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Ann Thorac Surg 2005;80:928-933
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Clopidogrel and Bleeding After Coronary Artery Bypass Graft Surgery

Cardiac and Thoracic Surgical Unit, Flinders Medical Centre and Flinders University, Adelaide, Australia

Accepted for publication March 18, 2005.

^_* Address reprint requests to Dr Baker, Cardiac and Thoracic Surgical Unit, Flinders Medical Centre, Flinders Dr, Bedford Park, Adelaide, SA 5042, Australia (Email: rob.baker{at}flinders.edu.au).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
BACKGROUND: There is evidence that clopidogrel (with or without aspirin) confers superior outcomes in patients with coronary artery disease. The purpose of this study is to review the effect of preoperative clopidogrel administration on clinical outcome, bleeding complications and resource utilization after coronary artery bypass graft surgery.

METHODS: Patient data were prospectively collected from 919 patients who had isolated coronary surgery during the period 2000 to 2003. Outcome comparisons were studied, firstly between patients who received preoperative clopidogrel with those who did not, and secondly between patients on clopidogrel only, aspirin only, both or neither medications.

RESULTS: Twenty-four patients (2.6%) were on clopidogrel only, 598 (65.1%) were on aspirin only, 61 (6.6%) were on both, and 236 (25.7%) were on neither. Clopidogrel (n = 85) versus no clopidogrel (n = 834): there were no significant differences in the off-pump patients. In the on-pump patients, the clopidogrel group had significantly increased bleeding (p = 0.02), blood transfused (p = 0.01), intensive care (p = 0.03), and hospital stays (p = 0.03). There were no significant differences in surgical reexploration, perioperative myocardial infarction, intraoperative balloon pump use, inotropic support or 30-day mortality. Clopidogrel versus aspirin versus both versus neither: patients on both clopidogrel and aspirin had significantly more postoperative bleeding than patients on aspirin alone or on neither medication.

CONCLUSIONS: The preoperative use of clopidogrel in patients undergoing coronary artery bypass graft surgery showed limited clinical benefits; however, its use significantly increased the risk of bleeding, blood transfusion, and resource utilization.

	Introduction

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Coronary artery bypass graft (CABG) surgery has become a commonly performed operation, with more than 800,000 patients undergoing this procedure worldwide each year [1]. Postoperative bleeding is a significant cause of morbidity and mortality, requiring transfusion of blood and blood products and sometimes requiring surgical reexploration for control of bleeding. Transfusion exposes patients to a variety of potential complications. Reoperation for bleeding may occur in as many as 2% of patients and this complication has been associated with increased mortality and length of hospital stay [2]. The main causes of bleeding include incomplete surgical hemostasis, defective coagulation and platelet dysfunction. Platelet dysfunction after cardiac surgery may be due to the effect of cardiopulmonary bypass (CPB) or preoperative antiplatelet medications. Cardiopulmonary bypass activates platelets, and as a result reduces platelet count and reduces their ability to generate an effective clot [3]. Aspirin is the main antiplatelet medication used in patients with coronary artery disease, but there is growing evidence that the use of the more potent antiplatelet clopidogrel, on its own or in combination with aspirin, has superior outcomes in both chronic and acute settings [4, 5].

Clopidogrel and ticlopidine are thienopyridines. They are prodrugs that are metabolized in the liver into active metabolites that are noncompetitive antagonists of the platelet adenosine diphosphate receptor, P2Y₁₂. Clopidogrel is an acetate derivative of ticlopidine and has several advantages, including more rapid onset of action, more potent antiplatelet effect, and lower incidence of severe neutropenia and thrombotic thrombocytopenic purpura [6]. The antiplatelet effect of clopidogrel is time and dose dependent. Maximal inhibition of platelet aggregation of 50% to 60% can be achieved with a dose of 75 mg daily (without loading dose) within 4 to 7 days, or more rapidly with a loading dose of 300 to 600 mg within 4 to 24 hours [7–9]. This level of platelet inhibition caused a twofold increase in the bleeding time of healthy human volunteers [10]. Platelet function recovered completely 7 days after stopping clopidogrel in healthy volunteers [11].

Several large randomized studies have demonstrated the superior antiplatelet action of clopidogrel in combination with aspirin in the setting of percutaneous coronary intervention [12, 13]. It is now common to give patients both clopidogrel and aspirin at the time of coronary stent implantation, and some centers now give patients clopidogrel and aspirin before a diagnostic angiogram for maximum antiplatelet activity at the time of possible stent placement [14]. Clopidogrel has also been found to have beneficial effects in patients with acute coronary syndrome without ST-segment elevation [15].

