Asian Cardiovasc Thorac Ann 2007;15:313-319
© 2007 Asia Publishing EXchange Ltd
Tranexamic Acid and Primary Coronary Artery Bypass Surgery: a Prospective Study
Madan M Maddali, MD,
Muthukkumar C Rajakumar, MCh
Departments of Anesthesia and Cardiothoracic Surgery, Royal Hospital, Muscat, Oman
For reprint information contact:Madan M Maddali, MD Tel/Fax: 968 2459 0192 Email: madan{at}omantel.net.om, Royal Hospital, PB No. 1331, PC: 111, Seeb, Muscat, Sultanate of Oman.
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ABSTRACT
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Tranexamic acid was used to reduce postoperative drainage and allogenic blood transfusion requirements in patients undergoing on-pump primary coronary bypass surgery. Over 12 months, 222 patients participated in this prospective, randomized, placebo-controlled, double-blind study conducted at a tertiary center. Half of the patients were randomly allocated to receive tranexamic acid as a bolus (10 mg·kg–1) prior to sternotomy, followed by an infusion (1 mg·kg–1·hr–1) up to the time of starting of protamine. The other 111 patients received a saline bolus and infusion. Postoperative drainage and transfusion requirements were measured in all patients. Markers of graft patency, hemostasis, hemodynamic stability, and fibrinolysis were evaluated. Chest closure time, renal function parameters, allergic reactions, incidence of stroke, re-exploration, and hospital mortality were also noted. Postoperative drainage was significantly less and blood conservation considerably better when tranexamic acid was used. Post-bypass hemostasis was achieved faster, fibrinolysis was less, and there was no evidence of increased incidence of graft occlusion in the group given tranexamic acid.
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INTRODUCTION
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One of the main causes of postoperative morbidity in cardiac surgical patients is excessive bleeding requiring transfusion of blood components after cardiopulmonary bypass (CPB).1 Thrombin generation occurs during CPB despite systemic heparinization.2 This leads to generalized fibrinolysis during and immediately after CPB, with deleterious effects on platelet function. Increased fibrinolytic activity and platelet dysfunction are important causes of postoperative bleeding. Antifibrinolytic drugs are used to prevent platelet dysfunction and decrease perioperative bleeding. Varying results in terms of perioperative blood loss and blood transfusion requirements in different clinical settings have been described with the use of tranexamic acid (TA). This synthetic antifibrinolytic drug acts by forming a reversible complex with plasminogen and plasmin through the lysine-binding sites, blocking interaction with the specific lysine residues of fibrin. This retards fibrinolysis because although plasmin is still formed, it is unable to bind to fibrin.3 Tranexamic acid also preserves platelet function by reducing the effect of plasmin on platelet glycoprotein 1b receptors. The primary objective of this study was to determine the effectiveness of TA in reducing postoperative drainage in patients undergoing primary, elective, on-pump coronary artery bypass grafting (CABG).
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PATIENTS AND METHODS
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A prospective, randomized, placebo-controlled, double-blind trial was designed to determine the hemostatic and antifibrinolytic effects of TA in CABG. After approval by the hospital ethics committee, 222 patients undergoing primary nonemergency CABG, who gave written informed consent, were enrolled between December 1st 2004 to end November 2005. Randomization was based on a computer-generated code and sequentially numbered, sealed, opaque envelopes opened by a nurse in the operating room. This ensured that only the nurse who prepared the infusions knew whether a patient received the drug or placebo. Staff in the operating room and in the post-cardiac surgical unit were not aware of the treatment. Patients requiring concomitant noncoronary procedures and those with a history of bleeding diathesis or known coagulation factor deficiency were excluded from the study. Further exclusion criteria were left ventricular ejection fraction < 40%, coagulopathies (elevated prothrombin time with international normalized ratio > 1.2, activated partial thromboplastin time > 40 sec, platelet count < 100 x 109/L), plasma creatinine > 200 µmol·L–1, hepatic dysfunction, preoperative hemoglobin < 10 g·dL–1, antiplatelet drug treatment within 7 days of surgery, and known allergy to TA. Demographic data and operative characteristics were recorded. Preoperative laboratory tests included hemoglobin (Hb), prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, platelet count, renal (urea and creatinine), and hepatic parameters (total bilirubin, total protein, albumin, globulin, alanine aminotransferase, alkaline phosphatase).
