Impact of Clopidogrel Plus Aspirin Versus Aspirin Alone on the Progression of Native Coronary Artery Disease After Bypass Surgery: Analysis From the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) Randomized Trial Dai Une, Talal Al-Atassi, Alexander Kulik, Pierre Voisine, Michel Le May and Marc Ruel Circulation. 2014;130:S12-S18 doi: 10.1161/CIRCULATIONAHA.113.008227 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/130/11_suppl_1/S12
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Impact of Clopidogrel Plus Aspirin Versus Aspirin Alone on the Progression of Native Coronary Artery Disease After Bypass Surgery Analysis From the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) Randomized Trial Dai Une, MD; Talal Al-Atassi, MD; Alexander Kulik, MD, MPH; Pierre Voisine, MD; Michel Le May, MD; Marc Ruel, MD, MPH Background—The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown. Methods and Results—In the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) trial, a total of 113 patients were randomized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting. In this secondary analysis, the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses graded serially by using 6 thresholds (grade 0 [0%–24%], grade 1 [25%–37%], grade 2 [38%–62%], grade 3 [63%–82%], grade 4 [83%–98%], and grade 5 [99%–100%]). We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups. A total of 543 preoperative stenoses and occlusions were quantified and followed. At 1-year postoperatively, there were 103 evolving (94 worsened, 9 improved) and 22 new lesions. The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease (P≤0.02). There were no differences in clinical events between treatment groups, and the proportion of patients with evolving or new lesions was also similar (70% versus 74%, aspirin–clopidogrel versus aspirin–placebo, respectively; P=0.8). However, in evolving or new lesions, the mean grade change (1.1±1.0 versus 1.6±1.1, respectively; P=0.01) and the proportion of new occlusions (7% versus 22%; P=0.02) were lower in the aspirin–clopidogrel group. Conclusions—The addition of clopidogrel to aspirin correlates with less worsening of native coronary artery disease 1 year after coronary artery bypass grafting. These findings may help guide post–coronary artery bypass grafting antiplatelet therapy. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00228423. (Circulation. 2014;130[suppl 1]:S12-S18.) Key Words: clopidogrel ◼ coronary artery disease ◼ platelet aggregation
D
ual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been reported to improve the clinical outcomes of patients with acute coronary syndrome or percutaneous coronary intervention (PCI) compared with aspirin alone.1–3 In addition, animal studies have suggested that clopidogrel may be protective against arterial atherosclerosis.4,5 Therefore, it is possible that DAPT may prevent atherosclerosis or atherothrombotic events after coronary artery bypass grafting (CABG) and in turn affect clinical outcomes. Although previous studies have examined the effect of DAPT on graft patency and clinical outcomes after CABG,6–9
none to our knowledge has addressed its effects on progression of native coronary artery disease (CAD). The issue is relevant because CAD progression occurs more frequently than graft failure after CABG and can lead to myocardial infarction, revascularization, and death.10 The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) randomized trial was designed to evaluate whether DAPT with aspirin and clopidogrel is more protective than aspirin alone against saphenous vein graft (SVG) intimal hyperplasia and occlusion 1 year after CABG.6,11 In the present secondary analysis, we compared preoperative and 1-year
From the Division of Cardiac Surgery (D.U., T.A.-A., M.R.) and Division of Cardiology (M.L.M.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Lynn Heart and Vascular Institute, Boca Raton, FL (A.K.); Division of Cardiac Surgery, Hôpital Laval, Quebec City, Quebec, Canada (P.V.); and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.R.). Guest Editor for this manuscript was Frank Sellke, MD. Presented at the 2013 American Heart Association meeting in Dallas, TX, November 16–20, 2013. Correspondence to Marc Ruel, MD, MPH, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin St, Suite 3402, Ottawa, Ontario, Canada. E-mail [email protected] © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.008227
Downloaded from http://circ.ahajournals.org/ at WELLINGTON MEDICAL LIBRARY on October 6, 2014 S12
Une et al Clopidogrel and Aspirin on Native Coronary Disease S13 postoperative angiograms to quantitatively assess whether the addition of clopidogrel to aspirin inhibits the progression of native CAD or the development of new coronary lesions after CABG.
Methods The study is a secondary analysis of prospectively collected data in the CASCADE randomized controlled trial, which was a dual-center, double-blind, placebo-controlled trial. Details of the study protocol were previously published.6,11 The trial was approved by each institutional research ethics board, and informed patient consent was obtained before enrollment at each center.
