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Ann Thorac Surg 2009;88:59-62. doi:10.1016/j.athoracsur.2009.04.024
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Clopidogrel and Aspirin Versus Clopidogrel Alone on Graft Patency After Coronary Artery Bypass Grafting

Changqing Gao, MD*, Chonglei Ren, MD, Dong Li, MD, Libing Li, MD

Department of Cardiovascular Surgery, PLA General Hospital, PLA Institute of Cardiac Surgery, Beijing, China

Accepted for publication April 9, 2009.

* Address correspondence to Dr Gao, Department of Cardiovascular Surgery, PLA General Hospital; PLA Institute of Cardiac Surgery, 28 Fuxing Rd, Beijing, 100853, China (Email: gaochq301{at}yahoo.com).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Clopidogrel and aspirin are the most popular antiplatelet agents for anticoagulation management after coronary artery bypass grafting (CABG) in clinical practice, but there is neither a standard antiplatelet therapy for patients undergoing CABG, nor an exact conclusion about its effects on graft patency until now.

Methods: One-hundred and ninety-seven selected patients undergoing CABG were assigned to two groups according to antiplatelet drug: the clopidogrel group of 102 patients who received clopidogrel (75 mg) daily; and the combination group of 95 patients who received clopidogrel (75 mg) plus aspirin (100 mg) daily. Multislice computed tomography angiography was performed to evaluate graft patency at 1 month and 12 months after CABG.

Results: There were no significant differences between the two groups in preoperational data. At 1 month and 12 months after CABG graft patency rates of clopidogrel group were, respectively, 99.0% and 96.9% for the left internal mammary artery (LIMA) and 98.1% and 93.5% for the saphenous vein grafts; those of the combination group were, respectively, 98.9% and 97.8% for LIMA, and 98.2% and 96.3% for saphenous vein grafts. There were no significant differences in graft patency between the two groups (p > 0.05).

Conclusions: Either clopidogrel plus aspirin or clopidogrel alone maintain high graft patency in the early postoperative phase after CABG. The observed trend toward higher patency rates in patients treated with clopidogrel plus aspirin compared to those in the clopidogrel group did not reach statistical significance.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Graft patency after coronary artery bypass grafting (CABG) relates to many factors [1]. Antiplatelet therapy after CABG can lessen the formation of thrombus and improve graft patency [2]. Clopidogrel and aspirin are the most popular antiplatelet agents for anticoagulation management after CABG in clinical practice, but there is neither standard antiplatelet therapy for patients undergoing CABG, nor an exact conclusion about its effects on graft patency until now. The aim of this study is to compare the effect of clopidogrel used in combination with aspirin or clopidogrel alone on graft patency after CABG and provide some evidence and recommendations for clinical management.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Patients
One hundred ninety-seven consecutive patients undergoing elective CABG (accounting for 43.8% of patients undergoing CABG) by the same surgeon (Prof Gao) at PLA General Hospital from August 2005 to February 2007 were enrolled in the study with approval from the Institutional Review Board and with informed consent.

The patients with the following conditions were excluded: abnormal quantity of platelets before operation (less than 100 x 109/L or more than 300 x 109/L); previous CABG (patients were often infused fresh platelet after CABG) or other cardiac surgery; need for concomitant valve surgery or aneurysm resection; and infusion of fresh platelet during or after CABG. After operation, according to postoperative antiplatelet therapy, the patients were randomized into two groups; the clopidogrel group and the combination group. On alternating weeks patients were administered either clopidogrel or a combination of clopidogrel and aspirin. Each patient of the clopidogrel group received clopidogrel (75 mg) daily, and each of combination group received clopidogrel (75 mg) plus aspirin (100 mg) daily. There were no significant differences between the two enrolled groups in preoperational data (such as age, gender, weight index, body surface area, hemoglobin, fibrinogen, platelet amount, smoking and drinking history, case history of hypertension, diabetes mellitus, hyperlipemia, myocardial infarction, and percutaneous coronary intervention) (p > 0.05) (Table 1).


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  		Table 1 Preoperative Clinical Characteristics in Clopidogrel and Combination Groups
 
Surgical Procedures
All operations were performed by a single experienced surgeon and all patients were managed by a single team. All patients received either off-pump coronary artery bypass grafting (OPCAB) or conventional coronary artery bypass grafting (CCABG) according to patient's conditions [3]. General anesthesia in a fixed protocol was used and median sternotomy was performed; the radial artery-saphenous vein graft (SVG) and left internal mammary artery (LIMA) were harvested simultaneously. The LIMA was routinely anastomosed to the left anterior descending artery, and the SVG or radial artery graft was anastomosed to other target vessels. Standard bypass techniques were employed [3]. The flow value of bypass was measured and recorded with the ultrasound flowmeter to conform the graft patency [4]. In both groups intravenous nitroglycerin was administered routinely, and a minimal dose of dopamine was used if necessary after surgery. Electrocardiogram, invasive blood pressure, pulmonary artery pressure, central venous pressure, serum electrolyte, artery blood gas analysis, and drainages were monitored and recorded postoperatively. There were no significant differences between the two enrolled groups in intraoperative and postoperative data (p > 0.05) (Table 2).


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  		Table 2 Operative Data in Clopidogrel and Combination Group
 
Administration of Antiplatelet Agents
Preoperation antiplatelet therapy was discontinued for at least 5 TO 7 days prior to CABG surgery in all patients. After surgery, the antiplatelet agents were given orally as soon as possible after extubation and administered through a nasogastric tube for the patients whose tracheal intubation was not removed in the first postoperative day. All patients received clopidogrel (75 mg) or clopidogrel (75 mg) plus aspirin (100 mg) daily after operation.

Graft Patency By 64-Multislice Computed Tomography Angiography (MSCTA)
A 64-MSCTA was used to assess the graft patency at 1 month and 12 months after surgery in all patients. The angiographic analysis was the same as that in our early studies [5, 6]. The MSCTA data were analyzed by two radiologists and a cardiac surgeon together. The graft patency was assessed not only at the anastomotic site but along the main body of the graft as well.

Statistical Analysis
Statistical processing was carried out by the first author (CG) with SPSS software 13.0 (Chicago, IL). All continuous variables in normal distribution are expressed as a mean ± standard error of the mean. The unpaired Student t test or t’ test was used to compare these continuous variables between groups. Numeration data were analyzed using the {chi}2 test. Statistical significance was assumed at a probability level of less than 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
One hundred ninety-seven patients were enrolled in the study and included in the final analysis. All patients were treated with antiplatelet agents and performed MSCTA in schedule. There were no obvious bleeding events or other adverse effects in all patients. There were no deaths related to the operation or antiplatelet therapy in all 197 patients.

At 1 month and 12 months after operation the graft patency rates of the clopidogrel group were, respectively, 99.0% and 96.9% for 98 LIMA grafts (Fig 1), and 98.1% and 93.5% for 154 SVGs (Fig 2); those of the combination group were, respectively, 98.9% and 97.8% for 90 LIMA grafts, and 98.2% and 96.3% for 163 SVGs. There were no significant differences in graft patency between the two groups at either 1 month (LIMA: 99.0% vs 98.9%, p = 0.77; SVG: 98.1% vs 98.2%, p = 0.73) or 12 months after CABG (LIMA: 96.9% vs 97.8%, p = 0.91; SVG: 93.5% vs 96.3%, p = 0.25).


Figure 1
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  		Fig 1. Graft patency rates at 1 month after coronary artery bypass grafting. (Grey column = clopidogrel group; black column = combination group; LIMA = left anterior mammary artery; SV = saphenous vein.)

 

Figure 2
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  		Fig 2. Graft patency rates at 12 months after coronary artery bypass grafting. (Grey column = clopidogrel group; black column = combination group; LIMA = left anterior mammary artery; SV = saphenous vein.)

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
There are many causes for graft stenosis after CABG, which has different pathologic characteristics and etiology in different periods [7]. The main reason for graft stenosis and occlusion is the formation of thrombus, which relates to the surgical anastomosis techniques, the graft quality, and the coagulation function in the perioperative period. Anticoagulant therapy, mostly with antiplatelet agents, is very important for graft patency after CABG besides surgical factors, which can depress the formation of thrombus, prevent graft occlusion, and protect graft patency [1, 8–10].

Aspirin has been used for many years as the sole antiplatelet agent for improving graft patency and reducing related complications after CABG [11]. Aspirin, a conventional antiplatelet agent, mainly selectively depresses platelet cycloxygenase-1 and interrupts the formation of thromboxane A2. Clopidogrel, a new antiplatelet agent, irreversibly inhibits adenosine diphosphate (ADP)-induced platelet aggregation by selectively binding to ADP receptors on the platelet surface [12, 13].

Recently, the Clopidogrel in Unstable Angina to Prevent Recurrent Events investigators have demonstrated that the combination of aspirin plus clopidogrel exerts a synergistic inhibition of platelet aggregation significantly more than either agent alone, and might result in even better outcomes than does clopidogrel alone [14]. Several experimental studies also support the synergy of dual therapy with clopidogrel and aspirin [15–17]. Dunning and colleagues [18] and Motwani and Topol [7] showed that the combination of clopidogrel plus aspirin would be more significant in improving the SVG graft patency than artery graft, where intimal overhyperplasia more easily occurs and vein grafts tend to be arterialized in the first operative year. It could also be relevant to the synergistic effects on antithrombus and inhibition of intimal hyperplasia with the combination of two agents instead of clopidogrel alone [19].

