Clopidogrel Treatment Before Coronary Artery Bypass Graft Surgery Increases Postoperative Morbidity and Blood Product Requirements

Clopidogrel Treatment Before Coronary Artery Bypass Graft Surgery Increases Postoperative Morbidity and Blood Product Requirements Farzan Filsoufi, MD,* Parwis B. Rahmanian, MD,* Javier G. Castillo, MD,* Ronald A. Kahn, MD,† Gregory Fischer, MD,† and David H. Adams, MD* Objectives: An increasing number of patients are referred for coronary artery bypass graft surgery while treated with clopidogrel. This agent inhibits the platelet P2Y12 adenosine-5=-diphosphate (ADP) receptor, which results in an inhibition of platelet aggregation. The aim of this study was to determine the effect of preoperative clopidogrel treatment on postoperative bleeding, mortality, and morbidity in patients after coronary artery bypass graft surgery. Design: Retrospective cohort study. Setting: University hospital (single institution). Participants: One hundred forty-four patients who underwent isolated coronary artery bypass graft surgery. Interventions: Seventy-two patients who received clopidogrel during the preoperative period formed the study group. Seventy-two patients (matched based on age, sex, and preoperative risk profile) served as the control group. Measurements and Main Results: Clopidogrel-treated patients received significantly more platelet (4.4 ⴞ 5.7 v 1.3 ⴞ 3.2 U, p < 0.001) and red blood cell (5.1 ⴞ 4.2 v 2.6 ⴞ 2.6 U, p < 0.001) transfusions compared with the control group. All-cause mortality and morbidity were significantly higher

in clopidogrel-treated patients (n ⴝ 7, 9% v n ⴝ 1, 1%; p ⴝ 0.031). In addition, the lengths of stay in the intensive care unit and the hospital were significantly longer in these patients (2.5 ⴞ 2.7 v 1.4 ⴞ 0.9 days, p ⴝ 0.002; 9.9 ⴞ 11 v 6 ⴞ 2.5 days, p ⴝ 0.003). Despite an increased morbidity in the clopidogrel group, the midterm survival was similar between the 2 groups (1-year and 5-year survival 97% ⴞ 2% and 95.7% ⴞ 3% v 100% ⴞ 0% and 87% ⴞ 10%, respectively; p ⴝ 0.885). Conclusions: Preoperative clopidogrel is associated with increased transfusion requirement after coronary artery bypass graft surgery. The present data suggest that all-cause mortality and major morbidity may also increase in these patients. In clopidogrel-treated patients, coronary artery bypass graft surgery should be delayed in the absence of specific medical indications as recommended by recent American Heart Association guidelines. © 2008 Elsevier Inc. All rights reserved.

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pletely. A few studies have suggested that CABG surgery in patients receiving clopidogrel is associated with increased postoperative blood loss and blood products requirements3,4; however, the impact of clopidogrel treatment before CABG surgery on postoperative mortality and morbidity remains largely unknown.5,6 Herein, the authors report their experience in a recent cohort of patients who underwent CABG surgery and were treated with clopidogrel preoperatively, with an emphasis on bleeding complications, transfusion requirements, hospital outcome, and late survival. The authors particularly analyzed postoperative morbidities that may be related directly to bleeding complications and blood transfusions.

ERCUTANEOUS CORONARY INTERVENTION (PCI) has become the preferred therapeutic approach in many patients with severe coronary artery disease. Periprocedural and 1-month treatments with clopidogrel are administered after PCI with bare metal stents to reduce the risk of early stent thrombosis.1 More recently, the new-generation drug-eluting stents were introduced into clinical practice to reduce the rate of in-stent restenosis. However, it has been suggested that they are associated with a higher rate of late stent thrombosis. In patients who have received a drug-eluting stent, it is recommended to continue treatment with clopidogrel for at least 1 year.1 The administration of a loading dose of clopidogrel is also beneficial in patients with a non–ST-elevation acute coronary syndrome (NSTE ACS). In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events trial, it has been shown that patients who received aspirin and clopidogrel within 24 hours of onset of NSTE ACS had an improved outcome with a reduced rate of a composite of mortality and cardiovascular morbidity (9.3%) compared with patients with only aspirin (11.4%, p ⬍ 0.001).2 Currently, an increasing number of patients are referred for coronary artery bypass graft (CABG) surgery while they are treated with clopidogrel. The potential impact of this preoperative treatment on surgical outcome has not been investigated com-

