Pharmacodynamic and Pharmacokinetic of Switching From Cangrelor to Prasugrel in ACS Patients Undergoing PCI

Study Overview
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Brief Summary
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Cangrelor is an intravenous P2Y12 inhibitor utilized as a bridge to achieve adequate platelet inhibition until oral P2Y12 inhibitors achieve their full antiplatelet effects in patients undergoing coronary stenting. Although in this setting the potent oral P2Y12 inhibitor prasugrel is commonly utilized, there is very limited data on the optimal approach for switching between these therapies. The overarching aim of this investigation is to rule out a drug drug interaction (DDI) when cangrelor and prasugrel are concomitantly administered in patients undergoing coronary stenting.

Detailed Description
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Cangrelor is an intravenous P2Y12 inhibitor utilized as a bridge to achieve adequate platelet inhibition until oral P2Y12 inhibitors achieve their full antiplatelet effects in patients undergoing coronary stenting. Although in this setting the potent oral P2Y12 inhibitor prasugrel is commonly utilized, there is very limited data on the optimal approach for switching between these therapies. In particular, ruling out a drug-drug interaction (DDI) is critical to this extent as the presence of a DDI would translate into reduced or abolished antiplatelet effects exposing these acute patients to an increased thrombotic risk. There is an unmet need to better elucidate pharmacodynamic profiles associated with the transition from cangrelor to prasugrel therapy. Of note, prasugrel has recently gone off patent and the availability of a generic formulation will favorably impact its use. Pharmacodynamic studies provide some support on the safety of administering prasugrel at the start of cangrelor infusion. However, the available data does not allow to rule out a DDI given that there was no comparator arm in which prasugrel was either given alone or at the end of cangrelor infusion. The methodological approach for this assessment should rely on comprehensive pharmacodynamics investigations aimed to assess levels of P2Y12 receptor inhibition, pharmacokinetic investigations to assess systemic levels of the drug/drug metabolite, and mechanistic investigations by assessment of levels of P2Y12 receptor gene expression. The overarching aim of this investigation is to rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing coronary stenting.

Official Title
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Pharmacodynamic and Pharmacokinetic Profiles on Switching From Cangrelor to Prasugrel in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The Switching Antiplatelet -6 (SWAP-6) Study

Conditions
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Coronary Artery Disease, Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Cangrelor
* Drug: Prasugrel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with NSTE-ACS (UA or NSTEMI) undergoing PCI. NSTE-ACS will be defined as the presence of cardiac ischemic symptoms with ischemic changes (but not ST-segment elevation) on electrocardiogram with or without a positive troponin. However, normal electrocardiograms will be acceptable if the investigator will consider an ACS presentation likely. Age between 18 and 75 years old Exclusion Criteria: Inability to provide written informed consent Age >75 years Weight <60 Kg ST-segment elevation myocardial infarction On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 7 days Known allergies to prasugrel or cangrelor Considered at high risk for bleeding History of ischemic or hemorrhagic stroke or transient ischemic attack On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxoban) Planned treatment with glycoprotein IIb/IIIa inhibitors (only bailout use allowed) Fibrinolytics within 24 hours Known platelet count <80x106/mL Known hemoglobin <10 g/dL Active bleeding Known end stage renal disease on hemodialysis Known severe hepatic dysfunction Intubated patients (prior to randomization) Pregnant females [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study]

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prasugrel<br>Prasugrel only administered at the start of PCI | Drug: Prasugrel<br>* Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration<br>* Other names: Effient;|
| Experimental: Prasugrel + Cangrelor<br>Cangrelor plus prasugrel concomitantly administered at the start of PCI | Drug: Cangrelor<br>* Cangrelor will be used at the FDA recommended dose using a 30 μg/kg bolus followed by 4 μg/kg/min infusion. The total infusion will last 2 hours.<br>* Other names: Kengreal;Drug: Prasugrel<br>* Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration<br>* Other names: Effient;|
| Active Comparator: Cangrelor followed by Prasugrel<br>Cangrelor administered at the start of PCI plus prasugrel administered at the end of the cangrelor infusion | Drug: Cangrelor<br>* Cangrelor will be used at the FDA recommended dose using a 30 μg/kg bolus followed by 4 μg/kg/min infusion. The total infusion will last 2 hours.<br>* Other names: Kengreal;Drug: Prasugrel<br>* Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration<br>* Other names: Effient;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet reactivity measured by VerifyNow | The primary end point of the study will be the non-inferiority in P2Y12 reaction units (PRU) of cangrelor plus prasugrel concomitantly administered at the start of PCI versus prasugrel only administered at the start of PCI. | 4 hours |