Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgery Emmanouil I. Kapetanakis, MD; Diego A. Medlam, MD; Kathleen R. Petro, MD; Elizabeth Haile,

Effect of Clopidogrel Premedication Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgeryin Off-Pump Cardiac Surgery

Effect of Clopidogrel Premedication Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgeryin Off-Pump Cardiac Surgery

Emmanouil I. Kapetanakis, MD; Diego A. Medlam, MD; Kathleen Emmanouil I. Kapetanakis, MD; Diego A. Medlam, MD; Kathleen R. Petro, MD; Elizabeth Haile, MS;R. Petro, MD; Elizabeth Haile, MS;

Peter C. Hill, MD; Mercedes K.C. Dullum, MD; AmmarPeter C. Hill, MD; Mercedes K.C. Dullum, MD; Ammar

S. Bafi, MD; Steven W. Boyce, MD; Paul J. Corso, MDS. Bafi, MD; Steven W. Boyce, MD; Paul J. Corso, MD

Published in Circulation Published in Circulation

Are We Forfeiting the Benefits of Reduced Are We Forfeiting the Benefits of Reduced

Hemorrhagic Sequelae?Hemorrhagic Sequelae?

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IntroductionIntroductionIntroductionIntroduction

• Premedication with clopidogrel has reduced Premedication with clopidogrel has reduced thrombotic complications after percutaneous thrombotic complications after percutaneous coronary revascularization procedures.coronary revascularization procedures.

• However, because of the enhanced and irreversible However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of surgical revascularization have a higher risk of bleeding complications and transfusion bleeding complications and transfusion requirements. requirements.

• A principal benefit of surgical coronary A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae.its lower hemorrhagic sequelae.

• Premedication with clopidogrel has reduced Premedication with clopidogrel has reduced thrombotic complications after percutaneous thrombotic complications after percutaneous coronary revascularization procedures.coronary revascularization procedures.

• However, because of the enhanced and irreversible However, because of the enhanced and irreversible platelet inhibition by clopidogrel, patients requiring platelet inhibition by clopidogrel, patients requiring surgical revascularization have a higher risk of surgical revascularization have a higher risk of bleeding complications and transfusion bleeding complications and transfusion requirements. requirements.

• A principal benefit of surgical coronary A principal benefit of surgical coronary revascularization without cardiopulmonary bypass is revascularization without cardiopulmonary bypass is its lower hemorrhagic sequelae.its lower hemorrhagic sequelae.

Circulation Circulation 2006;133:1667-16742006;133:1667-1674

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IntroductionIntroductionIntroductionIntroduction

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

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


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Study DesignStudy DesignStudy DesignStudy Design

Primary Endpoint: Primary Endpoint: The need for reexploration as a result of bleeding exclusive of any The need for reexploration as a result of bleeding exclusive of any other cardiac or noncardiac causeother cardiac or noncardiac cause

Secondary EndpointsSecondary Endpoints: perioperative transfusion requirements, morbidity, and mortality: perioperative transfusion requirements, morbidity, and mortality

Primary Endpoint: Primary Endpoint: The need for reexploration as a result of bleeding exclusive of any The need for reexploration as a result of bleeding exclusive of any other cardiac or noncardiac causeother cardiac or noncardiac cause

Secondary EndpointsSecondary Endpoints: perioperative transfusion requirements, morbidity, and mortality: perioperative transfusion requirements, morbidity, and mortality

Pre PCIPre PCI 300mg oral 300mg oral loading dose loading dose clopidogrel or 75 mg daily oral clopidogrel or 75 mg daily oral

regimen within 7 days of surgeryregimen within 7 days of surgeryn=281n=281

Pre PCIPre PCI 300mg oral 300mg oral loading dose loading dose clopidogrel or 75 mg daily oral clopidogrel or 75 mg daily oral

regimen within 7 days of surgeryregimen within 7 days of surgeryn=281n=281

1572 patients undergoing isolated off-pump CABG surgery between January 2000 and June 2002.

All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet glycoprotein inhibitors, or thrombolytics were excluded.glycoprotein inhibitors, or thrombolytics were excluded.

1572 patients undergoing isolated off-pump CABG surgery between January 2000 and June 2002.

All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet All patients received Aspirin before surgery. Patients with recent preoperative exposure to Coumadin, platelet glycoprotein inhibitors, or thrombolytics were excluded.glycoprotein inhibitors, or thrombolytics were excluded.

No exposure to clopidogrel or surgery No exposure to clopidogrel or surgery was postponed at least 7 days after was postponed at least 7 days after

discontinuing clopidogreldiscontinuing clopidogreln=1291n=1291

No exposure to clopidogrel or surgery No exposure to clopidogrel or surgery was postponed at least 7 days after was postponed at least 7 days after

discontinuing clopidogreldiscontinuing clopidogreln=1291n=1291


Intraoperative porcine heparin with an initial dose using a minimum standard of 400 U/kg and 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 secondsadditional dosing during procedure to maintain the target activated clotting time of >480 seconds

Intraoperative porcine heparin with an initial dose using a minimum standard of 400 U/kg and 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 secondsadditional dosing during procedure to maintain the target activated clotting time of >480 seconds

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Results: Primary EndpointResults: Primary EndpointResults: Primary EndpointResults: Primary Endpoint

6.4%

1.4%

0%

1%

2%

3%

4%

5%

6%

7%

Clopidogrel Group Unexposed Group

6.4%

1.4%

0%

1%

2%

3%

4%

5%

6%

7%

Clopidogrel Group Unexposed Group

• The unadjusted The unadjusted reexploration as a reexploration as a result of bleeding rate result of bleeding rate in the group that was in the group that was administered administered clopidogrel was 6.4% clopidogrel was 6.4% compared with 1.4% compared with 1.4% for the unexposed for the unexposed group (group (p<p<0.01)0.01)

Reexploration as a Result of Bleeding Rate (%)Reexploration as a Result of Bleeding Rate (%)

kgkg


p < 0.01

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Table 1: Patient Demographic And Pre-operative Table 1: Patient Demographic And Pre-operative Characteristics (Univariable Analysis)Characteristics (Univariable Analysis)

Table 1: Patient Demographic And Pre-operative Table 1: Patient Demographic And Pre-operative Characteristics (Univariable Analysis)Characteristics (Univariable Analysis)


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

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


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Table 2: Patient Intraoperative Characteristics and Table 2: Patient Intraoperative Characteristics and Outcomes (Univariable Analysis)Outcomes (Univariable Analysis)

Table 2: Patient Intraoperative Characteristics and Table 2: Patient Intraoperative Characteristics and Outcomes (Univariable Analysis)Outcomes (Univariable Analysis)


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Table 2: Patient Postoperative Characteristics Table 2: Patient Postoperative Characteristics and Outcomes (Univariable Analysis, cont.)and Outcomes (Univariable Analysis, cont.)

Table 2: Patient Postoperative Characteristics Table 2: Patient Postoperative Characteristics and Outcomes (Univariable Analysis, cont.)and Outcomes (Univariable Analysis, cont.)


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Table 3: Hemorrhagic Outcomes of Interest And Table 3: Hemorrhagic Outcomes of Interest And Significant Predictors (Multivariable Analysis)Significant Predictors (Multivariable Analysis)

Table 3: Hemorrhagic Outcomes of Interest And Table 3: Hemorrhagic Outcomes of Interest And Significant Predictors (Multivariable Analysis)Significant Predictors (Multivariable Analysis)


www.theplatelet.org Circulation Circulation 2006;133:1667-16742006;133:1667-1674

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

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

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

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


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DiscussionDiscussionDiscussionDiscussion

• A number of studies have demonstrated an increased incidence of A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it.for surgical reexploration to control it.

• Yende and Wunderink were among the first to report that patients receiving Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements.transfusion requirements.

• This study demonstrated that patients who were exposed to clopidogrel and This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets. PRBC transfusions, and a 2.5-times-higher demand of platelets.