Table 1. Preoperative and Perioperative Characteristics of Patients Aspirin–Clopidogrel (n=46) Age, y
Aspirin–Placebo (n=46)
P Value
64.6±7.5
67.4±7.1
0.1
Female, %
11% (5/46)
13% (6/46)
1.0
BMI, kg/m2
28.8±4.0
28.3±3.9
0.6
Diabetes mellitus, %
24 (11/46)
35 (16/46)
0.4
Hypertension, %
74 (34/46)
83 (38/46)
0.4
Hyperlipidemia, %
89 (41/46)
91 (42/46)
1.0
Smoker, %
74 (34/46)
76 (35/46)
1.0
Population
Left main lesion, %
35 (16/46)
48 (22/46)
0.3
In the CASCADE trial, 113 patients who underwent elective CABG with ≥2 SVGs were enrolled at the University of Ottawa Heart Institute (Ottawa, Ontario, Canada) or at Hôpital Laval (Quebec City, Quebec, Canada) from 2006 to 2009. Preoperative coronary angiogram was performed in all patients. Immediately after surgery, patients were randomized either to the aspirin–clopidogrel group, who received aspirin 162 mg plus clopidogrel 75 mg daily, or to the aspirin–placebo group, who received aspirin 162 mg plus placebo daily. Study medications were started on the day of surgery and continued for 12 months in a double-blinded fashion. Among the 113 patients, the present study assessed the progression of native CAD in the 92 patients who underwent postoperative angiogram at the 2 centers 1 year after CABG (Figure). Patient characteristics are shown in Table 1.
Three vessel disease, %
87 (40/46)
80 (37/46)
0.6
Patient Follow-Up Follow-up was performed in clinic at 1, 6, and 12 months after operation and telephone postoperative assessments at 3 and 9 months. Postoperative management was standardized in both groups. All medications were prescribed according to current American College of Cardiology/American Heart Association guidelines and as clinically indicated, including the use of statins, β-blockers, calcium-channel blockers, and angiotensin-converting enzyme inhibitors. Aggressive diabetes mellitus (DM) management and smoking cessation counseling were performed as indicated.12 One-year follow-up was performed on all 113 patients. Patients (n=92) underwent postoperative angiogram and intravascular ultrasound 12 months after CABG.
Review and Grading of Angiograms All 92 patients with a full pair of preoperative and postoperative angiograms had their films reviewed and graded, in blinded fashion to treatment, by a minimum of 2 investigator physicians, including ≥1 cardiologist and 1 surgeon (with ≥1 being M.R., A.K., M.L.M., or P.V.). The location and degree of each stenosis were recorded.
CCS class 3 or 4, %
59 (27/46)
54 (25/46)
0.8
NYHA 3 or 4, %
28 (13/46)
17 (8/46)
0.3
7 (3/46)
1.0
LVEF 2 cm where it had been seen preoperatively, the filling defect was considered to represent a new occlusion. Evolving CAD was defined as a lesion with ≥1 grade change in the severity of stenosis, calculated as the difference between the preoperative and postoperative grade. A worsening lesion was given a positive value and an improving lesion a negative value. A new lesion was defined as ≥25% postoperative stenosis where the stenosis was preoperatively
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/130/11_suppl_1/S12
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
Downloaded from http://circ.ahajournals.org/ at WELLINGTON MEDICAL LIBRARY on October 6, 2014
Impact of Clopidogrel Plus Aspirin Versus Aspirin Alone on the Progression of Native Coronary Artery Disease After Bypass Surgery Analysis From the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) Randomized Trial Dai Une, MD; Talal Al-Atassi, MD; Alexander Kulik, MD, MPH; Pierre Voisine, MD; Michel Le May, MD; Marc Ruel, MD, MPH Background—The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown. Methods and Results—In the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) trial, a total of 113 patients were randomized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting. In this secondary analysis, the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses graded serially by using 6 thresholds (grade 0 [0%–24%], grade 1 [25%–37%], grade 2 [38%–62%], grade 3 [63%–82%], grade 4 [83%–98%], and grade 5 [99%–100%]). We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups. A total of 543 preoperative stenoses and occlusions were quantified and followed. At 1-year postoperatively, there were 103 evolving (94 worsened, 9 improved) and 22 new lesions. The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease (P≤0.02). There were no differences in clinical events between treatment groups, and the proportion of patients with evolving or new lesions was also similar (70% versus 74%, aspirin–clopidogrel versus aspirin–placebo, respectively; P=0.8). However, in evolving or new lesions, the mean grade change (1.1±1.0 versus 1.6±1.1, respectively; P=0.01) and the proportion of new occlusions (7% versus 22%; P=0.02) were lower in the aspirin–clopidogrel group. Conclusions—The addition of clopidogrel to aspirin correlates with less worsening of native coronary artery disease 1 year after coronary artery bypass grafting. These findings may help guide post–coronary artery bypass grafting antiplatelet therapy. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00228423. (Circulation. 2014;130[suppl 1]:S12-S18.) Key Words: clopidogrel ◼ coronary artery disease ◼ platelet aggregation
D
ual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been reported to improve the clinical outcomes of patients with acute coronary syndrome or percutaneous coronary intervention (PCI) compared with aspirin alone.1–3 In addition, animal studies have suggested that clopidogrel may be protective against arterial atherosclerosis.4,5 Therefore, it is possible that DAPT may prevent atherosclerosis or atherothrombotic events after coronary artery bypass grafting (CABG) and in turn affect clinical outcomes. Although previous studies have examined the effect of DAPT on graft patency and clinical outcomes after CABG,6–9
none to our knowledge has addressed its effects on progression of native coronary artery disease (CAD). The issue is relevant because CAD progression occurs more frequently than graft failure after CABG and can lead to myocardial infarction, revascularization, and death.10 The Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) randomized trial was designed to evaluate whether DAPT with aspirin and clopidogrel is more protective than aspirin alone against saphenous vein graft (SVG) intimal hyperplasia and occlusion 1 year after CABG.6,11 In the present secondary analysis, we compared preoperative and 1-year
From the Division of Cardiac Surgery (D.U., T.A.-A., M.R.) and Division of Cardiology (M.L.M.), University of Ottawa Heart Institute, Ottawa, Ontario, Canada; Lynn Heart and Vascular Institute, Boca Raton, FL (A.K.); Division of Cardiac Surgery, Hôpital Laval, Quebec City, Quebec, Canada (P.V.); and Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada (M.R.). Guest Editor for this manuscript was Frank Sellke, MD. Presented at the 2013 American Heart Association meeting in Dallas, TX, November 16–20, 2013. Correspondence to Marc Ruel, MD, MPH, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin St, Suite 3402, Ottawa, Ontario, Canada. E-mail [email protected] © 2014 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.008227
Downloaded from http://circ.ahajournals.org/ at WELLINGTON MEDICAL LIBRARY on October 6, 2014 S12
Une et al Clopidogrel and Aspirin on Native Coronary Disease S13 postoperative angiograms to quantitatively assess whether the addition of clopidogrel to aspirin inhibits the progression of native CAD or the development of new coronary lesions after CABG.
Methods The study is a secondary analysis of prospectively collected data in the CASCADE randomized controlled trial, which was a dual-center, double-blind, placebo-controlled trial. Details of the study protocol were previously published.6,11 The trial was approved by each institutional research ethics board, and informed patient consent was obtained before enrollment at each center.
Table 1. Preoperative and Perioperative Characteristics of Patients Aspirin–Clopidogrel (n=46) Age, y
Aspirin–Placebo (n=46)
P Value
64.6±7.5
67.4±7.1
0.1
Female, %
11% (5/46)
13% (6/46)
1.0
BMI, kg/m2
28.8±4.0
28.3±3.9
0.6
Diabetes mellitus, %
24 (11/46)
35 (16/46)
0.4
Hypertension, %
74 (34/46)
83 (38/46)
0.4
Hyperlipidemia, %
89 (41/46)
91 (42/46)
1.0
Smoker, %
74 (34/46)
76 (35/46)
1.0
Population
Left main lesion, %
35 (16/46)
48 (22/46)
0.3
In the CASCADE trial, 113 patients who underwent elective CABG with ≥2 SVGs were enrolled at the University of Ottawa Heart Institute (Ottawa, Ontario, Canada) or at Hôpital Laval (Quebec City, Quebec, Canada) from 2006 to 2009. Preoperative coronary angiogram was performed in all patients. Immediately after surgery, patients were randomized either to the aspirin–clopidogrel group, who received aspirin 162 mg plus clopidogrel 75 mg daily, or to the aspirin–placebo group, who received aspirin 162 mg plus placebo daily. Study medications were started on the day of surgery and continued for 12 months in a double-blinded fashion. Among the 113 patients, the present study assessed the progression of native CAD in the 92 patients who underwent postoperative angiogram at the 2 centers 1 year after CABG (Figure). Patient characteristics are shown in Table 1.
Three vessel disease, %
87 (40/46)
80 (37/46)
0.6
Patient Follow-Up Follow-up was performed in clinic at 1, 6, and 12 months after operation and telephone postoperative assessments at 3 and 9 months. Postoperative management was standardized in both groups. All medications were prescribed according to current American College of Cardiology/American Heart Association guidelines and as clinically indicated, including the use of statins, β-blockers, calcium-channel blockers, and angiotensin-converting enzyme inhibitors. Aggressive diabetes mellitus (DM) management and smoking cessation counseling were performed as indicated.12 One-year follow-up was performed on all 113 patients. Patients (n=92) underwent postoperative angiogram and intravascular ultrasound 12 months after CABG.
Review and Grading of Angiograms All 92 patients with a full pair of preoperative and postoperative angiograms had their films reviewed and graded, in blinded fashion to treatment, by a minimum of 2 investigator physicians, including ≥1 cardiologist and 1 surgeon (with ≥1 being M.R., A.K., M.L.M., or P.V.). The location and degree of each stenosis were recorded.
CCS class 3 or 4, %
59 (27/46)
54 (25/46)
0.8
NYHA 3 or 4, %
28 (13/46)
17 (8/46)
0.3
7 (3/46)
1.0
LVEF 2 cm where it had been seen preoperatively, the filling defect was considered to represent a new occlusion. Evolving CAD was defined as a lesion with ≥1 grade change in the severity of stenosis, calculated as the difference between the preoperative and postoperative grade. A worsening lesion was given a positive value and an improving lesion a negative value. A new lesion was defined as ≥25% postoperative stenosis where the stenosis was preoperatively
