High Ticagrelor Loading Dose in STEMI

Study Overview
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Brief Summary
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Ticagrelor is a reversible direct acting P2Y12 antagonist, which has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Ticagrelor is considered a first line therapy to be administered as soon as possible in ACS patients. However, the pharmacodynamic effects of ticagrelor at the recommended 180mg loading dose are delayed in patients with STEMI undergoing primary PCI. The use of higher loading dose regimens of ticagrelor has therefore been advocated. The proposed investigation will have a prospective, randomized, parallel design in which STEMI patients undergoing primary PCI will be randomized to receive three different loading dose of ticagrelor (180 mg, 270 mg and 360 mg). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that a higher loading dose regiment will achieve more promptly enhanced platelet inhibitory effects.

Detailed Description
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Dual antiplatelet therapy consisting of aspirin and a P2Y12 receptor antagonist is the cornerstone of treatment for prevention of thrombotic events in patients with acute coronary syndromes (ACS). Ticagrelor is a reversible direct acting P2Y12 antagonist, which has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events, including cardiovascular mortality. Ticagrelor was recently approved for clinical use in ACS patients, at a dose of 180 mg loading dose and 90 mg twice/day maintenance dose. Ticagrelor is considered a first line therapy to be administered as soon as possible in ACS patients, including those presenting with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, there are discordant data on the onset of its antiplatelet effects in this particular setting. In particular, the pharmacodynamic effects of ticagrelor at the recommended 180mg loading dose are delayed in patients with STEMI undergoing primary PCI. The use of higher loading dose regimens of ticagrelor has therefore been advocated. However, if the administration of a higher ticagrelor loading dose may overcome this limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, parallel design in which STEMI patients undergoing primary PCI will be randomized to receive three different loading dose of ticagrelor (180 mg, 270 mg and 360 mg). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that a higher loading dose regiment will achieve more promptly enhanced platelet inhibitory effects. This study will provide insights on the pharmacodynamic effects of higher ticagrelor loading doses and will help clinicians choose the most appropriate treatment to avoid complications related to inadequate platelet inhibition in the early phase of patients with STEMI undergoing primary PCI.

Official Title
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Pharmacodynamic Profiles of Ticagrelor in Patients With ST Elevation Myocardial Infarction: A Randomized Comparison of Different Loading Dosage Regimens

Conditions
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Coronary Artery Disease

Intervention / Treatment
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* Drug: Ticagrelor 180mg
* Drug: Ticagrelor 270mg
* Drug: Ticagrelor 360mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ST-elevation myocardial infarction undergoing primary PCI. Age between 18 and 80 years old. Exclusion Criteria: History of prior intracranial bleeding. On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 30 days. Known allergies to aspirin or ticagrelor. On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban). Treatment with IIb/IIIa glycoprotein inhibitors. Fibrinolytics within 24 hours Known blood dyscrasia or bleeding diathesis. Known platelet count <80x106/mL. Known hemoglobin <10 g/dL. Active bleeding. Hemodynamic instability. Known creatinine clearance <30 mL/minute. Known severe hepatic dysfunction. Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection. Current treatment with drugs interfering with CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. 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: 80 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ticagrelor 180<br>Standard ticagrelor 180mg loading dose | Drug: Ticagrelor 180mg<br>* Rndomization to standard or high ticagrelor loading dose regimens<br>* Other names: Brilinta;|
| Experimental: Ticagrelor 270mg<br>High ticagrelor 270mg loading dose | Drug: Ticagrelor 270mg<br>* Randomization to standard or high loading dose regimen<br>* Other names: Brilinta;|
| Experimental: Ticagrelor 360mg<br>High ticagrelor 360mg loading dose | Drug: Ticagrelor 360mg<br>* Randomization to standrad or high loading dose regimen<br>* Other names: Brilinta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet Reactivity by VerifyNow P2Y12 | The primary end-point of the study was the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 1 hour after administration | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Profiles of Ticagrelor (AUC0-t) | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. | 24 hours | 
| Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | Secondary outcomes included the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 30 min and 2, 4, 8, 24 hours after ticagrelor loading dose administration | 30 min and 2, 4, 8, 24 hours | 
| Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | Secondary outcomes included the comparison of the platelet reactivity index (PRI) determined by vasodilator-stimulated phosphoprotein (VASP) at 30 min and 1, 2, 4, 8, 24 hours after ticagrelor loading dose administration | 30 min and 1, 2, 4, 8, 24 hours | 
| Pharmacokinetic Profiles of Ticagrelor (Tmax) | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. | 24 hours | 
| Pharmacokinetic Profiles of Ticagrelor (Cmax) | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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platelet function, ticagrelor, STEMI