Coronary Artery Disease
Conditions
Keywords
clopidogrel, prasugrel, ticagrelor
Brief summary
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.
Detailed description
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.
Interventions
DRUGPrasugrel
Maintenance dose will be maintained for 10±3 days.
DRUGTicagrelor
Maintenance dose will be maintained for 10±3 days.
Sponsors
Scott R. MacKenzie Foundation
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Prospective randomized
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Unit (PRU) | at 24 hours post loading dose | Platelet reactivity measured by VerifyNow and reported as PRU |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Prasugrel Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).
Prasugrel: Maintenance dose will be maintained for 10±3 days. | 7 |
| Ticagrelor Patients will be randomly (1:1) assigned to receive FDA approved doses of either prasugrel (60 mg loading dose - 10 mg/day maintenance dose) or ticagrelor (180 mg loading dose - 90 mg b.i.d maintenance dose).
Ticagrelor: Maintenance dose will be maintained for 10±3 days. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Prasugrel | Ticagrelor | Total |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 8 | 60 years STANDARD_DEVIATION 8 | 59 years STANDARD_DEVIATION 8 |
| diabetes mellitus | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
P2Y12 Reaction Unit (PRU)
Platelet reactivity measured by VerifyNow and reported as PRU
Time frame: at 24 hours post loading dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel | P2Y12 Reaction Unit (PRU) | 5 PRU | Standard Deviation 10 |
| Ticagrelor | P2Y12 Reaction Unit (PRU) | 24 PRU | Standard Deviation 22 |
Comparison: The primary endpoint is non-inferiority in PRU, at 24 hours of prasugrel versus ticagrelor. Under the assumption of 0 difference at 24 hours in mean PRU between ticagrelor and prasugrel and a common standard deviation of 50 PRU, a sample size of 22 patients per group allows for the 95% CI to stay within ± 45 PRU with a 90% power and alpha = 0.05.p-value: <0.0595% CI: [-38, 2]ANCOVA