In-Hospital Patients Exposed to Clopidogrel Before Coronary Artery Bypass Graft Surgery: A Word of Caution

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1 In-Hospital Patients Exposed to Before Coronary Artery Bypass Graft Surgery: A Word of Caution Raimondo Ascione, MD, MCh, Arup Ghosh, FRCS, Chris A. Rogers, PhD, Alan Cohen, FRCA, Chris Monk, FRCA, and Gianni D. Angelini, MD, MCh Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom Background. The aim of our study was to investigate the independent effect of preoperative exposure to aspirin, heparin, and clopidogrel on early clinical outcomes of in-hospital referral patients undergoing first time coronary artery bypass graft (CABG) surgery. Methods. Outcomes for in-hospital referrals for CABG between January 2001 and January 2002 were prospectively recorded. Exposure to aspirin, heparin, and clopidogrel during the 5 days before surgery was recorded, and their effect on outcome was explored using multiple regression methods. The effect of clopidogrel given within 48 hours before surgery versus stopped at least 48 hours before the operation was also investigated. Results. In-hospital referral patients represented 40% (473 of 1,185) of the total surgical population; 304 (64.7%) were prescribed aspirin, 116 (24.7%) heparin, 91 (19.4%) clopidogrel, and 133 (28.3%) had all anticoagulants stopped 5 days before surgery. In-hospital mortality was 2.3% (95% confidence interval [CI]: 1.1 to 4.1) and was highest among those exposed to clopidogrel (odds ratio 16.9, 95% CI: 2.10 to 136, p 0.008). Seven of the 11 deaths occurred in patients given clopidogrel. Postoperative intraaortic balloon pump, arrhythmia, reintubation, and stroke were all significantly more common when clopidogrel was prescribed (relative risk estimates all greater than 1.5, p values all < 0.021). Blood loss was 37% higher in the patients given clopidogrel (95% CI: 3% to 82%, p 0.033). patients were more likely to need a reoperation for bleeding (p < 0.001) and require transfusions (p < 0.015). Intubation time and hospital stay were also longer (p and p 0.019, respectively). Heparin was also associated with longer hospital stay (p < 0.001) and aspirin use with reduced stay (p 0.041), but for all other outcomes, no association with aspirin or heparin use was found. Comparison of subgroups of clopidogrel patients suggested mortality was highest when clopidogrel was given in the 48 hours before surgery. Conclusions. Our study suggests that among in-hospital referral patients, preoperative exposure to clopidogrel within 5 days before CABG may increase early mortality and morbidity, and that the mortality risk is greatest when the drug is given within 48 hours of surgery. (Ann Thorac Surg 2005;79:1210 6) 2005 by The Society of Thoracic Surgeons Since the advent of coronary stenting, a variety of antiplatelet therapies have been proposed to prevent stent thrombosis [1]. The adenosine diphosphate (ADP) receptor antagonist ticlopidine combined with aspirin has been recently replaced by clopidogrel on the basis of a superior safety and tolerability [1 4]. is currently used to reduce ischemic events in patients with a history of previous stroke, myocardial infarction, or peripheral vascular disease [5]. More recently, there has been a trend toward extending the use of clopidogrel to patients presenting with acute coronary syndrome and non ST-elevation myocardial infarction [6]. The in Unstable Angina to prevent Recurrent Events (CURE) trial [7] suggests that in such patients clopidogrel pretreatment, followed by long-term therapy, is beneficial in reducing major cardiovascular Accepted for publication Sept 24, Address reprint requests to Dr Ascione, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom; r.ascione@ bristol.ac.uk. events. Hospitalized patients, however, may require urgent coronary surgery during the same admission, and in this respect the preoperative exposure to anticoagulant drugs may increase postoperative bleeding. The aim of this study was to investigate the effect of preoperative exposure to aspirin, heparin, and clopidogrel on early in-hospital outcomes among in-hospital referral patients requiring CABG during the same hospital admission. Material and Methods Patient Selection A consecutive series of in-hospital referrals for first-time CABG operated on between January 2001 and January 2002 were studied. In-hospital referral at our institution is defined as any patient with unstable angina or unfavorable coronary anatomy (ie, significant left main stem disease plus significant right coronary disease), or both, referred for surgery to be carried out as soon as possible during the 2005 by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg ASCIONE ET AL 2005;79: CLOPIDOGREL EXPOSURE BEFORE CABG 1211 same admission (within 1 to 14 days). These patients are managed on the cardiac ward till the day before surgery under the care of an independent consultant cardiologist, who also decides on the most appropriate antiplatelet/ anticoagulant regimen. Emergency CABG operations were excluded. Antiplatelet/anticoagulant therapies with aspirin, heparin, and clopidogrel received within 5 days of surgery were documented for each patient. The project was approved by the Clinical Audit Committee. Anesthetic and Surgical Techniques Anesthetic technique, heparin, and protamine management were standardized for all patients and has been previously reported [8]. For patients undergoing on-pump CABG, nonpulsatile flow was used (2.4 L m 2 min 1 ). Systemic temperature was kept between 34 C and 36 C. Myocardial protection was achieved by using intermittent anterograde hyperkalemic warm blood cardioplegia [8]. For patients undergoing off-pump CABG, the target vessel was exposed, opened, an intracoronary shunt was used, and the anastomosis performed using a pressure stabilizer [9]. Postoperative Management Patients were transferred to the intensive care unit (ICU) and managed according to unit protocols [6 8]. Patients were extubated as soon as they met the following criteria: hemodynamic stability, no excessive bleeding ( 80 ml/ h), normothermia, and consciousness with pain control. Fluid management postoperatively consisted of 5% dextrose infused at 1 ml kg 1 h 1, with additional Gelofusine or blood to maintain normovolemia and hematocrit greater than 24%. Aspirin 300 mg daily was started on the first postoperative day. Management of Postoperative Bleeding and Related Treatment On arrival in the ICU, all patients underwent a routine coagulation screening. In the case of excessive bleeding (more than 150 ml/h for longer than 2 consecutive hours), derangements of the coagulation profile were treated with a diagnosis-directed therapy. Elevation of activated clotting time (ACT) of longer than 30 seconds when compared with baseline was treated with an additional 25 mg dose of protamine. Values of prothrombin time, activated partial thromboplastin time, and International Normalized Ratio (INR) of more than 1.5 times control, suggesting factor deficiency, were corrected by infusion of fresh frozen plasma. A platelet count of less than 80,000/ L was an indication for platelet transfusion. A hematocrit of less than 24% was corrected by transfusion of red blood cells. The total blood loss was measured starting immediately after closure of the chest in the operating theater until the chest drains were removed, providing the drainage was less than 20 ml/h for 3 consecutive hours. Indications for reopening were a blood loss greater than 500 ml over the first hour, more than 300 ml for 2 consecutive hours, more than 200 ml for 3 consecutive hours, or more than 1 L over the first 8 hours. Data Collection, Monitoring, and Definitions All perioperative clinical and outcome data were collected prospectively and entered into the Patient Activity Tracking System (PATS) database (Dendrite Systems, London, UK). Antiplatelet/anticoagulant therapy data for the first 3 months of the study were extracted retrospectively from the clinical notes, whereas thereafter the data were collected prospectively. Ascertainment was checked against the unit database, and data for a small number of cases missed were obtained retrospectively. Clinical diagnostic criteria for preoperative and postoperative myocardial infarction were new Q waves of greater than 0.04 ms or a reduction in R waves greater than 25%, or both, in at least two leads. Pacing, arrhythmias, and inotrope requirement were recorded and defined as previously reported [10]. Pulmonary complications included chest infection, ventilation failure, reintubation, and tracheostomy. Postoperative blood loss was defined as total chest tube drainage [11]. Patients with focal neurologic deficits (motor weakness, dysphasia, aphasia, cognitive deficits, seizures, or coma) were evaluated by staff intensivists. The clinical diagnosis of stroke was made by the intensivist and confirmed by a neurologist on the basis of the clinical findings. A computed tomography scan was routinely