The Effect Of Ticagrelor On Saphenous Vein Graft Patency In Patients Undergoing Coronary Artery Bypass Grafting Surgery

Study Overview
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Brief Summary
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In the POPular CABG study we investigate if the addition of ticagrelor, a drug that inhibits blood platelets from clotting, to treatment with aspirin will reduce the rate of saphenous vein graft occlusion as assessed with coronary computed tomography angiography at 1 year after coronary artery bypass grafting surgery.

Detailed Description
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Rationale: Acetylsalicylic acid (ASA) is used to prevent the occlusion of grafts placed during coronary artery bypass grafting surgery (CABG) and to reduce the incidence of atherothrombotic events during follow-up. Graft occlusion occurs predominantly in saphenous vein grafts (SVGs) and can result in symptoms of chest pain, myocardial infarction (MI) and even death. The anti-thrombotic effect of ASA is a result of the inhibition of the generation of thromboxane A2 (TXA2) in blood platelets. Despite ASA therapy, 6.8% to 26% of SVGs occlude in the first year after CABG, mainly due to thrombus formation. This might be due to the fact that ASA is not equally effective in all patients, indicated by a substantial amount of patients that still generate TXA2 and show activated platelets, despite adequate ASA use. We hypothesize that more potent platelet inhibition by the addition of ticagrelor to standard ASA therapy could decrease the rate of SVG occlusion. Main objective: To investigate whether a combination of ticagrelor 90mg twice daily and ASA 80mg once daily is superior to ASA 80mg once daily alone in the prevention of SVG occlusion in patients who underwent CABG with use of one or more SVGs, as assessed with coronary computed tomography angiography (CCTA) at 1 year after randomization. Study design: Randomized, double-blind, placebo-controlled, multicenter trial. Number of patients: Approximately 500 patients will be randomized. Study population: Patients undergoing CABG with one or more SVGs, CABG being an isolated procedure or part of combined surgery. Informed consent procedure, screening and sample size: We will screen patients and obtain informed consent before CABG. After CABG patients who gave informed consent are screened again to check if the patient fulfills the inclusion criteria and does not have any exclusion criteria. A total of 500 patients will receive randomized study medication after CABG. Intervention: Patients will be randomly assigned to treatment with 90mg of ticagrelor or a matching placebo twice daily in addition to standard treatment with ASA for the duration of 1 year. Patients will be prescribed 80mg of ASA once daily according to routine clinical practice. Graft patency will be assessed with CCTA 1 year after randomization. If the patient consents to participate in the substudies, platelet function tests will be performed before surgery and 3 days and 1 year after randomization. Thirty day and one-year follow-up of clinical events will be obtained for all patients by screening the (electronic) patient file, telephonic interviews, study site visits and possibly with questionnaires.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial Investigating The Effect Of Ticagrelor On Saphenous Vein Graft Patency In Patients Undergoing Coronary Artery Bypass Grafting Surgery (The POPular CABG Study)

Conditions
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Coronary Artery Disease, Stable Angina, Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Ticagrelor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: More than 21 years of age Planned coronary artery bypass grafting (CABG) with the use of 1 or more saphenous vein grafts, CABG being an isolated procedure or part of a combined aortic valce replacement surgery with bioprothesis. Exclusion Criteria: Unable to give informed consent or a life expectancy of less than 1 year Concomitant valve, aorta or rhythm surgery during the same session, (excluding aortic bioprothesis) Inability to undergo coronary computed tomography angiography, in the investigator's opinion, for instance due to severe claustrophobia or contrast allergy Use of oral anticoagulants (acenocoumarol, phenprocoumon, dabigatran, rivaroxaban, etc) and a contraindication for discontinuation of this medication or the expectation that the patient will have an indication for the use of these drugs after surgery Placement of a drug-eluting stent in a coronary or cerebral artery within 6 months of CABG or placement of a bare-metal stent in a coronary or cerebral artery within 1 month of CABG Use of antiplatelet drugs other than aspirin (clopidogrel, prasugrel, ticagrelor, dipyridamol, etc.) and a contraindication for discontinuation of this medication after CABG, according to the treating physician or the investigator Women who are known to be pregnant, who have given birth within the past 90 days or who are breastfeeding Pre-menopausal women without adequate contraception Severe renal function impairment requiring dialysis Moderate or severe hepatic impairment Active malignancy with increase in bleeding risk, in the investigator's opinion Use of strong inhibitors of CYP3A4 (e.g. ketaconazole, clarithromycin, nefazodone, ritonavir, atazanavir) Clinically significant out of range values for platelet count or haemoglobin at screening, in the investigator's opinion Contraindication for the use of ticagrelor or aspirin (i.e. history of intracranial bleeding, high bleeding risk, previous allergic reaction), in the investigator's opinion Previous inclusion in this study

Ages Eligible for Study
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Minimum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor<br>Ticagrelor 90mg twice daily for 1 year on top of ASA | Drug: Ticagrelor<br> <br> * Other names: Brillinta;|
| Placebo Comparator: Placebo<br>Placebo matching ticagrelor 90mg twice daily on top of ASA | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saphenous vein graft occlusion | As assessed with coronary computed tomography angiography or clinically indicated coronary angiography | 1 year after coronary artery bypass grafting | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saphenous vein graft failure | Composite of saphenous vein graft occlusion as assessed with coronary computed tomography angiography or clinically indicated coronary angiography, saphenous vein graft revascularization, myocardial infarction in the myocardial territory supplied by a saphenous vein graft or sudden death | 1 year after coronary artery bypass grafting | 
| Significant saphenous vein graft stenosis | As assessed with coronary computed tomography angiography or clinically indicated coronary angiography | 1 year after coronary artery bypass grafting | 
| BARC minor (type 1 or 2) and major (type 3, 4 or 5) bleeding | Bleeding Academic Research Consortium bleeding criteria | 30 days after coronary artery bypass grafting | 
| BARC minor (type 1 or 2) and major (type 3, 4 or 5) bleeding | Bleeding Academic Research Consortium bleeding criteria | 1 year after coronary artery bypass grafting | 
| TIMI minor and major bleeding | Thrombolysis in Myocardial Infarction bleeding criteria | 30 days after coronary artery bypass grafting | 
| TIMI minor and major bleeding | Thrombolysis in Myocardial Infarction bleeding criteria | 1 year after coronary artery bypass grafting | 
| High platelet reactivity | As assessed with platelet function tests. | Within 72h before coronary artery bypass grafting | 
| High platelet reactivity | As assessed with platelet function tests. | 3 days after coronary artery bypass grafting | 
| High platelet reactivity | As assessed with platelet function tests. | 1 year after coronary artery bypass grafting | 
| Level of GDF-15 | Growth differentiation factor 15 level | Within 72h before coronary artery bypass grafting | 
| Level of GDF-15 | Growth differentiation factor 15 level | 3 days after coronary artery bypass grafting | 
| Level of GDF-15 | Growth differentiation factor 15 level | 1 year after coronary artery bypass grafting | 
| Arterial graft occlusion | As assessed with coronary computed tomography angiography or clinically indicated coronary angiography | 1 year after coronary artery bypass grafting | 
| All graft occlusion | As assessed with coronary computed tomography angiography or clinically indicated coronary angiography | 1 year after coronary artery bypass grafting | 
| Significant arterial graft stenosis | As assessed with coronary computed tomography angiography or clinically indicated coronary angiography | 1 year after coronary artery bypass grafting | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CABG, Ticagrelor, Graft, Patency