB and decrease postoperative bleeding. Tranexamic acid prevents plasmin formation and inhibits fibrinolysis (10). Several studies and metaanalyses have shown a reduction in postoperative bleeding and transfusion requirements of this antifibrinolytic drug (11–19) . Aspirin-treated patients were excluded from the investigation in one study (11). Some of the patients included in the other studies had been treated with aspirin before surgery (12–17) , but none of these studies included only aspirin-treated patients. In one study (14), patients were defined as being treated with aspirin if they had taken their last aspirin as long as 7 days before surgery. Other studies did not specify the time between the last aspirin and surgery. In this study, we investigated the effect of a single dose of tranexamic acid on postoperative bleeding and transfusion requirements in coronary artery bypass grafting (CABG) in patients treated with aspirin until the day before surgery.
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Methods |
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The study was a prospective, randomized, double-blinded, placebo-controlled, parallel-group trial. The study was conducted at St. Elisabeth Heart Clinic, which is a part of a 900-bed tertiary teaching hospital. Annually approximately 620 cardiac patients are operated on at the clinic, among them 450 for CABG. After approval of the Regional Committee for Medical Research Ethics, Health Region IV, Norway, 80 patients with stable angina pectoris scheduled for first-time CABG were included in the study after giving written, informed consent. All patients were asked to continue their aspirin medication until the day before surgery. Patients were excluded if they were receiving treatment with heparin or low-molecular-weight heparin, oral anticoagulants, nonsteroidal antiinflammatory drugs, or other platelet inhibitors.
The Unit for Applied Clinical Research at the Norwegian University of Science and Technology randomized the patients into two groups by means of a computer program: one group received tranexamic acid (Group T), and the other group received placebo (Group P). Tranexamic acid 100 mg/mL or placebo was prepared by the hospital pharmacy and delivered in identical 50-mL syringes. Group T received tranexamic acid 30 mg/kg as a bolus injection, and Group P received a bolus injection of the corresponding volume of a 0.9% sodium chloride solution. The injections were given over 5 min immediately before the start of CPB. Maintenance infusions of tranexamic acid or placebo were not given. A standard anesthetic technique with morphine and scopolamine for premedication and with fentanyl, thiopental, diazepam, and pancuronium for induction was used. Anesthesia was maintained with nitrous oxide (before CPB), isoflurane, and small additional doses of fentanyl as required (the total dose of fentanyl was approximately 10 µg/kg). During CPB, anesthesia was maintained with diazepam, midazolam, or both. Blood pressure was controlled with glyceryl trinitrate before and after CPB and with sodium nitroprusside during CPB. Before CPB, heparin 300 U/kg (Leo, Copenhagen, Denmark) was given through a central venous catheter to achieve a celite activated clotting time (ACT) (Hemocron 801; Techidyne Corp., Edison, NJ) of more than 480 s. The ACT was measured in duplicate, and the mean value was used. Additional heparin was given when needed to keep the ACT above the target. During CPB, the ACT was monitored every 20 min. The perfusion circuit was primed with 1800 mL of Ringer’s acetate solution, to which 7500 U of heparin was added. A membrane oxygenator without heparin coating was used. Cold crystalloid hyperkalemic antegrade cardioplegia (St. Thomas I, containing 20 mmol K+, 16 mmol Mg2+, 1.2 mmol Ca2+, and 1 mmol procaine) and moderate hypothermia to 34°C were used during CPB. Pump flow was 2.4 L/min/m2 during normothermia and 2.0–2.4 L/min/m2 at 34°C. The patient was warmed to a rectal temperature of at least 36°C before termination of CPB. After CPB, protamine sulfate 1 mg for every 100 U of previously administered heparin (prime heparin was not included) was given to achieve an ACT within 10% of the baseline value. Additional doses of protamine were given when necessary.
No attempts were made to measure blood loss during the operation. Cardiotomy suction was used while the patient was fully anticoagulated, and the blood was returned to the patient without centrifugation. Postoperative blood loss from the mediastinal and pleural drains was collected in a sterile cardiotomy reservoir and autotransfused to the patients for up to 8 h. Blood loss was recorded every 4 h for 16 h. Incidents of reexploration for bleeding were recorded. The criteria for transfusion of packed red cells were a hematocrit value less than 20% during CPB and less than 25% in the postoperative phase. Fresh-frozen plasma, platelets, and additional doses of tranexamic acid and desmopressin were given at the discretion of the attending physician when he or she considered this to be appropriate for the treatment of increased postoperative bleeding. We had no strictly defined criteria for this treatment, because it was considered not feasible in our everyday care for the patients. Transfusions and doses of tranexamic acid and desmopressin were recorded for the first 16 h and for the whole hospital stay. (The mean postoperative hospital stay after CABG at our institution is 6.7 days.)