From the Departments of *Cardiothoracic Surgery and †Anesthesiology, Mount Sinai School of Medicine, New York, NY. Address reprint requests to Farzan Filsoufi, MD, Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, 1190 Fifth Avenue, Box 1028, New York, NY, 10029. E-mail: Farzan.filsoufi@ mountsinai.org © 2008 Elsevier Inc. All rights reserved. 1053-0770/08/2201-0012$34.00/0 doi:10.1053/j.jvca.2007.10.009 60

KEY WORDS: coronary artery bypass graft surgery, clopidogrel, bleeding, mortality, morbidity

METHODS The authors conducted a retrospective study among 2,725 consecutive patients who underwent isolated CABG procedures at the authors’ institution between January 1998 and December 2005. The protocol was approved by the local institutional review board and complied with the Health Insurance Portability and Accountability Act regulations and the ethical guidelines of the 1975 declaration of Helsinki, as revised in 2000. The approval included a waiver of informed consent. Clinical variables were prospectively entered into the New York State Department of Health (NYSDH, State Cardiac Advisory Committee) data registry. The NYSDH data registry represents a mandatory verified peerreviewed data-collection system including all adult cardiac surgery procedures in the state New York and records and analyzes data in a strictly supervised and widely reported fashion. Patient demographics and risk factors, operative information, and postoperative outcome data were retrospectively analyzed. Additional information was obtained from patient charts when necessary. Follow-up survival information was obtained by crossmatching patients’ social security numbers with the Web-based social security death index. Table 1 summarizes preoperative variables included in this study and their definition as indicated. A total of 72 patients with clopidogrel treatment at the time of surgery were identified and served as the study group. This included patients in whom clopidogrel was discontinued within 72 hours of

Journal of Cardiothoracic and Vascular Anesthesia, Vol 22, No 1 (February), 2008: pp 60-66

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Table 1. Variables Included in this Study Variables Age Sex Preoperative variables Weight (kg) Height (cm) Body Mass Index (kg/m2) Diabetes mellitus requiring medication Hypertension Preoperative renal insufficiency (creatinine ⬎2.5 mg/dL or dialysis) Prior cerebrovascular accident Peripheral vascular disease Chronic obstructive pulmonary disease Hepatic failure (Liver disease and bilirubin ⬎2 mg/dL and albumin ⬍3.5 g/dL) Prior myocardial infarction Prior cardiac surgery Congestive heart failure (NYHA class III and IV) Active endocarditis Ejection fraction (%) Urgent operation (requiring operation during current hospitalization) Emergent operation (refractory unrelenting cardiac compromise requiring emergency operation) Preoperative intra-aortic balloon pump Intraoperative variables Type of procedure (conventional CABG, off-pump CABG) Cardiopulmonary bypass time Cross clamp time (X-clamp time) Number of grafts Postoperative variables Hospital mortality Renal failure (Creatinine ⬎2.5 mg/dL more than 7 days or dialysis) Respiratory failure (prolonged ventilator therapy (⬎72 h), reintubation or tracheostomy) Stroke (new permanent neurological event) Postoperative myocardial infarction Bleeding requiring reoperation Deep sternal wound infection Unplanned reoperation Gastrointestinal complication Length of hospital stay Abbreviations: CABG, coronary artery bypass grafting; NYHA, New York Heart Association.

surgery. To create an appropriate comparison group, patients without clopidogrel treatment who underwent isolated CABG surgery during the same timeframe were selected if age, sex, ejection fraction, and predicted mortality by EuroSCORE were within the same range as the clopidogrel cases. SAS software (SAS Institute Inc, Cary, NC) was used to create a random sample. Using this technique, 72 patients without clopidogrel treatment at the time of surgery with similar demographics and risk profile were identified and served as the control group. Outcome measures for this study included hospital mortality, postoperative bleeding and major complications (respiratory failure, renal failure, deep sternal wound infection, stroke, and gastrointestinal complications), time on ventilator, length of stay in the intensive care unit, and hospital and late survival. Hospital mortality was defined as death after the procedure before patient discharge regardless of the duration

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of hospitalization. Patients who died after discharge from the hospital but within 30 days after the procedure were also considered as hospital deaths. Bleeding was assessed by chest-tube output within 48 hours after surgery, transfusion requirements, and the need for reoperation. Respiratory failure was defined as prolonged ventilator therapy (⬎72 hours) or the need for reintubation or tracheostomy. Renal failure was defined as creatinine ⬎2.5 mg/dL for more than 7 postoperative days or the need for dialysis. Stroke was defined as a new permanent neurologic event occurring peri- or postoperatively. The definition of these complications was based on the NYSDH data-registry definitions. All procedures were performed by using standard anesthetic and surgical techniques adapted to the individual procedures. Anesthesia was induced with midazolam, 40 to 60 ␮g/kg, and fentanyl, 20 ␮g/kg. After induction, anesthesia was maintained with isoflurane. A small skin incision and a full sternotomy were performed in all patients. Twentysix percent (n ⫽ 38) of procedures were performed without the use of cardiopulmonary bypass (CPB) (off-pump coronary artery bypass). The remaining 74% (n ⫽ 106) procedures were performed by using CPB. After systemic heparinization obtained an activated coagulation time of at least 400 seconds, CPB was established between the ascending aorta and the right atrium by using a 2-stage cannula. During CPB, a minimum flow of 2.2 L/min/m2 and a perfusion pressure of ⬎60 mmHg were maintained in all patients. After aortic cross-clamp and cardioplegic arrest, distal anastomoses were performed first followed by proximal anastomoses using the single cross-clamp technique. Aortic crossclamp was released thereafter, and patients were weaned from CPB after a short reperfusion. Off-pump CABG surgery was performed based on the surgeon’s preferences. However, this technique was favored in elderly patients, particularly those with significant comorbidities such as renal dysfunction. In patients undergoing off-pump coronary artery bypass, heparin was administered to achieve an activated coagulation time of 300 seconds. Coronary stabilizer and cardiac positioning devices were used to improve the exposure of the coronary arteries and to facilitate the distal anastomoses under beating-heart conditions. Intracoronary shunts were inserted to avoid myocardial ischemia during the construction of the distal anastomoses. Proximal anatomoses were created using a side-bite clamp. Protamine was administered based on the heparin level after the completion of the coronary anastomoses. Antifibrinolytic therapy consisted of ␧-aminocaproic acid in 138 (96%) patients, whereas aprotinin was administered in only 6 (4%) patients; all the latter were clopidogrel recipients. A loading dose of ␧-aminocaproic acid (150 mg/kg) was administered for 30 minutes followed by a continuous infusion of 15 mg/kg/min. No ␧-aminocaproic acid was added to the CPB circuit prime. The infusion was continued until the end of surgery. Aprotinin was administered at a loading dose of 2,000,000 KIU intravenously for a 30-minute period. After completion of the loading dose, a maintenance dose of 500,000 KIU was started and continued until the surgical procedure was finished. In addition 2,000,000 KIU were added to the CPB circuit prime. The decision regarding the administration of ␧-aminocaproic acid or aprotinin was based on the individual cardiac surgeon’s and anesthesiologist’s preference. Postoperatively, all patients were transferred to the intensive care unit. Patients were weaned from the ventilator when hemodynamic stability was achieved, no major postoperative bleeding (chest tube output ⬍100 mL/h), no signs of tamponade, and no evidence for hemothorax in chest x-ray occurred, and adequate consciousness was obtained. Red blood cell transfusions and the administration of blood products such as platelets, fresh frozen plasma, and cryoprecipitate were based on individual physician’s preference. The authors did not use a specific bleeding management algorithm in this study. Normally distributed continuous variables are presented as mean ⫾ standard deviation and otherwise as median ⫾ interquartile range. Categoric variables are shown as the percentage of the sample. A

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Table 2. Demographics and Risk Factors

Table 4. Operative Data

Clopidogrel Group Control Group (n ⫽ 72) (n ⫽ 72) p Value

Age (y) Age ⬎70 (y) Sex (female) BMI (kg/m2) BMI ⬎30 Congestive heart failure Previous myocardial infarction Previous cerebrovascular accident Peripheral vascular disease COPD Renal failure or dialysis Diabetes mellitus Hypertension Previous cardiac operation IABP Ejection fraction (%) Ejection fraction ⱕ30% On aspirin Coronary disease extent One vessel Two vessels Three vessels Previous PCI Priority Elective Urgent Emergent EuroSCORE (%)

63 ⫾ 11 13 (18) 29 (40) 28 ⫾ 6 66 (92) 11 (15) 36 (50)

63 ⫾ 11 13 (18) 29 (40) 27 ⫾ 6 72 (100) 4 (6) 28 (39)

0.98 0.59 0.57 0.19 0.43 0.05 0.12

9 (12)

9 (12)

0.60

10 (14) 1 (1) 6 (8) 38 (53) 31 (43) 4 (8) 4 (6) 47 ⫾ 13 15 (21) 65 (90)

8 (11) 0 (0) 3 (4) 34 (47) 18 (25) 1 (1) 3 (4) 45 ⫾ 15 13 (18) 63 (88)

0.40 0.50 0.25 0.31 0.02 0.18 0.50 0.36 0.42 0.49 0.60

6 (8) 10 (14) 56 (78) 45 (63)

7 (10) 12 (17) 53 (74) 22 (31)

26 (36) 39 (54) 7 (10) 8.3 ⫾ 11

34 (47) 32 (45) 6 (8) 6.6 ⫾ 6

⬍0.001 0.21

0.24

Abbreviations: COPD, chronic obstructive pulmonary disease; PCI, percutaneous coronary intervention; IABP, intra-aortic balloon pump; BMI, body mass index.

p value ⬍0.05 was considered statistically significant for all used tests. The chi-square test and Fischer exact test were used to evaluate the potential relationship between clopidogrel treatment and hospital mortality and morbidities in the entire study population. Long-term survival was analyzed by using Kaplan-Meier survival curves. Differences in patient characteristics were controlled by Cox proportional hazard analysis. The statistical analyses were performed with the use of SAS 9.0 and SPSS 15 (SPSS Inc, Chicago, IL). RESULTS

There were no significant differences in the main demographic characteristics and risk profile between clopidogrel-

Clopidogrel Group (n ⫽ 72)

Aprotinin administration Aminocaproic acid administration Off-pump procedures Number of grafts (mean ⫾ SD) Aortic cross-clamp time (min) Cardiopulmonary bypass time (min)

Control Group (n ⫽ 72)

6 (8) 0 (0) 68 (92) 72 (100) 19 (26) 19 (26) 3.3 ⫾ 1.2 3.3 ⫾ 1.3 95 ⫾ 32 95 ⫾ 28 125 ⫾ 49 112 ⫾ 40

p Value

0.014 0.014 0.58 0.46 0.14 0.38

treated patients and the control group (Table 2). However, patients with clopidogrel treatment were more likely to be hypertensive and as expected presented significantly more often with a history of previous PCI compared with the control group (n ⫽ 45 [63%] v n ⫽ 22 [31%], p ⬍ 0.001). There was no difference in regard to the urgency of the procedure between clopidogrel-treated patients and the control group. The predicted mortality by EuroSCORE was similar (8.3% ⫾ 11 % v 6.6% ⫾ 6%, p ⫽ 0.24). The exposure to aspirin was also the same in the treatment and control groups. There were no differences with respect to preoperative hemoglobin, hematocrit, platelet count, international normalized ratio, prothrombin time, partial thromboplastin time, and fibrinogen when clopidogrel patients were compared with the control group (Table 3). The distribution of conventional CABG and off-pump CABG surgery were identical between the 2 groups (n ⫽ 19). The procedure was performed with a mean number of 3.3 ⫾ 1.2 and 3.3 ⫾ 1.3 grafts in the study and control group, respectively (p ⫽ 0.46). The mean CPB and cross-clamp times were 125 ⫾ 49 and 95 ⫾ 32 minutes in the study group compared with 112 ⫾ 40 and 95 ⫾ 28 minutes in the control group (p ⫽ 0.38 and p ⫽ 0.14, respectively) (Table 4). Patients with clopidogrel treatment received significantly more red blood cells (5.1 ⫾ 4.2 U v 2.6 ⫾ 2.6 U, p ⬍ 0.001) and platelets (4.4 ⫾ 5.7 U v 1.3 ⫾ 3.2 U, p ⬍ 0.001) compared with the control group. There was no difference in the administration of fresh frozen plasma and cryoprecipitate between the 2 groups (Table 5). Only 8% (n ⫽ 6) of clopidogrel-treated patients did not require any transfusion compared with 26% (n ⫽ 19) of the control group (p ⫽ 0.004). Postoperative chest-tube output (within 48 hours after CABG surgery) was not different when comparing the study and control groups

Table 3. Preoperative Laboratory Values

Hemoglobin (g/dL) Hematocrit (%) Platelets (⫻103/␮L) Fibrinogen PT (s) INR PTT (s)

Clopidogral Group (n ⫽ 72)

Control Group (n ⫽ 72)

p Value

13 ⫾ 1.8 36 ⫾ 5 215 ⫾ 74 460 ⫾ 109 14 ⫾ 1.1 1.1 ⫾ 0.38 38 ⫾ 16

12 ⫾ 1.9 37 ⫾ 5 223 ⫾ 63 406 ⫾ 101 14 ⫾ 2.1 1.2 ⫾ 0.9 37 ⫾ 14

0.23 0.35 0.47 0.05 0.89 0.58 0.74

Abbreviations: INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time.

Table 5. Blood Product Requirements, Blood Loss, and Time on Ventilation Postoperative Outcome

Clopidogrel Group (n ⫽ 72)

Control Group (n ⫽ 72)

p Value

Red blood cells (U)* Fresh frozen plasma (U)* Platelets (U)* Cryoprecipitates (U)* Chest-tube output (mL) Time on ventilation (h)

5.1 ⫾ 4.2 1.4 ⫾ 2.8 4.4 ⫾ 5.7 4.3 ⫾ 5.7 960 ⫾ 362 31 ⫾ 97

2.6 ⫾ 2.6 1.0 ⫾ 1.9 1.3 ⫾ 3.2 0.6 ⫾ 3.2 851 ⫾ 570 13 ⫾ 21

⬍0.001 0.11 ⬍0.001 0.25 0.54 0.39

*Pooled units (5 units per pool).

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Table 6. Mortality, Morbidity, Intensive Care Unit, and Hospital Length of Stay

Postoperative Outcome

Any major complication or death Mortality In-hospital mortality Morbidity Postoperative stroke Postoperative myocardial infarction Postoperative renal failure, dialysis Respiratory failure Deep sternal wound infection Postoperative systemic infection Reexploration for bleeding Gastrointestinal complications LOS in the ICU (days) LOS in hospital (days)

Clopidogrel Group (n ⫽ 72)

Control Group (n ⫽ 72)

p Value

7 (9)

1 (1)

0.03

3 (4.2)

0 (0)

0.12

1 (1) 0 (0)

0 (0) 0 (0)

0.50 NA

0 (0)

0 (0)

NA

3 (4) 1 (1) 2 (3) 0 (0) 1 (1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2.5 ⫾ 2.7 1.4 ⫾ 0.9 9.9 ⫾ 11 6 ⫾ 2.5

0.31 0.25 0.50 NA NA 0.002 0.083

Abbreviations: ICU, intensive care unit; LOS, length of stay; NA, not applicable.

(960 ⫾ 362 mL v 850 ⫾ 570 mL, p ⫽ 0.54). No cases of reoperation for bleeding occurred in the present study. Three deaths occurred in this series, all in the study group. However, the mortality between the 2 groups was not significantly different. All these deaths were cardiac related and were not caused by bleeding complications. Postoperative morbidities in clopidogrel recipients included respiratory failure (n ⫽ 3), stroke (n ⫽ 1), sternal wound infection (n ⫽ 2), and postoperative sepsis (n ⫽ 1) (Table 6). When analyzing a composite of major morbidities and hospital mortality, 10 events occurred in 7 (9%) patients with clopidogrel treatment compared with 1 (1%) event in the control group (p ⫽ 0.031). The mean length of stay in the intensive care unit and the hospital was significantly longer when comparing the study and control groups (2.5 ⫾ 2.7 v 1.4 ⫾ 0.9 days, p ⫽ 0.002; 9.9 ⫾ 11 v 6 ⫾ 2.5 days, p ⫽ 0.003). Follow-up information was obtained for all surviving patients. The mean follow-up time was 2.2 ⫾ 1.2 years. The midterm survival of discharged patients was not different in patients receiving clopidogrel compared with patients without this medication at time of surgery. One-year and 5-year survival rates were 97% ⫾ 2% and 95.7% ⫾ 3% for patients with clopidogrel and 100% ⫾ 0% and 87% ⫾ 10% for the control group, respectively (p ⫽ 0.89). Figure 1 shows Kaplan-Meier survival curves. DISCUSSION

This retrospective study was conducted to analyze the impact of preoperative treatment with clopidogrel at the time of CABG surgery on early and midterm outcome. Patients with clopidogrel treatment had a significantly increased requirement for platelet and red blood cell transfusions compared with the nonclopidogrel recipients. The present data suggest that allcause mortality and morbidity were higher in patients with clopidogrel treatment. In addition, the lengths of stay in the

