Antithrombotic Effects of Ticagrelor Versus Clopidogrel

Study Overview
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Brief Summary
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The purpose of this study is to determine whether treatment with ticagrelor (plus aspirin and bivalirudin) is more effective than treatment with clopidogrel (plus aspirin and bivalirudin).

Detailed Description
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The HORIZONS-AMI Trial compared the effectiveness of heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) versus bivalirudin in acute myocardial infarction (AMI) patients undergoing stent deployment 1. Overall the data showed benefits associated with the bivalirudin treatment with lower rates of all-cause mortality, cardiac mortality, re-infarction and non-CABG related major bleeding; However, the data seems to indicate a non-significant increase in acute stent thrombosis in the bivalirudin group. This observation seems to suggest the potential benefits of adding an antiplatelet agent to bivalirudin. A study by Dangas G et al found that in the HORIZONS-AMI patients, the group receiving 600 mg loading-dose of clopidogrel had significantly lower 30-day unadjusted rates of mortality, reinfarction and stent thrombosis than the 300 mg loading-dose group, without increase in bleeding rate. Furthermore, even though the benefits of bivalirudin were independent of the clopidogrel loading dose; the 600mg LD was associated with more benefits with both anticoagulation regimens. Similar observations have been reported in the ARMYDA-6 MI study. It is our hypothesis that using ticagrelor instead of clopidogrel, given its more potent and faster activity, would have greater antithrombotic activity and therefore may reduce the rate of acute stent thrombosis when administered in combination with bivalirudin + ASA in AMI patients. To investigate this hypothesis, we will compare the antithrombotic effects of ticagrelor with clopidogrel, when administered in combination with ASA and bivalirudin, in healthy human volunteers using a cross-over study design. The antithrombotic activity will be assessed pre-treatment and 2-hours and 24-hours post treatment, using methodologies including Badimon Perfusion chamber, VerifyNow P2Y12 assay, platelet aggregation with Multiplate Analyzer and Thromboelastography.

Official Title
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Randomized, Crossover Study of the Antithrombotic Effects of Ticagrelor Plus Aspirin Versus Clopidogrel Plus Aspirin When Administered With Bivalirudin

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Ticagrelor + ASA + Bivalirudin
* Drug: Clopidogrel + ASA + Bivalirudin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female volunteers between 18 and 65 years old. Body mass index (BMI) 18 - 30 kg/m2 inclusive. Healthy as assessed by a detailed medical history and physical examination. Laboratory est results within the normal range. Ability to provide signed informed consent. Exclusion Criteria: History of clinically relevant disease, bleeding, acute infectious disease or signs of acute illness. Allergy or hypersensitivity to aspirin or thienopyridines, or atopy diagnosed by a physician. Use of medication within one month prior to study drug administration. History of drug abuse or alcohol consumption >20 g/day. Inability to abstain from intensive muscular effort or sport competition. Loss of >400 mL blood or blood donation within 3 months. Positive serology for hepatitis B (HBs Ag) or hepatitis C. Conditions associated with hemorrhagic risk. Positive pregnancy test.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor + ASA + Bivalirudin<br>Single loading dose of Ticagrelor (180 mg given as two 90 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour. | Drug: Ticagrelor + ASA + Bivalirudin<br>* Single loading dose of Ticagrelor (180 mg given as two 90 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.<br>* Other names: Angiomax (bivalirudin);|
| Active Comparator: Clopidogrel + ASA + Bivalirudin<br>Single loading dose of Clopidogrel (600 mg given as two 300 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour. | Drug: Clopidogrel + ASA + Bivalirudin<br>* Single loading dose of Clopidogrel (600 mg given as two 300 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.<br>* Other names: Angiomax (bivalirudin);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | Change in thrombus size at 1 hour as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size. | Pre-treatment baseline and 1 hour | 
| Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | Change in thrombus size at 24 hours as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size. | Pre-treatment baseline and 24 hrs post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity | Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition | Pre-treatment baseline | 
| Platelet Reactivity | Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition | 1 hr post-treatment | 
| Platelet Reactivity | Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition | 24-hours post-treatment | 
| Blood Thrombogenicity | Coagulation times, assessed using the ROTEM thromboelastometry | Pre-treatment baseline | 
| Blood Thrombogenicity | Coagulation times, assessed using the ROTEM thromboelastometry | 1 hr post-treatment | 
| Blood Thrombogenicity | Coagulation times, assessed using the ROTEM thromboelastometry | 24-hours post-treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiplatelet, ticagrelor, clopidogrel, bivalirudin, thrombosis