• Preoperative clopidogrel administration was the single most predictive factor for Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion.reexploration because of hemorrhage and for blood product transfusion.

• A number of studies have demonstrated an increased incidence of A number of studies have demonstrated an increased incidence of postoperative bleeding and associated transfusion requirements and the need postoperative bleeding and associated transfusion requirements and the need for surgical reexploration to control it.for surgical reexploration to control it.

• Yende and Wunderink were among the first to report that patients receiving Yende and Wunderink were among the first to report that patients receiving clopidogrel before CABG were almost 6 times more likely to require surgical clopidogrel before CABG were almost 6 times more likely to require surgical reexploration to control hemorrhage and had a 20% increase in PRBC reexploration to control hemorrhage and had a 20% increase in PRBC transfusion requirements.transfusion requirements.

• This study demonstrated that patients who were exposed to clopidogrel and This study demonstrated that patients who were exposed to clopidogrel and subsequently underwent OPCAB surgery were 4 to 5 times more likely to subsequently underwent OPCAB surgery were 4 to 5 times more likely to require reexploration to control hemorrhage, had a significant 3-fold increase in require reexploration to control hemorrhage, had a significant 3-fold increase in PRBC transfusions, and a 2.5-times-higher demand of platelets. PRBC transfusions, and a 2.5-times-higher demand of platelets.

• Preoperative clopidogrel administration was the single most predictive factor for Preoperative clopidogrel administration was the single most predictive factor for reexploration because of hemorrhage and for blood product transfusion.reexploration because of hemorrhage and for blood product transfusion.


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Discussion (cont.)Discussion (cont.)Discussion (cont.)Discussion (cont.)

• Neither previous studies nor this one demonstrated significant differences in Neither previous studies nor this one demonstrated significant differences in clinical outcome or operative mortality in patients premedicated with clinical outcome or operative mortality in patients premedicated with clopidogrel.clopidogrel.

• The efficacy of clopidogrel has engrained it in clinical practice, and, because The efficacy of clopidogrel has engrained it in clinical practice, and, because mortality rates after surgery appear unaffected, there is no urgency to modify mortality rates after surgery appear unaffected, there is no urgency to modify the current practice of clopidogrel administration.the current practice of clopidogrel administration.

• However, increased blood product transfusion exposes patients to However, increased blood product transfusion exposes patients to transfusion-related complications while reexploration as a result of bleeding transfusion-related complications while reexploration as a result of bleeding has been shown to increase the need for mechanical ventilation, total length has been shown to increase the need for mechanical ventilation, total length of hospital stay, operative mortality, and associated costs.of hospital stay, operative mortality, and associated costs.

• Recent studies have also shown that postoperative blood transfusion is an Recent studies have also shown that postoperative blood transfusion is an independent predictor of increased long-term mortality after cardiac surgery.independent predictor of increased long-term mortality after cardiac surgery.


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Study LimitationsStudy LimitationsStudy LimitationsStudy 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 Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint.however, it is unlikely to have affected the primary endpoint.

• More significantly, a breakdown analysis by individual surgeons More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions.overall platelet administration, refuting any bias assertions.

• The study did not possess a large enough patient sample size to The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality.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 Possibility that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, patients who received antiplatelet agents preoperatively, consequently lowering their threshold for platelet administration; consequently lowering their threshold for platelet administration; however, it is unlikely to have affected the primary endpoint.however, it is unlikely to have affected the primary endpoint.

• More significantly, a breakdown analysis by individual surgeons More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, refuting any bias assertions.overall platelet administration, refuting any bias assertions.

• The study did not possess a large enough patient sample size to The study did not possess a large enough patient sample size to reflect statistically significant differences on mortality.reflect statistically significant differences on mortality.


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SummarySummarySummarySummary

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

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


Documents

Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgery Emmanouil I. Kapetanakis, MD; Diego A. Medlam, MD; Kathleen R. Petro, MD; Elizabeth Haile,