ICU and the hospital were significantly longer in clopidogreltreated patients compared with patients without this medication. Despite an increased morbidity in the clopidogrel group, the midterm survival was similar between the 2 groups. Clopidogrel, a thienopyridine, acts by directly inhibiting the platelet P2Y12 adenosine 5=-diphosphate (ADP) receptor, reducing ADP-mediated platelet activation and subsequent platelet aggregation.7 The ADP-receptor blockade is irreversible; therefore, the duration of the therapeutic effect of clopidogrel depends on the circulating lifespan of platelets, which ranges between 5 and 10 days. It has been shown that clopidogrel significantly reduces the rate of stent thrombosis8 and has synergistic and accelerated platelet inhibitory effects when combined with aspirin.9 In addition, it has been shown that clopidogrel improves the outcome of patients with NSTE ACS.2 In the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events trial, a multicenter study analyzing more than 12,000 patients with NSTE ACS, patients who received clopidogrel together with aspirin within 24 hours after the event had a significantly reduced mortality and cardiovascular morbidity compared with patients who received aspirin alone.2 Today, clopidogrel has become an indispensable therapy in patients undergoing percutaneous coronary interventions. With the broader prescription of clopidogrel among patients with coronary artery disease, the prevalence of clopidogreltreated patients requiring surgical revascularization has steadily increased during the recent era. The timing of surgery in this subgroup of patients remains controversial. It has been suggested that CABG surgery in these patients is associated with coagulopathy leading to an increased transfusion requirement compared with patients without this treatment.3,10 In 2001, Yende and Wunderink3 analyzed 247 patients undergoing CABG surgery including 51 patients with clopidogrel treatment and reported that this treatment significantly increased the rate of blood product transfusions after surgery. These data were confirmed by Mehta et al4 who evaluated a multicenter series of patients with NSTE ACS undergoing CABG surgery. The authors reported a significant increase in blood transfusion requirements when recent clopidogrel-treated patients were compared with patients who underwent CABG surgery more than 5 days after clopidogrel discontinuation (odds ratio, 1.36). In the present series, the authors also observed an increased rate of red blood cell and platelet transfusion in clopidogrel-treated patients. The amount of red blood cell administration was twice as high in the clopidogrelexposed patients compared with the control group. Only 8% of clopidogrel-treated patients did not require any transfusion. Some authors also observed an increased rate of reoperation for bleeding in clopidogrel-treated patients after CABG surgery.3,11 Yende et al3 reported a 9.8% incidence of re-exploration for bleeding among clopidogrel-treated patients (compared with 1.6% in the control group, p ⫽ 0.01) and identified clopidogrel treatment as an independent risk factor for this condition (odds ratio ⫽ 6.9). Similar results were presented by Hongo et al11 who analyzed a series of 224 patients undergoing CABG surgery (clopidogrel exposure within 7 days, n ⫽ 59, and no clopidogrel exposure, n ⫽ 165) and showed a 10-fold increase in reoperation for bleeding in clopidogrel-treated patients (6.8%) compared with those without clopidogrel (0.6%,

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Fig 1. Unadjusted (A) and adjusted (B) survival curves of discharged patients who received clopidogrel and those who did not. (Color version of figure is available online.)

p ⫽ 0.018). This was not confirmed by the present study in which no reoperation for bleeding occurred in this patient population. This is probably related to a meticulous and prolonged hemostasis during the surgical procedure in all patients at risk for bleeding. In addition, an aggressive approach to the

management of postoperative bleeding with the early administration of blood products in patients with coagulopathy as well as a liberal use of antifibrinolytic agents have probably contributed to minimizing the risk of this complication. Currently, the authors systematically perform a thromboelastogram in

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clopidogrel-exposed patients after the completion of CPB in the operating room. In addition, the authors also have point-of-care testing for both platelet count and platelet function. Depending on the clinical presentation and the presence and severity of coagulation disorder, the authors proceed with early blood product transfusion. Particularly, normal platelet count with decreased function is a trigger for platelet transfusion. Postoperative bleeding complications have been shown to adversely impact postoperative outcomes.12,13 However, most studies on the effect of clopidogrel in coronary surgery focus mainly on bleeding and transfusion requirements and do not provide information with respect to mortality and morbidity in this subgroup of patients. A few observational studies have reported controversial data with respect to the influence of preoperative clopidogrel on postoperative complications. Kapetanakis et al5 reported an increased rate of complications including stroke (2.9% v 1.7%, p ⬍ 0.01) and myocardial infarction (2.2% v 0.7%, p ⬍ 0.01) in clopidogrel-treated patients undergoing CABG surgery. Ascione et al6 analyzed their series of patients undergoing isolated CABG surgery and reported the highest mortality rate in patients exposed to clopidogrel within 5 days of surgery compared with patients without clopidogrel (8% v 1%, p ⫽ 0.008). These authors also reported an increased rate of reintubation, stroke, need for intra-aortic balloon pump support, and arrhythmia in clopidogrel-treated patients. In contrast, Hongo et al11 could not identify clopidogrel treatment before CABG surgery as a predictor of postoperative complications. In the present study, the authors observed that all-cause mortality and morbidity were significantly increased in clopidogrel-treated patients compared with patients without this medication (9% v 1%, p ⫽0.031). The 2 most common complications were respiratory failure and infections. The authors were not able to show a direct causative relationship between blood product transfusion and the occurrence of this complication; however, prior reports have shown that the transfusion of large amounts of blood products after cardiac surgery lead to an increased rate of these 2 complications.14,15 Finally, similar to other previous studies,11 the authors have shown that the length of stay in the intensive care unit and the hospital were significantly longer in clopidogrel-treated patients. These findings raise major concerns regarding increased hospital costs after early surgical intervention in this group of patients. A careful analysis of previous studies and the present results indicates that medical circumstances were not the primary reason for early revascularization in most clopidogrel-exposed patients. In a multicenter study analyzing NSTE ACS patients referred for CABG surgery, Mehta et al4 reported that the overwhelming majority of patients with clopidogrel treatment underwent early CABG surgery without a specific medical indication. The authors assumed that economic constraints and improved perioperative management of coagulopathy in cardiac surgery patients achieved during the recent era were potential explanations for this early intervention. The present data as well as others indicate that even today, despite the progress in the management of coagulation disorder, major postoperative bleeding remains a significant issue for which there is no optimal treatment and favors the occurrence of other postoperative complications. This underlines that CABG surgery should be delayed in clopidogrel-treated patients unless there is a clear

