Clinical trial NCT01898442: High Ticagrelor Loading Dose in STEMI
Official title: Pharmacodynamic Profiles of Ticagrelor in Patients With ST Elevation Myocardial Infarction: A Randomized Comparison of Different Loading Dosage Regimens
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Coronary Artery Disease
Keywords: platelet function
ticagrelor
STEMI
Lead sponsor: University of Florida
Sponsor class: OTHER
First posted: 2013-07-12
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Platelet Reactivity by VerifyNow P2Y12
timeFrame: 1 hour
Secondary outcomes:
measure: Platelet Reactivity by VerifyNow P2Y12 at Other Time Points
timeFrame: 30 min and 2, 4, 8, 24 hours
measure: Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points
timeFrame: 30 min and 1, 2, 4, 8, 24 hours
measure: Pharmacokinetic Profiles of Ticagrelor (Tmax)
timeFrame: 24 hours
measure: Pharmacokinetic Profiles of Ticagrelor (Cmax)
timeFrame: 24 hours
measure: Pharmacokinetic Profiles of Ticagrelor (AUC0-t)
timeFrame: 24 hours
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Dominick Angiolillo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Franchi F, Rollini F, Cho JR, Bhatti M, DeGroat C, Ferrante E, Dunn EC, Nanavati A, Carraway E, Suryadevara S, Zenni MM, Guzman LA, Bass TA, Angiolillo DJ. Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Results of a Prospective Randomized Pharmacokinetic and Pharmacodynamic Investigation. JACC Cardiovasc Interv. 2015 Sep;8(11):1457-1467. doi: 10.1016/j.jcin.2015.02.030.