Ann Thorac Surg 2001;71:1508-1511
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
Is tranexamic acid safe in patients undergoing coronary endarterectomy?
Marc A. Ruel, MDa,
Feng Wang, MDa,
Michael E. Bourke, MDa,
Jean-Yves Dupuis, MDa,
James A. Robblee, MDa,
Wilbert J. Keon, MDa,
Fraser D. Rubens, MDa
a Department of Surgery and Anesthesia, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
Accepted for publication January 13, 2001.
Address reprint requests to Dr Rubens, H211, 40 Ruskin St, Ottawa, Ontario, KIY 4W7 Canada
e-mail: frubens{at}ottawaheart.ca
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Abstract
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Background. Patients undergoing coronary endarterectomy during coronary artery bypass grafting (CABG) are at increased risk of perioperative myocardial infarction due to coronary intimal disruption. Data assessing the safety of the antifibrinolytic drug tranexamic acid (TA) in patients undergoing this procedure are lacking.
Methods. From September 1997 to December 1999, 221 patients underwent nonemergency primary CABG with endarterectomy of the right coronary artery alone in 149, the left anterior descending in 35, or both right and left anterior descending in 27. TA was administered intraoperatively to 87 patients (TA group: average total dose 62 ± 4.4 mg/kg; range 20 to 109 mg/kg), and was not administered to 134 patients (No TA group).
Results. The patient characteristics of the 2 groups were similar. In-hospital mortality consisted of 2 patients in the TA group and 4 patients in the No TA group. Perioperative myocardial infarction rates were 2% and 5% in the TA and No TA groups, respectively (p = 0.49). The relative risk for any type of perioperative cardiac ischemic event in the TA group versus the No TA group was 0.77 (95% CI; 0.4, 1.2). Patients in the TA group had a significant reduction in postoperative chest tube drainage (685 versus 894 mL in the TA versus No TA groups, respectively) and in the use of fresh-frozen plasma (p = 0.03).
Conclusions. These results suggest that the clinical effectiveness of tranexamic acid in reducing postoperative blood loss in patients undergoing coronary endarterectomy is not associated with a higher incidence of myocardial ischemia-related complications.
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Introduction
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As progressively sicker patients are being referred for coronary artery bypass grafting (CABG), more patients are seen with diffuse coronary disease not amenable to conventional distal anastomotic techniques. Coronary endarterectomy remains a major adjunct in achieving complete revascularization of these challenging patients [1, 2]. However, endarterectomy leaves a disrupted arterial surface that rapidly becomes covered by a fibrin-platelet layer, potentially leading to thrombotic occlusion of the lumen [3]. As a result, this procedure has been associated with an increased incidence of perioperative myocardial infarction, low cardiac output syndrome, and graft occlusion [4–7].
Tranexamic acid (TA) is an antifibrinolytic agent commonly employed to reduce blood losses and transfusion requirements after cardiopulmonary bypass. Its efficacy has been demonstrated with several dose regimens, and many centers now routinely use the drug [8–12]. However, controversy remains regarding the safety of this group of drugs during cardiac surgery as they may potentiate the risk of coronary and renal vascular thrombosis [11, 12]. Adding to these concerns is the difficulty in predicting preoperatively which patients actually need to undergo coronary endarterectomy, with TA being administered prior to arteriotomy and definitive coronary assessment. This study was therefore undertaken to ascertain whether the use of TA in patients undergoing coronary endarterectomy would significantly increase the incidence of perioperative cardiac complications, thereby reflecting the risk of graft or coronary thrombosis [13].
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Patients and methods
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Patients
From September 1997 to December 1999, 294 patients underwent coronary endarterectomy at the University of Ottawa Heart Institute. Patients having emergency, redo, or combined procedures, as well as patients on intraaortic balloon pump (IABP) or with acute cardiac ischemia preoperatively were excluded from the series. A total of 221 patients were included in the study (Table 1). Left ventricular functional class and Adult Cardiac Care Network of Ontario risk score were determined preoperatively [14, 15]. Data were entered prospectively into a dedicated computerized database and analyzed retrospectively. The study’s methods were approved by the Ottawa Heart Institute Research Ethics Committee for the ongoing analysis of quality of care.