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medical indication for urgent surgical revascularization. The authors, therefore, recommend a strict application of the American Heart Association/American College of Cardiology guidelines, which encourage that CABG surgery should be delayed for 5 to 7 days after the exposure to clopidogrel.16 If CABG surgery cannot be delayed, the potential benefit needs to be weighed against the risks, and additional measures should be taken to reduce the risk of postoperative bleeding.4 In a recent study, Chen et al17 analyzed 45 patients who received clopidogrel within 6 days of CABG surgery and used an algorithm-driven treatment for the management of postoperative bleeding. Clinical criteria, laboratory parameters, and the assessment of platelet function by ADP aggregometry were used for decision making regarding blood product transfusion. By using this approach, the authors were able to significantly reduce the units of blood products on average by 30% compared with their historic data. The authors also suggested that the ADP aggregometry test can identify patients at risk for bleeding and may facilitate the decision whether to delay or proceed with CABG surgery. In patients with the need for immediate coronary revascularization, they recommend platelet transfusion to achieve a target ADP aggregation response of at least 40% at the time of surgery.17 Finally, the use of antifibrinolytic agents may play an important role in significantly reducing the rate of postoperative bleeding in clopidogrel-receiving patients. In a 2005 study, van der Linden et al18 presented their data from a randomized placebo-controlled study including 75 clopidogreltreated patients with unstable angina referred for surgery. Patients received either aprotinin or placebo during the conventional CABG procedure. The authors were able to show that the administration of aprotinin significantly reduces the rate of postoperative bleeding and transfusion requirements. In this study, 57% of the aprotinin group received transfusions, whereas 79% of the control group were exposed to blood products (p ⫽ 0.02). However, these findings are tempered by the association between aprotinin and adverse outcomes after cardiac surgery.19 With the recent withdrawal of aprotinin from the market in the United States, other antifibrinolytics could be used if desired by the surgical team. LIMITATIONS

This study was a retrospective analysis with a small sample size; therefore, conclusions are limited in their applicability. Data were, however, prospectively entered according to the NYSDH data registry, and a control group was defined for risk-adjusted analysis. Another limitation is that the information about clopidogrel treatment was available for both cardiac surgeons and anesthesiologists and might have created a bias in favor of early administration of blood products in the clopidogrel group. In addition, similar to all other previous studies, the authors did not use a predetermined algorithm for a decisionmaking process regarding blood product administration. Finally, it has been suggested that potential confounders such as a higher proportion of nonelective cases or accumulation of preoperative risk factors in clopidogrel recipients may influence postoperative results.20 However, in the present study performed by using a risk-adjusted control group, the authors attempted to eliminate the impact of confounding factors. There were no differences in terms of preoperative risk factors or priority of procedure.

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