Long-Term Effect of Dual Antiplatelet Treatment after Off-Pump Coronary Artery Bypass Grafting

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1 Wiley Periodicals, Inc. ORIGINAL ARTICLE Long-Term Effect of Dual Antiplatelet Treatment after Off-Pump Coronary Artery Bypass Grafting Jose Lopez, M.D.,* Carlos Morales, M.D.,* Pablo Avanzas, M.D.,y Francisco Callejo, M.D.,* Daniel Hernandez-Vaquero, M.D.,* and Juan C. Llosa, M.D.* *Department of Cardiac Surgery, University Central Hospital of Asturias, Oviedo, Asturias, Spain; and ydepartment of Cardiology, University Central Hospital of Asturias, Oviedo, Asturias, Spain ABSTRACT Objectives: Recent studies have found increased long-term cardiovascular morbidity after offpump coronary artery bypass surgery (OPCAB). We evaluated the efficacy and safety of dual antiplatelet therapy (DAT) in the prevention of cardiovascular events at two years after OPCAB surgery. Methods: Retrospective study that included all patients that underwent OPCAB surgery in our institution between 2009 and Single or dual antiplatelet therapy was initiated at hospital discharge, and its effect in patients prognosis was analyzed. Follow-up was conducted by telephone and using the hospital databases. The primary end-point was the composite of acute coronary syndrome (ACS), revascularization, stroke, or cardiovascular death. Results: The study included 237 patients divided into: (A) 128 patients who received single antiplatelet therapy and (B) 109 patients who received dual antiplatelet therapy. The mean follow-up was months (standard deviation 0.5 months). 13.9% of patients had a primary end-point event. Patients in group A had a higher event rate compared with group B (18.8% vs. 8.3%, p = 0.02), with a significant reduction in hospital readmissions for ACS (10.9% vs. 3.7%, p = 0.035). In the multivariate analysis, dual antiplatelet therapy was an independent protective factor in the occurrence of events (hazard ratio = 0.395, 95% CI, to 0.885, p = 0.024). There were no significant differences between the two groups with respect to bleeding events. Conclusion: Dual antiplatelet therapy after OPCAB surgery is associated with a decrease in the appearance of new cardiovascular events, due to a reduction in the number of hospital readmissions for ACS. doi: /jocs (J Card Surg 2013;28: ) Coronary artery bypass surgery has shown its efficacy in the treatment of ischemic heart disease and provides excellent medium and long-term results to reduce mortality and improve symptoms. 1 The longterm success of coronary surgery is based on graft patency. Antiplatelet therapy plays an essential role in achieving this goal, since platelets are intimately related to the pathogenesis of thrombosis of the grafts. According to current recommendations, patients undergoing coronary artery bypass surgery should receive antiplatelet therapy with acetylsalicylic acid (ASA; class Ia recommendation) for life, or if a patient is intolerant to aspirin, then clopidogrel (class IIa recommendation) should be provided. 2 Furthermore, ASA treatment Conflict of interest: There are no conflict of interest in the submission. Address for correspondence: Dr. Jose Lopez Menendez, M.D., Department of Cardiac Surgery, University Central Hospital of Asturias, C/Celestino Villamil s/n, Oviedo, Asturias, Spain. Fax: (þ34) ; jose_lm78@icloud.com should be initiated within the first 48 hours postoperatively. It is the most critical time period to prevent early thrombosis of the grafts. 3 Despite adequate treatment with ASA, a significant number of coronary grafts suffer early closure, 4 which results in cardiovascular events following surgery. 5 This closure is due to an increased tendency to thrombosis, as well as an increased resistance to the ASA antiplatelet action, which occurs in the first days after surgery. 6 ASA resistance appears in about 30% of patients that have undergone off-pump coronary artery bypass surgery. 7 Another mechanism related to graft closure is the phenomenon of intimal hyperplasia. 8 This platelet-mediated pathogenesis may foment post-operative graft closure after one year. It affects 10 15% of saphenous vein grafts. Experimental evidence shows that intimal hyperplasia may increase with the use of clopidogrel. 9 Multiple studies have been conducted (with mixed results) to evaluate whether the use of dual antiplatelet therapy (DAT) in the first months after