performed in these patients as soon as the clinical condition allowed the patient to be moved. Renal complications included acute renal failure as defined by the requirement of hemodialysis. Finally, infective complications were defined by positive culture and requirement for antibiotic therapy [10]. In calculating the Thrombolysis In Myocardial Infarction (TIMI) risk score [12], we were unable to include family history as a risk factor for coronary artery disease, as this is not recorded in the database. Statistical Analysis The data are presented for the study population as a whole and for three subgroups: patients whose anticoagulant therapy was stopped 5 days before surgery; patients who received only aspirin or heparin, or both; and patients who were given clopidogrel (with or without aspirin or heparin, or both). The effect of different anticoagulant therapies on inhospital outcomes was assessed using standard regression methods: multiple linear regression for continuous variables, logistic regression for binary variables, and Cox proportional hazards regression for time to event variables. Model assumptions were checked and, where untenable, alternative models were explored. Analyses were carried out using Stata version 8.2 (Stata Corporation, College Station, TX). All analyses were adjusted for differences in preoperative risk factors (demographic and cardiac factors, and comorbidity), and differences in operative procedure among patients. These potential confounding variables were specified in advance of the analysis, and no attempt was made to assess their statistical significance, either individually or together. Potential confounders were excluded only when the analysis became unstable and the

3 1212 ASCIONE ET AL Ann Thorac Surg CLOPIDOGREL EXPOSURE BEFORE CABG 2005;79: regression coefficients could not be estimated. That occurred when a variable was completely confounded with the outcome. (Details of the variables included in the adjustment are given in the footnote to Table 3). Three indicator variables (one for each drug) were used to describe the anticoagulant therapy for each patient. For example, a patient receiving aspirin only was coded aspirin yes, heparin no, clopidogrel no. Recording the therapy in this way allowed us to assess the independent effect of each drug (while controlling for baseline and operative differences between patients). Results are presented as the effect of each anticoagulant/ antiplatelet compared with not taking the therapy. The effect of taking combinations of drugs is assumed to be additive. This assumption was examined for all outcomes. The power to detect interactions (ie, evidence of nonadditivity) was low as the study size was small and many outcomes were rare, but the likelihood of a type I (false positive) error was high, because of the number of assessments made. Where evidence of an interaction between anticoagulant drugs was indicated, bootstrapping, with 2,000 replications, was used to assess the robustness of the finding to changes in the data. Where the bootstrap-corrected estimate was statistically significant at the 5% level, the effects are reported separately for the drugs given alone and in combination. Robust confidence intervals were calculated, taking account of clustering of patients within surgeons. Outcomes with fewer than 10 events were not subjected to statistical analysis. No correction was made for number of outcomes assessed, but our interpretation of the findings takes into account both the consistency and magnitude of the associations, as well as their statistical significance. A posthoc analysis, subdividing the clopidogrel use into (a) clopidogrel stopped at least 48 hours before surgery and (b) clopidogrel taken within 48 hours of the operation, was carried out for those outcomes where an association with clopidogrel use was found in the main analysis. Differences in risk for the two subgroups were compared using the 2 test (binary and time-to-event variables) or the F-test (continuous variables). Results From a database of 1,185 cases operated on during the study period, 473 eligible patients were identified. Three eligible patients were excluded because the baseline data were missing. The study population, therefore, comprised 470 patients. One hundred and thirty-three (28.2%) had become clinically stable and the drugs were stopped at least 5 days before surgery, 304 (64.7%) continued to take aspirin (dose ranging from 75 to 325 mg), 116 (24.7%) heparin (60-U/kg bolus