Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-function: a Validation Study

Therapeutic inhibition of platelet activation is essential for the management of ischemic
cardiovascular disease. The use of platelet adenosine diphosphate (ADP) P2Y12 receptor
antagonists (clopidogrel, prasugrel, and ticagrelor) in addition to aspirin are associated
with a decrease in cardiovascular events in high-risk coronary artery disease (CAD) patients.
Clopidogrel is the most broadly utilized P2Y12 receptor antagonist. However, among
clopidogrel treated patients, there is broad variability in antiplatelet drug response which
is known carry prognostic implications. Polymorphisms of the cytochrome P450 (CYP) 2C19
enzyme has been consistently shown to modulate clopidogrel response. Accordingly, the Food
and Drug Administration (FDA) has issued a warning on the potential for reduced efficacy of
clopidogrel among carriers of loss-of-function alleles (LOF) for CYP2C19 and suggest
considering alternative antiplatelet therapies for these individuals.

The pharmacodynamic (PD) effects of prasugrel and ticagrelor are not affected by CYP2C19
genetic polymorphisms. However, to date there are no head-to-head PD comparisons between
these agents among patients with different CYP2C19 genetic polymorphisms which is currently
under investigation in CAD patients undergoing PCI at UF Health-Jacksonville (UFJ 2014-12,
NCT 02065479). In order to rule out play of chance findings, pharmacogenetic investigations
require external validation cohorts to support the study findings. Therefore, the present
randomized study is designed to serve as an external validation cohort conducted in patients
with established CAD not undergoing PCI testing the non-inferiority in platelet reactivity of
prasugrel versus ticagrelor among CYP2C19 LOF allele carriers.

Inclusion criteria:

- Patients with CAD [defined as the presence of at least a 50% stenosis in a major
epicardial vessel or major branch, or any prior coronary revascularization (PCI or
coronary bypass graft surgery)] on treatment with either aspirin (81mg/day) or aspirin
and clopidogrel (75m/day) for at least 30 days as per standard of care

- Participated in UFJ 2016-14 study with genetic buccal swab test and have at least one
CYP 2C19 LOF allele (CYP2C19*2 and CYP2C19*3)

- Women of childbearing age must use reliable birth control (i.e. oral contraceptives)
while participating in the study.

Exclusion criteria:

- Known allergies to prasugrel or ticagrelor

- Weight <60kg

- Considered at high risk for bleeding

- Currently active bleeding

- History of ischemic or hemorrhagic stroke or transient ischemic attack, or
intracranial hemorrhage

- Known severe hepatic dysfunction

- On treatment with oral anticoagulant therapy (Vitamin K antagonists, dabigatran,
apixaban, rivaroxaban)

- Platelet count <80x106/mL

- Hemoglobin <10 g/dL.

- Creatinine Clearance <30 mL/minute

- 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): CYP3A Inhibitors (ketoconazole, itraconazole, voriconazole,
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir,
and telithromycin ) and CYP3A Inducers (rifampin, phenytoin, carbamazepine, and
phenobarbital)

- Pregnant or breastfeeding females