2 J CARD SURG LÓPEZ, ET AL ;28: LONG-TERM EFFECT OF DUAL ANTIPLATELET TREATMENT revascularization may be beneficial to maintain coronary graft patency. The objective of this study is to evaluate the efficacy and safety of DAT during the first postoperative year in preventing the occurrence of new cardiovascular events after OPCAB surgery. MATERIALS AND METHODS Study design This was a retrospective cohort study, with a twoyear follow-up after surgery. Study population All patients discharged from hospital after having undergone isolated off-pump coronary artery bypass surgery in our Institution during 2009 and 2010 were included in the study. Patients who required postoperative anticoagulation treatment for any reason (ten patients) and those with proven intolerance to antiplatelet agents (two patients) were excluded. Patients were classified into two groups, depending on the administered antiplatelet therapy after surgery: 1. Group A: Single antiplatelet therapy (SAT) with ASA or clopidogrel. ASA was administered 100 mg daily; clopidogrel was administered 75 mg daily without a loading dose. 2. Group B: DAT with ASA 100 mg daily and clopidogrel 75 mg daily during the first postoperative year, and then continue with single antiplatelet therapy with ASA 100 mg daily for life, according to clinical practice guidelines. 2 The decision to start single or dual antiplatelet therapy upon discharge was made by the operating surgeon based on practitioner preferences. During 2009 most of the surgeons in our institution administered SAT, with a slow trend of changing protocols to DAT, so all surgical teams were included in both groups. We did not make any other change in surgical or medical protocols during that time interval. Followup was limited to two years after surgery, not taking into account events that occurred beyond that time. All patients who were taking ASA before surgery continued on that same regimen until discontinuing the day before the operation. The ASA antiplatelet therapy was resumed the day after the operation as long as there was no evidence of significant bleeding. If any patient was receiving clopidogrel prior to surgery, this was discontinued, whenever possible, at least five days prior to the operation. The DAT adding 75 mg of clopidogrel (without loading dose) to ASA was initiated prior to discharge, after removal of the chest drains, between the fourth and seventh postoperative day in most of the cases. Patients with a known intolerance to ASA received single antiplatelet therapy with clopidogrel, according to the current clinical practice guideline recommendations. Any additional secondary prevention drugs such as beta blockers, calcium antagonists, statins, angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers (ACE Inhibitors/ARBs) were initiated according to current cardiological recommendations. 2 Study variables The study variables were recorded prospectively at the time of surgery, and they were collected from the hospital databases. Demographic, clinical and surgical characteristic data were obtained from each patient. The following variables were included: demographic (sex, age, weight, and height), surgical risk (logistic Euro- SCORE I), cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia and smoking), a history of prior coronary intervention, drug treatment upon discharge (antiplatelet therapy, beta blockers, calcium channel blockers, angiotensin-converting-enzyme inhibitors, and statins), laboratory variables (platelet count, urea, and creatinine), and surgical variables (left internal mammary artery use, right internal mammary artery use, radial artery use, complete revascularization, total arterial revascularization, number of grafts, affected vessels, the urgency of the operation). Clinical follow-up A postoperative clinical follow-up was conducted for two years, by telephone consultation and by a review of hospital databases in cases of readmission. 89.5% of the study patients were contacted by phone, with no significant differences between the two groups (SAT 90.6%; DAT 88.1%; p ¼ 0.524). The mean follow-up time was months (SD 0.5 months). Defining the study objectives The primary objective of the study was monitoring the presence of any of the following conditions: hospitalization for acute coronary syndrome (ACS), revascularization, stroke, or cardiovascular death. 1. ACS: Defined by the European Society of Cardiology clinical practice guidelines 15,16 as requiring hospitalization. This includes patients with ACS with ST-segment elevation 16 and without ST-segment elevation New revascularization: The performance of at least one new angioplasty with or without stenting after surgery. 3. Cerebrovascular accident 17 : The onset of a new neurological deficit of vascular origin that lasts more than 24 hours or results in death. 4. Cardiovascular death 17 : All deaths from a known cardiovascular cause or any death of an unknown etiology. The safety end-points, considered as the presence of major and minor bleeding, are according to the following definitions 18 : 1. Major bleeding, potentially life-threatening: Clinically apparent with a drop in hemoglobin of >5 g/dl, or a