followed by infusion adjusted to maintain partial thromboplastin time of 60 to 85 s), and 91 (19.4%) were given clopidogrel (loading dose of 300 mg orally and then 75 mg daily). Aspirin alone (162, 34.5%) was the most common therapy given, followed by aspirin and heparin (73, 15.5%) and aspirin and clopidogrel (43, 9.1%). The use of clopidogrel increased during the study period from 6% in the first quarter to 36% in the last quarter. The distribution of baseline prognostic factors is shown in Table 1. A high TIMI and Canadian Cardiovascular Score, congestive heart failure, use of intravenous nitrates, and previous cardiological intervention rates were all higher among patients treated with anticoagulant/antiplatelet compared with patients who were stabilized, but were similar for those treated with clopidogrel and those given aspirin or heparin, or both, without clopidogrel. No other differences were identified between groups. With regard to operative details, in total, 295 operations (62.8%) were carried out off-pump, and the numbers were similar across the stable and treated groups. The use of left internal mammary artery was also similar across the stable and the anticoagulated groups, ranging from 92% to 93%. The use of a second arterial conduit was 41%, 23%, and 38% in the stable, aspirin/heparin, and clopidogrel groups, respectively. There were no differences in cross-clamp and cardiopulmonary bypass time between groups. The in-hospital outcome is reported in Tables 2, 3, and 4. There were 11 in-hospital deaths (2.3%). After adjustment differences in preoperative and operative risk factors between patients, clopidogrel was found to be associated with an estimated 17-fold increase in risk of death (odds ratio 16.9, 95% CI: 2.10 to 136, p 0.008). There was no relation between in-hospital death and use of either aspirin or heparin (p 0.16 and p 0.10, respectively). Causes of in-hospital death included 2 strokes, 2 myocardial infarctions, 5 low cardiac output, and 2 septicemia events. Postoperative intraaortic balloon pump, arrhythmia, reintubation, and neurologic complications, including stroke, were found to be independently associated with clopidogrel, but not with aspirin or heparin (Table 3). increased the risk of all these complications by more than 50% (relative risk estimates all greater than 1.5, p values all 0.021). For stroke, the estimated risk was more than 8 times higher when clopidogrel was given in the 5 days before surgery (p 0.016). There were 10 (6 permanent and 4 transient) in-hospital strokes (2.2%); 6 patients had been prescribed clopidogrel (4 permanent and 2 transient). All 6 permanent stroke patients were investigated with computed tomography scan, which showed 2 hemorrhagic (both in the clopidogrel group) and 4 ischemic etiologies. On average, patients prescribed clopidogrel lost 37% more blood than those not prescribed the drug (95% CI: 3% to 82%, p 0.033) after adjustment for demographic, comorbid, cardiac and operative differences between patients. patients were also more likely to need a reoperation for bleeding/tamponade (p 0.001). Conversely, heparin and aspirin were not associated with increased blood loss, or reoperation for bleeding/tamponade (p 0.58 for all comparisons). Platelet and fresh frozen plasma transfusion rates increased 4-fold (p for both outcomes) when clopidogrel was used but no association with aspirin or heparin use was found (p 0.26 for all comparisons). The pattern for red cells usage was somewhat different; the data suggest

4 Ann Thorac Surg ASCIONE ET AL 2005;79: CLOPIDOGREL EXPOSURE BEFORE CABG 1213 Table 1. Baseline Characteristics Variable No Anticoagulants Given (n 133) Anticoagulants Excluding (n 246) (n 91) Total (n 470) Number (%) Number (%) Number (%) Number (%) Age (years) 63 (56 70) 65 (58 72) 65 (56 70) 64 (57 71) Male sex 108 (81) 191 (78) 76 (83) 375 (80) Dyspnea class (37) 86 (35) 34 (37) 169 (36) History of hypertension 84 (63) 145 (59) 49 (54) 278 (60) Diabetes mellitus 22 (16) 44 (18) 13 (14) 79 (17) Cerebrovascular disease 8 (6) 29 (12) 11 (12) 48 (10) Peripheral vascular disease 15 (11) 27 (11) 9 (10) 51 (11) Anticoagulant therapy Aspirin 0 (0) 235 (95) 69 (76) 304 (65) Intravenous heparin 0 (0) 84 (34) 32 (35) 116 (25) 0 (0) 0 (0) 91 (100) 91 (19) CCS score (57) 177 (72) 72 (78) 325 (70) Previous MI 56 (42) 126 (51) 46 (51) 228 (49) Congestive heart failure 9 (7) 38 (15) 10 (11) 57 (12) Triple-vessel disease 92 (69) 161 (65) 62 (69) 31 (67) Previous cardiological intervention 4 (3) 35 (14) 10 (11) 49 (10) Intravenous nitrates 2 (1.5) 43 (17) 14 (15) 59 (13) Ejection fraction 50% TIMI score 36 (27) 86 (35) 34 (38) 156 (33) Low 118 (89) 87 (35) 39 (43) 244 (52) Intermediate 15 (11) 136 (55) 47 (52) 198 (42) High 0 (0) 23 (9) 5 (5) 28 (6) Parsonnet score 4 (3 10) 5 (3 10) 4 (2 8) 5 (3 10) Data are reported as number and percentage (categorical data), mean and standard deviation (normally distributed continuous variables), or median and interquartile range (continuous variables with a skewed distribution). CCS Canadian Cardiovascular Society score; MI myocardial infarct; TIMI Thrombolysis In Myocardial Infarction. that the combination of clopidogrel and aspirin was associated with an increased risk of a red cell transfusion, but when either drug was given alone (or with heparin) the risk was not significantly different to when the drug was not prescribed (table 4). Preoperative anticoagulant therapy did not appear to influence postoperative ITU stay (p 0.12 for all comparisons). In contrast, patients prescribed clopidogrel or heparin stayed in hospital significantly longer than other patients (p clopidogrel and p heparin), while aspirin was associated with a shorter stay (p 0.041). The estimated risk of discharge for the clopidogrel group was 0.73, which indicates that at any given time, patients who were not prescribed clopidogrel were 1.37 times ( ) more likely to be discharged than clopidogrel patients. patients were also intubated for longer than other patients (p 0.021), where the intubation times were similar. For all other outcomes considered there were no significant differences between the anticoagulant therapies. Posthoc Analysis Of the 91 patients prescribed clopidogrel in the 5 days before surgery, 22 (24%) had the drug stopped at least 2 days before the operation; the remaining 66 patients were prescribed the drug in the immediate preoperative period. For the majority of outcomes, there was no evidence to suggest a difference in risk between the two subgroups. However, 6 of the 7 deaths in clopidogrel group were from the subgroup prescribed clopidogrel in the 48 before surgery. After adjustment for baseline characteristics, patients given clopidogrel within the last 48 hours before surgery suffered a significantly higher risk of in-hospital death (odds ratio 21.7, 95% CI: 2.93 to 160, vs odds ratio 2.52, 95% CI: 0.34 to 18.8, p ).) than those having the drug stopped between 2 and 5 days before surgery. They also suffered a significantly higher transfusion requirement of red cells and clotting factors (both p 0.05). Comment The main finding of this study is that in-hospital patients referred for CABG during the same admission, preoperative exposure to clopidogrel within 5-days before surgery was associated with an increased incidence of early mortality and morbidity. After adjustment for preoperative and operative differences between patients, clopidogrel was found to be independently associated with an estimated 17-fold increase in risk of death and significantly worse peri-

5 1214 ASCIONE ET AL Ann Thorac Surg CLOPIDOGREL EXPOSURE BEFORE CABG 2005;79: Table 2. Outcomes After Surgery Variable No Anticoagulants Given (n 133) Anticoagulants Excluding (n 246) (n 91) Total (n 470) Number (%) Number (%) Number (%) Number (%) In-hospital death 2 (1) 2 (0.8) 7 (8) 11 (2) Perioperative myocardial infarction 2 (1) 4 (2) 2 (2) 8 (2) Postoperative IABP 3 (2) 3 (1) 6 (7) 12 (3) Intraoperative or postoperative inotropes 48 (36) 113 (46) 58 (64) 219 (47) Postoperative arrhythmia 24 (18) 48 (19) 29 (32) 101 (21) SVT/AF 19 (14) 40 (16) 23 (25) 82 (17) Acute renal failure requiring dialysis 2 (1) 1 (0.4) 3 (3) 6 (1) Neurological complication 5 (4) 3 (1) 7 (8) 15 (3) Permanent stroke 2 (1) 0 (0) 4 (4) 6 (1) Transient stroke 0 (0) 2 (1) 2 (2) 4 (1) Reoperation for bleeding/tamonade 2 (1) 9 (4) 11 (12) 22 (5) Postoperative blood loss (ml) 800 ( ) 700 ( ) 1000 ( ) 750 ( ) Red blood cells transfusion 39 (30) 86 (36) 56 (62) 181 (40) Platelets transfusion 11 (8) 29 (12) 43 (48) 83 (18) Fresh frozen plasma transfusion 2 (1) 16 (7) 20 (22) 38 (8) Intubation time (hours) 7 (6 12) 7 (5 11) 9 (6 16) 7 (5 13) Hospital postoperative stay (days) 6 (5 8) 6 (5 8) 7 (6 11) 6 (5 8) Data are presented as median and interquartile range, mean and standard deviation, or number and percentage of patients. IABP intraaortic balloon pump; SVT/AF supraventricular tachycardia/atrial fibrillation. operative outcomes. patients were more likely to experience