Half of the patients (TA group) received an intravenous loading dose of 10 mg·kg–1 TA (Cyklokapron 100 mg·mL–1, Pharmacia Ltd., UK) before the skin incision, followed by a continuous infusion of 1 mg·kg–1·hr–1 until commencement of protamine reversal after separation from CPB. The other 111 patients (control group) received a bolus and continuous infusion of normal saline. Demographic data and operative characteristics were similar in both groups (Table 1
). Aspirin was discontinued before surgery (median, 7 days), and no patients were on preoperative heparin, ticlopidine, clopidogrel, or nitroglycerine infusion. The anesthetic protocol consisted of intravenous thiopental, fentanyl citrate, midazolam, and pancuronium bromide in body weight-related doses. Maintenance of anesthesia was with propofol, fentanyl, and isoflurane, with standard monitoring: 5-lead electrocardiogram (EKG) with ST-segment monitoring, pulse oxymetry, end-tidal CO2, nasopharyngeal and skin temperatures, urine output, invasive arterial pressure and Swan Ganz catheter measurements. Cardiopulmonary bypass was instituted with a 1,500 mL crystalloid priming volume and mild hypothermia (32°C) with a Trillium Affinity NT oxygenator (Medtronic Inc, Minneapolis, MN, USA) and a Sarns CPB machine (Sarns, Ann Arbor, MI, USA) at a flow rate of 2.6 L·min–1·m–2. Myocardial protection was achieved with cardioplegia delivered at 20°C in a 4:1 ratio of blood and St. Thomas’ Hospital solution (Martindale Pharmaceuticals, Essex, UK) using a MYOtherm XP 41B cardioplegia delivery system (Medtronic Inc, Minneapolis, MN, USA). During CPB, homologous donor packed red blood cells were transfused if the patient’s Hb was < 6 g·dL–1. Systemic heparinization was carried out before CPB with unfractionated heparin at an initial dose of 300 IU·kg–1. A Celite activated clotting time (ACT) 
480 sec was targeted. This was achieved with additional heparin doses of 100 IU·kg–1 if necessary. The effect of heparin was reversed at the end of CPB with protamine.
Cardiopulmonary bypass data including ACT, heparin dose needed for an ACT 480 sec, total heparin, total protamine used to normalize the ACT, heparin: protamine ratio, CPB time, aortic cross clamp time, and chest closure time (from separation from CPB to sternal approximation) were recorded. Activated clotting time was measured before and after heparin administration, every 30 min during CPB, and after protamine infusion. Immediately on reaching the post-cardiac surgical unit, the coagulation assessment was repeated. Postoperative bleeding, total transfusions (packed red blood cells and blood products), and fibrinolytic activity (crosslinked D-dimer level) were assessed. Re-exploration was performed if bleeding was > 200 mL·hr–1 for 6 hr consecutively or > 400 mL during the first hour. The cause of bleeding was documented. All blood and blood products given during the entire hospital stay were recorded. We did not use a cell saver perioperatively. Markers of perioperative myocardial infarction (MI) were assessed on reaching the post-cardiac surgical unit, 6 and 24 hr later: new persistent Q waves in more than 2 leads on serial EKG recordings, elevated cardiac troponin T levels, and signs of hemodynamic instability as reflected in increased inotropic requirements or need for intra-aortic balloon counter pulsation. Other clinical outcomes analyzed were re-exploration, postoperative renal insufficiency (plasma creatinine > 200 µmol·L–1), drug reactions (anaphylaxis, convulsions, and gastrointestinal tract complications), convulsive seizures, stroke (defined as hemiparesis, hemiplegia, aphasia, or confusion and disorientation), and hospital mortality.