3 368 LÓPEZ, ET AL. J CARD SURG LONG-TERM EFFECT OF DUAL ANTIPLATELET TREATMENT 2013;28: transfusion of at least 4 U PRBC; or fatal; or intracranial; or intrapericardial with cardiac tamponade; or resulting in hypovolemic shock or severe hypotension that requires vasopressors or surgery. Other major bleeding: Clinically apparent, with a drop in hemoglobin of 3 to 5 g/dl, or that requires a transfusion of 2 to 3 U PRBC; or significantly disabling. 2. Minor bleeding: Requiring medical intervention to stop or treat bleeding. Statistical analysis The statistical analysis was performed using the IBM SPSS Statistics for Mac (Version 20.0, IBM Corp., Armonk, NY, USA). The continuous variables were expressed as mean standard deviation (SD). The categorical variables were expressed as frequency and proportions. Student s unpaired t-test was used to compare the continuous variables, and the chi square test was used for the categorical variables. Multivariate analysis was performed using Cox proportional hazards regression, and output as hazard ratios, with 95% confidence intervals, was used to assess the variables associated with subsequent events during the followup. All the variables in which association with the combined event was significant or close to significance (p-value <0.1) in the univariate analysis were entered in the multivariate model. The EuroSCORE I was not included in the multivariate model because it is a composite of several of the variables that were studied individually (age, sex, creatinine, emergency of the operation, and ventricular function are included in the EuroSCORE I). Time to major adverse cardiovascular event was determined for the study groups by the Kaplan Meier method, and groups were compared with log-rank test. A p-value of less than 0.05 was considered statistically significant. Ethical considerations The identification of the patients is encoded, complying with the requirements of the Organic Law on Data Protection 15/1999. The Clinical Research Ethics Committee of the Hospital authorized the completion of this project. RESULTS Study patient characteristics A total of 258 patients were operated with off-pump coronary artery bypass surgery throughout this study. A total of 21 patients from this number were excluded (10 required oral anticoagulation, two did not receive antiplatelet therapy upon discharge due to intolerance, and ninewhodiedbeforedischarge),sotheresultingstudy population included 237 patients. Group A consisted of 128 patients (54%) who received single antiplatelet therapy with ASA (or clopidogrel if intolerant to ASA) upon discharge and group B consisted of 109 patients (46%) who received DAT with ASA and clopidogrel. Table 1 shows the baseline characteristics of the study population overall and by subgroups. Baseline TABLE 1 Baseline Parameters of the Study Population Total (N = 237) SAT (N = 128) DAT (N = 109) P-Value Age, years (SD) (9.96) (9.87) 63.2 (9.45) <0.001 Male sex, n (%) 181 (76.4) 91 (71.1) 90 (82.6) Logistic EuroSCORE I, % (SD) 4.16 (5.08) 4.43 (4.96) 3.83 (5.21) Prior coronary intervention, n (%) 32 (13.5) 15 (11.7) 17 (15.6) Preserved ventricular function, n (%) 183 (77.2) 99 (77.3) 84 (77.1) Cardiovascular risk factors Hypertension, n (%) 160 (67.5) 84 (65.6) 76 (69.7) Dyslipidemia, n (%) 159 (67.1) 86 (67.2) 73 (67) Diabetes mellitus, n (%) 94 (39.7) 50 (39.1) 44 (40.4) History of smoking, n (%) 125 (52.7) 58 (61.5) 67 (45.3) Preoperative laboratory data Creatinine, mg/dl (SD) 1.07 (0.72) 1.07 (0.54) 1.06 (0.88) Platelet count, 1000/mL (SD) (69) 234 (71) 229 (67) Surgical procedure data Number of grafts, n (SD) 2.47 (0.953) 2.33 (0.97) 2.63 (0.91) Complete revascularization, n (%) 185 (78.1) 95 (74.2) 90 (82.6) ITA graft, n (%) 211 (89.4) 116 (90.6) 95 (88) Total arterial revascularization, n (%) 62 (27.2) 37 (30.1) 25 (23.8) Medical treatment after hospital discharge Beta blockers, n (%) 191 (80.6) 104 (81.2) 87 (79.8) Calcium antagonist, n (%) 51 (21.5) 21 (16.4) 30 (27.5) Statins, n (%) 216 (91.1) 118 (92.2) 98 (89.9) ACE inhibitors/arbs, n (%) 86 (36.3) 51 (39.8) 35 (32.1) SAT, single antiplatelet therapy; DAT, dual antiplatelet therapy; SD, standard deviation; ITA, internal thoracic artery; ACE, angiotensin converting enzyme; ARBS, angiotensin receptor blockers. Bold values in Table 1 are those in which a statistical significant difference was found (P < 0.05). These values are also the ones commented in the text as differences found between groups.

