CASCADE: No significant benefit of clopidogrel in reducing graft disease after CABG

NOVEMBER 17, 2009 | Sue Hughes

 AHA 2009

Orlando, FL - There was no significant benefit of one year's treatment with clopidogrel on reducing vein graft intimal hyperplasia in CABG patients in the CASCADE trial.

The trial was presented by Dr Alexander Kulik (University of Ottawa Heart Institute, ON) at the American Heart Association 2009 Scientific Sessions.

Kulik explained that long-term benefits of CABG are compromised by vein graft disease, with up to 15% of grafts occluding within one year and almost half occluding by 10 years. Vein graft disease is caused by an initial injury to the grafts when they are harvested, which attracts platelets and starts the thrombotic process, leading to intimal hyperplasia and atherosclerosis. 'Intimal hyperplasia is the foundation for graft atherosclerosis, and clopidogrel has been shown to inhibit intimal hyperplasia in cell-culture studies and animal models," he added.

He and his colleagues therefore decided to conduct the CASCADE trial to evaluate clopidogrel in CABG patients. The trial randomized 113 patients undergoing primary multivessel CABG with at least two saphenous vein grafts (SVGs) to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin plus placebo. Clopidogrel was started on the day of surgery when the chest tube drainage had subsided and was continued for one year.

The primary outcome was vein graft intimal area as assessed by intravascular ultrasound (IVUS). IVUS was performed in 90 patients and showed a 14.8% reduction in intimal area in the clopidogrel group, which did not reach statistical significance.

CASCADE primary end point

 There were also no significant differences in secondary end points of vein graft patency, major cardiovascular events, or major bleeding, although postoperative chest tube drainage after drug administration was slightly increased with clopidogrel.

  CASCADE secondary end points

Kulik concluded: "These results do not support the use of dual antiplatelet therapy for the prevention of vein graft disease after CABG."

He estimated that around 20% to 30% of surgeons probably already use clopidogrel for this purpose after CABG, despite the fact there have not been any clinical data. "Given the absence of important benefits in our study, the price of the drug, and the bleeding side effects of the drug, I would say that fewer surgeons will be prescribing it from now on," Kulik commented.

Designated discussant of the CASCADE study, Dr Joseph Sabik (Cleveland Clinic, OH), noted that it is the platelets adhering to the intimal injury in the vein grafts that starts the whole process of vein graft disease. "Using antiplatelet drugs to try to prevent this makes good sense, as it is targeting the very beginning of the cascade of thrombosis," he commented.

He suggested several factors that could have contributed to the lack of a significant result in the study. "They did show a 14.8% reduction in the primary end point, but they needed a 20% reduction for significance, so perhaps the study was not powered adequately," he said. "Perhaps they needed more patients and/or longer follow-up," he added. Sabik also wondered whether patients were tested for clopidogrel resistance and if newer antiplatelet agents may show better results.