Acute Coronary Syndrome, Coronary Artery Disease
Conditions
Brief summary
Cangrelor is an intravenous P2Y12 inhibitor utilized as a bridge to achieve adequate platelet inhibition until oral P2Y12 inhibitors achieve their full antiplatelet effects in patients undergoing coronary stenting. Although in this setting the potent oral P2Y12 inhibitor prasugrel is commonly utilized, there is very limited data on the optimal approach for switching between these therapies. The overarching aim of this investigation is to rule out a drug drug interaction (DDI) when cangrelor and prasugrel are concomitantly administered in patients undergoing coronary stenting.
Detailed description
Cangrelor is an intravenous P2Y12 inhibitor utilized as a bridge to achieve adequate platelet inhibition until oral P2Y12 inhibitors achieve their full antiplatelet effects in patients undergoing coronary stenting. Although in this setting the potent oral P2Y12 inhibitor prasugrel is commonly utilized, there is very limited data on the optimal approach for switching between these therapies. In particular, ruling out a drug-drug interaction (DDI) is critical to this extent as the presence of a DDI would translate into reduced or abolished antiplatelet effects exposing these acute patients to an increased thrombotic risk. There is an unmet need to better elucidate pharmacodynamic profiles associated with the transition from cangrelor to prasugrel therapy. Of note, prasugrel has recently gone off patent and the availability of a generic formulation will favorably impact its use. Pharmacodynamic studies provide some support on the safety of administering prasugrel at the start of cangrelor infusion. However, the available data does not allow to rule out a DDI given that there was no comparator arm in which prasugrel was either given alone or at the end of cangrelor infusion. The methodological approach for this assessment should rely on comprehensive pharmacodynamics investigations aimed to assess levels of P2Y12 receptor inhibition, pharmacokinetic investigations to assess systemic levels of the drug/drug metabolite, and mechanistic investigations by assessment of levels of P2Y12 receptor gene expression. The overarching aim of this investigation is to rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing coronary stenting.
Interventions
DRUGCangrelor
Cangrelor will be used at the FDA recommended dose using a 30 μg/kg bolus followed by 4 μg/kg/min infusion. The total infusion will last 2 hours.
DRUGPrasugrel
Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration
Sponsors
University of Florida
Scott R. MacKenzie Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Laboratory personnel will be blinded to treatment assignments
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with NSTE-ACS (UA or NSTEMI) undergoing PCI. NSTE-ACS will be defined as the presence of cardiac ischemic symptoms with ischemic changes (but not ST-segment elevation) on electrocardiogram with or without a positive troponin. However, normal electrocardiograms will be acceptable if the investigator will consider an ACS presentation likely. * Age between 18 and 75 years old
Exclusion criteria
* Inability to provide written informed consent * Age \>75 years * Weight \<60 Kg * ST-segment elevation myocardial infarction * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 7 days * Known allergies to prasugrel or cangrelor * 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, edoxoban) * Planned treatment with glycoprotein IIb/IIIa inhibitors (only bailout use allowed) * Fibrinolytics within 24 hours * Known platelet count \<80x106/mL * Known hemoglobin \<10 g/dL * Active bleeding * Known end stage renal disease on hemodialysis * Known severe hepatic dysfunction * Intubated patients (prior to randomization) * 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 |
|---|---|---|
| Platelet Reactivity Measured by VerifyNow | 4 hours | The primary end point of the study will be the non-inferiority in P2Y12 reaction units (PRU) of cangrelor plus prasugrel concomitantly administered at the start of PCI versus prasugrel only administered at the start of PCI. |
Countries
United States
Participant flow
Recruitment details
Between February 18, 2021 and February 2, 2023, 359 patients provided written informed consent to participate in the study
Pre-assignment details
282 patients were excluded because they had at least one exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Prasugrel Prasugrel only administered at the start of PCI
Prasugrel: Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration | 25 |
| Prasugrel + Cangrelor Cangrelor plus prasugrel concomitantly administered at the start of PCI
Cangrelor: Cangrelor will be used at the FDA recommended dose using a 30 μg/kg bolus followed by 4 μg/kg/min infusion. The total infusion will last 2 hours.
Prasugrel: Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration | 25 |
| Cangrelor Followed by Prasugrel Cangrelor administered at the start of PCI plus prasugrel administered at the end of the cangrelor infusion
Cangrelor: Cangrelor will be used at the FDA recommended dose using a 30 μg/kg bolus followed by 4 μg/kg/min infusion. The total infusion will last 2 hours.
Prasugrel: Prasugrel will be used in line with FDA recommendations using a 60mg LD followed by a 10mg daily maintenance dose started 24 hours after LD administration | 27 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Protocol Violation | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Prasugrel | Total | Cangrelor Followed by Prasugrel | Prasugrel + Cangrelor |
|---|---|---|---|---|
| Acute coronary syndrome | 9 Participants | 29 Participants | 10 Participants | 10 Participants |
| Age, Continuous | 62 years STANDARD_DEVIATION 9 | 63 years STANDARD_DEVIATION 8 | 63 years STANDARD_DEVIATION 8 | 64 years STANDARD_DEVIATION 8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 7 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 20 Participants | 59 Participants | 18 Participants | 21 Participants |
| Sex: Female, Male Female | 3 Participants | 17 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Male | 22 Participants | 60 Participants | 20 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 | 0 / 27 |
| other Total, other adverse events | 8 / 25 | 2 / 25 | 4 / 27 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 | 2 / 27 |
Outcome results
Primary
Platelet Reactivity Measured by VerifyNow
The primary end point of the study will be the non-inferiority in P2Y12 reaction units (PRU) of cangrelor plus prasugrel concomitantly administered at the start of PCI versus prasugrel only administered at the start of PCI.
Time frame: 4 hours
Population: Patient with valid primary end point data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prasugrel | Platelet Reactivity Measured by VerifyNow | 23 PRU | Standard Deviation 31 |
| Prasugrel + Cangrelor | Platelet Reactivity Measured by VerifyNow | 153 PRU | Standard Deviation 104 |
| Cangrelor Followed by Prasugrel | Platelet Reactivity Measured by VerifyNow | 65 PRU | Standard Deviation 84 |
Comparison: The primary hypothesis of our study was that in patients receiving concomitant administration of cangrelor and prasugrel (experimental arm), platelet inhibition as assessed by PRU would be noninferior to patients receiving prasugrel only (active control)95% CI: [85, 176]ANCOVA