4 J CARD SURG LÓPEZ, ET AL ;28: LONG-TERM EFFECT OF DUAL ANTIPLATELET TREATMENT TABLE 2 Follow Up Total (N = 237) SAT (N = 128) DAT (N = 109) P-Value Follow-up time, months (SD) (0.54) (0.43) (0.65) Primary objective Composite end-point, n (%) 33 (13.9) 24 (18.8) 9 (8.3) ACS, n (%) 18 (7.6) 14 (10.9) 4 (3.7) New revascularization, n (%) 12 (5.1) 7 (5.5) 5 (4.6) Stroke, n (%) 3 (1.3) 1 (0.8) 2 (1.8) Cardiovascular death, n (%) 8 (3.4) 6 (4.7) 2 (1.8) Safety objectives Major bleeding, n (%) 2 (0.8) 1 (0.8) 1 (0.9) Minor bleeding, n (%) 7 (3) 3 (2.3) 4 (3.7) DAT, dual antiplatelet therapy; SAT, single antiplatelet therapy; ACS, acute coronary syndrome. Bold values in Table 2 are those in which a statistical significant difference was found (P < 0.05). These values are also the ones commented in the text as differences found between groups. When any patient had more than one event, only the first one was taken into account (for example, ACS followed by new revascularization). differences included: patients in the DAT group had a significantly lower mean age, a higher proportion of males, and a smaller percentage of smoking history compared to the single antiplatelet group. There were no other significant differences in the preoperative variables. The number of grafts performed was significantly higher in the DAT group ( vs ; p ¼ 0.017), but there was no significant difference in the degree of complete revascularization, the use of the left internal mammary artery or total arterial revascularization. Medication regimen at discharge was similar in both groups except for a greater use of calcium channel blockers (p ¼ 0.038) in the DAT group. Event analysis The mean follow-up time was (0.5) months. The overall analysis of events (Table 2) shows that the primary objective occurred in 13.9% of patients, presented as 7.6% readmission for ACS, 5.1% for new coronary revascularization, 1.3% due to a stroke and 3.4% died during the follow-up period. Regarding the subgroup analysis, the study s primary objective occurred in 18.8% of patients treated with single antiplatelet therapy, compared with 8.3% of patients with DAT (p ¼ 0.020; Fig. 1). These differences in the occurrence of events were largely based on a higher number of hospital readmissions due to ACS. 10.9% of patients with single antiplatelet therapy required readmission, compared to 3.7% with dual antiplatelet therapy (p ¼ 0.035). There were no differences in the number of new unplanned coronary interventions or new stroke incidents during follow-up. Mortality was slightly lower in the DAT group, although this difference did not reach statistical significance. In the univariate analysis (Table 3), the logistic EuroSCORE I correlated significantly with the occurrence of events. The use of a left internal mammary artery (p ¼ 0.046), beta-blockers (p ¼ 0.043), and statins (p ¼ 0.009) was associated with a lower rate of events. DAT was found to be a protective factor in the occurrence of events, with a HR of (95% CI, to 0.918; p ¼ 0.029). As a sensitivity analysis, patients taking clopidogrel in the SAT group were excluded. The SAT group consisted of 118 patients with ASA, and 10 patients with clopidogrel. Patients with clopidogrel alone had worse outcome than patients with ASA; 19 (17.3%) patients with ASA had an event, while 5 (27.8%) patients with clopidogrel had an event, but this difference did not reach statistical significance (p ¼ 0.290). Excluding patients taking clopidogrel alone in SAT, there were 19 events (17.3%) in SAT versus 9 events (8.3%) in DAT, maintaining statistical significance (p ¼ 0.046) with chi square test. Furthermore, the multivariate analysis using Cox proportional hazards regression (Table 4) shows an independent association of DAT with the study s primary objective, with a hazard ratio of (95% CI, to 0.885, p ¼ 0.024). The presence of Figure 1. Cumulative event-free survival during follow-up. DAT, dual antiplatelet therapy; SAT, single antiplatelet therapy. Survival groups were compared with log-rank test.

