Clinical trial NCT02352402: The Effect Of Ticagrelor On Saphenous Vein Graft Patency In Patients Undergoing Coronary Artery Bypass Grafting Surgery
Official title: 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)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Coronary Artery Disease
Stable Angina
Acute Coronary Syndrome
Keywords: CABG
Ticagrelor
Graft
Patency
Lead sponsor: St. Antonius Hospital
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2015-02-02
Enrollment: 487
Sex: ALL
Minimum age (years): 22
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Saphenous vein graft occlusion
timeFrame: 1 year after coronary artery bypass grafting
Secondary outcomes:
measure: Saphenous vein graft failure
timeFrame: 1 year after coronary artery bypass grafting
measure: Significant saphenous vein graft stenosis
timeFrame: 1 year after coronary artery bypass grafting
measure: BARC minor (type 1 or 2) and major (type 3, 4 or 5) bleeding
timeFrame: 30 days after coronary artery bypass grafting
measure: BARC minor (type 1 or 2) and major (type 3, 4 or 5) bleeding
timeFrame: 1 year after coronary artery bypass grafting
measure: TIMI minor and major bleeding
timeFrame: 30 days after coronary artery bypass grafting
measure: TIMI minor and major bleeding
timeFrame: 1 year after coronary artery bypass grafting
measure: High platelet reactivity
timeFrame: Within 72h before coronary artery bypass grafting
measure: High platelet reactivity
timeFrame: 3 days after coronary artery bypass grafting
measure: High platelet reactivity
timeFrame: 1 year after coronary artery bypass grafting
measure: Level of GDF-15
timeFrame: Within 72h before coronary artery bypass grafting
measure: Level of GDF-15
timeFrame: 3 days after coronary artery bypass grafting
measure: Level of GDF-15
timeFrame: 1 year after coronary artery bypass grafting
measure: Arterial graft occlusion
timeFrame: 1 year after coronary artery bypass grafting
measure: All graft occlusion
timeFrame: 1 year after coronary artery bypass grafting
measure: Significant arterial graft stenosis
timeFrame: 1 year after coronary artery bypass grafting
Other outcomes:
Locations:
city: Nieuwegein
country: Netherlands
facility: St Antonius Hospital
state: Utrecht
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Nijmegen
country: Netherlands
facility: Radboud UMC
city: Rotterdam
country: Netherlands
facility: Erasmus Erasmus UMC
Study officials:
affiliation: St. Antonius Hospital
name: Jurriën M ten Berg, MD, PhD
role: STUDY_CHAIR
References:
citation: Willemsen LM, Janssen PWA, Hackeng CM, Kelder JC, Tijssen JGP, van Straten AHM, Soliman-Hamad MA, Deneer VHM, Daeter EJ, Sonker U, Klein P, Ten Berg JM. 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-Rationale and design of the POPular CABG trial. Am Heart J. 2020 Feb;220:237-245. doi: 10.1016/j.ahj.2019.12.001. Epub 2019 Dec 13.
citation: Willemsen LM, Janssen PWA, Peper J, Soliman-Hamad MA, van Straten AHM, Klein P, Hackeng CM, Sonker U, Bekker MWA, von Birgelen C, Brouwer MA, van der Harst P, Vlot EA, Deneer VHM, Chan Pin Yin DRPP, Gimbel ME, Beukema KF, Daeter EJ, Kelder JC, Tijssen JGP, Rensing BJWM, van Es HW, Swaans MJ, Ten Berg JM. Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG): A Randomized, Double-Blind, Placebo-Controlled Trial. Circulation. 2020 Nov 10;142(19):1799-1807. doi: 10.1161/CIRCULATIONAHA.120.050749. Epub 2020 Aug 31.
citation: Feitosa MPM, Soffiatti CD, Linhares Filho JPP, Batista DV, Lobo Filho HG, Lima EG, Serrano Junior CV. Dual platelet antiaggregation therapy after myocardial revascularization surgery. Rev Assoc Med Bras (1992). 2019 Mar;65(3):316-318. doi: 10.1590/1806-9282.65.3.316. Epub 2019 Apr 11.