The use of clopidogrel in these settings may result in patients (who are found to have significant coronary disease requiring CABG in the same admission) presenting for major surgery with significant platelet inhibition. Two recent studies have noted this increased use of clopidogrel in patients presenting for CABG, and have demonstrated that these patients have an increased incidence of bleeding-related complications after CABG [2, 14]. The purpose of this study was to review the effect of the preoperative use of clopidogrel on clinical outcomes, bleeding-related complications, and resource utilization after CABG in our institution.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Patients
Nine hundred and nineteen patients who underwent isolated CABG at the Flinders Medical Centre between July 1, 2000, and June 30, 2003, were included. Preoperative patient characteristics, intraoperative variables, and postoperative outcomes were prospectively collected and recorded in a cardiac surgery database. Patients who had off-pump coronary artery bypass graft surgery (OPCABG) were included. The mean age of these patients was 63.6 years, 76% were male, 11.9% had OPCABG, and 6.3% had emergent surgery. Of the patients who were receiving aspirin, the usual dose was 150 mg daily. All patients receiving clopidogrel were on a maintenance dose of 75 mg daily, and none had a loading dose before surgery.

A glycoprotein IIb/IIIa inhibitor was used in only 10 patients. Of these, 4 were also on clopidogrel, and one had an OPCABG procedure. Owing to the small number, the use of glycoprotein IIb/IIIa inhibitors was not analyzed separately. Similarly, only 4 patients had perioperative antifibrinolytic therapy, and hence this was not analyzed separately.

Postoperatively, patients were managed in a general intensive care unit staffed by intensive care specialists. Decisions regarding the management of hemodynamic and ventilatory parameters and the transfusion of blood and blood products were made by these intensivists according to standard unit protocol. Chest tube outputs were used as the primary measure of postoperative bleeding, and our analyses were based on the total volume of loss during the patient’s stay in the intensive care unit (ICU). On the first postoperative day, aspirin 150 mg daily, subcutaneous heparin 5,000 units twice daily, and a statin were commenced.

Of the 919 patients studied, 24 patients (2.6%) were on clopidogrel only, 598 (65.1%) were on aspirin only, 61 (6.6%) were on both, and 236 (25.7%) were on neither (that is, not on aspirin nor clopidogrel within 7 days of surgery). The first analysis was performed between patients who received clopidogrel within 7 days of surgery and those who did not receive clopidogrel or ceased it more than 7 days before surgery. The clinical outcomes analyzed were perioperative myocardial infarction (defined by the presence of new Q waves on electrocardiography), intra-aortic balloon pump usage, inotropic support, volume of chest drain loss, transfusion of blood and blood products, surgical reexploration for bleeding, length of ventilation, length of ICU stay, length of postoperative hospital stay, and mortality within 30 days of operation.

A second analysis was performed taking into account exposure to aspirin within 7 days of surgery. Four groups were identified: patients who received clopidogrel and aspirin, clopidogrel only, aspirin only, and neither. Comparisons of major outcomes were performed.

Statistical Analysis
Proportions were expressed as a percentage, parametric continuous variables were expressed as mean ± SD, and nonparametric continuous variables were expressed as median (range). In the two group analysis, differences in proportions were compared using ² or Fisher’s exact tests, parametric continuous variables were compared using the t test, and nonparametric continuous variables were compared using the Mann-Whitney test. A two-tailed p value of 0.05 or less was considered statistically significant.

In the second analysis of the four groups, the Kruskal-Wallis test was used to identify the major outcomes in which there was a significant variance between the groups. A p value of 0.05 or less was considered statistically significant. In the major outcomes where there was a significant variance between groups, pair-wise Mann-Whitney tests were performed, applying the modified Bonferroni adjustment [16], to identify the groups that had statistically significant differences. Statistical analyses were performed with SPSS for Windows Release 12.0 (SPSS, Chicago, Illinois).

	Results

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Clopidogrel Versus No Clopidogrel
The baseline characteristics of these patients are presented in Table 1 for OPCABG and CABG on CPB. There were no statistically significant differences between clopidogrel and no clopidogrel groups in OPCAB patients. In patients who had CABG on CPB, the two groups were comparable with regard to sex distribution, logistic EuroSCORE, the incidence of diabetes, renal failure, the urgency of operation, the incidence of severe left ventricular dysfunction, Canadian Cardiovascular Society (CCS) angina grade, previous myocardial infarction, the duration of aortic cross-clamp, the duration of CPB, and the duration of procedure. The clopidogrel group had significantly lower age (60.8 versus 64.1 years, p = 0.03), body surface area (1.87 m² versus 1.92 m², p = 0.02), and previous percutaneous coronary intervention (16.9% versus 8.7%, p = 0.02).