5 370 LÓPEZ, ET AL. J CARD SURG LONG-TERM EFFECT OF DUAL ANTIPLATELET TREATMENT 2013;28: TABLE 3 Univariate Analysis Hazard Ratio (95% CI) P-value Age ( ) Logistic EuroSCORE I ( ) Sex (male) ( ) Prior revascularization ( ) Ventricular dysfunction ( ) Cardiovascular risk factors Arterial hypertension ( ) Dyslipidemia ( ) Diabetes mellitus ( ) History of smoking ( ) Preoperative laboratory data Creatinine ( ) Platelet count ( ) Surgical procedure data Complete revascularization ( ) ITA graft ( ) Total arterial revascularization ( ) Medical treatment after hospital discharge DAT ( ) Beta blockers ( ) Calcium antagonists ( ) Statins ( ) ACE inhibitors/arbs ( ) Association with the composite end-point. ITA, internal thoracic artery; ACE, angiotensin converter enzyme; ARBS, angiotensin receptor blockers. Bold values in Table 3 are those in which a statistical significant difference was found (P < 0.05). These values are also the ones commented in the text as differences found between groups. diabetes mellitus also shows an independent association to the study s combined event (HR 2.050; 95% CI, HR to 0.885, p ¼ 0.045). Including/forcing-in all variables in the multivariate analysis where there was a statistically significant imbalance in the baseline characteristic, in addition to those identified for inclusion in the univariate analysis, did not affect inferences. The analysis of the timing of the occurrence of events during follow-up (Table 5) shows DAT as being primarily associated with the reduction of late events (after six months); while the rate of early events (within six months after surgery) was similar between the two groups. TABLE 4 Multivariate Analysis Hazard ratio (95% CI) P-Value Age ( ) Male sex ( ) Diabetes mellitus ( ) DAT ( ) Beta blockers ( ) Statins ( ) ITA graft ( ) Adjusted effect of DAT on the combined event. DAT, dual antiplatelet therapy; ITA, internal thoracic artery. Bold values in Table 4 are those in which a statistical significant difference was found (P < 0.05). These values are also the ones commented in the text as differences found between groups. Safety end-points During follow-up, two patients suffered a major bleeding episode (0.8%) and seven patients suffered a minor bleeding episode (3%; Table 2). DAT did not lead to a significant increase in major bleeding episodes (p ¼ 0.909) nor in minor bleeding episodes (p ¼ 0.548). Major bleeding episodes were: (a) SAT: one patient suffered acute upper digestive tract hemorrhage 4.5 months after surgery, with hemodynamic instability, requiring urgent surgery. Active arterial bleeding was found in proximal jejunum. Ten centimeters of intestine were resected, with direct tract reconstruction, with a good outcome; (b) DAT: one patient had an intracranial hemorrhage 21 months after surgery (with SAT at that time, as established in protocol), with a fatal outcome. Minor episodes were digestive tract hemorrhages not fulfilling major bleeding criteria. Months TABLE 5 Months Until Appearance of First Event SAT (N = 128) DAT (N = 109) N (% events in group) <6 9 (7.0) 7 (6.4) (5.5) 1 (0.9) (3.9) 0 (0.0) >18 3 (2.3) 1 (0.9) Total 24 (18.8) 9 (8.3) SAT, single antiplatelet therapy; DAT, dual antiplatelet therapy.

6 J CARD SURG LÓPEZ, ET AL ;28: LONG-TERM EFFECT OF DUAL ANTIPLATELET TREATMENT DISCUSSION The main finding of our study is that DAT during the first postoperative year after off-pump coronary artery bypass surgery (OPCAB) is associated with a decrease in the occurrence of late cardiovascular events, especially by reducing the number of hospital readmissions due to ACS. OPCAB is a widely used surgical revascularization method, with multiple studies that show a trend towards better perioperative outcomes, in experienced institutions, when compared to conventional on-pump surgery. 19 Despite this perioperative improvement, recent publications have questioned the long-term durability of the grafts that have been performed, 5,20 including a possible increased tendency for patients to develop new ischemic events. Due to concerns about reduced graft patency after OPCAB surgery multiple studies have been conducted in which DAT was started after hospital discharge, maintained for a year, in analogy with the current recommendations after percutaneous revascularization. 2 In the CURE-CABG study 21 there was a reduction in the trend toward major cardiac events in patients who were treated with DAT after coronary revascularization surgery, although it was not statistically significant. This trend was consistent with the other groups of the CURE study (patients in the medical therapy and percutaneous intervention arm). Furthermore, experimental studies 9 have shown that clopidogrel inhibits intimal hyperplasia, while ASA appears not to reduce it. Intimal hyperplasia appears to correlate with graft closure after the first postoperative year. 8 The CASCADE study 13 evaluated the effect of clopidogrel in reducing saphenous vein graft intimal hyperplasia after CABG, as determined by intravascular ultrasound (IVUS) at one year. It consisted of a randomized, double-blinded trial, in which 113 patients were randomized into two groups, to receive single or dual antiplatelet therapy. No significant differences were found between the groups in terms of intimal hyperplasia as determined by IVUS, although there was a nonsignificant trend of reduction in the vascular wall thickness in the group treated with ASA þ clopidogrel, with a 7% decrease in wall thickness. There were no clinical differences found between the groups, although the study was not powered for this. In 2006 a study was published 22 demonstrating a reduction in long-term cardiovascular morbidity after the addition of clopidogrel for 30 days after surgery, with a significant reduction in the recurrence of ischemic symptoms. In a randomized study, 11 the increased saphenous vein graft patency with the addition of clopidogrel was demonstrated by multidetector computed tomography. Although these differences did not have clinical correlation, three months after surgery the percentage of graft patency rose from 85.7% to 91.6%, with DAT as an independent variant in preventing graft closure in the multivariate analysis. Similar results were found in the study by Ibrahim et al., 12 although a statistically significant difference in patency was not reached. In the present study, only patients undergoing coronary surgery without cardiopulmonary bypass were included, because recent publications 5,20 seemed to indicate that these patients have a higher risk of new events occurring in long-term follow-up, and therefore they may benefit more from DAT than patients operated with conventional surgery. 12,22 After a two-year follow-up, we found a significant reduction in the number of hospital readmissions caused by new episodes of ACS. Angiographic studies indicate that among patients who present with a new episode of unstable angina, non-st elevation ACS or ST-elevation ACS, the culprit lesion in 70% to 85% of cases is an atherosclerotic vein graft stenosis, often with superimposed thrombus. 4 Thus, this lower number of admissions due to ACS could translate to a greater maintenance of graft patency, although no imaging study has been carried out to corroborate this idea. The event rate in the first six postoperative months was similar in both groups; DAT was primarily associated with the reduction of late events, as seven of the nine events with DAT occurred within the first six postoperative months, with few events occurring after that. This early closure, similar in both groups, without the influence of administered antiplatelet therapy, could be perioperative graft occlusion due to varying technical problems (suboptimal grafts, small calibre coronaries, etc.). Dual antiplatelet therapy may prolong the durability of optimal grafts. As regards safety, DAT did not increase the number of bleeding episodes. Limitations The main limitation of the hypothesis of this study is the lack of randomization, which leads us to find differences in the baseline characteristics of both groups. For example, among patients treated with single antiplatelet therapy upon discharge, there was a higher proportion of women and older patients. 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