Operative procedures
All procedures were conducted using standard techniques of CABG and coronary endarterectomy [1]. Eighty-seven patients received tranexamic acid at a mean total dose of 62 ± 4.4 mg/kg (range 20 to 109 mg/kg) prior to median sternotomy. The choice of whether to administer TA or not was left to the anesthesiologist and not randomized; this choice was based on personal preferences and was not influenced by intraoperative factors. Each anesthesiologist rotated with different surgeons in a random fashion throughout the study period.
Antegrade cold crystalloid cardioplegia was used in all cases. Coronary endarterectomy was performed on dominant right coronary (RCA) or left anterior descending (LAD) arteries that were either totally occluded or diffusely atherosclerotic with an outflow caliber of 1 mm or less. RCA endarterectomies were initially attempted in a closed fashion and converted to an open approach if tapered ends that included the origins of both posterior descending artery and main left ventricular branches could not be extirpated [16]. LAD endarterectomies were either initiated in an open fashion or routinely converted if the involved diagonal and septal branches were not satisfactorily included in the specimen. Open endarterectomies were roofed using either the widely spatulated end of the bypass conduit or with the addition of a patch arterioplasty consisting of saphenous vein material [16]. The relative frequencies of use of each endarterectomy and reconstruction techniques are found in Table 2.
Postoperative management
Acetylsalicylic acid 650 mg PR was administered to all patients once chest tube output was 50 mL/h or less. Patients who underwent open RCA or LAD endarterectomies also received intravenous dipyridamole at 10 mg/h, which was discontinued on the 1st postoperative day.
Outcome measures
The study’s primary end-point was the incidence of early postoperative cardiac events (PCE). These include: (1) Electrocardiographic (ECG) evidence of myocardial infarction (defined as new Q-waves or loss of R-wave progression); (2) biochemical evidence of myocardial infarction (defined as peak serum troponin-T > 1.5 µg/L or peak serum creatine kinase-MB fraction [CK-MB] level >70 µg/L with MB fraction 
5%); (3) low cardiac output syndrome (defined as the need at any time for inotropic or IABP support to treat a cardiac index 
2.0); and (4) ventricular fibrillation or tachycardia requiring treatment. Serum markers for myocardial damage were measured 6, 18, and 48 hours after operation, using an Abbott’s AxSYM analyzer (Abbott, Mississauga, Canada) for creatine kinase-MB isoenzymes and a third generation Roche’s Elecsys assay for troponin-T (Roche, Laval, Canada). Electrocardiograms were taken preoperatively, after arrival to the intensive care unit (ICU), and on the first 2 postoperative days. Secondary end-points consisted of in-hospital mortality, ICU and hospital lengths of stay, cumulative 12-hour chest tube losses, blood product transfusions, reopening rates, and postoperative increases in serum creatinine (SCr) levels (defined as [maximum postoperative SCr–preoperative SCr] x 100%/preoperative SCr).
Data analysis
Data are expressed as mean ± standard error of the mean. Analysis of normally distributed data was done with a two-tailed Student’s t test. A Wilcoxon log-rank test was used for blood loss and transfusion data. Categorical data were analyzed with a 
2 test or Fisher’s exact test when appropriate. A p value of less than 0.05 was considered statistically significant. The study sample size was sufficient to allow detection of a 1.5x relative risk for PCE in any group with a ß-error of less than 0.20 and a power greater than 80%.
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Results
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The 2 groups of patients had similar preoperative characteristics and risk-severity scores. There were no differences in operative data, including the number of grafts and types of endarterectomy as shown on Table 2. There were 6 in-hospital deaths (4 No TA, 2 TA, p = 0.76), 4 of which were of cardiac cause (3 No TA, 1 TA, p = 0.94). Incidences of postoperative cardiac events (PCE) are shown in Table 3. There was no difference in the incidence of myocardial infarction by ECG (p = 0.49) or biochemical criteria (p = 0.37), as well as in the overall likelihood of PCE between the 2 groups (p = 0.37). The relative risk of PCE in the TA group was 0.77 [95% CI; 0.4, 1.2], indicating the absence of a trend for patients in the TA group to experience more events.
