Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgery Emmanouil I. Kapetanakis, MD; Diego A. Medlam, MD; Kathleen R. Petro, MD; Elizabeth Haile, MS; Peter C. Hill, MD; Mercedes K.C. Dullum, MD; Ammar S. Bafi, MD; Steven W. Boyce, MD; Paul J. Corso, MD Published in Circulation Are We Forfeiting the Benefits of Reduced Hemorrhagic Sequelae?

Premedication with clopidogrel has reduced thrombotic complications after percutaneous coronary revascularization procedures.Premedication with clopidogrel has reduced thrombotic complications after percutaneous coronary revascularization procedures. However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of bleeding complications and transfusion requirements.However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of bleeding complications and transfusion requirements. A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae.A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae. Premedication with clopidogrel has reduced thrombotic complications after percutaneous coronary revascularization procedures.Premedication with clopidogrel has reduced thrombotic complications after percutaneous coronary revascularization procedures. However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of bleeding complications and transfusion requirements.However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of bleeding complications and transfusion requirements. A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae.A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae. Circulation 2006;133:

The purpose of this study was to evaluate the effect of preoperative clopidogrel administration in the incidence of hemostatic reexploration, blood product transfusion rates, morbidity, and mortality in patients undergoing off-pump coronary artery bypass graft surgery using a large patient sample and a risk- adjusted approach.The purpose of this study was to evaluate the effect of preoperative clopidogrel administration in the incidence of hemostatic reexploration, blood product transfusion rates, morbidity, and mortality in patients undergoing off-pump coronary artery bypass graft surgery using a large patient sample and a risk- adjusted approach. Circulation 2006;133:

Study Design  Primary Endpoint: The need for reexploration as a result of bleeding exclusive of any other cardiac or noncardiac cause Secondary Endpoints: perioperative transfusion requirements, morbidity, and mortality  Secondary Endpoints: perioperative transfusion requirements, morbidity, and mortality  Primary Endpoint: The need for reexploration as a result of bleeding exclusive of any other cardiac or noncardiac cause Secondary Endpoints: perioperative transfusion requirements, morbidity, and mortality  Secondary Endpoints: perioperative transfusion requirements, morbidity, and mortality Pre PCI 300mg oral loading dose clopidogrel or 75 mg daily oral regimen within 7 days of surgery n=281 n= patients undergoing isolated off-pump CABG surgery between January 2000 and June All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet glycoprotein inhibitors, or thrombolytics were excluded patients undergoing isolated off-pump CABG surgery between January 2000 and June All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet glycoprotein inhibitors, or thrombolytics were excluded. No exposure to clopidogrel or surgery was postponed at least 7 days after discontinuing clopidogrel n=1291 n=1291 Circulation 2006;133: Intraoperative porcine heparin with an initial dose using a minimum standard of 400 U/kg and additional dosing during procedure to maintain the target activated clotting time of >480 seconds

Results: Primary Endpoint The unadjusted reexploration as a result of bleeding rate in the group that was administered clopidogrel was 6.4% compared with 1.4% for the unexposed group (p<0.01) Reexploration as a Result of Bleeding Rate (%) kg Circulation 2006;133: p < 0.01

Table 1: Patient Demographic And Pre-operative Characteristics (Univariable Analysis) Circulation 2006;133:

Table 1: Patient Demographic And Pre-operative Characteristics (Univariable Analysis, cont.) Circulation 2006;133:

Table 2: Patient Intraoperative Characteristics and Outcomes (Univariable Analysis) Circulation 2006;133:

Table 2: Patient Postoperative Characteristics and Outcomes (Univariable Analysis, cont.) Circulation 2006;133:

Table 3: Hemorrhagic Outcomes of Interest And Significant Predictors (Multivariable Analysis) Circulation 2006;133:

Circulation 2006;133: Table 3: Hemorrhagic Outcomes of Interest And Significant Predictors (Multivariable Analysis, cont.)

Table 4: Hemorrhagic Outcomes of Interest And Significant Predictors (Propensity Score-Matched Analysis) Circulation 2006;133:

A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it.A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it. Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements.Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements. This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets.This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets. Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion.Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion. A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it.A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it. Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements.Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements. This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets.This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets. Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion.Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion. Circulation 2006;133:

Discussion (cont.) Neither previous studies nor this one demonstrated significant differences in clinical outcome or operative mortality in patients premedicated with clopidogrel.Neither previous studies nor this one demonstrated significant differences in clinical outcome or operative mortality in patients premedicated with clopidogrel. The efficacy of clopidogrel has engrained it in clinical practice, and, because mortality rates after surgery appear unaffected, there is no urgency to modify the current practice of clopidogrel administration.The efficacy of clopidogrel has engrained it in clinical practice, and, because mortality rates after surgery appear unaffected, there is no urgency to modify the current practice of clopidogrel administration. However, increased blood product transfusion exposes patients to transfusion-related complications while reexploration as a result of bleeding has been shown to increase the need for mechanical ventilation, total length of hospital stay, operative mortality, and associated costs.However, increased blood product transfusion exposes patients to transfusion-related complications while reexploration as a result of bleeding has been shown to increase the need for mechanical ventilation, total length of hospital stay, operative mortality, and associated costs. Recent studies have also shown that postoperative blood transfusion is an independent predictor of increased long-term mortality after cardiac surgery.Recent studies have also shown that postoperative blood transfusion is an independent predictor of increased long-term mortality after cardiac surgery. Circulation 2006;133:

Study Limitations Limitations inherent in any retrospective single-institution analysis.Limitations inherent in any retrospective single-institution analysis. Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint.Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint. More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions.More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions. The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality.The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality. Limitations inherent in any retrospective single-institution analysis.Limitations inherent in any retrospective single-institution analysis. Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint.Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint. More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions.More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions. The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality.The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality. Circulation 2006;133:

Clopidogrel administration in the setting of ACS or for therapeutic PCIs mitigates the benefit of OPCAB of reduced bleeding-related morbidity, producing instead an increase in the risk for bleeding, consequent hemostatic reexploration, and blood product use.Clopidogrel administration in the setting of ACS or for therapeutic PCIs mitigates the benefit of OPCAB of reduced bleeding-related morbidity, producing instead an increase in the risk for bleeding, consequent hemostatic reexploration, and blood product use. Circulation 2006;133: