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| Name | Class |
|---|---|
| Sanofi | INDUSTRY |
| Bristol-Myers Squibb | INDUSTRY |
The purpose of this study is to determine whether the combination of clopidogrel with aspirin prevents the development of blockages (atherosclerosis) in vein grafts one year after coronary artery bypass surgery (CABG) compared to aspirin alone.
Saphenous vein graft disease remains a major limitation of coronary artery bypass graft surgery (CABG). The process of saphenous vein intimal hyperplasia is mediated by platelet aggregation and begins just days after surgical revascularization. Subsequently, areas of intimal hyperplasia in turn develop graft atherosclerotic disease and its sequelae. Clopidogrel improves outcomes in patients with atherosclerotic disease, and is effective at reducing intimal hyperplasia in animal models of thrombosis. Therefore, the goal of this study will be to evaluate the efficacy of clopidogrel and aspirin therapy versus aspirin alone in the prevention of saphenous vein graft intimal hyperplasia following one year after CABG.
Patients undergoing multi-vessel CABG and in whom at least two saphenous vein grafts will be used are eligible for the study. Patients will be randomized to receive daily clopidogrel 75 mg or placebo, in addition to daily aspirin 162 mg, for the duration of one year starting as soon as postoperative bleeding has been ruled out on the day of surgery. At the end of one year, all patients will undergo coronary angiography and intravascular ultrasound assessment of one saphenous vein graft as selected by randomization. The study will be powered to test the hypothesis that clopidogrel and aspirin will reduce vein graft intimal hyperplasia by 20% compared to aspirin alone at one year following bypass surgery.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 75mg Clopidogrel | Active Comparator | 75mg clopidogrel. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. |
|
| Placebo | Placebo Comparator | Water pill. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Clopidogrel 75 mg daily | Drug | Daily dose of 75 mg Clopidogrel |
| |
| Measure | Description | Time Frame |
|---|---|---|
| Vein Graft Intimal Area | IVUS imaging 12 months post-CABG, and the average intimal area in the proximal 40 mm of one vein graft per patient will be assessed | One year following surgery |
| Measure | Description | Time Frame |
|---|---|---|
| Vein Graft Angiographic Patency | Postoperative angiogram 12 months post-CABG | One year following surgery |
| Incidence of Major Adverse Coronary Events Within One Year Following Surgery | 1 year |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Marc Ruel, MD, MPH | Ottawa Heart Institute Research Corporation | Principal Investigator |
| Alexander Kulik, MD | Ottawa Heart Institute Research Corporation | Study Director |
| Michel Le May, MD | Ottawa Heart Institute Research Corporation | Study Director |
| George A Wells, PhD | Ottawa Heart Institute Research Corporation | Study Director |
| Thierry G Mesana, MD, PhD | Ottawa Heart Institute Research Corporation | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Ottawa Heart Institute | Ottawa | Ontario | K1Y 4W7 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8772748 | Background | Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol. 1996 Sep;28(3):616-26. doi: 10.1016/0735-1097(96)00206-9. | |
| 9521341 | Background |
| Label | URL |
|---|---|
| University of Ottawa Heart Institute Website | View source |
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Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 75mg Clopidogrel | 75mg clopidogrel. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. Clopidogrel 75 mg daily: Daily dose of 75 mg Clopidogrel |
| FG001 | Placebo | Water pill. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. water pill daily: Daily dose of water pill (placebo) |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 75mg Clopidogrel | 75mg clopidogrel. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. Clopidogrel 75 mg daily: Daily dose of 75 mg Clopidogrel |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Vein Graft Intimal Area | IVUS imaging 12 months post-CABG, and the average intimal area in the proximal 40 mm of one vein graft per patient will be assessed | Posted | Mean | Standard Deviation | mm | One year following surgery |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 75mg Clopidogrel | 75mg clopidogrel. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. Clopidogrel 75 mg daily: Daily dose of 75 mg Clopidogrel |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myocardial infarction | Cardiac disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Minor bleeding | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Marc Ruel | University Of Ottawa Heart Institute | mruel@ottawaheart.ca |
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| ID | Term |
|---|---|
| D050197 | Atherosclerosis |
| ID | Term |
|---|---|
| D001161 | Arteriosclerosis |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000077144 | Clopidogrel |
| D014867 | Water |
| ID | Term |
|---|---|
| D013988 | Ticlopidine |
| D058924 | Thienopyridines |
