Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study

Surgery

Randomized trial of aspirin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study Jack C. J. Sun, MD, MSc, a Kevin H. T. Teoh, MD, MSc, a Andre Lamy, MD, MSc, a Tej Sheth, MD, b Mary Lou Ellins, MD, c Hyejung Jung, BSc, MSc, d Salim Yusuf, MD, DPhil, e Sonia Anand, MD, PhD, e Stuart Connolly, MD, MSc, b Richard P. Whitlock, MD, MSc, a and John W. Eikelboom, MD, MSc e Hamilton, Canada

Background Routine use of postoperative aspirin after coronary artery bypass grafting (CABG) reduces graft failure and cardiovascular events. The efficacy and safety of adding clopidogrel to aspirin for the prevention of graft failure and cardiovascular events after CABG are unknown. We performed a pilot study measuring safety and efficacy outcomes of aspirin and clopidogrel therapy after CABG. Methods We randomized 100 patients undergoing CABG to receive placebo or clopidogrel started after surgery and for 30 days. All patients received aspirin 81 mg daily. Graft patency was measured by cardiac computed tomography angiography at 30 days. Results Clinical follow-up was complete for 99 patients, and 79 (80%) underwent computed tomography angiography. The proportion of patients with ≥1 occluded graft was not significantly different between placebo and clopidogrel groups (9/ 39 [23.1%] vs 7/40 [17.5%], relative risk 0.95, 95% CI 0.80-1.14, P = .54). Among radial artery grafts, the placebo group had a significantly higher number of occlusions or “string signs” compared with the clopidogrel group (7/16 [43.8%] vs 2/19 [10.5%], relative risk 0.24, 95% CI 0.06-1.00, P = .05). There was no difference between placebo and clopidogrel groups in the safety outcomes of total postoperative bleeding, transfusions, bleeding events, and reexploration and in the efficacy outcomes of nonfatal myocardial infarction, stroke, and death. Conclusions This pilot study confirms a high rate of graft occlusion after CABG surgery and suggests that the addition of clopidogrel to aspirin is feasible and safe and may be superior for prevention of graft failure in radial artery grafts. (Am Heart J 2010;160:1178-84.)

Coronary artery bypass grafting (CABG) reduces symptoms and improves long-term survival in patients with severe coronary artery disease.1 Despite improvements in outcomes after CABG during the past 30 years, thrombotic

From the aDivision of Cardiac Surgery, McMaster University, Hamilton, Canada, bDivision of Cardiology, McMaster University, Hamilton, Canada, cDepartment of Radiology, McMaster University, Hamilton, Canada, dPopulation Health Research Institute, McMaster University, Hamilton, Canada, and eDepartment of Medicine, McMaster University, Hamilton, Canada. Clinical trial registration information: clinicaltrials.gov identifier NCT00330772. http:// clinicaltrials.gov/ct2/show/NCT00330772. Submitted January 17, 2010; accepted July 28, 2010. Reprint requests: Jack C. J. Sun, MD, MSc, Division of Cardiac Surgery, Hamilton General Hospital, 237 Barton St. E, Hamilton, Ontario, Canada, L8L 2X2. E-mail: [email protected] 0002-8703/$ - see front matter © 2010, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.07.035

and thromboembolic complications remain a major problem during and after surgery. Recent large, randomized, controlled trials have reported rates of mortality of 1.4% to 3.5%,2-4 stroke of 2.0%,4 and myocardial infarction (MI) of 3.3% to 9.8%2,4 at 30 days after surgery, and 1-year bypass graft failure rates of 10.9% to 26.4%.2,3 These rates of graft failure are consistent with historically reported rates of 15% to 20% at 1 year and 1% to 4% per year thereafter.5,6 Like other vascular complications that can occur after CABG surgery, the mechanisms of graft failure involve platelet activation and atherothrombosis7; and graft failure is independently predictive of the subsequent risk of death, MI, and need for repeated revascularization.3,8 Aspirin started 6 to 48 hours after CABG reduces graft failure,9 morbidity, and mortality.10 Aspirin inhibits platelets by blocking cyclooxygenase-1, thereby suppressing production of thromboxane, a powerful platelet agonist

