Coronary Artery Disease
Conditions
Keywords
ST-elevation myocardial infarction, prasugrel, pharmacodynamic, pharmacokinetic
Brief summary
Prasugrel has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Prasugrel is approved in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) at a dosage of 60 mg loading dose (LD) followed by 10 mg/day. However, a delay in the onset of its antiplatelet effects in this particular setting has been consistently shown. administration of clopidogrel and ticagrelor crushed tablets has been tested and a faster and greater bioavailability compared to the whole tablets has been observed. However, if the administration of a crushed prasugrel LD may overcome the above limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, design in which STEMI patients undergoing primary PCI will be randomized to receive two different formulation of prasugrel LD (60 mg whole tablets and 60 mg crushed tablets). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that crushed LD regiment will achieve more prompt and 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). Prasugrel, a third generation thienopyridine, is an orally administered prodrug that needs single-step hepatic biotransformation into its active metabolite to irreversibly block the P2Y12 receptor. Prasugrel has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Prasugrel is approved in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) at a dosage of 60 mg loading dose (LD) followed by 10 mg/day. However, a delay in the onset of its antiplatelet effects in this particular setting has been consistently shown. The STEMI setting is characterized by conditions, such as impaired absorption and hepatic metabolism, patients either intubated, in shock or unable to swallow, which may affect the pharmacoki¬netic and pharmacodynamic effects of orally administered antiplatelet drugs. The administration of clopidogrel and ticagrelor crushed tablets has been tested and a faster and greater bioavailability compared to the whole tablets has been observed. However, if the administration of a crushed prasugrel LD may overcome the above limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, design in which STEMI patients undergoing primary PCI will be randomized to receive two different formulation of prasugrel LD (60 mg whole tablets and 60 mg crushed tablets). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that crushed LD regiment will achieve more prompt and enhanced platelet inhibitory effects. This study will provide insights on the pharmacodynamic effects of crushed prasugrel LD 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.
Interventions
DRUGprasugrel
the effects of whole tablets versus crushed tablets will be compared
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with ST-elevation myocardial infarction undergoing primary PCI * Age between 18 and 75 years old
Exclusion criteria
* Age \>75 years * Weight \<60 Kg * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 7 days * Known allergies to aspirin or prasugrel * Considered at high risk for bleeding * History of ischemic or hemorrhagic stroke or transient ischemic attack * On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban, apixaban) * 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 * Pregnant females\* * Women of childbearing age must use reliable birth control (i.e. oral contraceptives) while participating in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| P2Y12 Reaction Units (PRU) | 2 hrs | The primary end-point of the study is the comparison in platelet reactivity expressed as PRU determined by VerifyNow P2Y12 between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Index (PRI) | 2 hrs | The secondary end-point of the study is the comparison in platelet reactivity expressed as PRI determined by whole blood vasodilator-stimulated phosphoprotein (VASP) between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration |
Countries
United States
Participant flow
Recruitment details
Between October 15, 2014, and August 12, 2015, there were a total of 123 patients presenting with a STEMI at the University of Florida Health-Jacksonville, that were screened.
Pre-assignment details
45 patients did not meet study entry criteria, while 78 provided their written informed consent to participate in the study and, of these, 52 were randomized. the remaining subjects were not randomized because of exclusion criteria emerged after consenting.
Participants by arm
| Arm | Count |
|---|---|
| Prasugrel Crush Prasugrel 60mg loading dose as crushed tablets | 26 |
| Prasugrel Tablets Prasugrel 60 mg loading dose whole tablets | 24 |
| Total | 50 |
Baseline characteristics
| Characteristic | Prasugrel Crush | Total | Prasugrel Tablets |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 9 | 58 years STANDARD_DEVIATION 10 | 58 years STANDARD_DEVIATION 10 |
| Gender Female | 7 Participants | 13 Participants | 6 Participants |
| Gender Male | 19 Participants | 37 Participants | 18 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 | 7 Participants | 13 Participants | 6 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 | 19 Participants | 37 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 26 | 0 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 |
Outcome results
Primary
P2Y12 Reaction Units (PRU)
The primary end-point of the study is the comparison in platelet reactivity expressed as PRU determined by VerifyNow P2Y12 between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration
Time frame: 2 hrs
Population: The primary population was defined as patients who received the randomized treatment and had a valid primary end point value (PRU at 2 hours) and was considered for analysis of all endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel Crush | P2Y12 Reaction Units (PRU) | 95 PRU |
| Prasugrel Tablets | P2Y12 Reaction Units (PRU) | 164 PRU |
p-value: 0.02295% CI: [10, 126]ANOVA
Secondary
Platelet Reactivity Index (PRI)
The secondary end-point of the study is the comparison in platelet reactivity expressed as PRI determined by whole blood vasodilator-stimulated phosphoprotein (VASP) between prasugrel 60 mg and crushed prasugrel 60 mg at 2 hours after LD administration
Time frame: 2 hrs
Population: The primary population was defined as patients who received the randomized treatment and had a valid primary end point value (PRU at 2 hours) and was considered for analysis of all endpoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Prasugrel Crush | Platelet Reactivity Index (PRI) | 33 PRI |
| Prasugrel Tablets | Platelet Reactivity Index (PRI) | 61 PRI |
p-value: 0.005ANOVA