	Comment

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Our study has demonstrated that exposure to clopidogrel before CABG increased the amount of postoperative blood loss and the number of blood units transfused, supporting the previous findings by Yende and Wunderink [2] and Hongo and colleagues [14]. These studies demonstrated increased postoperative bleeding and transfusion requirement, especially when clopidogrel was used in combination with aspirin. This finding was also supported by the recent paper by Englberger and associates [17] who reported increased bleeding and platelet and fresh frozen plasma transfusion in patients receiving clopidogrel within 3 days of surgery. Interestingly, unlike the current study, all patients received low-dose aprotonin treatment. However, Karabulut and Toraman [18] showed no increase in bleeding and transfusion requirements after preoperative use of clopidogrel. Our study has also demonstrated a significantly increased ICU and postoperative hospital stay in clopidogrel recipients, similar to a recent study by Chu and coworkers [19]. These patients stayed an average of 13.7 hours and 1.9 days longer than nonrecipients, respectively. Increased ICU and hospital stay significantly impacts on the cost of CABG and will also expose patients to potential hospital stay-related complications.

In the setting of a patient presenting for CABG with recent clopidogrel exposure, Hongo and colleagues [14] have suggested delaying the procedure if it can be done safely. The optimal time delay between the last dose of clopidogrel and CABG is unknown. The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial suggests that the incidence of major bleeding is higher among patients who have clopidogrel exposure within 5 days of surgery compared with those with a delay of greater than 5 days [15]. Studies on the antiplatelet effect of clopidogrel have shown that platelet function recovers completely 7 days after stopping therapy in healthy volunteers [11]. This series was performed before the change to the American College of Cardiology/American Heart Association Task Force on Practice Guidelines recommending reducing the time period of exposure before surgery. The guideline now states that "if clinical circumstances permit, clopidogrel should be withheld for 5 days before the performance of CABG surgery" [20].

For patients whose CABG cannot be delayed safely, prophylactic platelet transfusion has been suggested [2, 14], although there is currently little evidence that this is of benefit. The antifibrinolytic agent aprotinin has been found to reduce bleeding and transfusion requirements in patients exposed to aspirin [21], but it has not been shown to be beneficial in patients exposed to clopidogrel, although the numbers studied were small [2]. Only 2 of our patients were treated with aprotinin, neither of whom was in the clopidogrel group. In our institution, we currently do not use platelets or aprotinin in a prophylactic manner. The timing and use of interventions such as prophylactic platelet transfusion and aprotinin treatment in clopidogrel recipients is still unclear. A strict transfusion algorithm can reduce the transfusion requirement for all blood components. Preheparin testing of platelet function with adenosine diphosphate aggregometry can identify patients at highest risk for perioperative bleeding and transfusions and might further reduce the perioperative transfusion requirement [22].

Contrary to earlier concepts, it has now been established that preoperative aspirin does not generally increase postoperative bleeding, and may actually decrease mortality among patients having CABG [23, 24]. We also found that aspirin use is not associated with increased bleeding. Clopidogrel and aspirin effect platelet inhibition through different mechanisms; clopidogrel acts by inhibiting adenosine diphosphate-dependent platelet activation and aspirin acts by inhibiting thromboxane-dependent platelet activation. It has been postulated that the combination of clopidogrel and aspirin produces a synergistic effect on platelet inhibition [25] that increases bleeding postoperatively. The addition of clopidogrel to aspirin preoperatively has been reported to significantly increase the risk of postoperative bleeding and blood transfusion [2, 14], and this was shown to be the case in the current study.

This study is limited in that it is a retrospective analysis of data. Patients on preoperative clopidogrel and nonrecipients were comparable with regard to the major determinants of prognosis, except for body surface area in which the clopidogrel group had a lower area. It has been suggested that patients with lower body surface area bleed more after CABG [26], and this uneven distribution may have affected our results. In addition, the decision to transfuse blood and blood products was not made independent of the knowledge of clopidogrel exposure by the treating medical staff. Similarly, the decision to return patients to theatre for hemostasis, whilst based on objective measures such as drain losses and hemodynamics, was not made independent of the knowledge of clopidogrel exposure. Another limitation of this study is the relatively small number of patients (8) in the OPCABG group receiving clopidogrel. There is currently little information in the literature of the effect of clopidogrel, alone or in combination with aspirin, on bleeding after CABG in a prospective, randomized manner. A cost analysis would also help in studying the financial impact of preoperative clopidogrel exposure.

This study has demonstrated an increased risk of postoperative bleeding, increased need for blood transfusion, and increased length of postoperative intensive care unit and hospital stays for patients exposed to clopidogrel before coronary artery bypass graft surgery. This study has also confirmed the previous finding that the combination of clopidogrel and aspirin significantly increases postoperative bleeding. Further studies are required to define protocols for the preoperative and postoperative management of these patients.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
The authors thank Adrian Esterman, PhD, for his assistance in statistical analyses.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments 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): Pallav J. Shah John L. Knight Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Leong, J.-Y. Articles by Knight, J. L. Search for Related Content PubMed PubMed Citation Articles by Leong, J.-Y. Articles by Knight, J. L.