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and vasoconstrictor. Despite the routine use of aspirin, incomplete inhibition of thromboxane production occurs in more than one half of patients undergoing CABG, a phenomenon that is commonly referred to as aspirin resistance.11 Patients who develop aspirin resistance are at increased risk of cardiovascular events12 and may have an increased risk of developing graft failure following CABG.13 Clopidogrel is a thienopyridine antiplatelet that inhibits platelet aggregation via antagonism of the adenosine diphosphate receptor. Adding clopidogrel to aspirin reduces cardiovascular events in patients with recent MI,14,15 including those who subsequently undergo CABG.16 We hypothesized that enhancement of platelet inhibition achieved by adding clopidogrel to aspirin would improve outcomes after CABG, potentially by overcoming aspirin resistance. Thus, we performed a randomized, blinded, placebo-controlled pilot study evaluating efficacy and safety outcomes of clopidogrel compared with placebo commenced after CABG for prevention of graft failure and major cardiovascular events.

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mg) and aspirin (325 mg) via nasogastric tube at 6 to 48 hours postoperatively if bleeding was not an issue. The following day, they were started on daily doses of clopidogrel (75 mg) and aspirin (81 mg) given orally or via nasogastric tube. All patients were continued on study medication for ≥30 days and thereafter continued indefinitely on aspirin 81 mg once daily. Clopidogrel tablets were provided by Bristol-Myers Squibb Canada and were encapsulated in opaque gelatin capsules provided by the hospital pharmacy. Placebo tablets consisted of opaque gelatin capsules identical in color, taste, and smell, but containing lactose powder.

Outcomes

A computer-generated randomization sequence was created in blocks by the hospital pharmacy. After informed consent was obtained, patients were randomized to clopidogrel or placebo using numbered, pre-prepared bags. All study personnel remained blinded to treatment allocation.

The major goal of this pilot study was to assess feasibility. Our primary efficacy outcome was graft patency measured by cardiac CT angiography; and our secondary efficacy outcomes included MI, stroke, and death. Our safety outcomes included postoperative bleeding, transfusion, and reexploration. Graft patency was measured at 30 days, and all other outcomes were measured in-hospital and at 30 days. Cardiac CT angiograms were reported by a single reader, an interventional cardiologist trained in cardiac CT; and grafts were categorized as patent, occluded, or string sign (diffuse luminal narrowing). Stenosed grafts without diffuse luminal narrowing were considered to be patent. Patients were followed in-hospital by a study coordinator who recorded MI, stroke, and death as well as safety outcomes. Outcomes were measured for each patient after randomization and included the perioperative period before receiving study medications. Postoperative MI was not independently assessed, but rather diagnosed by attending physicians. Common definitions for post-CABG MI include creatine kinase–MB N10 times the upper limit of normal or N5 times the upper limit of normal with new Q waves N30 milliseconds in 2 contiguous leads on electrocardiogram. New ST elevation in contiguous leads on electrocardiogram or echocardiographic finding of a new wall motion abnormality is also used. Myocardial infarction was also recorded if myocardial infarction, MI, heart attack, or other similar terms were used in the medical record to document that the patient had suffered a postoperative MI. Postoperative bleeding was measured by mediastinal chest tube drainage at 1 hour and at 12 hours, and the total drained before chest tubes were removed. The number and type of transfusions received as well as any need for reexploration were recorded. Bleeding events were categorized as major and minor. Major bleeding events included intracranial hemorrhage, intraocular bleeding leading to vision loss, bleeding requiring surgical intervention at a site separate from the original operative site, bleeding causing death, or bleeding requiring transfusion of N1 unit of red blood cells. Minor bleeding events were defined as bleeding requiring modification of antithrombotic drug regimens or transfusion of 1 unit of red blood cells.

Interventions

Statistical methods

Patients in the placebo group received a loading dose of aspirin (325 mg) via nasogastric tube at 6 to 48 hours postoperatively if bleeding was not an issue (generally b50-100 mL/h). The following day, they were started on daily doses of placebo and aspirin (81 mg) given orally or via nasogastric tube. Patients in the clopidogrel group received loading doses of clopidogrel (300

Continuous variables are expressed as mean (SD) or median (interquartile range [IQR]), and categorical variables are reported as number (percentage). The significance of any difference between treatment groups in the proportion of patients with ≥1 occluded graft or with a secondary outcome was assessed using Fisher exact test, and continuous variables

Methods Study design This was a prospective, randomized, blinded, placebocontrolled, single-center pilot study performed at an academic hospital performing N1,550 open-heart procedures per year.