Continuous numeric data are presented as mean ± standard deviation and [median]. The data were analyzed using the 2-tailed paired samples t test. A value of p < 0.05 was considered significant (95% confidence interval). The sample size calculation was based on retrospective data from our institution, showing that 100 consecutive patients undergoing elective primary CABG had a median total postoperative blood loss of 1,000 mL, and were transfused with a median 1,085 mL of allogenic blood. The primary endpoint was to reduce the postoperative drainage by 30%. To achieve this, a minimum sample size of 74 patients was needed in each group (type 1 error: 5%, variance error: 1). All 222 patients completed the study according to the protocol and were considered for statistical analysis. Data were analyzed using the commercial statistical package SPSS for Windows, version 11.0 (SPSS, Inc., Chicago, IL, USA).
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RESULTS
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All patients survived the procedure and none exhibited any allergic or anaphylactic reactions, stroke, or permanent myocardial ischemic changes. The preoperative and immediately postoperative hematological values were comparable between the groups (Table 2). The postoperative crosslinked D-dimer levels were elevated in both groups, but more so in the control group. The baseline preoperative hepatic parameters were normal in both groups. The pre- and postoperative renal parameters were within the normal range in both groups. However, the median creatinine value in the TA group, although within normal limits, was elevated significantly (Table 3). The baseline and final ACT achieved, CPB time, and aortic cross clamp time were comparable in both groups (Table 4). The dose of heparin to achieve the target ACT of 480 sec was significantly higher in the TA group, as well as the total heparin administered to each patient. The heparin: protamine ratio was similar in both groups.
The chest closure time was significantly longer in the control group. The volume of blood drained via mediastinal and pleural drains from chest closure until chest tube removal represented total blood loss. Administration of allogenic blood depended on postoperative drainage, hemodynamic, and laboratory data. Postoperatively, packed red blood cells were transfused if the patient’s Hb was < 8 g·dL–1; those aged > 70 years were transfused when Hb was < 10 g·dL–1. Fresh frozen plasma was transfused when the postoperative international normalized ratio was > 1.5 or with bleeding > 200 mL·hr–1 for 2 consecutive hours. The criteria for platelet transfusion were postoperative platelet count < 50 x 109/L and bleeding > 200 mL·hr–1 for 2 consecutive hours, or if the Sonoclot results (Sonoclot Analyzer; Sienco, Inc., Morrison, CO, USA) were abnormal. The total postoperative drainage and transfusion requirements were considerably lower in the TA group, although chest tube removal times were similar in both groups (Table 5). In the TA group, 7 patients exhibited ST-segment elevation (leads II, III, and aVF) in the EKG recorded on reaching the post-cardiac surgical unit. In the control group, 6 patients exhibited ST-segment elevation, and 3 had ST-segment depression (leads II, III, and a VF). All were short-lived and subsided spontaneously with no alteration in hemodynamic support or recourse to additional measures. Transesophageal echocardiography in these patients did not reveal any new areas of hypokinesia or akinesia when compared to the preoperative workup. Troponin T was elevated in both groups for 24 hours postoperatively (Table 6). Inotropic usage was similar in both groups (85% in the TA group vs. 89% in the control group). The most frequently used inotrope was adrenaline, at comparable doses in both groups (TA group, 0.07 ± 0.06 [0.02] µg·kg–1·min–1; control group, 0.06 ± 0.05 [0.02] µg·kg–1·min–1). The median duration of inotropic usage was also similar in both groups (TA group, 25th to 75th percentile: 550–670 min [600 min]; control group, 25th to 75th percentile: 590–670 min [625 min]). Postoperative intra-aortic balloon counter pulsation support was not required in any patient. Three patients in each group were re-explored for bleeding; a surgical cause was found in all except one in the control group who had generalized oozing.