Table 4 displays 12-hour chest tube losses, reopening rates, and transfusion data. Patients who received TA bled less (p = 0.006) and received significantly less homologous fresh-frozen plasma (p = 0.03). There was also a trend towards reduction in platelet use (p = 0.09), but no significant difference in reopening rates (p = 0.48) or in the overall incidence of transfusion (p = 0.32).
Postoperative increases in serum creatinine levels were not different between the 2 groups (6.7% versus 17.5% SCr increase in the No TA and TA groups, respectively; p = 0.18). Median ICU and hospital lengths of stay were also comparable (1.1 ± 0.6 and 6 ± 0.8 days versus 1.9 ± 0.2 and 7.7 ± 0.5 days in the No TA and TA groups; p = 0.21 and p = 0.42, respectively).
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Comment
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Coronary endarterectomy carries a well-recognized risk for early graft or coronary thrombosis that likely accounts for the vast majority of early graft failures [3, 17–19]. Consequently, increases in perioperative myocardial infarction rates are often seen when patients undergoing endarterectomy are compared with those having conventional CABG [4, 5, 7, 20, 21]. The use of an antifibrinolytic agent in patients undergoing this procedure could therefore promote thrombosis of the denuded arterial segment. This study was undertaken to evaluate the safety of tranexamic acid in this particular patient population.
In this study, intraoperative administration of tranexamic acid to patients undergoing coronary endarterectomy did not result in an increased incidence of perioperative myocardial infarction or other adverse cardiac events. Our perioperative myocardial infarction rates of 2% and 5% in the TA and No TA groups, respectively, are comparable to those reported in the literature after coronary endarterectomy [4, 5, 7, 21]. Nevertheless, TA exerted its expected antifibrinolytic effect by decreasing the total postoperative blood loss and the number of fresh-frozen plasma transfusions. These findings hence suggest that perioperative cardiac complications in patients undergoing coronary endarterectomy are not made more frequent by the intraoperative use of tranexamic acid.
Limitations of the study
To prove the safety of TA use, clinical outcomes should ideally be correlated to radiologic demonstration of graft patency. However, colleagues at our institution have previously demonstrated angiographically that perioperative myocardial infarction after CABG most commonly is secondary to graft occlusion [13]. In this regard, with the intent of increasing sensitivity for cardiac outcomes likely related to myocardial ischemia, events such as low cardiac output and ventricular tachyarrythmias requiring treatment were also included in the study’s primary end-points. To increase specificity, all patients with preoperative instability or ischemia, as well as those undergoing redo or combined procedures were excluded from the series.
This study only addresses short-term patient outcomes; however, it is unlikely that TA has a delayed influence on graft thrombosis or on the recurrence of myocardial ischemia. The study design was also nonrandomized, and despite the 2 groups of patients exhibiting similar preoperative characteristics and receiving identical care, the possibility remains that an unidentified confounding factor may have influenced results. One possible confounder was that some anesthetists at our institution use TA more frequently than others. They, however, rotated randomly with different surgeons throughout the study period, therefore limiting this possible confounding factor to individual anesthetist outcomes.
In this study, a reduction in the overall incidence of transfusions was not demonstrated but did not constitute one of its primary objectives, which instead focused on the cardiac and renal effects of tranexamic acid in this patient population particularly predisposed to thrombotic complications. Although a trend was noted, the study was not sufficiently powered to show a significant difference in the likelihood of transfusion, which has been relatively low at our institution despite the absence of strict transfusion guidelines.
Our findings therefore indicate that intraoperative use of tranexamic acid in patients undergoing coronary endarterectomy is safe and effective in reducing postoperative blood loss. Although we are encouraged by the apparent safety of tranexamic acid in patients undergoing coronary endarterectomy, we recognize the necessity for a prospective randomized trial to confirm these results and evaluate the cost-effectiveness of TA administration in this setting.
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Acknowledgments
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The authors extend their gratitude to Drs Daylily S. Ooi and John P. Veinot, Department of Laboratory Medicine, University of Ottawa, for their help in the conduct of the study.
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Abstract
Introduction