Participants The study was approved by the research ethics board of the institution, and written informed consent was obtained from each patient in the study. Patients were eligible if they were ≥18 years of age and were scheduled for on-pump CABG with ≥1 free bypass graft (aortocoronary graft). Patients were excluded if they had a clear indication for anticoagulation or an adenosine diphosphate receptor antagonist; were allergic to aspirin or clopidogrel; had a history of bleeding diatheses, significant gastrointestinal bleeding, intracranial hemorrhage, or liver failure; had a contraindication for cardiac computed tomography (CT) angiography (renal insufficiency or failure with creatinine N130 μmol/L, allergy to contrast dye, severe claustrophobia); or planned redo CABG or concomitant cardiac procedures (eg, valve repair/replacement).

Randomization

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Table I. Demographics and characteristics for all patients All patients

Characteristic Mean age, y (SD) Female sex, n (%) BMI (SD) Previous MI, n (%) Previous stroke, n (%) PAD, n (%) CHF, n (%) CCS class of angina, n (%) 1 2 3 4 Left ventricular grade, n (%) 1 2 3 4 Hypertension, n (%) Diabetes, n (%) Hyperlipidemia, n (%) Current smoker, n (%) Previous smoker, n (%) Target vessel stenosis, n (%) Left main ≥50% Right coronary artery ≥70% Circumflex artery ≥70% Left anterior descending artery ≥70% Degree of coronary disease, n (%) Left main stenosis only Left main + 3-vessel Left main + 2-vessel Left main + single-vessel 3-vessel only 2-vessel only Single-vessel only

ASA + placebo (n = 50)

Patients with CT angio

ASA + clopidogrel (n = 49)

ASA + placebo (n = 39)

ASA + clopidogrel (n = 40)

64.5 7 32.6 16 3 5 3

(9.3) (14.0) (24.4) (32.0) (6.0) (10.0) (6.0)

66.0 3 28.6 23 2 2 4

(9.4) (6.1) (5.2) (46.9) (4.1) (4.1) (8.2)

63.5 5 29.1 15 1 5 3

(8.1) (12.8) (4.3) (38.5) (2.6) (12.8) (7.7)

65.0 (9.6) 2 (5.0) 28.5 (5.3) 17 (42.5) 0 (0.0) 2 (5.0) 3 (7.5)

2 15 26 5

(4.0) (30.0) (52.0) (10.0)

2 15 27 4

(4.1) (30.6) (55.1) (8.2)

1 12 20 4

(2.6) (30.8) (51.3) (10.3)

2 (5.0) 11 (27.5) 24 (60.0) 3 (7.5)

17 14 19 0 35 17 42 2 29

(34.0) (28.0) (38.0) (0.0) (70.0) (34.0) (84.0) (4.0) (58.0)

18 11 19 1 34 18 33 7 21

(36.7) (22.4) (38.8) (2.0) (69.4) (36.7) (67.3) (14.3) (42.9)

14 12 13 0 25 14 32 2 22

(35.9) (30.8) (33.3) (0.0) (64.1) (35.9) (82.1) (5.1) (56.4)

14 (35.0) 8 (20.0) 17 (42.5) 1 (2.5) 27 (67.5) 13 (32.5) 26 (65.0) 7 (17.5) 17 (42.5)

8 38 39 42

(16.0) (76.0) (78.0) (84.0)

16 40 40 39

(32.7) (81.6) (81.6) (79.6)

5 30 30 32

(12.8) (76.9) (76.9) (82.1)

13 (32.5) 32 (80.0) 33 (82.5) 32 (80.0)

2 3 1 2 23 18 1

(4.0) (6.0) (2.0) (4.0) (46.0) (36.0) (2.0)

0 3 9 4 24 7 2

(0.0) (6.1) (18.4) (8.2) (49.0) (14.3) (4.1)

2 2 0 1 18 15 1

(5.1) (5.1) (0.0) (2.6) (46.2) (38.5) (2.6)

0 (0.0) 3 (7.5) 7 (17.5) 3 (7.5) 19 (47.5) 6 (15.0) 2 (5.0)

BMI, Body mass index; PAD, peripheral arterial disease; CHF, congestive heart failure; CCS, Canadian Cardiovascular Society.

