Dual Antiplatelet Therapy in Patients With Aspirin Resistance Following Coronary Artery Bypass Grafting

Reactive platelet hyperactivity following coronary artery bypass grafting (CABG) might lead to thrombotic complications and major ischemic cardiac events. The aim of this study is to evaluate the changes in platelet reactivity following CABG and to clarify a potentially beneficial effect of dual antiplatelet therapy in the group of patients with documented aspirin resistance following CABG. Platelet function will be assessed by multiple electrode aggregometry. Aortocoronary vein graft disease is comprised of three distinct but interrelated pathological processes: thrombosis, intimal hyperplasia and atherosclerosis. Early vein thrombosis is a major cause of vein graft attrition during the first month after CABG.

Bypass patency can be improved with antiplatelet therapy which is the mainstay of treatment for patients after CABG. A beneficial effect of acetylsalicylic acid (ASA) on vein graft patency has been previously shown. Some patients experience thrombotic events despite continuous aspirin administration after CABG. The investigators hypothesized that low responsiveness to aspirin might be a precipitating factor for adverse thrombotic events following CABG.

Low responsiveness to ASA, as assessed by platelet function tests, varies widely among patients. The etiology of postoperative platelet hyperactivity remains to be elucidated.

In this study a new point-of-care assay named multiple electrode aggregometry (MEA) using a device called Multiplate analyzer (Dynabyte, Munich, Germany) has been utilized. It allows for rapid and standardized assessment of platelet function parameters.

This is a prospective randomized trial. The aim of the study is to document whether introduction of dual antiplatelet therapy in patients with ASA resistance will lead to a lower incidence of major adverse cardiac events (MACE) at a six month follow up. The composite endpoint will include death, non-fatal myocardial infarction, stroke and cardiac rehospitalization. All patients will receive 300 mg of ASA starting 6 hours after surgery, provided that the chest tube output is minimal. On postoperative day 4 their platelet function will be assessed using the above mentioned MEA. The patients found to be aspirin resistant will then undergo the process of randomization. The first arm will include patients with ASA resistance in whom no additional antiaggregation will be administered. In the second arm the investigators will include patients who were randomized to receive 75 mg of clopidogrel in addition to the standard antiplatelet regimen of 300 mg of ASA.

Platelet function monitoring allows for individual tailoring of the antiplatelet therapy. The goal of this study is to define whether this strategy will lead to improved patient outcomes. Both major and minor bleeding complications will be strictly monitored and reported.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Aspirin Resistance
• Intervention / Treatment: Drug: Clopidogrel

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 4

Contacts and Locations

Study Locations

• Croatia
  • Zagreb, Croatia, 10000
    • Medical school Zagreb, University hospital center Zagreb

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Isolated coronary artery bypass grafting
• Patients older than 18 years
• Written informed consent
• Accurate antiplatelet therapy administration documentation

Exclusion Criteria:

• Missing consent
• Patients with cardiac surgical procedures other than isolated CABG
• Antiplatelet therapy other than aspirin 300 mg after CABG
• Previous PCI requiring clopidogrel therapy after CABG
• Patients with unknown preoperative anti-platelet status
• Urgent or emergent surgery
• Off-pump CABG
• Re-Do CABG
• Patients younger than 18 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: aspirin low responders monotherapy; patients with inappropriate response to aspirin assessed by multiple electrode aggregometry
Active Comparator: aspirin low responders dual antiplatelet therapy; patients with inappropriate response to aspirin 300 mg therapy after CABG, randomized to receive clopidogrel 75 mg in addition to aspirin	Drug: Clopidogrel; patients with inappropriate response to aspirin 300 mg after CABG, assessed by multiple electrode aggregometry are randomized to receive clopidogrel 75 mg daily dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MACE events	MACE: death; non-fatal myocardial infarction; stroke; cardiac rehospitalization	6 months

Collaborators and Investigators

• Sponsor: University of Zagreb

Publications and helpful links

General Publications

• Kopjar T, Petricevic M, Gasparovic H, Svetina L, Milicic D, Biocina B. Postoperative Atrial Fibrillation Is Associated With High On-Aspirin Platelet Reactivity. Ann Thorac Surg. 2015 Nov;100(5):1704-11. doi: 10.1016/j.athoracsur.2015.05.001. Epub 2015 Jul 26.
• Petricevic M, Kopjar T, Gasparovic H, Milicic D, Svetina L, Zdilar B, Boban M, Mihaljevic MZ, Biocina B. Impact of aspirin resistance on outcomes among patients following coronary artery bypass grafting: exploratory analysis from randomized controlled trial (NCT01159639). J Thromb Thrombolysis. 2015 May;39(4):522-31. doi: 10.1007/s11239-014-1127-9.
• Gasparovic H, Petricevic M, Kopjar T, Djuric Z, Svetina L, Biocina B. Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting. Am J Cardiol. 2014 May 15;113(10):1660-7. doi: 10.1016/j.amjcard.2014.02.024. Epub 2014 Mar 1.
• Gasparovic H, Petricevic M, Kopjar T, Djuric Z, Svetina L, Biocina B. Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639]. Trials. 2012 Aug 25;13:148. doi: 10.1186/1745-6215-13-148.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 1, 2013

Study Registration Dates

• First Submitted: July 8, 2010
• First Submitted That Met QC Criteria: July 8, 2010
• First Posted (Estimate): July 9, 2010

Study Record Updates

• Last Update Posted (Estimate): August 28, 2013
• Last Update Submitted That Met QC Criteria: August 27, 2013
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Keywords: coronary artery bypass grafting; aspirin resistance; multiple electrode aggregometry; multiplate
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Coronary Artery Disease; 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; Clopidogrel
• Other Study ID Numbers: 8.1-10/41-2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No