Preoperative hemoglobin and plasma creatinine levels were recorded. Hematocrit, platelet count, international normalized ratio, activated partial thromboplastin time, fibrinogen, and D-dimer values were recorded before surgery and in the morning on the first postoperative day. D-dimer levels were considered negative when present in concentrations <0.5 mg/mL.
The sample size calculation was based on the findings of Horrow et al. (11). On the basis of a clinically relevant blood loss difference of 200 mL and an SD for blood loss of 300 mL, we determined a sample size of 40 patients in each group given 80% power and 
= 0.05.
Data are presented as means (SD) and medians (range). Statistical analyses were performed with the program package SPSS for Windows®, Version 11.0 (SPSS Inc., Chicago, IL). For comparative statistics, 
2 tests, the Mann-Whitney U-test, and Student’s t-test were used as appropriate. P values <0.05 were considered statistically significant.
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Results |
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Eighty patients were included in the study. One patient in the placebo group was excluded because a heparin-coated pump circuit was used. Baseline patient data and data on surgical procedures from the remaining 79 patients are presented in Table 1. There were no differences between the two groups with respect to previous diseases such as myocardial infarction, heart failure, diabetes, chronic obstructive pulmonary disease, peripheral vascular disease, cerebrovascular disease, or smoking habits. Preoperative medication, heart rate, and blood pressure did not differ between groups. The aspirin dose was either 75 mg (12 patients in Group T, 9 patients in Group P) or 160 mg (28 patients in Group T, 30 patients in Group P). There were no differences in the ACT values before heparin, after heparin, or after protamine and no differences in the total dose of heparin or the protamine dose given between the two groups (Table 2).
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The preoperative and postoperative laboratory test results are presented in Table 3. A significant difference in the postoperative D-dimer values between the two groups was observed (P < 0.001).
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The postoperative bleeding volumes are presented in Figure 1. There was a significant difference in total postoperative bleeding between the two groups (475 [269] mL versus 713 [243] mL; P < 0.001). All patients had mediastinal shed blood retransfused. The volume retransfused is presented in Figure 2. The placebo group had significantly more blood retransfused (566 [274] mL versus 356 [280] mL; P = 0.001). One patient in Group P bled 795 mL during the first 3 h and was reexplored. No surgical source of bleeding was found, and it was concluded that the patient had diffuse microvascular bleeding.
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There was no significant difference in the number of transfusions of blood products between the groups. Twenty percent of the patients in each group received at least one transfusion. Seven patients in Group T received a total of 13 U of packed red cells, whereas 8 patients in Group P received a total of 22 U (P = 0.60). In addition, one patient in both groups received 2 U of fresh-frozen plasma, and one patient in both groups received 2 U of platelets (from eight donors). The number of blood product donor exposures per patient was 0.57 in Group T and 0.82 in Group P (P = 0.88).
In the postoperative phase, tranexamic acid was given to two patients in Group T and five patients in Group P by the attending physician, whereas no patients in Group T and two patients in Group P also received desmopressin. Both drugs were given during the first four postoperative hours. Two of the patients in Group P who received tranexamic acid also received transfusions of packed red cells during the first 16 postoperative hours, and one patient had packed red cells later during the hospital stay. The remaining four patients did not receive packed red cells. These patients had large hematocrit values before surgery and did not reach the transfusion criterion despite increased postoperative bleeding.
One patient in Group P had a pulmonary embolism during the postoperative phase. The patient made a full recovery. No other thromboembolic complications were recorded, nor did the study patients experience any other major complications.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our results show that a single dose of tranexamic acid given before CPB significantly reduces postoperative bleeding in CABG patients treated with aspirin until the day before surgery. In previous investigations on the effect of tranexamic acid in cardiac surgery, the study drug was administered by a bolus injection followed by an infusion for several hours. Because fibrinolysis may start before CPB, previous investigators have chosen to give the bolus dose after the induction of anesthesia (11,14–17) . In contrast, our patients received a single bolus dose immediately before CPB. Despite these differences in the administration of tranexamic acid, we found a similar reduction in postoperative bleeding when compared with former studies (11,12,14,15) . Also, our findings on D-dimer values show that giving tranexamic acid immediately before CPB counteracts fibrinolysis to the same extent as in the studies in which tranexamic acid was given after the induction of anesthesia (11,14,15,17) .
Earlier investigations have shown that tranexamic acid must be given before CPB to exert a maximal reduction in postoperative bleeding (13,16) . However, predicting whether a particular patient will benefit from treatment is difficult. Others have investigated whether preoperative laboratory tests can be used to predict postoperative bleeding. Wahba et al. (20) found that a combination of laboratory testing for hyperfibrinolysis and platelet dysfunction was useful to predict abnormal bleeding. However, such tests are usually performed in the clinical chemistry department and may not be available at all times. Point-of-care tests for platelet dysfunction represent an interesting alternative in this respect, but published results have not been convincing (21). Waiting with the administration of tranexamic acid until immediately before CPB allows for the use of point-of-care tests into the early phase of surgery before deciding whether tranexamic acid should be given. Future studies should evaluate whether the use of such tests can provide additional information on whether a particular patient may benefit from tranexamic acid.
According to our routine, tranexamic acid and desmopressin were given as treatment for postoperative bleeding at the discretion of the attending physician. Two patients in Group T received tranexamic acid during the early postoperative phase. According to the study by Casati et al. (16), additional tranexamic acid given in the postoperative phase does not result in any further reduction in postoperative bleeding. Five patients in Group P received treatment with tranexamic acid during the early postoperative phase, and two of these patients were also treated with desmopressin. Because tranexamic acid was given to more patients in Group P than in Group T, a positive effect of this treatment would be a reduction in the difference in postoperative bleeding and postoperative D-dimer values between the two groups.
One patient in the placebo group had a pulmonary embolism. No other patients had severe thromboembolic complications. The possibility of thromboembolic complications and, in particular, graft occlusion with myocardial ischemia and infarction caused by tranexamic acid, must be considered when giving this drug to these patients. Several publications have focused on this issue (18,19,22,23) . There is no available evidence that prophylactic use of tranexamic acid causes graft occlusion or other thromboembolic complications. Future studies on the use of tranexamic acid in cardiac surgery should systematically record postoperative myocardial ischemia and infarction. However, it is important to be aware that controlled clinical studies are not suitable for detecting infrequent adverse drug reactions (24).
The patients in the tranexamic acid group bled less after surgery and had a smaller volume of blood retransfused than the patients in the placebo group. Although they also had a numerically smaller number of units of packed red cells, this difference was not statistically significant. One important reason for this could be that our study was not primarily powered to show a difference in transfusion requirements. However, other factors may also have influenced this finding. The patients underwent first-time CABG and were in a relatively good condition (ejection fraction, >60%) before surgery, conferring to them a decreased risk for postoperative bleeding and other adverse outcomes. The retransfusion of mediastinal shed blood and the transfusion criterion permitting transfusion of packed red cells only when the hematocrit was less than 25% also may have decreased the total transfusion requirements.
Because our study was not powered to show small, but clinically significant, differences in transfusion requirements, there may still be a positive effect of tranexamic acid. Because we were unable to demonstrate such a difference and because there are some concerns about the safety of the drug, prophylactic treatment with tranexamic acid cannot be recommended for all patients. A study by Dacey et al. (25) shows that age, body-surface area, CPB time, and the number of distal anastomoses are significantly associated with rates of reexploration for hemorrhage. The authors conclude that for patients at risk, the surgeons should have low thresholds to initiate pharmacological therapy that could reduce postoperative bleeding. Moreover, patients who are reexplored often receive several transfusions of blood products. Because prophylactic treatment with tranexamic acid reduces postoperative bleeding, one may speculate that it could also reduce the total number of transfusions given to patients who are at increased risk of bleeding compared with patients included in this study. Future studies should focus on the effect of tranexamic acid in groups of patients treated with aspirin who are at increased risk of postoperative bleeding, such as those undergoing combined procedures and reoperative cardiac surgery.
In summary, we have shown that tranexamic acid given as a single bolus dose before the start of CPB reduces postoperative bleeding in first-time CABG patients treated with aspirin until the day before surgery.
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Acknowledgments |
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The authors would like to express their thanks to the Unit for Applied Clinical Research at the University of Trondheim for help with the randomization procedure, to Arne Krogstad for clinical assistance, and to Olav Spigset for methodological and statistical advice.
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References |
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- Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990; 76: 1680–97.
[Abstract/Free Full Text] - Gibbs NM, Weightman WM, Thackray NM, et al. The effects of recent aspirin ingestion on platelet function in cardiac surgical patients. J Cardiothorac Vasc Anesth 2001; 15: 55–9.[Web of Science][Medline]
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[Abstract/Free Full Text] - Moulton MJ, Creswell LL, Mackey ME, et al. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996; 111: 1037–46.
[Abstract/Free Full Text] - Rijken DC, de Munk GA, Jie AF. Interaction of plasminogen activators and plasminogen with heparin: effect of ionic strength. Thromb Haemost 1993; 70: 867–72.[Medline]
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[Abstract/Free Full Text] - Brown RS, Thwaites BK, Mongan PD. Tranexamic acid is effective in decreasing postoperative bleeding and transfusions in primary coronary artery bypass operations: a double-blind, randomized, placebo-controlled trial. Anesth Analg 1997; 85: 963–70.[Abstract]
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- Wahba A, Rothe G, Lodes H, et al. Predictors of blood loss after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 1997; 11: 824–7.[Medline]
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- Ruel MA, Wang F, Bourke ME, et al. Is tranexamic acid safe in patients undergoing coronary endarterectomy? Ann Thorac Surg 2001; 71: 1508–11.
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