(chest tube output, transfusion) was assessed using 2-sample t tests. The significance of any differences between randomized treatment groups in the total numbers of occluded bypass grafts was assessed by logistic regression using the generalized estimating equations method for nonindependent outcomes. A 2-sided P value b .05 was considered statistically significant. This research was supported by research grants from BristolMyers-Squibb Canada, the Hamilton Health Sciences New Investigator Fund, and Physicians Services' Incorporated. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents.

Results Participants One hundred eligible patients were recruited between November 2006 and February 2008. One patient had his elective surgery cancelled several times to accommodate

more urgent cases and withdrew from the study before surgery. He did not receive any study medication and was excluded from the analysis. Of the remaining 99 patients, 50 were randomized to receive placebo and 49 were randomized to receive clopidogrel. Study medications were given at a median of 6.7 and 7.2 hours postoperatively for the placebo and clopidogrel groups, respectively. The baseline characteristics of all randomized patients and of those with CT angiographic follow-up are presented in Table I. Intraoperative data for all patients and for those with CT angiographic follow-up are presented in Table II.

Graft patency A total of 80 of 99 patients underwent CT angiography. Of the 19 patients who did not undergo CT angiography, 14 declined to undergo angiography, 4 had postoperative renal insufficiency that excluded them from undergoing

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Table II. Operative data for all patients All patients

Variable No. of grafts No. of distal anastomoses No. of proximal aortic anastomoses Type of grafts, n (%) Left internal mammary artery Right internal mammary artery Saphenous vein Radial artery Time in operating room, min (SD) CPB time, min (SD) Cross-clamp time, min (SD) Antifibrinolytic use, n (%)

Patients with CT angio

ASA + placebo (n = 50)

ASA + clopidogrel (n = 49)

ASA + placebo (n = 39)

ASA + clopidogrel (n = 40)

197 197 132

198 198 138

154 154 103

161 161 112

51 (25.9) 8 (4.1) 115 (58.4) 23 (11.7) 250.2 (75.0) 99.1 (28.6) 80.4 (29.1) 50 (100.0)

50 (25.3) 7 (3.5) 115 (58.1) 26 (13.1) 253.8 (112.0) 97.7 (21.5) 76.6 (26.6) 49 (100.0)

40 (26.0) 6 (3.9) 92 (60.0) 16 (10.4) 253.6 (72.4) 99.8 (30.0) 82.4 (29.4) 39 (100.0)

41 (25.5) 7 (4.3) 93 (57.8) 20 (12.4) 266.3 (102.5) 99.9 (22.0) 79.9 (26.7) 40 (100.0)

Table III. Graft patency data for patients with follow-up angiography ASA + placebo (n = 39)

ASA + clopidogrel (n = 40)

P value

11/154 (7.1%) 0/43 (0.0%) 0/7 (0.0%) 6/88 (6.8%) 5/16 (31.3%) 0/0 2/154 (1.3%) 5/38 (13.2%) 9/39 (23.1%) 7/16 (43.8%) 5/16 (31.3%) 7/16 (43.8%) 49.5 (34.0)

8/161 (5.0%) 1/41 (2.4%) 0/5 (0.0%) 6/93 (6.5%) 1/20 (5.0%) 0/2 1/161 (0.6%) 6/39 (15.4%) 7/40 (17.5%) 2/20 (10.0%) 1/19 (5.3%) 2/19 (10.5%) 51.0 (27.0)

.43 .32 – .92 .06 – .54 .78 .54 .03 .07 .05 .92

Occluded grafts, n/total (%) LIMA RIMA SVG Radial artery Other Angiographic string sign, n/total (%) Patients with ≥1 occluded saphenous vein graft, n (%) Patients with ≥1 occluded graft, n (%) Occluded or string sign radial artery, n/total (%) Patients with ≥1 occluded radial artery graft, n (%) Patients with ≥1 occluded or string sign radial artery graft, n (%) Median time (IQR) to CT scan, d

angiography, and 1 patient died postoperatively before scheduled CT scan. One additional patient had an uninterpretable scan due to inadequate heart rate control. Graft patency data for the 2 groups are presented in Table III. Computed tomography angiography was performed at a median time of 50 days after surgery. There was no overall difference in the total number of occluded grafts in the placebo and clopidogrel groups (11/154 [7.1%] placebo vs 8/161 [5.0%] clopidogrel, P = .43). There was also no difference in the number of patients with ≥1 occluded graft in the placebo and clopidogrel groups (9/39 [23.1%] placebo vs 7/40 [17.5%] clopidogrel, relative risk 0.95, 95% CI 0.80-1.14, P = .54). Among radial artery grafts, the placebo group had a significantly higher occlusion or string sign rate compared with the clopidogrel group (7/16 [43.8%] placebo vs 2/20 [10.0%] clopidogrel, P = .03). The number of patients with ≥1 occluded or string sign radial artery graft was also significantly higher in the placebo group (7/16 [43.8%] placebo vs 2/19 [10.5%] clopidogrel, relative risk 0.24, 95% CI 0.06-1.00, P = .05).

Myocardial infarction, stroke, and death Secondary efficacy outcomes are presented in Table IV. There were no nonfatal MIs, strokes, or deaths in the placebo group and no nonfatal MIs, 1 stroke, and 1 death in the clopidogrel group. These differences were not statistically significant.

Safety outcomes Safety outcomes are presented in Table IV. Total median postoperative chest tube output was not significantly different between the placebo and clopidogrel groups (710 mL [IQR 430] placebo vs 800 mL [IQR 500] clopidogrel, P = .58), nor were the mean transfusion requirements (2.0 units [3.9] placebo vs 1.4 units [2.7] clopidogrel, P = .7). One patient in the placebo group and no patient in the clopidogrel group required reoperation for bleeding (P = .48). There was no significant difference in the total number of bleeding events between placebo and clopidogrel

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Table IV. Clinical outcomes for all patients Outcome

ASA + placebo (n = 50)

Median (IQR) chest tube output, mL 1 h postop 62.5 (85.0) 12 h postop 450.0 (380.0) Total 710.0 (430.0) Mean (SD) transfusions, units PRBC 0.90 (1.70) FFP 0.57 (1.17) Platelets 0.43 (1.53) Cryoprecipitate 0.08 (0.34) Total 1.98 (3.92) Bleeding events Major 3 (6.0%) Minor 5 (10.0%) Total 8 (16.0%) Reoperation, n (%) 1 (2.0%) Nonfatal MI, n (%) 0 (0.0%) Stroke, n (%) 0 (0.0%) Death, n (%) 0 (0.0%) Median (IQR) 50.5 (32.0) follow-up, d

ASA + clopidogrel (n = 49)

P value

65.0 (100.0) 520.0 (310.0) 800.0 (500.0)

.53 .75 .58

0.59 0.41 0.33 0.04 1.37

(1.19) (1.00) (1.48) (0.20) (2.66)

.52 .44 .39 .63 .70

3 4 7 0 0 1 1 47.0

(6.1%) (8.2%) (14.3%) (0.0%) (0.0%) (2.0%) (2.0%) (37.0)

1.00 1.00 1.00 .48 – .47 .47 .70

groups (8/50 [16.0%] placebo vs 7/49 [14.3%] clopidogrel, P = 1.0).

Discussion Our study shows that it is feasible to perform a randomized trial to evaluate the safety and efficacy of postoperative clopidogrel for the prevention of graft failure and major cardiovascular events in patients undergoing CABG. Not all patients enrolled in the trial underwent cardiac CT angiography, but all but one of the scans that were performed yielded high-quality images that allowed accurate assessment of graft patency. The addition of clopidogrel to aspirin did not significantly reduce the risk of graft occlusion but reduced radial graft occlusion or string sign without a significant increase in postoperative bleeding, transfusion, and reexploration. There was no significant difference between the 2 treatment groups in terms of baseline characteristics. The apparent benefits of clopidogrel compared with placebo on radial graft patency is based on a post hoc analysis and is unexpected because the study was designed to assess feasibility and was not powered for efficacy. Radial artery use was not randomized in this study, and the rate of radial graft occlusion in the placebo group was substantially higher than the 1% to 14% rates reported in the literature17-22 and remains unexplained. Regression analysis was performed to determine if there was a relationship between time of administration of study medication and postoperative chest tube output. We found an inverse relationship where earlier administration of study medication was associated with lower

chest tube output. This likely confirms that antiplatelet therapy is being started sooner in patients with lower chest tube output and later in those with higher outputs. There is a paucity of data on the safety and efficacy of thienopyridine antiplatelet drugs given post-CABG. Ticlopidine, another thienopyridine, was shown in a randomized trial of 173 CABG patients to significantly reduce saphenous vein graft occlusion at 1 year when compared with placebo.23 Most reports of post-CABG experience with the combination of clopidogrel and aspirin are from small observational studies of patients undergoing offpump CABG (OPCAB)24-27 that suggest that postoperative clopidogrel is safe and does not cause a significant increase in bleeding. There is to date only one other randomized study of aspirin and clopidogrel versus aspirin alone, and it also involved an OPCAB population.28 The study randomized 29 patients to receive either clopidogrel 75 mg daily and aspirin 150 mg daily or aspirin 150 mg daily for 30 days after OPCAB. The primary end point was a measurement of platelet inhibition using thromboelastography. They found that the clopidogrel group had better platelet inhibition overall. Prevention of graft failure after CABG is important because bypass graft occlusion is a powerful predictor of adverse events. In the PREVENT IV study, patients found to have ≥1 failed vein graft had 2 times higher incidence of perioperative MI and 13 times higher incidence of the composite of death, MI, or repeated revascularization compared with patients who had completely patent grafts at 12 to 18 months.3 The pathophysiology of graft occlusion within the first postoperative month is predominantly thrombosis triggered by surgical trauma to the graft and altered hemodynamics leading to endothelial damage and dysfunction.29 Multiple additional factors can further promote the risk of thrombotic graft occlusion including preexisting vein abnormalities, vein distension, vessel ischemia (from loss of vaso vasorum), and physical or technical factors resulting from low flow, size mismatches between graft and recipient coronary artery, and anastomotic errors that lead to kinks and turbulent flow. Antiplatelet drugs are not only effective for prevention of bypass graft occlusion but may also prevent distal embolization and associated ischemic myocardial injury.30 PAPA CABG is the largest randomized trial to date examining the effect of clopidogrel compared with placebo on major outcomes in aspirin-treated patients undergoing on-pump CABG. Our use of randomization, blinding, and placebo controlling minimized the potential for bias; and we achieved 80% follow-up using CT angiography. To optimally test the efficacy of clopidogrel, our protocol mandated the use of a 300-mg loading dose of clopidogrel 6 hours post-CABG. There is evidence that clopidogrel commenced at a dose of 75 mg daily without

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a loading dose does not provide adequate platelet inhibition after on-pump CABG.31

Study limitations The loading dose of clopidogrel or placebo in the immediate postoperative period could not be blinded in our protocol. The clopidogrel used in the study was encapsulated and could not be administered via nasogastric tube. To overcome this problem, the ICU nurse caring for the patient at the time of administration of the initial loading dose of clopidogrel was potentially unblinded. All ICU nurses were informed about the study protocol and knew not to disclose the treatment allocation. It seems highly unlikely that lack of blinding could have impacted the primary efficacy outcome of graft patency or even stroke, but could have affected safety outcomes such as transfusion and potentially reoperation. The diagnosis of perioperative MI was not independently assessed and was likely underestimated in the results. This is a pilot study performed at a single, large tertiary center, which may limit the generalizability of the results.

Conclusions Based on the results of our pilot study, a large randomized trial to evaluate the efficacy of clopidogrel compared with placebo for the prevention of graft failure and major cardiovascular events in aspirin-treated patients undergoing CABG appears feasible and safe. Furthermore, the high rate of graft occlusion after CABG underscores the urgent need for randomized trials to identify more effective treatments to reduce thromboembolic complications after CABG surgery.

Acknowledgements We would like to thank Toni Rizzo, Poonam Sharma, and Mary Helen Blackall for recruiting the patients and coordinating the study, as well as colleagues in the McMaster University Division of Cardiac Surgery for their support.

Disclosures Dr Sun has also received a research grant from GlaxoSmith-Kline Canada. Dr Eikelboom has received honoraria and/or research support from Astra-Zeneca, Bayer, Bristol-Myers-Squibb, Eisai, Eli Lilly, Glaxo-Smith-Kline, Johnson and Johnson, McNeil, and Sanofi-Aventis. Dr Yusuf has received grants, speaking honoraria, and consulting fees from Sanofi-Aventis and Bristol-MyersSquibb. There are no other conflicts of interest to report.

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