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

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)

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.

Study Overview

• Status: Unknown
• Conditions: Coronary Artery Disease; Acute Coronary Syndrome; Stable Angina
• Intervention / Treatment: Drug: Placebo; Drug: Ticagrelor

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.

• Study Type: Interventional
• Enrollment (Anticipated): 487
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Eindhoven, Netherlands, 5623 EJ
    • Catharina Ziekenhuis
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Groningen, Netherlands
    • Universitair Medisch Centrum Groningen
  • Nijmegen, Netherlands
    • Radboud UMC
  • Rotterdam, Netherlands
    • Erasmus Erasmus UMC
  • Utrecht
    • Nieuwegein, Utrecht, Netherlands, 3435CM
      • St Antonius Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 22 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ticagrelor; Ticagrelor 90mg twice daily for 1 year on top of ASA	Drug: Ticagrelor; Other Names: Brilique; Brillinta
Placebo Comparator: Placebo; Placebo matching ticagrelor 90mg twice daily on top of ASA	Drug: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: J.M. ten Berg
• Collaborators: AstraZeneca
• Investigators: Study Chair: Jurriën M ten Berg, MD, PhD, St. Antonius Hospital Nieuwegein

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: March 1, 2015
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: September 19, 2014
• First Submitted That Met QC Criteria: January 30, 2015
• First Posted (Estimate): February 2, 2015

Study Record Updates

• Last Update Posted (Actual): April 27, 2020
• Last Update Submitted That Met QC Criteria: April 23, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Ticagrelor; CABG; Patency; Graft
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Pain; Neurologic Manifestations; Coronary Disease; Chest Pain; Angina Pectoris; Coronary Artery Disease; Acute Coronary Syndrome; Angina, Stable; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Ticagrelor
• Other Study ID Numbers: POPCABG; 2014-002142-50 (EudraCT Number)