In Vitro Pharmacodynamic Effects of Cangrelor in Ticagrelor Treated Patients

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.

Inclusion criteria:

1. Patients with angiographically documented coronary artery disease.

2. Age between 18 to 80 years

3. On treatment per standard of care with ticagrelor 90mg/b.i.d. and aspirin <100mg/day
for at least 14 days.

Exclusion criteria

1. History of intracranial bleeding

2. Known severe hepatic dysfunction

3. Known hypersensitivy

4. Active bleeding or propensity to bleed

5. Platelet count <80x106/mL

6. Hemodynamic instability

7. Serum creatinine <30 mL/min

8. Use of oral anticoagulants (Vitamin K antagonist, dabigatran, rivaroxaban, apixaban)

9. Recent (<14 days) antiplatelet treatment with a glycoprotein IIb/IIIa inhibitor

10. Blood dyscrasia

11. Patients with sick sinus syndrome (SSS) or II or III degree AV block without
pacemaker

12. Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor):
Ketoconazole, itraconazole, voriconazole, clarithromicin, nefazodone, ritonavir,
saquinavir, nelfinavir, indinavir, atazanavir and telithromizycin

13. Hemoglobin < 10g/dL

14. Pregnant females [women of childbearing age must use reliable birth control (i.e.
oral contraceptives) while participating in the study].