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
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| water pill daily |
| Drug |
Daily dose of water pill (placebo) |
|
| Incidence of Major Bleeding Events Within One Year Following Surgery | 1 year |
| Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998 Mar 10;97(9):916-31. doi: 10.1161/01.cir.97.9.916. |
| 1531345 | Background | Jawien A, Bowen-Pope DF, Lindner V, Schwartz SM, Clowes AW. Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J Clin Invest. 1992 Feb;89(2):507-11. doi: 10.1172/JCI115613. |
| 9759636 | Background | Herbert JM, Dol F, Bernat A, Falotico R, Lale A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost. 1998 Sep;80(3):512-8. |
| 8343491 | Background | Herbert JM, Tissinier A, Defreyn G, Maffrand JP. Inhibitory effect of clopidogrel on platelet adhesion and intimal proliferation after arterial injury in rabbits. Arterioscler Thromb. 1993 Aug;13(8):1171-9. doi: 10.1161/01.atv.13.8.1171. |
| 11958809 | Background | Hermann A, Weber AA, Schror K. Clopidogrel inhibits platelet adhesion and platelet-dependent mitogenesis in vascular smooth muscle cells. Thromb Res. 2002 Jan 15;105(2):173-5. doi: 10.1016/s0049-3848(01)00403-0. No abstract available. |
| 9832493 | Background | Harker LA, Marzec UM, Kelly AB, Chronos NR, Sundell IB, Hanson SR, Herbert JM. Clopidogrel inhibition of stent, graft, and vascular thrombogenesis with antithrombotic enhancement by aspirin in nonhuman primates. Circulation. 1998 Dec 1;98(22):2461-9. doi: 10.1161/01.cir.98.22.2461. |
| 10859288 | Background | Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000 Jun 20;101(24):2823-8. doi: 10.1161/01.cir.101.24.2823. |
| 11157686 | Background | Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation. 2001 Jan 23;103(3):363-8. doi: 10.1161/01.cir.103.3.363. |
| 15313956 | Background | Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation. 2004 Sep 7;110(10):1202-8. doi: 10.1161/01.CIR.0000140675.85342.1B. Epub 2004 Aug 16. |
| 16219100 | Result | 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 Oct 11;6(1):15. doi: 10.1186/1468-6708-6-15. |
| 21135365 | Result | Kulik A, Le May MR, Voisine P, Tardif JC, Delarochelliere R, Naidoo S, Wells GA, Mesana TG, Ruel M. Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) Trial. Circulation. 2010 Dec 21;122(25):2680-7. doi: 10.1161/CIRCULATIONAHA.110.978007. Epub 2010 Dec 6. |
| 21958773 | Result | Kulik A, Voisine P, Mathieu P, Masters RG, Mesana TG, Le May MR, Ruel M. Statin therapy and saphenous vein graft disease after coronary bypass surgery: analysis from the CASCADE randomized trial. Ann Thorac Surg. 2011 Oct;92(4):1284-90; discussion 1290-1. doi: 10.1016/j.athoracsur.2011.04.107. |
| 24030409 | Result | Une D, Kulik A, Voisine P, Le May M, Ruel M. Correlates of saphenous vein graft hyperplasia and occlusion 1 year after coronary artery bypass grafting: analysis from the CASCADE randomized trial. Circulation. 2013 Sep 10;128(11 Suppl 1):S213-8. doi: 10.1161/CIRCULATIONAHA.112.000328. |
| 25200049 | Result | Une D, Al-Atassi T, Kulik A, Voisine P, Le May M, Ruel M. 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. Circulation. 2014 Sep 9;130(11 Suppl 1):S12-8. doi: 10.1161/CIRCULATIONAHA.113.008227. |
| 28734623 | Derived | Hage A, Voisine P, Erthal F, Larose E, Glineur D, Chow B, Tremblay H, Fortier J, Ko G, Une D, Farkouh M, Mesana TG, LeMay M, Kulik A, Ruel M. Eight-year follow-up of the Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) trial. J Thorac Cardiovasc Surg. 2018 Jan;155(1):212-222.e2. doi: 10.1016/j.jtcvs.2017.06.039. Epub 2017 Jun 24. |
| Protocol Violation |
|
| Physician Decision |
|
Water pill. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery.
water pill daily: Daily dose of water pill (placebo)
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Vein Graft Angiographic Patency | Postoperative angiogram 12 months post-CABG | Posted | Number | percentage | One year following surgery |
|
|
|
| Secondary | Incidence of Major Adverse Coronary Events Within One Year Following Surgery | Posted | Count of Participants | Participants | 1 year |
|
|
|
| Secondary | Incidence of Major Bleeding Events Within One Year Following Surgery | Posted | Count of Participants | Participants | 1 year |
|
|
|
| 0 |
| 56 |
| 4 |
| 56 |
| 3 |
| 56 |
| EG001 | Placebo | Water pill. 162mg ASA is also given, but is a standard-of-care post operative to cardiac surgery. water pill daily: Daily dose of water pill (placebo) | 1 | 57 | 5 | 57 | 3 | 57 |
| Cerebrovascular accident | Cardiac disorders | Systematic Assessment |
|
| Hospitalization for Coronary Ischemia | Cardiac disorders | Systematic Assessment |
|
The first publication will be a joint effort between all contributing parties. At least 30 days before submission for publication, the partnership will be provided the proposed publication and will be given 30 days to respond with approval or requests for holds. All contributing parties must be acknowledged in all publications.
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006878 | Hydroxides |
| D000468 | Alkalies |
| D007287 | Inorganic Chemicals |
| D000838 | Anions |
| D007477 | Ions |
| D004573 | Electrolytes |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |