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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Clopidogrel dose adjustment


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: control group<br>Patients in this group will receive standard clopidogrel dose | |
| Experimental: interventional group<br>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<br>* 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)<br>* Other names: antiplatelet therapy tailoring;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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clopidogrel, platelet reactivity, acute coronary syndrome, tailoring therapy, outcome