Percutaneous Coronary Intervention, ST Segment Elevation Myocardial Infarction
Conditions
Keywords
ticagrelor, cangrelor
Brief summary
In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel. The PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.
Detailed description
In STEMI patients undergoing PPCI there is a delayed onset of action of oral P2Y12 receptor inhibitors, including prasugrel and ticagrelor, which require more than 2 hours to exert their full antiplatelet effects, and thus exposing these high-risk patients to an increased risk of early thrombotic complications. The mechanism of this delayed onset of antiplatelet effect is likely multifactorial due to the presence in the setting of STEMI of specific conditions that translate into delayed drug absorption which in turn affect the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of oral P2Y12 receptor inhibitors. Crushing prasugrel and ticagrelor improves their PK and PD profiles as it favors drug absorption and onset of antiplatelet effects and because of this, it is commonly used in STEMI patients undergoing PPCI. However, despite the use of crushed tablets, up to one-third of patients may still have high on-treatment platelet reactivity (HPR) within the first 2 hours after loading dose (LD) administration of these oral agents. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events compared with clopidogrel in P2Y12 receptor naïve patients undergoing PCI. To date most studies have explored cangrelor in the setting of PCI subjects treated with clopidogrel and the clinical profile of cangrelor among patients treated with prasugrel or ticagrelor is currently unknown. This is noteworthy because ACS patients, in particular STEMI undergoing PPCI, are commonly treated with either prasugrel or ticagrelor. PD investigations conducted in vitro or ex vivo in stable patients have shown cangrelor to be associated with enhanced platelet inhibition compared with that induced by prasugrel and ticagrelor. However, the PD effects of cangrelor in STEMI patients undergoing PPCI treated with a newer generation P2Y12 receptor inhibitor and how this compares with a crushed formulation of the oral drug is unexplored. The aim of this prospective randomized study is to investigate the PD effects of cangrelor in STEMI patients undergoing PPCI treated with crushed ticagrelor.
Interventions
DRUGCangrelor
Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h.
OTHERPlacebo
Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h.
Sponsors
Chiesi Farmaceutici S.p.A.
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with STEMI undergoing primary PPCI * Age \> 18 years old
Exclusion criteria
* Inability to provide written informed consent * Known history of prior intracranial bleeding * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in the prior 10 days * Known allergies to aspirin, ticagrelor or cangrelor * On treatment with oral anticoagulant * Treatment with glycoprotein IIb/IIIa inhibitors * Fibrinolytics within 24 hours * Active bleeding * High risk of bleeding * Known platelet count \<80x106/mL * Known hemoglobin \<10 g/dL * Intubated patients (prior to randomization) * Known creatinine clearance \<30 mL/minute or on hemodialysis. * Known severe hepatic dysfunction * 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): Ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromizycin. * Pregnant or lactating females.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by VerifyNow PRU | 30 minutes | Platelet reactivity at 30 minutes after starting cangrelor or placebo assessed by VerifyNow PRU and reported as P2Y12 Reaction Units (PRU) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity Measured by Vasodilator-stimulated Phosphoprotein (VASP) | 30 minutes | Platelet reactivity at 30 minutes after starting cangrelor or placebo measured by VASP and reported as platelet reactivity index (PRI%). Higher PRI% means higher platelet reactivity. |
Countries
United States
Participant flow
Recruitment details
Between December 10, 2017 and July 17, 2018, there were a total of 99 STEMI patients with intent to undergo P-PCI that presented to our Institution, of whom 69 provided their written informed consent to participate in the study.
Pre-assignment details
19 patients were not randomized because PCI was not performed or had newly identified exclusion criteria
Participants by arm
| Arm | Count |
|---|---|
| Cangrelor Cangrelor will be administered as 30 μg/kg bolus followed by 4 μg/kg/min infusion for 2 hours
Cangrelor: Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h. | 25 |
| Placebo Normal saline bolus and infusion for 2 hours
Placebo: Patients will be randomly assigned 1:1 to receive either cangrelor or matching placebo. The bolus will be administered at the same time of a 180 mg crushed ticagrelor loading dose and infusion will be continued for 2 h. | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Cangrelor | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 11 | 60 years STANDARD_DEVIATION 10 | 60 years STANDARD_DEVIATION 10 |
| 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 | 5 Participants | 9 Participants | 14 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 | 20 Participants | 16 Participants | 36 Participants |
| Radial access | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
| Use of glycoprotein IIb/IIIa inhibitors | 1 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 1 / 25 |
| other Total, other adverse events | 3 / 25 | 3 / 25 |
| serious Total, serious adverse events | 0 / 25 | 1 / 25 |
Outcome results
Primary
Platelet Reactivity Measured by VerifyNow PRU
Platelet reactivity at 30 minutes after starting cangrelor or placebo assessed by VerifyNow PRU and reported as P2Y12 Reaction Units (PRU)
Time frame: 30 minutes
Population: The analyzed patients included all patients with pharmacodynamic data and without a major protocol deviation thought to affect the pharmacodynamic effects of ticagrelor or cangrelor.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cangrelor | Platelet Reactivity Measured by VerifyNow PRU | 63 P2Y12 reaction units (PRU) |
| Placebo | Platelet Reactivity Measured by VerifyNow PRU | 214 P2Y12 reaction units (PRU) |
p-value: <0.00195% CI: [108, 195]ANCOVA
Secondary
Platelet Reactivity Measured by Vasodilator-stimulated Phosphoprotein (VASP)
Platelet reactivity at 30 minutes after starting cangrelor or placebo measured by VASP and reported as platelet reactivity index (PRI%). Higher PRI% means higher platelet reactivity.
Time frame: 30 minutes
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cangrelor | Platelet Reactivity Measured by Vasodilator-stimulated Phosphoprotein (VASP) | 29 platelet reactivity index (PRI) |
| Placebo | Platelet Reactivity Measured by Vasodilator-stimulated Phosphoprotein (VASP) | 72 platelet reactivity index (PRI) |