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DISCUSSION
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We chose patients undergoing primary CABG for this study for two reasons. Firstly, our institution is the only tertiary cardiac care center in the country and we have several surgeons at various stages of expertise and training performing primary CABG. This might be the reason for the high postoperative drainage and transfusion requirements, as per our pilot study. Secondly, this type of surgery does not usually involve excessive blood loss. Patients at particularly high risk of postoperative bleeding were excluded from the study. The extensively studied antifibrinolytic drug aprotinin is efficacious but expensive, and can be associated with anaphylactic reactions on re-exposure, making it unsuitable for routine use in first-time procedures that are usually associated with the lowest risk of excessive postoperative blood loss. In addition, there is a suggestion that continued use of aprotinin is not prudent as it is associated with serious end-organ damage.4 The Food and Drug Administration issued a Public Health Advisory on February 8, 2006, alerting that aprotinin has been linked to higher risks of serious side effects including renal problems, myocardial events, and strokes in patients undergoing CABG. Neither of the alternative blood-sparing drugs, epsilon aminocaproic acid (EACA) and TA, is associated with increased risk of such events.4 TA has greater efficacy, a longer half-life, stronger plasminogen binding, and a more sustained antifibrinolytic effect than EACA.5 Hence, TA was evaluated in our clinical setting. We initiated TA therapy before skin incision because after incision there is a rapid release of tissue plasminogen activator with subsequent fibrinolysis.6
The ideal dosage of TA remains controversial. The dosage in this study was that used by Horrow and colleagues.7 The use of a bolus followed by a maintenance infusion addresses the fast metabolism of TA (half-life, 80 min) and prolongs its efficacy.3 Fiechtner and colleagues8 reported that this dosing regimen results in adequate plasma concentrations to prevent fibrinolysis, with relatively stable drug levels throughout CPB. A recent study showed that this dosage reduces postoperative bleeding.9 We discontinued TA infusion on starting heparin reversal with protamine because it has been shown that antifibrinolytic treatment during the postoperative period does not necessarily reduce postoperative bleeding.10 We demonstrated that patients who were treated with TA had significantly less postoperative bleeding and less need for blood and blood products compared to those who received a placebo. The same team of surgeons with various skill levels was involved in both groups. We therefore deduce that TA was responsible for the decreased postoperative blood loss. These findings are consistent with other reports that illustrate the efficacy of TA in reducing blood loss after primary cardiac surgery.11,12 However, it is essential to mention that pharmacological aids such as TA and aprotinin are only additional tools to reduce blood loss. The achievement of adequate surgical hemostasis continues to be of utmost importance, especially when groups of surgeons with varied experience operate.
Fibrinolysis has long been considered important in postoperative bleeding, and D-dimer concentration is accepted as a sensitive quantitative measure of fibrinolysis.6 The D-dimer assay detects a plasmin-derived proteolytic fragment of crosslinked fibrin released by fibrinolytic activity. A recent study demonstrated that TA is effective in reducing bleeding through the prevention of fibrinolysis in patients undergoing CABG with or without CPB.13 In the present study, crosslinked D-dimer levels were elevated following CPB in both groups, as expected, but the levels were lower in the TA group, confirming that TA inhibited intraoperative fibrinolysis. As TA is eliminated primarily via glomerular filtration, and as > 95% of the dose is excreted in the urine unchanged within 24 hr, we measured renal parameters in both groups. The post-CPB creatinine values in the TA group were significantly elevated although still within the normal range. This possibly indicates that one should be careful in administering TA to patients with renal insufficiency, or at least adjust the dose of TA. The initial mean dose of heparin for achieving an ACT 480 sec was significantly higher in the TA group. As unfractionated heparin acts primarily through antithrombin III, we suspect that TA in some way lowered antithrombin III activity; this is the subject of an ongoing study in our unit.