Our study showed that either clopidogrel plus aspirin or clopidogrel alone could maintain higher graft patency in the early postoperative phase after CABG. There were no significant differences in graft patency between the two group (p > 0.05), but there was an observed trend toward higher patency rates in patients treated with clopidogrel plus aspirin than those in the clopidogrel group. Absence of significant differences in graft patency between dual therapy and clopidogrel alone indicates that both therapies may depress the formation of thrombus. In addition, the results suggest that the administration of clopidogrel alone is as good as the dual therapy in maintaining the graft patency in the early stage after CABG.

Some believed that clopidogrel plus aspirin may increase bleeding risks and the bleeding occurrence was related to the dose of aspirin [11]. In our study we found that combination of clopidogrel (75 mg) with aspirin (100 mg) daily did not increase postoperative bleeding in comparison with clopidogrel alone (p > 0.05), and we believe that clopidogrel plus aspirin in routine dose is safe in the early stage after CABG.

The limitations of the study lie in the following aspects. We did not evaluate platelet function. Consequently, the interindividual variability in the antiplatelet therapy was not taken into account [20, 21]. We might have underestimated the patency rates because the patients who returned to hospital for the MSCTA at 1 year after surgery might have some complaint symptoms, so the patency rates observed might be lower than the actual patency rates. It is presently not known whether clopidogrel improves graft patency over that of aspirin only in coronary artery grafts.

In conclusion, either clopidogrel plus aspirin or clopidogrel alone therapies can maintain a fairly high graft patency rate in the early phase after CAGB. The combination of clopidogrel plus aspirin has no advantage over clopidogrel alone, whether clopidogrel plus aspirin therapy is better than clopidogrel alone needs confirming through further long-term and large-sample randomized studies.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Goldman S, Copeland J, Moritz T, et al. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a veterans administration cooperative study Circulation 1988;77:1324-1332.[Abstract/Free Full Text]
  2. CAPR IE Steering Committee A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPR IE) Lancet 1996;348:1329-1339.[Medline]
  3. Gao C, Li BJ, Xiao CS, et al. Clinical analysis of 1018 cases of coronary artery bypass grafting[in Chinese] Zhonghua Wai Ke Za Zhi 2005;43:929-932.[Medline]
  4. Gao C, Zhang T, Li BJ, et al. A comparative study on grafts' blood flow after on-pump and off-pump coronary artery bypass surgeries[in Chinese] Zhonghua Wai Ke Za Zhi 2005;43:1429-1431.[Medline]
  5. Liu ZY, Gao CQ, Li LB, et al. Diagnostic study on the coronary artery bypass graft lesions using 64-slice computed tomography angiography Zhonghua Wai Ke Za Zhi 2008;46:245-247.[Medline]
  6. Gao CQ, Liu ZY, Li LB, et al. Comparison of graft patency for off-pump and conventional coronary arterial bypass grafting using 64-slice multidetector spiral computed tomography angiography Interact Cardiovasc Thorac Surg 2009;8:325-329.[Abstract/Free Full Text]
  7. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention Circulation 1998;97:916-931.[Abstract/Free Full Text]
  8. Stein PD, Schunemann HJ, Dalen JE, et al. Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest 2004;126(suppl 3):600S-608S.[Abstract/Free Full Text]
  9. Poston RS, Gu J, Brown JM, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting J Thorac Cardiovasc Surg 2006;131:122-130.[Abstract/Free Full Text]
  10. Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit Thromb Haemost 1998;80:512-518.[Medline]
  11. Gavaghan TP, Gebski V, Baron DW. Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery Circulation 1991;83:1526-1533.[Abstract/Free Full Text]
  12. Harker LA, Marzec UM, Kelly AB, et al. Clopidogrel inhibition of stent, graft and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates Circulation 1998;98:2461-2469.[Abstract/Free Full Text]
  13. Ibrahim K, Tjomsland O, Halvorsen D, et al. Effect of clopidogrel on midterm graft patency following off-pump coronary revascularization surgery Heart Surg Forum 2006;9:E581-E856.[Medline]
  14. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK, Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation N Engl J Med 2001;345:494-502.[Medline]
  15. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronaryartery stents N Engl J Med 1996;334:1084-1089.[Medline]
  16. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting: Stent Anticoagulation Restenosis Study Investigators N Engl J Med 1998;339:1665-1671.[Medline]
  17. Müller C, Büttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents Circulation 2000;101:590-593.[Abstract/Free Full Text]
  18. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, Nashef SA, EACTS Audit and Guidelines Committee Guideline on antiplatelet and anticoagulation management in cardiac surgery Eur J Cardiothorac Surg 2008;34:73-92.[Abstract/Free Full Text]
  19. Kulik A, Le May M, Wells GA, Mesana TG, Ruel M. The clopidogrel after surgery for coronary artery disease (CASCADE) randomized controlled trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery[NCT00228423] Curr Control Trials Cardiovasc Med 2005;6:15.[Medline]
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