Reversibility of Dual Antiplatelet Therapy by Platelets

Study Overview
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Brief Summary
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The objective of the study is to test the hypothesis whether or not autologous stored platelets are able to offset the antiplatelet effect of aspirin and clopidogrel as assessed by state-of-the-art platelet function assays.

Detailed Description
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Dual antiplatelet therapy with aspirin and clopidogrel is a well established strategy to prevent thrombotic complications in patients with high platelet reactivity following plaque rupture in acute coronary syndromes (ACS) or percutaneous coronary interventions. Current practice guidelines for antiplatelet therapy advocate a one to 12 months dual antiplatelet therapy after bare metal stent PCI and a 12 months dual antiplatelet therapy after PCI in patients with ACS and drug eluting stent PCI. Although oral antiplatelet therapy is associated with both, short- as well as long-term clinical efficacy, irreversible platelet inhibition carries a substantial risk of bleeding particularly in patients presenting for surgery. Empiric therapy of bleeding consists of platelet transfusion. However, there are currently no pharmacodynamic studies assessing the effect of stored platelets on in-vitro platelet function tests. Healthy volunteers will donate platelets, take aspirin and clopidogrel for 3 days (loading dose aspirin 300 mg, clopidogrel 300 mg, maintenance dose aspirin 100 mg, clopidogrel 75 mg) and platelets will be retransfused on the 4th day. Pharmacodynamic measurements of platelet function will be performed at baseline, after drug intake before retransfusion, immediately after retransfusion and 24 hours thereafter.

Official Title
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Reversibility of Dual Antiplatelet Therapy by Platelets.Phase II Study

Conditions
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Bleeding

Intervention / Treatment
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* Other: autologous stored platelets
* Other: administration of autologous stored platelets
* Biological: autologous stored platelets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent Healthy volunteers, male or female (after exclusion of pregnancy if they are on birth control pill or have a contraceptive coil implanted) Age of consent Weight: 70 kg - 100 kg Platelet count 240 000 to 440 000/µL Hematocrit > 40% readiness to refrain from any activities prone to injury during the study period. Exclusion criteria: Allergy against aspirin or clopidogrel History of bleeding History of peptic ulcer Intake of aspirin or NSAR during the last ten days before screening Gastrointestinal disease precluding resorption of aspirin and clopidogrel Scheduled surgery Any current medication History of hepatic disease 20µm ADP induced aggregation < 60% at screening CYP2C19 polymorphisms Donation of blood within the preceding 4 weeks Neurotic disease Current smoking Drug addiction Intake of grapefruits during the last 10 days before

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: autologous stored platelets<br> | Other: autologous stored platelets<br>* Administration of autologous stored platelets<br>Other: administration of autologous stored platelets<br>* administration of autologous stored platelets<br>Biological: autologous stored platelets<br>* transfusion of autologous stored platelets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic assessment of platelet function as assessed by 5 and 20 micromolar ADP | pharmacodynamic measurements of platelet function will be assessed at baseline, after 3 days administration of aspirin and clopidogrel (300 mg loading with aspirin and clopidogrel, maintenance with 100 mg aspirin and 75 mg clopidogrel, respectively) after retransfusion of stored platelets and 24 hours thereafter | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic assessment of platelet function as assessed by 20 mM arachidonic acid | pharmacodynamic measurements of platelet function will be assessed at baseline, after 3 days administration of aspirin and clopidogrel (300 mg loading with aspirin and clopidogrel, maintenance with 100 mg aspirin and 75 mg clopidogrel, respectively) after retransfusion of stored platelets and 24 hours thereafter | 7 days | 
| Pharmacodynamic assessment of platelet function as assessed by Vasodilator stimulated phosphoprotein (VASP) phosphorylation (platelet reactivity index; PRI) | pharmacodynamic measurements of platelet function will be assessed at baseline, after 3 days administration of aspirin and clopidogrel (300 mg loading with aspirin and clopidogrel, maintenance with 100 mg aspirin and 75 mg clopidogrel, respectively) after retransfusion of stored platelets and 24 hours thereafter | 7 days | 
| Pharmacodynamic assessment of platelet function as assessed by expression of GP IIb/IIIa receptors and P-selectin (Mean fluorescence intensity %) | pharmacodynamic measurements of platelet function will be assessed at baseline, after 3 days administration of aspirin and clopidogrel (300 mg loading with aspirin and clopidogrel, maintenance with 100 mg aspirin and 75 mg clopidogrel, respectively) after retransfusion of stored platelets and 24 hours thereafter | 7 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aspirin, clopidogrel, pharmacodynamics, platelet transfusion