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Ann Thorac Surg 2004;78:1536-1541
© 2004 The Society of Thoracic Surgeons
a Division of Cardiac Surgery, London Health Sciences Centre, London, Ontario, Canada
b Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada
Accepted for publication March 8, 2004.
* Address reprint requests to Dr Quantz, Division of Cardiac Surgery, University Campus, LHSC, Room 6OF3, 339 Windermere Rd, London, Ontario N6A 5A5, Canada
maquantz{at}uwo.ca
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsCommentReferences |
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METHODS: Data were collected prospectively on 312 consecutive urgent or emergent coronary artery bypass patients from July 1999 through April 2001 at a tertiary care center. Patients were stratified into three groups: clopidogrel within 4 days of operation (n = 41), clopidogrel continued until 5 to 8 days before operation (n = 39), and clopidogrel discontinued more than 8 days before operation or were never taking clopidogrel (n = 232).
RESULTS: Preoperative and intraoperative characteristics were similar among all groups. Mediastinal and pericardial chest tube losses in the first 24 hours were 1,044 ± 750 mL in the clopidogrel within 4 days group, 528 ± 250 mL in the clopidogrel 5 to 8 days group, and 573 ± 329 mL in the clopidogrel more than 8 days group (p < 0.01). The mean total blood product transfusions were 12.2 ± 15.4 U, 1.2 ± 2.0 U, and 2.6 ± 5.7 U, respectively (p < 0.001). Reoperation for bleeding was noted in 14.6%, 2.6%, and 1.7%, respectively (p = 0.002). The median hospital lengths of stay for the three groups were 9 days, 7 days, and 7 days, respectively (p = 0.018). There were no statistically significant differences in mortality rate, myocardial infarction, stroke, mediastinitis, or postoperative renal failure among the groups. Multivariable analysis revealed that clopidogrel within 0 to 4 days of operation was an independent predictor of transfusion requirements (OR 4.22, 95% confidence interval [CI] 2.07, 9.34, p = 0.001), intensive care unit (ICU) length of stay (OR 3.14, 95% CI 1.40, 7.04, p = 0.006), and total hospital length of stay (coefficient 7.65, se 2.41, p = 0.002).
CONCLUSIONS: Clopidogrel within 4 days of coronary bypass surgery is associated with increased blood losses and reoperation for bleeding and, according to multivariable models, is an independent risk factor for increased transfusion requirements and prolonged ICU and hospital length of stay.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Significant morbidity and mortality can arise from uncontrolled postoperative blood loss [2]. Blood transfusions are frequently required not only to replace hemoglobin losses but also to replenish coagulation factors and functioning platelets. Use of antifibrinolytic agents has been shown to decrease the amount of bleeding after cardiac surgery [3]. Reoperation for bleeding is required in approximately 2% to 3% of cases of coronary artery bypass grafting (CABG) and only 50% of the time is an identifiable cause found [2, 4]. Persistent bleeding may lead to disseminated intravascular coagulopathy, hemodynamic instability, and death.
Platelet function is integral to hemostasis in the early postoperative period [5, 6]. Preoperative antiplatelet agents have the potential to deliver an additional insult to already dysfunctional platelets. These agents should be discontinued at the appropriate time to ensure adequate platelet function at time of operation. However, ongoing ischemia may necessitate continuation of these antiplatelet agents. Although controversial, preoperative aspirin may have a small effect to enhance postoperative bleeding but it does not affect transfusion rates [7, 8]. Glycoprotein IIb/IIIa inhibitors in the setting of cardiac surgery can cause a significant coagulopathy if received within the immediate preoperative period [9, 10]. Clopidogrel (CL), a thienopyridine, is an inhibitor of platelet aggregation that works by irreversible blockade of adenosine diphosphate (ADP) mediated platelet activation. It has been demonstrated to reduce early stent failure [11], improve outcome after acute coronary syndromes [12], and decrease all cause combined cardiovascular mortality [13]. As a result, more patients are undergoing urgent or emergent CABG while under the influence of clopidogrel. However, the effect of clopidogrel on postoperative bleeding in coronary artery bypass surgery has not yet been fully investigated. Our a priori hypothesis was that the immediate preoperative use of clopidogrel would be associated with an increased incidence of postoperative bleeding, concomitant with increased intensive care unit (ICU) and hospital lengths of stay.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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The patients were subdivided into three groups: clopidogrel discontinued 0 to 4 days before operation (CL 0 to 4, n = 41), clopidogrel discontinued 5 to 8 days (CL 5 to 8, n = 39) before operation, and clopidogrel discontinued greater than 8 days before operation or were not taking the medication (CL > 8, n = 232). The subdivision at 8 days was chosen based on the length of activity of clopidogrel, which permanently inactivates platelet function for the lifespan of the platelet. We further subdivided the group with a clopidogrel effect into 0 to 4 days and 5 to 8 days to try to identify if a difference exists depending on timing and drug clearance. Although some have suggested a dose related response [12], we did not subdivide patients by loading or maintenance dosages, as we felt that even a 75 mg dose was sufficient to cause postoperative bleeding complications.
Statistical analysis was carried out using GraphPad Prism version 2.1 (San Diego, CA) and SAS version 8.2 (Cary, NC). Categorical variables were evaluated using 
2 analysis or Fischer's exact test. Depending on the distribution, continuous variables were analyzed using analysis of variance (ANOVA) with Tukey's multiple comparison test or Kruskal-Wallis with Dunn's comparisons. Predicted risk scores for in-hospital mortality and hospital length of stay were calculated using previously validated models of the cardiac care network of Ontario [14]. Multivariable models were created using logistic regression techniques for dichotomous outcomes and linear regression techniques for continuous outcomes. In addition to CL, the independent variables considered for use in the multivariable models included age, gender, history of hypertension, diabetes, or elevated cholesterol, aspirin use, Canadian Cardiovascular Society (CCS) classification, left ventricular grade, baseline renal function, on-pump status, procedure, and aprotinin dosage. Utilizing the univariable statistics for CL, multivariable models excluding CL were then derived. Clopidogrel was then added back to those models to determine the independent impact of CL and identify independent risk factors for transfusion requirements, ICU, and hospital length of stay. A p value less than 0.05 was considered to be statistically significant.
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Results |
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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It has been shown that aprotinin can ameliorate the amount of blood loss following aortocoronary bypass surgery in patients taking aspirin [18]. Aspirin works to prevent platelet aggregation by blocking the cyclooxygenase pathway and therefore inhibiting thromboxane A2 formation. This mechanism is quite different from ADP blockade provided by clopidogrel. It is unknown whether the beneficial effect of aprotinin on patients taking aspirin can be expected from patients taking clopidogrel. Because the majority of our patients received aprotinin, it was not possible to perform a meaningful analysis correlating aprotinin use and blood loss in our population. Although our data identified a statistically significant difference in the dosing of aprotinin among the three groups, the difference was probably not clinically significant; furthermore CL 0 to 4 patients received more, not less, aprotinin that the other groups. It has already been shown that there is little difference in blood loss profile between "low dose" and "full dose" aprotinin [19]. Early research into protease-activated receptors suggests that aprotinin does not prevent ADP activation of platelet aggregation [20], however the effect of aprotinin and clopidogrel in cardiac surgery patients is unclear.
Theoretically, it would be optimal to refrain from using clopidogrel within one week of surgery to minimize one of the risks of postoperative coagulopathy. The action of clopidogrel is irreversible and therefore lasts the entire lifespan of the platelet. However, clopidogrel has been shown to be beneficial in many of the patients in our target population [11–13] and it seems to be prescribed with increasing frequency. One must balance the risk of further ischemic events against the risk of postoperative hemorrhage when prescribing clopidogrel in potential cardiac surgery patients. This may be troublesome when considering the routine administration of clopidogrel to potential PCI patients before establishing the anatomy and subsequently, the determination of surgical or nonsurgical management. Conversely, it may be safe to proceed with surgery in patients who discontinue clopidogrel greater than 5 days before operation. This study suggests a specific time period within which it is safe to proceed with surgery if the patient had been taking clopidogrel.
In our study, clopidogrel within 4 days was associated with significantly longer hospital lengths of stay. This was not demonstrated in similar series. With rising health care costs, conservation of resources is extremely important. We did not perform a cost analysis in our study and one could only speculate on the incremental resource consumption and cost differences in the CL 0 to 4 group, which had almost twice the ICU and total hospital length of stay of the other two groups. Nonetheless, these incremental costs would likely be substantial.
We did not perform an analysis comparing on-pump to off-pump patients because of the small numbers of patients enrolled in the off-pump group. Although we did identify the use of cardiopulmonary bypass as an independent risk factor for prolonged ICU length of stay on multivariable regression analysis, of the six patients in the CL 0 to 4 group who required reoperation for bleeding, two had their surgery performed off pump. It is possible that coagulopathic bleeding secondary to clopidogrel could potentially have been enhanced by the proinflammatory conditions of the cardiopulmonary bypass circuit, yet more investigation is needed into this area.
This study was initially undertaken because we had anecdotally noted an increase in postoperative blood losses in patients taking clopidogrel preoperatively. Bleeding after cardiac surgery is a multifactorial problem and it can often be difficult to eliminate all of the confounding factors. However, our data show that clopidogrel within 4 days of operation is associated with increased bleeding in the first 24 hours and is also an independent risk factor for increased transfusion requirements and prolonged hospital length of stay. One must exercise caution when prescribing clopidogrel to the prospective cardiac surgery patient, weighing the risk of further myocardial ischemia against the risk of postoperative blood loss and its sequelae.
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