Pharmacodynamic Evaluation of Switching From Prasugrel to Ticagrelor

Study Overview
=================
Brief Summary
-----------------
Recently, two new oral P2Y12 antagonists have been approved for clinical use: prasugrel, a third generation thienopyridine, and ticagrelor, a first in class cyclopentyltriazolopyrimidine (CPTP). These agents have been shown to be associated with more potent platelet inhibitory effects compared with clopidogrel. In addition, both agents have shown to be superior to clopidogrel in preventing recurrent ischemic events in the setting of acute coronary syndromes (ACS). Understanding how to switch patients from prasugrel to ticagrelor is an unmet need of clinical interest. The proposed PD investigation will have a prospective, randomized, parallel design aimed to show that switching patients from prasugrel to ticagrelor provides similar levels of platelet inhibition.

Detailed Description
-----------------
Dual antiplatelet therapy consisting of aspirin and a P2Y12 receptor antagonist is the cornerstone of treatment for secondary prevention of thrombotic events in patients with coronary artery disease. Recently, two new oral P2Y12 antagonists have been approved for clinical use: prasugrel, a third generation thienopyridine, and ticagrelor, a first in class cyclopentyltriazolopyrimidine (CPTP). These agents have been shown to be associated with more potent platelet inhibitory effects compared with clopidogrel. In addition, both agents have shown to be superior to clopidogrel in preventing recurrent ischemic events in the setting of acute coronary syndromes (ACS). Therefore, current guidelines recommend prasugrel or ticagrelor (as first line therapy according to European Society of Cardiology) in ACS patients undergoing percutaneous coronary intervention (PCI). Despite the broader indication for ticagrelor (also medically managed ACS) and its mortality benefit, prasugrel has a higher uptake than ticagrelor in the US market, likely due to its earlier approval. Further, implementation of prasugrel into institutional protocols, particularly for ST elevation myocardial infarction (STEMI) patients undergoing primary PCI, may also be a reason for the slow uptake of ticagrelor. However, many clinicians would indeed consider ticagrelor as the long-term treatment of choice for a variety of reasons. Therefore, understanding how to switch patients from prasugrel to ticagrelor is an unmet need of clinical interest. However, currently, there are no data on the pharmacodynamic (PD) effects of switching from prasugrel to ticagrelor. The proposed PD investigation will have a prospective, randomized, parallel design aimed to show that switching patients from prasugrel to ticagrelor provides similar levels of platelet inhibition. This study will provide insights on the PD effects of switching and will help clinicians to choose the most appropriate schema to avoid complications related to inadequate antiplatelet therapy in patients with coronary artery disease if switching from prasugrel to ticagrelor is desired.

Official Title
-----------------
Pharmacodynamic Evaluation of Switching From Prasugrel to Ticagrelor: The SWAP (SWitching Anti Platelet)-3 Study

Conditions
-----------------
Coronary Artery Disease, Acute Coronary Syndrome

Intervention / Treatment
-----------------
* Drug: Ticagrelor 180mg
* Drug: Prasugrel 10mg
* Drug: Ticagrelor 90mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with known coronary artery disease who presented with and ACS and underwent PCI. Age between 18 and 74 years old. On therapy with low-dose aspirin (81 mg) and prasugrel 10 mg/daily for at least 14 days as per standard of care Exclusion criteria: History of stroke, transient ischemic attack (TIA) or intracranial bleeding. Known allergies to ticagrelor. Weight < 60 Kg On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban). Treatment with IIb/IIIa glycoprotein inhibitors in the last 7 days. Blood dyscrasia or bleeding diathesis. Platelet count <80x106/mL. Hemoglobin <10 g/dL. Active bleeding. Hemodynamic instability. Creatinine Clearance <30 mL/minute. Known severe hepatic dysfunction. Patients with sick sinus syndrome (SSS) or high degree atrio-ventricular block without pacemaker protection. Current treatment with drugs interfering with cytochrom P450 3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin. Pregnant females.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 74 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor 180mg<br>Patients on prasugrel will switch to ticagrelor with a 180mg loading dose | Drug: Ticagrelor 180mg<br>* After providing written informed consent, eligible patients on maintenance prasugrel meeting inclusion and exclusion criteria will be randomized in a 1:1:1 fashion to one of the following treatment arms: A. Ticagrelor 180 mg loading dose (two 90mg ticagrelor tablets) followed by 90 mg BID maintenance dose for 7±2 days. B. Ticagrelor 90 mg (one 90mg ticagrelor tablet) followed by 90 mg BID maintenance dose for 7±2 days C. Prasugrel 10 mg once daily maintenance dose for 7±2 days<br>* Other names: Brilinta;|
| Experimental: Ticagrelor 90mg<br>Patients on prasugrel will switch to ticagrelor with a 90mg maintenance dose | Drug: Ticagrelor 90mg<br>* After providing written informed consent, eligible patients on maintenance prasugrel therapy meeting inclusion and exclusion criteria will be randomized in a 1:1:1 fashion to one of the following treatment arms: A. Ticagrelor 180 mg loading dose (two 90mg ticagrelor tablets) followed by 90 mg BID maintenance dose for 7±2 days. B. Ticagrelor 90 mg (one 90mg ticagrelor tablet) followed by 90 mg BID maintenance dose for 7±2 days C. Prasugrel 10 mg once daily MD for 7±2 days<br>* Other names: Brilinta;|
| Active Comparator: Prasugrel 10mg<br>Patients already on prasugrel, will maintain prasugrel | Drug: Prasugrel 10mg<br>* After providing written informed consent, eligible patients on maintenance prasugrel therapy meeting inclusion and exclusion criteria will be randomized in a 1:1:1 fashion to one of the following treatment arms: A. Ticagrelor 180 mg loading dose (two 90mg ticagrelor tablets) followed by 90 mg BID maintenance dose for 7±2 days. B. Ticagrelor 90 mg (one 90mg ticagrelor tablet) followed by 90 mg BID maintenance dose for 7±2 days C. Prasugrel 10 mg once daily MD for 7±2 days<br>* Other names: Effient;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity Measured as P2Y12 Reaction Units (PRU) Determined by Verify Now-P2Y12 Assay | The primary hypothesis of our study was that after 1 week of randomized treatment PRU levels would be non-inferior in patients switched from prasugrel to ticagrelor (two arms combined) compared with patients remaining on prasugrel. | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity Index (PRI) Measured by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP). | The secondary hypothesis of our study was that after 1 week of randomized treatment PRI levels would be non-inferior in patients switched from prasugrel to ticagrelor (two arms combined) compared with patients remaining on prasugrel. VASP was measured by quantitative flow cytometry using commercially available labelled monoclonal antibodies. | 7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
platelet reactivity, ticagrelor, prasugrel