arrhythmia and to require IABP support, they had longer intubation times and a higher reintubation rate, experienced 37% more blood loss, a higher rate of reopening for bleeding, an increased transfusion requirement, and an eight times higher risk of stroke compared with patients who were not prescribed clopidogrel. For most outcomes, the risk was similar for those prescribed clopidogrel in the two days before surgery and those who stopped taking the drug between 2 and 5 days before the operation. However, the death rate was significantly higher when the drug was given in the immediate preoperative period. The high early mortality in the clopidogrel group is, at least in part, a consequence of the marked increase in hospital morbidity; in addition to the two strokes and peri-operative myocardial infarctions, three patients were reoperated for bleeding, four had an IABP fitted, two were dialysed, and five of the seven lost 1000mls or more of blood. The marked increase in blood loss and transfusion requirements seen in our series is in keeping with the results of others [13 14]. Hongo et al [13] in a consecutive series of 224 patients, of whom 59 had preoperative clopidogrel exposure within 7 days before surgery, found that clopidogrel in combination with aspirin was associated with significantly higher bleeding, transfusion requirements, and a 10-fold increase reoperation for bleeding. Similar results were reported by Ray et al [14]. The potent inhibition of platelet function achieved by the combination of aspirin and clopidogrel has been reported to prolong bleeding time [15] with an increased risk of major hemorrhage [16]. Moreover, the combined antiplatelet effect of clopidogrel and aspirin might be amplified by CPB-related platelet dysfunction [17 18]. The higher incidence of stroke in patients with preoperative clopidogrel exposure was somewhat unexpected, considering that for nonsurgical patients there is evidence to suggest that clopidogrel, either alone or combined with aspirin, may prevent the occurrence of ischemic stroke [5]. Grau et al [19] found that the combination of clopidogrel and aspirin as compared with each drug alone led to a strong prolongation of collagen/adp closure times, which may indicate a lower risk of thrombosis but also a higher risk of hemorrhage. Hemorrhagia was the etiology in 2 out of 4 permanent stroke seen in our clopidogrel group. Another possible explanation could be the higher incidence of transfusion rate observed in the clopidogrel group, which has been reported as an independent predictor of stroke after CABG [20]. There are several limitations to the present study, which deserve mention. It might be argued that without blinding the patients and their carers, some of the outcomes could be biased by knowledge of the type of preoperative anticoagulant therapy. Although this is possible, we believe that the use of local guidelines on postoperative bleeding management would have minimized the opportunity for bias. Also, retrospective identification of the anticoagulant therapy for some patients could have been biased by the knowledge of the patients outcome. However, we don t believe this to be the case here as the anticoagulant therapy data were extracted

6 Ann Thorac Surg ASCIONE ET AL 2005;79: CLOPIDOGREL EXPOSURE BEFORE CABG 1215 Table 3. Effect Sizes (95% Confidence Intervals) of Anticoagulant Drugs After Adjustment Variable Aspirin IV Heparin In-hospital death 0.34 (0.07 to 1.52) 3.13 (0.80 to 12.2) 16.9 (2.10 to 136) Postoperative IABP 0.99 (0.17 to 5.49) 1.22 (0.58 to 2.52) 5.04 (1.72to14.8) Intraoperative or postoperative inotropes a 1.23 (0.83 to 1.80) 0.92 (0.55 to 1.51) 1.96 (0.91to4.20) Postoperative arrhythmia 1.23 (0.80 to 1.88) 0.97 (0.83 to 1.14) 1.73 (1.11to2.69) SVT/AF 1.45 (0.97 to 2.15) 0.95 (0.60 to 1.48) 1.52 (1.12to2.08) Postoperative neurological complication 0.60 (0.23 to 1.49) 0.37 (0.06 to 2.29) 7.13 (2.15to23.5) Stroke 0.49 (0.06 to 3.71) 0.31 (0.02 to 3.28) 8.44 (1.48to48.1) Reoperation for bleeding/tamonade 1.15 (0.40 to 3.26) 1.23 (0.44 to 3.37) 3.98 (2.47to6.41) Postoperative blood loss b 0.98 (0.84 to 1.15) 1.04 (0.88 to 1.22) 1.37 (1.03to1.82) Red cell transfusion required [Interaction between aspirin and clopidogrel (see Table 4)] Platelet transfusion required a 1.23 (0.85 to 1.76) 0.74 (0.38 to 1.44) 6.59 (3.95to11.0) Clotting factor transfusion required 1.23 (0.65 to 2.34) 0.91 (0.36 to 2.26) 4.88 (1.36to17.5) Intubation time c 0.92 (0.76 to 1.10) 0.99 (0.81 to 1.21) 0.73 (0.56to0.96) Intensive care unit length of stay c 1.06 (0.93 to 1.21) 0.93 (0.79 to 1.07) 0.83 (0.66to1.05) Hospital postoperative length of stay c,d 1.15 (1.00 to 1.32) 0.77 (0.68 to 0.85) 0.73 (0.56to0.95) a There was evidence to indicate the logistic model was a poor fit for these outcomes, suggesting that other confounding factors may be important. b Ratio of geometric means estimated from multiple regression model of ln(blood loss), omitting 2 outliers. c Hazard ratio estimated from a Cox proportional hazards regression model. d Model stratified by female sex or respiratory disease or both, and by female sex or preoperative arrhythmia or both, as nonproportional hazards were indicated. Estimates are adjusted for age, sex, body mass index, Parsonnet score, Canadian Cardiovascular Society score, dyspnea status, Thrombolysis in Myocardial Infarction score, previous myocardial infarction, cerebrovascular disease, peripheral vascular disease, hypertension, diabetes, ejection fraction, triple-vessel disease, preoperative arrhythmia, congestive heart failure, use of IV nitrates, on/off pump surgery, left internal mammary artery graft, use of a second arterial conduit, and operative urgency. Variables completely confounded with the outcome were omitted from the adjustment. Effects are odds ratios estimated from a logistic regression model except where indicated. IABP intraaortic balloon pump; IV intravenous; SVT/AF supraventricular tachycardia/atrial fibrillation. from the patient s clinical record by a research registrar who had no involvement in the analysis of the data or access to the study database. The only outcome that would have been immediately apparent was an inhospital death and higher in-hospital mortality was not anticipated a priori. It might also be argued that our findings could be due to different risk profiles. However, there is little in our data to suggest that the patients given clopidogrel were sicker than those given other anticoagulants/antiplatelet; more patients treated with clopidogrel had a poor ejection fraction, but not significantly so, TIMI scores and use of intravenous nitrates were similar for those treated with clopidogrel and those given aspirin and/or heparin without clopidogrel, and history of previous myocardial infarction was similar across the stable and treated groups. Although the adjusted effects may still be influenced by residual confounding, the magnitude of the increased risk of adverse outcomes shown with clopidogrel are such that it is unlikely that residual confounding could reverse the direction of these effects. Table 4. Effect of Interaction Between Aspirin and on Red Cell Transfusion After Adjustment Therapy Odds Ratio 95% Confidence Interval Aspirin without clopidogrel 0.94 (0.51 to 1.82) without aspirin 1.16 (0.18 to 7.42) Aspirin and clopidogrel 5.03 (3.03 to 8.33) While our study has allowed us to isolate the independent effect of each anticoagulant/antiplatelet therapy, the power to detect interactions (ie, nonadditive effects) was low and a larger study would provide additional insight in this regard. Similarly the subgroups examined in the posthoc analysis were small. The risk estimates for the group given clopidogrel in 48 hours before surgery were close to the overall estimates by virtue of this being the larger subgroup. The confidence intervals for the smaller group of 22 patients were necessarily wide and the lack of statistical significance for this subgroup should not be taken as confirmation of no effect; for the majority of outcomes there was insufficient evidence to indicate a differential effect between the two groups. Again a larger study is warranted. It might be argued that the findings of our study might not be applicable to a health-care system, where inhospital referral patients are offered an operation within 12 to 24 hours. A short waiting time, however, might be an argument against the use of preoperative clopidogrel in these patients. In conclusion, our data suggest that in in-hospital referral patients undergoing CABG, exposure to clopidogrel within 5 days before surgery may be associated with a significant increase in early in-hospital mortality and morbidity and that the mortality risk is greatest if the patient is exposed to clopidogrel in the 48 hours before surgery. However, our data are too few to allow us to make firm recommendations about when clopidogrel should be stopped. Since the advantages of clopidogrel in

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