CLINICAL PERSPECTIVE

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(Circulation. 2006;113:1667-1674.)
© 2006 American Heart Association, Inc.

Cardiovascular Surgery

Effect of Clopidogrel Premedication in Off-Pump Cardiac Surgery

Are We Forfeiting the Benefits of Reduced Hemorrhagic Sequelae?

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

From the Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center (E.I.K., D.A.M., K.R.P., P.C.H., M.K.C.D., A.S.B., S.W.B., P.J.C.), and Department of Epidemiology and Statistics, MedStar Research Institute (E.H.), Washington, DC.

Correspondence to Emmanouil I. Kapetanakis, MD, Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center, 110 Irving St NW, Room 1F-1207, Washington, DC 20010–2975 (e-mail emmanouil.kapetanakis{at}medstar.net); reprint requests to Paul J. Corso, MD, Chief, Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center, 106 Irving St NW, Suite 316, Washington, DC 20010–2975 (e-mail paul.j.corso@medstar.net).

Received June 27, 2005; revision received December 13, 2005; accepted January 20, 2006.

	Abstract

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

Methods and Results— Two hundred eighty-one patients (17.9%) did and 1291 (82.1%) did not receive clopidogrel before their surgery, for a total of 1572 patients undergoing isolated off-pump coronary artery bypass graft surgery between January 2000 and June 2002. Risk-adjusted logistic regression analyses and a matched pair analyses by propensity scores were used to assess the association between clopidogrel administration and reoperation as a result of bleeding, intraoperative and postoperative blood transfusions received, and the need for multiple transfusions. Hemorrhage-related preoperative risk factors identified in the literature and those found significant in a univariate model were used. The clopidogrel group had a higher likelihood of hemostatic reoperations (odds ratio [OR], 5.1; 95% confidence interval [CI], 2.47 to 10.47; P<0.01) and an increased need in overall packed red blood cell (OR, 2.6; 95% CI, 1.94 to 3.60; P<0.01), multiple unit (OR, 1.6; 95% CI, 1.07 to 2.48; P=0.02), and platelet (OR, 2.5; 95% CI, 1.77 to 3.66; P<0.01) transfusions. Surgical outcomes and operative mortality (1.4% versus 1.4%; P=1.00) were not statistically different.

Conclusions— Clopidogrel administration in the cardiology suite increases the risk for hemostatic reoperation and the requirements for blood product transfusions during and after off-pump coronary artery bypass graft surgery.

Key Words: clopidogrel • coronary artery bypass, off-pump • hemorrhage • platelets • reoperation

	Introduction

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The prevalence of percutaneous coronary intervention (PCI) as a treatment modality for coronary artery disease has been attributed to the development of improved patency stents and to the enhanced antiplatelet therapy provided by the new adenosine diphosphate receptor antagonist clopidogrel.^1–3 Its administration has reduced the high (18% to 24%) initial rate of stent thrombosis to a more acceptable (<2%) level.^4–8 The potent antiaggregant effect,⁹ rapid action,¹⁰ low rate of serious side effects^11,12 and better tolerability^11,13,14 of clopidogrel have established it, in combination with aspirin, as the gold standard for stent thrombosis prophylaxis.¹⁵ In many catheterization suites across the country, clopidogrel is given to patients before their diagnostic angiogram to ensure adequate platelet inhibition in case of an "ad hoc" coronary stent implantation.¹⁶ However, a number of patients premedicated with this combination are found to have coronary anatomy more amenable to surgical revascularization.

Editorial p 1638

Clinical Perspective p 1674

In addition, the encouraging results of the large multicenter, randomized Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE)¹¹ and Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE)¹⁷ trials, which demonstrated reduced risk of cardiovascular death, myocardial infarction (MI), cerebrovascular accidents, and recurrent ischemic events in patients with acute coronary syndrome,¹⁸ have prompted many emergency room physicians, internists, and cardiologists to aggressively prescribe prophylactic antiplatelet therapy with clopidogrel.¹⁶ A proportion of these patients will subsequently require urgent or emergent surgical revascularization.

