In Vitro Pharmacodynamic Effects of Cangrelor in Ticagrelor Treated Patients

In Vitro Pharmacodynamic Effects of Cangrelor on Platelet P2Y12 Receptor Mediated Signaling in Ticagrelor Treated Patients

Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing stent procedures who have not been pretreated with clopidogrel. In vitro investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the effects on platelet function achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor.

A higher degree of platelet inhibition remains the goal in the peri-interventional period in patients undergoing percutaneous coronary interventions (PCI) as this is associated with a lower rate of adverse ischemic events. Ticagrelor and prasugrel are novel and potent generation oral P2Y12 receptor inhibitors associated with a greater reduction in ischemic events compared with clopidogrel. However, both prasugrel and ticagrelor have recently showed variability in pharmacodynamic (PD) response, particularly in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI, exposing these patients to an increased risk of thrombotic complications. These findings support the need for intravenous agents with more rapid platelet inhibiting effects. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing PCI who have not been pretreated with clopidogrel. In vitro PD investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the PD effects achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor. The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. PD assessments will be done before and after incubation with cangrelor at 3 time-points. The study hypothesis is that in vitro incubation with cangrelor will lead to incremental P2Y12 receptor blockade, the extent of which will be inversely related to dose of ticagrelor.

The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.

The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.

The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.

The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.

Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP)

PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment

PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment

PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment

Inclusion criteria: Patients with angiographically documented coronary artery disease. Age between 18 to 80 years On treatment per standard of care with ticagrelor 90mg/b.i.d. and aspirin <100mg/day for at least 14 days. Exclusion criteria History of intracranial bleeding Known severe hepatic dysfunction Known hypersensitivy Active bleeding or propensity to bleed Platelet count <80x106/mL Hemodynamic instability Serum creatinine <30 mL/min Use of oral anticoagulants (Vitamin K antagonist, dabigatran, rivaroxaban, apixaban) Recent (<14 days) antiplatelet treatment with a glycoprotein IIb/IIIa inhibitor Blood dyscrasia Patients with sick sinus syndrome (SSS) or II or III degree AV block without pacemaker Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromicin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromizycin Hemoglobin < 10g/dL Pregnant females [women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study].