Chest closure time may be affected by factors such as hemodynamic stability, quality of the bone, and experience of the surgeons. These confounding factors were similar in both groups, and we consider chest closure time to be an indicator of hemostasis. Thus the shorter closure time in the TA group indicates faster achievement of hemostasis. Strategies of antifibrinolytic use to improve hemostasis during cardiac surgery may result in an increased risk of MI. Aprotinin has been investigated thoroughly in this regard. A meta-analysis suggested a nonsignificant increase in perioperative MI (8% vs 5.6%) when aprotinin was used.14 The occurrence of MI was 8.1% in patients treated with the conventional (high) dose of aprotinin compared with 3.9% in patients given lower doses.15 A multicenter study of coronary graft patency in patients having primary CABG reported that aprotinin may adversely affect vessel patency in those with poor quality primary distal target vessels.16 On the other hand, a meta-analysis by Levi and colleagues15 suggested that treatment with lysine analogs, such as TA and EACA, tended to decrease the frequency of perioperative MI. Therefore, TA appears to be benign in this respect, with no greater incidence of thrombotic events.3 The low risk of intravascular thrombosis with TA may be important in patients undergoing CABG with a newly vascularized myocardium.
The study has certain limitations. It is not a retrospective multicenter analysis including centers with various experiences. Markers for thrombin generation were not measured. The study is not sufficiently powered to determine differences in complications with low occurrence rates, such as graft occlusion, stroke, or infection. Postoperative coronary angiography or contrast-enhanced computed tomography was not carried out to assess the patency of grafts. It might be a criticism of this study that the markers of graft patency (ECG, troponin T levels, and hemodynamic stability) are in fact markers of perioperative myocardial damage. As both groups were closely matched in all respects, and echocardiography was performed to rule out perioperative MI, we suggest that these markers reflected graft adequacy. It is commonly assumed that Q waves on the EKG indicate major myocardial tissue damage. The appearance of new Q waves in more than 2 leads has been considered the most reliable criterion for diagnosis of perioperative MI. After on-pump CABG, the generally applied troponin discriminator limits are not valid because there is inevitable cardiac tissue damage during the surgical procedure. There is a strong correlation of CPB and aortic cross clamp times with troponin T levels.17 Even after uncomplicated cardiac surgery, a moderate increase of cardiac troponin T may occur, which may not reflect severe cardiac injury.18 However, perioperative MI can be reliably identified using the peak troponin concentration and the time of peak value. Studies have suggested troponin T levels of 3–3.5 ng·mL–1 indicate perioperative MI.19,20 None of our patients attained a level of 3 ng·mL–1. Seven patients in the TA group and 9 in the control group had ST-segment changes in the immediate postoperative ECG, mainly in the inferior leads. No patient in either group had a Q wave on the EKG. The requirements for inotropic support were similar in both groups, and no patient needed a ventricular assist device. Despite the fact that neither coronary angiogram nor high-resolution computed tomography was performed, we conclude on the basis of surrogate markers, as well as echocardiographic evidence, that there was no evidence of graft inadequacy. As the ST-segment changes did not produce any hemodynamic changes, we presume that they were due to less than optimal graft de-airing procedures prior to separation from CPB, or displacement of debris that could have migrated into the right coronary artery distribution area. There were no untoward reactions in either group and no difference in terms of other complications.
It was concluded that intraoperative use of TA in patients undergoing CABG with CPB is effective in reducing postoperative blood loss, need for allogenic blood transfusions, and fibrinolysis. Surgical hemostasis is achieved sooner. Cardiac troponin T was elevated in both groups as would be expected after aortic cross clamping, cardioplegic arrest, and handling of the heart on CPB, but did not reach levels that would indicate graft occlusion resulting in perioperative MI. There was no ECG evidence of perioperative MI. Thus it is presumed that there was no increased incidence of graft occlusion with TA. As there was an elevation of serum creatinine, albeit within the normal range, and as TA is excreted mainly through the kidneys, a large prospective randomized clinical trial is needed to confirm the absolute safety of tranexamic acid in patients with borderline renal failure.
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ACKNOWLEDGMENTS
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We acknowledge the support of Dr. Roger Green, FRCS, in the preparation of the manuscript. We thank Mr. Nasser Masoud Hammad Al-Khayari, Senior Health Information Supervisor, Quality Assurance Office, Royal Hospital, Muscat, for the statistical support extended to us.
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REFERENCES
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- Kojima T, Gando S, Kemmotsu O, Mashio H, Goda Y, Kawahigashi H, et al. Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001;15:60–4.[Medline]
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ABSTRACT
INTRODUCTION