Therefore, for cardiac surgeons, anesthesiologists, and intensivists alike, the enhanced and irreversible platelet inhibition produced by clopidogrel, which frequently is present in patients requiring coronary artery bypass graft (CABG) surgery, has become a concern.^16,19 A number of studies have reported that patients exposed to clopidogrel experience markedly increased postoperative bleeding and transfusion requirements, in addition to a nearly 10-fold increase in reexploration rates after CABG surgery.^15,16,19

Bleeding after CABG can be a combination of inadequate surgical hemostasis, coagulation, and platelet abnormalities.²⁰ Exposure to cardiopulmonary bypass (CPB) causes dilutional thrombocytopenia,^21,22 coagulopathy,²³ sheer-induced platelet dysfunction,^22,24 a systemic inflammatory response, and activation of plasminogen.^25,26

The safety and efficacy of off-pump CABG (OPCAB) have been confirmed through numerous reports.^27–30 As a result of eliminating the deleterious effects of CPB, OPCAB surgery yields a 2-fold reduction in postoperative bleeding, lower surgical reexploration rates, and a 20% to 25% decrease in transfusion requirements.^31,32 However, the action of clopidogrel may possibly reduce these advantages of OPCAB surgery by increasing perioperative hemorrhagic complications.

Consequently, this study was conducted to ascertain the effect of preoperative clopidogrel administration in the incidence of reexploration as a result of hemorrhage, perioperative transfusion requirements, morbidity, and mortality after OPCAB surgery.

	Methods

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Medical Ethics Approval
Before data identification and analysis, study approval was sought and obtained from the Investigational Review Board at our institution. Confidentiality of patient personal information was maintained at all times, consistent with the Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations.

Patient Population and Data
A search of the cardiac surgery research database at our institution for all patients undergoing isolated OPCAB surgery between January 2000 and June 2002 was performed. Patients who underwent emergent or salvage operations, who had a mini-lateral thoracotomy or a mini-sternotomy performed, or who had other cardiac or vascular surgical procedures were excluded from the study. Also excluded from the analysis were patients with recent preoperative exposure to Coumadin, platelet glycoprotein inhibitors, or thrombolytics. Accordingly, a total of 1572 consecutive (after the stated exclusions were applied) patients of 5 highly experienced OPCAB surgeons (P.J.C., S.W.B., M.K.C.D., A.S.B, and K.R.P.) were identified and analyzed. Preoperative patient characteristics and perioperative outcomes were collected prospectively during the patients’ hospitalization and entered into the cardiac surgery research database as part of routine clinical practice.

Study Group Creation and Anticoagulation
All patients who either received a 300-mg oral loading dose of clopidogrel before PCI or had been on a daily oral regimen of 75 mg within 7 days of surgery made up the clopidogrel group. They were compared with the remaining patients who had no exposure or whose surgery was postponed at least 7 days after discontinuing clopidogrel. All patients in both groups received aspirin before surgery. Intraoperative heparin anticoagulation was used in both groups. The initial dose was calculated using a minimum standard of 400 U/kg porcine heparin, with additional dosing administered during the procedure to maintain a target activated clotting time >480 seconds.

Hemorrhagic Outcomes Evaluated
The need for reexploration as a result of bleeding exclusive of any other cardiac or noncardiac cause was designated the primary end point of the study. Reexploration because of hemorrhage was indicated when chest tube drainage exceeded 500 mL in the first hour, 400 mL/h in the first 2 hours, 300 mL/h in the first 3 hours, or 200 mL/h in the first 4 hours or in the case of cardiac tamponade. Ultimately, the decision for hemorrhagic reexploration rested with the surgeons, who share uniformity in clinical practice.

In case of increased intraoperative bleeding, a number of steps were taken to achieve hemostasis. Surgical causes for bleeding were examined; adequate heparin reversal with protamine was administered to normalize the activated clotting time; and packed red blood cell (PRBC) transfusion was initiated as required. Aprotinin, aminocaproic acid, or other hemostatic agents were not routinely used.

Intraoperative and postoperative transfusion rates and quantities were recorded for the principal blood product types, including PRBCs, platelets, and fresh frozen plasma. The volume of blood captured and reinfused intraoperatively by a cell salvage device was not evaluated, but operative blood loss was. Clinical practice guidelines incorporated a PRBC transfusion initiation prompt at a hematocrit of 22 for patients 64 years of age or 24 for patients 65 years of age. Additional blood product transfusions were at the discretion of the individual surgeon, anesthesiologist, or intensivist.

Sample Size Calculations
Data from previously published studies were used to calculate the minimum samples needed to detect significant differences for the outcomes of interest. To calculate the sample size needed to detect significant differences for continuous variables, a study was used in which postoperative PRBC transfusion rates were compared in patients who received clopidogrel before undergoing CABG surgery and in patients who did not.¹⁶ Given a reported SD of 2.16 and aiming for a study power of 80% and an of 0.05, 70 patients in each group would be needed to detect a 1-unit difference in PRBC transfusion rates. Similarly, to determine the sample size needed to assess dichotomous variables, reoperation as a result of hemorrhage rates was used. Given a reoperation rate of 6.8% in the patients who received preoperative clopidogrel and 0.6% in patients who did not and aiming for a study power of 80% and an of 0.05, 137 study patients in each group would be needed.¹⁶ Finally, to assess the minimum sample size needed to evaluate operative mortality, data from the literature were used once more. Using data from a study in which mortality rates were compared in patients who received clopidogrel (1.4%) before undergoing CABG surgery and in patients who did not (0.8%) and aiming for a study power of 80% and an of 0.05, we determined that a total study population of 4743 in each group would be needed to assess a clinically meaningful difference.³³

Statistical Analysis
Data are expressed as percentages, mean±SD, or median (minimum, maximum). Continuous variables were compared by use of the Student t test assuming normal distributions or by the Wilcoxon rank sum test for variables with nonnormal distributions. Dichotomous variables were compared by the ² test or Fisher exact test when cell counts were <5. Ordinal categorical data were compared by use of the Cochran-Armitage test for trends. In all tests, values of P0.05 were considered significant. Mortality risk scores using Parsonnet’s model were calculated to assess differences in preoperative risk and to infer variability between study groups.^34,35

A multivariable logistic regression analysis was used to examine the effect of clopidogrel on the outcomes of interest, including the need for reoperation because of bleeding, PRBC and platelet transfusion rates, the transfusion of multiple PRBC units, and operative mortality. Forward stepwise selection was used to identify significant confounding variables. Potential preoperative confounding factors offered to the logistic regression model included age, female gender, weight, African ancestry, diabetes, renal insufficiency and hemodialysis, urgent case priority, number of grafted vessels, decreased left ventricular ejection fraction, repeated CABG, hypertension, history of MI, and preoperative hematocrit values. These factors have been reported in the literature as important determinants of perioperative hemorrhage.^36–38 Also offered to the logistic model were any significant or closely associated (P0.15) risk factors from the univariate analysis. Model fit analysis was evaluated with the Hosmer-Lemeshow goodness-of-fit statistic, as well as residual diagnostics (deviance and dfBetas). The C statistic was reported as a measure of predictive power. The presence of multicollinearity among the independent variables was checked using diagnostics such as the variation inflation factor and tolerance.

Furthermore, to reduce the effect of preoperative variability between the groups, a propensity score–matched pair analysis was performed. Initially, a logistic regression analysis was performed with the dependent variable being drug received (clopidogrel or not) and independent variables been preoperative confounding factors, which have been reported in the literature as important determinants of perioperative hemorrhage. These included age, female gender, weight, diabetes, hypertension, repeated CABG, urgent case priority, and number of grafted vessels.^37,38 The predicted probability (propensity score) of receiving clopidogrel preoperatively for each patient was subsequently computed from the logistic regression equation. Patients who received no clopidogrel were randomly matched on the basis of the closeness of their propensity score to patients who did. Previous studies have shown that matching on predicted probabilities (propensity scores) can control for selection bias.^39,40 A general estimating equation that adjusts for correlations between matched sets with a logit link function was used to evaluate the effect of clopidogrel on mortality and the postoperative hemorrhagic outcomes of interest.⁴¹ All statistical analyses were performed with SAS for Windows, version 8.0 (SAS Institute, Cary, NC).

The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

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Patient Characteristics and Perioperative Outcomes
A total of 281 patients (17.8%) received clopidogrel preoperatively, and 1291 (82.2%) did not. Patient demographic and preoperative characteristics are presented in Table 1. Although the patients who received clopidogrel had a slightly lower body weight and a higher incidence of preoperative MI and more of them required urgent revascularization, the study groups appeared comparable in preoperative characteristics and risk, with no statistically significant average risk scores as calculated by Parsonnet’s model (13.3±8.8 versus 13.1±8.6 [clopidogrel]; P=0.75). Perioperative outcomes are reported in Table 2. Postoperative rates of stroke, MI, renal failure and need for hemodialysis, need for prolonged ventilation, and intensive care unit length of stay were not significantly different between groups, but the group that received clopidogrel did have a higher median length of stay (4 versus 5 days; P=0.03).

View this table: [in this window] [in a new window]   TABLE 1. Patient Demographic And Pre-operative Characteristics (Univariable Analysis)

View this table: [in this window] [in a new window]   TABLE 2. Patient Perioperative Characteristics and Outcomes (Univariable Analysis)

Hemorrhage-Related Reexploration
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) (Table 2). A separate breakdown analysis of all patients who received clopidogrel by individual surgeons did not reveal significant variations in the incidence of hemostatic reexploration between them.

Subsequently, the risk-adjusted logistic regression analysis confirmed a 5.1-times (95% CI, 2.47 to 10.47; P<0.010) greater likelihood of hemorrhage-induced reexploration in the patients who received clopidogrel (Table 3). After matching 98.9% (n=278) of the clopidogrel-receiving patients to a comparable set of patients who were not exposed to clopidogrel (n=278) through propensity scores, a 3.9-times (95% CI, 1.42 to 10.46; P<0.01) greater likelihood for hemorrhage-related reexploration was demonstrated by the general estimating equation analysis (Table 4).

View this table: [in this window] [in a new window]   TABLE 3. Hemorrhagic Outcomes Of Interest And Significant Predictors (Multivariable Analysis)

View this table: [in this window] [in a new window]   TABLE 4. Hemorrhagic Outcomes of Interest and Significant Predictors (Propensity Score–Matched Analysis)

Allogeneic-Blood Transfusion Requirements
The unadjusted univariable analysis demonstrated that the patients who received clopidogrel had higher rates of intraoperative (22.1% [clopidogrel] versus 16.0%; P<0.01) and postoperative (55.9% [clopidogrel group] versus 34.4%; P<0.01) PRBC transfusions, plus a higher rate of intraoperative blood loss (Table 2). Intraoperative (3.2% [clopidogrel group] versus 1.0%; P<0.01) and postoperative (19.6% [clopidogrel group] versus 9.1%; P<0.01) platelet transfusion rates also were increased in the group administered clopidogrel. When each individual surgeon’s practice of platelet administration to the patients who had received clopidogrel was examined, no significant disparities were found between them. Postoperative fresh frozen plasma administration also was increased in the clopidogrel group (12.1% [clopidogrel group] versus 7.5%; P<0.01), but intraoperative administration was not (Table 2).

In the risk-adjusted multivariable logistic regression analysis model, the predicted odds of receiving a perioperative blood transfusion were 2.6 times (95% CI, 1.94 to 3.60; P<0.01) greater after clopidogrel administration (Table 3). Age, female gender, weight, African ancestry, renal failure, and >4 grafted vessels emerged as independent predictors of blood transfusion (Table 3). Clopidogrel administration also was associated with a 60% increase in the odds of receiving multiple units of perioperative blood transfusions (P=0.02) (Table 3). Similarly, patients who received clopidogrel had a 2.5-times (95% CI, 1.77 to 3.66; P<0.01) increased likelihood for perioperative platelets transfusion, with age, female gender, and weight being associated risk factors (Table 3).

In the matched-pair (matched patients, n=556) statistical analysis, clopidogrel administration was found to be associated with an increased need for PRBC (OR, 2.7; 95% CI, 1.86 to 3.92; P<0.01) and platelet (OR, 2.3; 95% CI, 1.48 to 3.71; P<0.01) transfusions (Table 4).

Operative Mortality
The unadjusted operative mortality rate was not significantly different between the 2 groups (1.4% versus 1.4%; P=1.00). Advanced age was identified in the multivariable logistic regression model as a predictor of mortality; however, preoperative clopidogrel administration was not (Table 3). Similarly, clopidogrel administration was not a significant predictor of operative mortality in the matched-pair analysis (Table 4).

	Discussion

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More research is expanding the clinical applicability of clopidogrel. The results of the CAPRIE trial, a large, randomized, double-blind, multicenter study involving 19 185 subjects, showed an almost 9% decrease in the relative risk for MI, ischemic stroke, or vascular death with prophylactic clopidogrel therapy.^11,42 Similarly, in the CURE trial, a randomized, double-blind, placebo-controlled study, 12 562 patients presenting within 24 hours of the onset of acute coronary symptoms experienced a 20% reduction in cardiovascular mortality, MI, and cerebrovascular accidents after administration of 300 mg clopidogrel in addition to aspirin.^17,18,42 The Clopidogrel for the Reduction of Events During Observation (CREDO) trial evaluated the safety and efficacy of clopidogrel, with or without a loading dose, when given in conjunction with aspirin before PCI. Patients receiving clopidogrel 6 hours before intervention exhibited a 35% reduction in mortality, MI, and urgent target-vessel revascularization interventions.⁴³ These findings confirm those of earlier studies demonstrating the increased efficacy of clopidogrel administration in preventing stent thrombosis after PCI.^1–3,6–8

Therefore, as the indications for clopidogrel use expand, an increasing percentage of patients presenting for surgical coronary revascularization do so subject to irreversible platelet inhibition. 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.^15,16,19 Yende and Wunderink¹⁹ 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. Similarly, in a more recently published cohort study involving 59 patients receiving clopidogrel within 7 days of CABG, increases in reoperation because of hemorrhage (6.8% versus 0.6%) and chest tube drainage (817±761 versus 501±427 mL) and in average amounts of PRBC (2.6 versus 1.6 U), platelet (0.9 versus 0.2 U), and fresh frozen plasma (0.8 versus 0.3 U) transfused were reported.¹⁶

In this study, we 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 had and a 2.5-times-higher demand of platelets. Preoperative clopidogrel administration emerged as the single most significant predictive factor for reexploration because of hemorrhage and for blood product transfusion. Not surprisingly because all have been previously identified in the literature, other common blood product transfusion risk factors included advanced age, female gender, and weight. Additionally, African ancestry, preoperative renal failure, and 4 grafted vessels were independent predictors for increased PRBC transfusions. As far as we can ascertain, this is the first report on the detrimental effects of clopidogrel after OPCAB surgery, bearing considerable clinical implications.

One of the principal benefits of OPCAB surgery is its lower rate of hemorrhagic sequelae,^31,32 but it now appears that preoperative clopidogrel administration ameliorates the beneficial effects of eliminating CPB. Therefore, despite its availability, OPCAB surgery does not seem capable of precluding the potential hemorrhagic complications created by clopidogrel administration. This finding bears considerable clinical implications, for it helps debunk the belief shared by many interventional cardiologists that clopidogrel hemorrhagic complications develop only if CABG surgery is performed using CPB. Consequently, avoidance of hemorrhagic complications can no longer be a carte blanche selection criterion for OPCAB surgery, particularly in clopidogrel-exposed patients.

In contrast, clopidogrel administration after OPCAB surgery might be of benefit for preserving graft patency. Although no studies have been performed using clopidogrel, the effects of the other thienopyridine, ticlopidine, on aortocoronary bypass graft patency have been examined in a randomized double-blind study.⁴⁴ When begun 2 days after CABG surgery, ticlopidine was shown to improve both immediate and 1-year graft patency. Therefore, given its improved safety profile and comparable efficacy, many institutions, including our own, use clopidogrel after OPCAB in an attempt to prevent graft occlusion in high-risk patients.

It is of interest that neither previous studies¹⁹ nor this one, despite its larger sample size and risk-adjusted methodology, demonstrated significant differences in clinical outcome or operative mortality in patients premedicated with clopidogrel. Because of the limited number of index events, the sample size required to make clinically meaningful conclusions is prohibitive for a single-institution study. However, the efficacy of the drug has engrained it in clinical practice to the point where avoidance of clopidogrel exposure does not seem possible. Because the mortality rates after surgery appear to have been unaffected, many physicians perceive no urgency or need to modify their current practice of clopidogrel administration.

However, increased blood product transfusion exposes patients to transfusion-related complications, whereas 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.^15,45,46 Cardiac surgeons were among the first to recognize the need for judicious blood product management. This impetus for blood conservation in cardiac surgery is driven not only by the infectious sequelae and immunological reactions associated with blood transfusion but also by periodic blood shortages nationwide. Furthermore, recent studies have demonstrated that postoperative blood transfusion is an independent predictor of increased long-term mortality after cardiac surgery and thus has a direct impact on patient prognosis.⁴⁷

The current strategy of delaying surgery until platelet function has adequately recovered not only increases patient risk and hospitalization costs but also is not feasible in patients requiring urgent or emergent surgical revascularization. In those patients, platelet transfusion has been used to control persistent hemorrhage postoperatively. However, for the reasons presented above, what may be optimal is a modification of the current practice of clopidogrel administration until after appropriate coronary anatomy for PCI has been identified.

Study Limitations
Limitations of this study include all those inherent in any retrospective single-institution analysis. All data elements, however, were prospectively entered into a cardiac surgery research database according to prespecified definitions, and the data analysis was performed using appropriately risk-adjusted statistical models to adjust for differences in preoperative risks factors. One might suggest that most surgeons and anesthetists were aware of patients who received antiplatelet agents preoperatively, possibly lowering their threshold for platelet administration. Although such a bias might have occurred, it is unlikely to have affected the primary end point (need for reexploration because of hemorrhage). More significantly, a breakdown analysis by individual surgeons revealed uniformity in reoperation because of hemorrhage rates and overall platelet administration, which refutes any bias assertions. Finally, because the study did not possess a large enough patient sample size to reflect statistically significant differences on mortality, regrettably, no conclusive assertions could be made about the effect of clopidogrel on operative mortality.

	Conclusions

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The now prevailing and routine clopidogrel administration in the setting of acute coronary syndrome or for therapeutic PCIs ameliorates 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.

	Acknowledgments

 
We would like to acknowledge the contribution of the late Dr Albert J. Pfister in the conception and design of this study.

Disclosures

None.

	References

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CLINICAL PERSPECTIVE

The efficacy and safety profile of clopidogrel have ingrained it in clinical practice as the gold standard for stent thrombosis prophylaxis after percutaneous coronary revascularization procedures and in producing improved clinical outcomes in patients with acute coronary syndrome. For cardiac surgeons, the enhanced and irreversible platelet inhibition produced by clopidogrel, which frequently is present in patients requiring CABG surgery, has become a concern. A principal benefit of surgical coronary revascularization on a beating heart is its lower hemorrhagic sequelae. However, this study demonstrated significant bleeding-related morbidity when patients underwent coronary revascularization procedures if they were administered clopidogrel, even when surgery is performed without the use of cardiopulmonary bypass (CPB). This finding has considerable clinical implications, for it helps debunk the belief shared by many interventional cardiologists that clopidogrel antiplatelet therapy complications are relevant only when CABG surgery is performed with CPB. It now seems that despite its availability, beating heart surgery does not obviate the potential hemorrhagic complications created by clopidogrel.

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