Overcoming High On-Treatment Platelet Reactivity (HPR) During Prasugrel Therapy With Ticagrelor

Study Overview
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Brief Summary
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The primary objective is to determine the pharmacodynamic effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable Coronary artery disease (CAD) patients who exhibit high-on prasugrel platelet reactivity defined as Vasodilator Stimulated Phosphoprotein-Phosphorylation (VASP-P) >50%.

Official Title
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Overcoming High On-Treatment Platelet Reactivity (HPR) During Prasugrel Therapy

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Prasugrel
* Drug: Ticagrelor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; age ≥ 18 and < 75 years Weight ≥ 60 kg Currently on ASA therapy and eligible to reduce ASA dose to 81 mg daily if on higher dosing On stable prasugrel maintenance dose for ≥1 month Stable CAD patients defined as: subjects with documented evidence of a history of atherosclerotic coronary artery disease/surgical revascularization (defined as either a prior myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery). A minimum of 1 month must have elapsed between a subject's enrolment and any acute event, revascularization procedure or hospitalization for chest pain for that subject. If female, may be enrolled if one of the following 3 criteria are met: 1)Had a hysterectomy or tubal ligation at least 6 months prior to signing ICF, 2)Post-menopausal for at least 1 year, 3)If of childbearing potential, will practice 1 of the following methods of birth control throughout the study: oral, injectable, or implantable hormonal contraceptives; intrauterine device; diaphragm plus spermicide; or female condom plus spermicide. Methods of contraception that are not acceptable are partner's use of condoms or partner's vasectomy. Able and willing to provide written informed consent before entering the study Exclusion Criteria: Subject plans to undergo coronary revascularization at any time during the trial Presence or history of any of the following: ischemic or hemorrhagic stroke; transient ischemic attack (TIA); intracranial neoplasm; arteriovenous malformation, or aneurysm; intracranial hemorrhage; head trauma (within 3 months of study entry) History of refractory ventricular arrhythmias with an increased risk of bradycardic events (eg, subjects without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree atrioventricular (AV) block or bradycardic-related syncope) History or evidence of congestive heart failure (New York Heart Association Class III or above ≤ 6 months before screening Severe hepatic impairment defined as ALT> 2.5 X ULN Uncontrolled hypertension, or systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at screening Severely impaired renal function (glomerular filtration rate < 30 mL/minute) or on dialysis Concomitant use with parenteral or oral anticoagulants Platelet count <100 X103

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Non-HPR group<br>The non-HPR group will have PD and genetic testing, with no change in medication. | |
| Active Comparator: HPR Group<br>This arm will be split into Group A and Group B which will receive Ticagrelor/Prasugrel in a crossover manner. | Drug: Prasugrel<br>* Patients will discontinue ticagrelor treatment and start 10 mg prasugrel daily while continuing 81 mg of aspirin daily.<br>Drug: Ticagrelor<br>* Patients will be given 180 mg of Ticagrelor followed by 90 mg twice a day while continuing 81 mg of aspirin daily).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic (PD) Vasodilator Stimulated Phosphoprotein-Phosphorylation(VASP-P) in High On Prasugrel Platelet Reactivity(HPPR) stable CAD patients | The primary objective is to determine the pharmacodynamic effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit high-on prasugrel platelet reactivity defined as VASP-P>50%. | 2 hours, 4 hours, and 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of HPPR | Determine the prevalence of HPPR in a stable PCI population. | 2 hours, 4 hours, and 14 days | 
| CYP2C19 relation to occurence of HPPR | Determine the relation of CYP2C19 activity to the occurrence of HPPR. | 2 hours, 4 hours, and 14 days | 
| PD VerifyNow in HPPR stable CAD patients | Evaluate the PD effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit HPPR defined as PRU >208 by VerifyNow P2Y12 | 2 hour, 4 hour, 14 days | 
| PD LTA in HPPR stable CAD patients | Evaluate the PD effect of ticagrelor dosing (180mg LD/ 90mg BID) at 2, 4 hours and 14 days in stable CAD patients who exhibit HPPR based on light transmittance aggregometry (5 and 20 uM ADP, 4ug/mL Collagen) | 2 hours, 4 hours, 14 days | 
| Frequency of HPR | To determine the frequency of HPR after switching from ticagrelor to prasugrel after 14 days of treatment. | 2 hours, 4 hours, and 14 days | 
| PD effect(Prasugrel) relation to CYP2C19 | To determine if the PD effect of prasugrel is related to the activity of CYP2C19 (phenotyping and genotyping) by measuring patients with and without HPPR. | 2 hours, 4 hours, and 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary artery disease, anti-platelet medications, Platelet-aggregation Inhibitors