Continuous Clopidogrel Dose Adjustment in Acute Coronary Syndrome Patients With High On-treatment Platelet Reactivity

Effect of Continuous Clopidogrel Dosing Targeted After Platelet Function Testing in Acute Coronary Syndrome Patients Undergoing Percutaneous Coronary Intervention With High On-treatment Platelet Reactivity

The purpose of this study is to determine whether continuous clopidogrel dose adjustment targeted after platelet function testing improves outcomes during 12 months of follow-up in acute coronary syndrome patients treated with coronary artery stenting and with determined high platelet reactivity on clopidogrel.

Study Overview

• Status: Completed
• Conditions: Acute Coronary Syndrome
• Intervention / Treatment: Drug: Clopidogrel dose adjustment

Detailed Description

Dual antiplatelet therapy (DAPT) with aspirin and P2Y12 receptor antagonists during 12 months presents cornerstone treatment in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is the most widely used P2Y12 inhibitor despite it's limitations that include highly variable P2Y12-receptor inhibition which causes wide interindividual platelet reactivity variability. Since high on-treatment platelet reactivity (HTPR) on clopidogrel is strongly associated with adverse events, antiplatelet therapy tailoring has been vastly investigated to determine whether individualized approach could improve outcomes. In the time of progressive personalized approach to therapy, effective strategies are needed to minimize the risk of ischemic adverse events without increasing the risk for bleeding.

Aim of this study is to investigate whether continuous clopidogrel dose adjustment according to platelet function testing (PFT) using Multiplate® function analyzer (Roche Diagnostics, Mannheim, Germany) could decrease the rate of adverse events in ACS patients treated with PCI and with HTPR during early and late period of DAPT treatment.

Cut off values for HTPR and enhanced platelet response were set according to the consensus statement at >46 U and <19 U, respectively. PFT and therapy tailoring was performed at day 1, 2, 3, 7, 30 and month 2, 3, 6, 9 and 12.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 4

Contacts and Locations

Study Locations

• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Centre Zagreb

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• acute coronary syndrome patients treated with successful PCI
• age 18-80 years
• determined high on-treatment platelet reactivity

Exclusion Criteria:

• continuous postinterventional glycoprotein (GP) IIbIIIa receptor inhibitor infusion
• thrombocytopenia (<150x109/L)
• significant renal insufficiency (creatinine>200 µmol/L)
• anemia (Htc<30%)
• hemorrhagic diathesis
• history of intracranial bleeding or ischemic cerebrovascular insult 6 months before
• major operation 6 weeks before
• concomitant chronic anticoagulation therapy
• age <18 years and >80 years

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control group; Patients in this group will receive standard clopidogrel dose
Experimental: interventional group; Patients in the interventional arm will receive clopidogrel dose adjustment to maintain optimal platelet reactivity determined by Multiplate function analyzer (19-46U). They will undergo platelet function testing on day 1,2,3,7,30 and month 2,3,6,9 and 12. On first two measurements patients will receive up to 2 additional clopidogrel loading doses (600 mg) and put on 150 mg and 75 mg a day if platelet reactivity >18U and <18U, respectively. Maintenance dose will be determined on following measurements - increased by 75 mg if >46U; not changed if 19-46U; decreased by 75 mg if <19U. Minimal dose - 75 mg; maximal dose 300 mg (for patients >70 years 150 mg)	Drug: Clopidogrel dose adjustment; Patients in the interventional arm will receive clopidogrel dose adjustment to maintain optimal platelet reactivity determined by Multiplate function analyzer (19-46U). They will undergo platelet function testing on day 1,2,3,7,30 and month 2,3,6,9 and 12. On first two measurements patients will receive up to 2 additional clopidogrel loading doses (600 mg) and put on 150 mg and 75 mg a day if platelet reactivity >18U and <18U, respectively. Maintenance dose will be determined on following measurements - increased by 75 mg if >46U; not changed if 19-46U; decreased by 75 mg if <19U. Minimal dose - 75 mg; maximal dose 300 mg (for patients >70 years 150 mg); Other Names: antiplatelet therapy tailoring

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical outcome - composite endpoint of total cardiovascular death, non-fatal myocardial infarction, target vessel revascularization and ischemic stroke	Data will be collected during the entire follow up period on interviews and analyzing patient medical data.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
number of bleeding events	BARC classification (Bleeding Academic Research Consortium); Type 0: no evidence of bleeding; Type 1: bleeding without need for hospitalization or treatment (e.g. bruising, hematoma, nosebleeds, etc.); Type 2: any clinically overt sign of hemorrhage that is actionable but does not meet criteria for type 3, 4 or 5.; Type 3: clinical, laboratory, and/or imaging evidence of bleeding, with healthcare provider responses; Type 4: Coronary Artery Bypass Graft-related bleeding; Type 5: Fatal bleeding	12 months

Collaborators and Investigators

• Sponsor: University of Zagreb
• Collaborators: Clinical Hospital Centre Zagreb; Ministry of Science, Education and Sport, Republic of Croatia
• Investigators: Study Chair: Davor Milicic, MD, PhD, University of Zagreb School of Medicine; Principal Investigator: Jure Samardzic, MD, University of Zagreb School of Medicine

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: March 19, 2014
• First Submitted That Met QC Criteria: March 22, 2014
• First Posted (Estimate): March 26, 2014

Study Record Updates

• Last Update Posted (Estimate): August 15, 2014
• Last Update Submitted That Met QC Criteria: August 14, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: acute coronary syndrome; outcome; clopidogrel; platelet reactivity; tailoring therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Syndrome; Acute Coronary Syndrome; 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: 108-1081875-1993-1