Trial of Clopidogrel After Surgery for Coronary Artery Disease (CASCADE Trial)

Condition(s) targeted: Atherosclerosis

Intervention: Clopidogrel 75 mg daily (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Ottawa Heart Institute

Official(s) and/or principal investigator(s):
Marc Ruel, MD, MPH, Principal Investigator, Affiliation: University of Ottawa Heart Institute
Alexander Kulik, MD, Study Director, Affiliation: University of Ottawa Heart Institute
Michel Le May, MD, Study Director, Affiliation: University of Ottawa Heart Institute
George A Wells, PhD, Study Director, Affiliation: University of Ottawa Heart Institute
Thierry G Mesana, MD, PhD, Study Director, Affiliation: University of Ottawa Heart Institute

Overall contact:
Marc Ruel, MD, MPH, Phone: 613-761-4893, Email: mruel@ottawaheart.ca

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.

Official title: Clopidogrel After Surgery for Coronary Artery Disease (CASCADE Trial): Does Clopidogrel Prevent Saphenous Vein Graft Disease After Coronary Bypass?

Study design: Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Single Group Assignment, Safety/Efficacy Study

Primary outcome: Vein graft intimal area, one year following surgery

Secondary outcome:

Vein graft angiographic patency, one year following surgery

Incidence of major adverse coronary events within one year following surgery

Incidence of major bleeding events within one year following surgery

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patients undergoing primary multi-vessel CABG with at least two saphenous vein

grafts, with or without the use of cardiopulmonary bypass.

Exclusion Criteria:

- Emergency surgery

- Valve surgery

- Redo CABG

- Left ventricle ejection fraction < 25%

- Serum creatinine > 130 µmol/L

- Preoperative use of clopidogrel (with the exception of the current admission)

- Preoperative use of warfarin; allergy to aspirin or clopidogrel.

- History of cerebrovascular accident

- History of severe liver disease

- Morbid obesity

- Current malignancy

Marc Ruel, MD, MPH, Phone: 613-761-4893, Email: mruel@ottawaheart.ca

University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada; Recruiting
Marc Ruel, MD, MPH, Phone: 613-761-4893, Email: mruel@ottawaheart.ca
Marc Ruel, MD, MPH, Principal Investigator

University of Ottawa Heart Institute Website

Related publications:

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.

Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation. 1998 Mar 10;97(9):916-31. Review.

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.

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.

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.

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. No abstract available.

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.

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.

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.

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. Epub 2004 Aug 16.

Starting date: May 2006
Ending date: November 2009
Last updated: March 19, 2009