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POSTOPERATIVE BLEEDING AFTER MYOCARDIAL REVASCULARIZATION
IN PATIENTS ON CLOPIDOGREL
MOHAMMED ABDEL-AAL MD., BAKIR M BAKIR MD., ANJUM JALAL FRCS-CTH, AHMED AL-SADDIQUE FACS. NASSER H. ALKHAMEES MB. MOHAMMED FOUDA FRCS Background: Clopidogrel (CL) is a potent inhibitor of platelet aggregation. It has become the standard of care
to prevent thrombotic complications following cardiological interventions. Platelet dysfunction is one of the
major reasons for postoperative bleeding following coronary artery surgery. The aim of this study was to
evaluate the effect of clopidogrel on bleeding and the use of blood and blood products after coronary artery
bypass grafting (CABG).
Methods: Data were prospectively collected on 286 consecutive patients who underwent isolated conventional
CABG (with cardiopulmonary bypass) and two groups were compared: group 1, those who had the drug
discontinued more than 7 days prior to surgery or were never on it (n = 201), to group 2, those with
clopidogrel exposure up until 72 hours prior to surgery (n = 85). The duration of the study covered the period
between April 2004 and March 2006. Preoperative patient characteristics, intraoperative variables, and
postoperative outcomes were prospectively collected and recorded in the cardiac surgery database.
Results: Chest tube drainage was significantly increased during the first 24 hours following CABG in the
group of patients who had clopidogrel treatment (1392 ± 212 vs.785.29 ± 145). These patients also required
more transfusion of packed red cells (4.23± 2.3 vs. 2.21± 1.5), platelets (4.1 ± 1.2 vs. 0.2 ± 0.6), and fresh
frozen plasma (3 ± 0.9 vs. 1.5± 1.1). Overall, the re-exploration rate due to bleeding was significantly higher
in the clopidogrel group (5.88% vs. 1.8%).
Conclusion: Patients using clopidogrel 3 days or less prior to CABG surgery have a significantly increased
risk of postoperative bleeding, with an increased need for surgical re-exploration as well as risks of
transfusion with blood and blood products after coronary artery bypass surgery. Platelets transfused before
chest closure had a beneficial effect on preservation of hemostasis.
Keywords: Myocardial revascularization, clopidogrel (CL), blood products, bleeding.
CLOPIDOGREL IS AN ACETATE DERIVATIVE OF loading dose) within 4 to 7 days, or more rapidly with a loading dose of 300 to 600 mg within 4 to 24 aggregation that works by irreversible blockade of hours. Platelet function recovers completely 7 days adenosine diphosphate (ADP) mediated platelet after stopping clopidogrel in healthy volunteers.2,3 activation.1 It has several advantages over other The cause of early postoperative bleeding antiplatelets, including more rapid onset of action, a following CABG may be multifactorial: insufficient more potent antiplatelet effect, and a lower incidence surgical hemostasis, disorders of the coagulation system due to hemodilution, and platelet dysfunction thrombocytopenic purpura(i). The antiplatelet effect as well as the negative effects of increased of clopidogrel is time and dose dependent. Maximal inhibition of platelet aggregation of 50% to 60% can procedures, and urgency status, which are the most be achieved with a dose of 75 mg daily (without a common causes for impaired hemostasis and postoperative bleeding.2 From the Department of Medicine King Fahad Cardiac Center, Platelet function is integral to hemostasis in the College of Medicine, King Saud University, Riyadh, Kingdom Of early postoperative period. Preoperative antiplatelet agents have the potential to deliver an additional Address reprint request and correspondence to Dr. Mohammed Abdel-Aal Department of Medicine King Fahad Cardiac Center, insult to already dysfunctional platelets. These agents King Khalid University Hospital, King Saud University, P O Box should be discontinued at the appropriate time to ensure adequate platelet function at the time of Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007 necessitate continuation of antiplatelet agents. whom systemic temperature was kept between 30°C Although controversial, preoperative aspirin may and 32°C. Myocardial protection was achieved by have a small effect in enhancing postoperative using intermittent anterograde hyperkalemic cold bleeding, but it does not affect transfusion rates. 7 Due to the advantages and superior action of Patients were transferred to the intensive care clopidogrel compared to other antiplatelet agents, it unit (ICU) and managed according to ICU protocols. is now common practice for cardiologists to give They were extubated following our usual criteria of patients both clopidogrel and aspirin at the time of hemodynamic stability and no excessive bleeding coronary angiography for possible coronary stent (less than 3-5 ml/kg/h), normothermia, and full implantation for maximum antiplatelet activity at consciousness. All patients underwent routine the time of stent placement. This results in patients coagulation screening. Transfusion of red blood cells with severe coronary artery disease requiring was performed when the hematocrit value was CABG during the same admission to present for less than 24%. Platelets were transfused when surgery with significant platelets’ function the total count was less than 50,000/µL or there inhibition.8 was excessive post-operative bleeding. The The aim of this work was to analyze the effect of decision for re-exploration was taken when bleeding clopidogrel on postoperative bleeding and blood exceeded 500 ml in the first hour, more than products transfusion requirements in patients who 200 ml/h during next 3 hours, or more than underwent isolated myocardial revascularization. 1 liter over 8 hours despite normalized coagulation Patients and Methods
Statistical Analysis
Data were collected prospectively on 286 consecutive patients who underwent isolated CABG Statistical analysis was carried out using analysis with CPB. Exclusion criteria included concomitant of variance (ANOVA), Fisher’s exact tests and the t valvular procedures, off-pump CABG, bleeding test. A P value of 0.05 or less was considered disorders identified preoperatively, and patients with impaired renal function. All patients were receiving aspirin, 81 mg/day. Patients receiving clopidogrel were on a maintenance dose of 75 mg daily or receiving the loading dose of 300 mg /day just There were no clinically or statistically significant differences in age, gender, risk factors, or Preoperative patient parameters, intraoperative other main profiles of the patients between both variables, and postoperative outcomes including groups (Table 1). blood loss in the first 24 hours, and transfusion requirements in the first 24 hours postoperatively, re- Table 1: Preoperative Patient Data.
exploration for bleeding, and length of ICU and total P value
hospital stays, were prospectively collected and Age 59.38 ± The patients were divided in two groups: group 1: those in whom clopidogrel was discontinued more than 7 days prior to surgery or were never taking it (n = 201) and group 2: those with clopidogrel Angina class exposure up until 72 hours prior to surgery (n = 85 from April 2004 to March 2006. The main Previous indications for clopidogrel treatment were prior infarction (%) percutaneous coronary intervention, unstable angina and patients with critical coronary artery disease NS: non significant. needing surgery within the same hospital admission. Anesthesia technique, heparin, and protamine management were standardized for all patients in The intraoperative data are presented in Table 2 Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007 in which there were no statistically significant
differences between the groups. Chest tube drainage
Acquired platelet dysfunction is one of the most was significantly increased during the first 24 hours commonly encountered haemostatic defects in following CABG in the group of patients who had patients undergoing cardiac surgical procedures. The clopidogrel treatment (1392 ± 212 vs. 785.29 ± 145) main factors that may affect bleeding and transfusion requirements in these patients are the presence of Those patients who received clopidogrel also risk factors for bleeding, as well as appropriate required more transfusion of packed red cells, (4.23± heparin dosing and protamine reversal, but an excess 2.3 vs. 2.21± 1.5), platelets (4.1 ± 1.2 vs. 0.2 ± 0.6) dose of protamine should be avoided in these and fresh frozen plasma (3 ± 0.9 vs. 1.5± 1.1; p < patients due to its adverse effects on coagulation 0.001) (Table 3). Re-exploration for postoperative factors and platelets.9,10 bleeding was significantly higher and was required in Differentiating between postoperative bleeding five (5.88%) patients of the CL group, while it was due to coagulopathy and surgical bleeding that required in four (1.8%) in the non-CL group. After re- should be corrected with re-exploration is not always exploration, no specific sources were identified and straightforward in the early postoperative period. bleeding was thought to be secondary to coagulopathy The differentiation becomes more difficult in the in all patients. The median ICU and hospital stay were face of preoperative clopidogrel administration, longer in the CL group (Table 4). We had a hospital mortality of 4 patients (1.3%) from low cardiac cardiologists.11,12 Our study has demonstrated that exposure to clopidogrel before CABG increased the amount of postoperative blood loss and the number chest drainge
of blood units transfused, supporting the previous findings by Yende and Wunderink,7 who reported
their experience with 247 patients, of which 51 received clopidogrel. Hongo and colleagues13
prospectively compared 224 patients, of whom 59 had preoperative clopidogrel exposure within 7 days before surgery, undergoing non-emergent CABG and observed the postoperative outcome of those with and without clopidogrel exposure. They found that chest tube drainage (1485cc) was significantly increased during the first 24 h following CABG in Figure 1: Postoperative blood loss
the group of patients who had clopidogrel treatment. output, including patients in both groups. These patients also required more transfusion of packed red cells, platelets, and fresh frozen plasma. Table (3): Transfusion requirements.
Overall, the re-exploration rate due to bleeding was Blood products
P value
significantly higher in the clopidogrel group. transfused
Similar results were reported by Ray et al.14 The
potent inhibition of platelet function achieved by the combination of aspirin and clopidogrel has been reported to prolong bleeding time with an increased risk of major hemorrhage. Moreover, the combined
Table 4: Postoperative outcome.
antiplatelet effect of clopidogrel and aspirin might be P value
amplified by CPB-related platelet dysfunction. This finding was also supported by Englberger and
associates 8 who reported increased bleeding and
platelet and fresh frozen plasma transfusion in
patients receiving clopidogrel within 3 days of surgery. However, Karabulut et al6 showed no
increase in bleeding and transfusion requirements Discussion
after preoperative use of clopidogrel and the cause in Journal of the Saudi Heart Association, Vol. 19, No. 3, September 2007 Our study has also demonstrated a significantly Karabulut H, Toraman F. Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery increased ICU and postoperative hospital stay in surgery Eur J Cardiothorac Surg 2004;25:419-423 clopidogrel recipients, similar to a study by Chu and
Yende S, Wunderink RG. Effect of clopidogrel on bleeding coworkers17 These patients stayed an average of
after coronary artery bypass surgery Crit Care Med 13.7 hours and 1.9 days longer than non-recipients, Englberger L, Faeh B, Berdat PA, Franz Eberli, Meier B, respectively. Increased ICU and hospital stay Carrel T. Impact of clopidogrel in coronary artery bypass significantly impacts on the cost of CABG and will grafting Eur J Cardiothorac Surg 2004;26:96-101. also expose patients to potential hospital stay-related Nurozler F, Kutlu T, Küçük G and Ökten C. Impact of clopidogrel on postoperative blood loss after non-elective coronary bypass surgery CardioVasc Thorac Surg One of the limitations of the present study, which deserves to be mentioned, is that we did not perform 10. Payne DA, Hayes PD. Combined therapy with clopidogrel an analysis comparing on-pump to off-pump patients and aspirin significantly increases the bleeding time through because of the small numbers of patients enrolled in a synergistic antiplatelet action J Vasc Surg 2002;35:1204-1209. 11. Harding SA, Boon NA, Flapan AD. Antiplatelet treatment In conclusion, bleeding after cardiac surgery is a in unstable anginaaspirin, clopidogrel, glycoprotein IIb/IIIa multifactorial problem and it can often be difficult to antagonist, or all three ? Heart 2002;88:11-14. eliminate all of the confounding factors. However, 12. Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of antiplatelet agents. The Task Force our data show that clopidogrel within 3 days of on the Use of Antiplatelet Agents in Patients with operation is associated with increased bleeding in the Atherosclerotic Cardiovascular Disease of the European first 24 hours and is thus an independent risk factor Society of Cardiology Eur Heart J 2004;25:166-181. for increased transfusion requirements and 13. Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in combination with aspirin when given before prolonged hospital length of stay. One must exercise coronary artery bypass grafting J Am Coll Cardiol caution when prescribing clopidogrel to the preoperative cardiac surgery patient, weighing the 14. Ray JG, Deniz S, Olivieri A, et al. Increased blood product risk of further myocardial ischemia against the risk use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel BMC Cardiovasc of postoperative blood loss and its sequelae. 15. Raimondo Ascione, MD, MCh*, Arup Ghosh, FRCS, Chris References
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