Coronary Artery Disease
Conditions
Keywords
ticagrelor, cangrelor, switching
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 ticagrelor is commonly utilized, there is very limited data on the optimal approach for switching between these therapies. The methodological approach for this assessment should rely on comprehensive pharmacodynamics (PD) investigations aimed to assess levels of P2Y12 receptor inhibition, pharmacokinetic (PK) 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 drug-drug interaction when ticagrelor is administered prior to cangrelor infusion.
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 ticagrelor 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. Despite the available evidence suggesting a lack of DDI with the use of ticagrelor in cangrelor treated patients, most data derive from studies in which ticagrelor was given at the time of initiation or during cangrelor infusion. To date, there is no data to fully rule out a DDI when ticagrelor is given prior to starting cangrelor infusion. The need for such investigation is underscored by the relatively high prevalence of pretreatment with ticagrelor in acute settings. The methodological approach for this assessment should rely on comprehensive pharmacodynamics (PD) investigations aimed to assess levels of P2Y12 receptor inhibition, pharmacokinetic (PK) 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 ticagrelor is administered prior to cangrelor infusion.
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 duration of cangrelor/placebo infusion will be 2 hours. After completing the first phase of the study, patients will undergo a 1-4 week wash-out period and then will cross-over to the alternative treatment in the second phase
DRUGPlacebo
Normal saline will be infused for 2 hours. After completing the first phase of the study, patients will undergo a 1-4 week wash-out period and then will cross-over to the alternative treatment in the second phase
Sponsors
Scott R. MacKenzie Foundation
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients, research staff and laboratory personnel will be blinded to treatment assignments. Masking and randomization of medications (cangrelor and placebo) will be performed by our institutional research pharmacy.
Intervention model description
The Switching Antiplatelet Therapy-5 (SWAP-5) study will be a prospective, randomized, double-blind, placebo controlled, cross-over PK and PD investigation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with known coronary artery disease (defined as prior type I myocardial infarction, coronary revascularization, percutaneous or surgical, or presence of at least a 50% stenosis in any major epicardial vessel). * Age \> 18 years old * On aspirin 81mg/qd for at least 1 month
Exclusion criteria
* Inability to provide written informed consent * Hemodynamic instability * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 30 days * Known allergies to ticagrelor or cangrelor * Considered at high risk for bleeding * History of intracranial bleeding/hemorrhagic stroke * On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxoban) within past 30 days * Known platelet count \<80x106/mL * Known hemoglobin \<10 g/dL * Active bleeding * Known end stage renal disease on hemodialysis * Known severe hepatic dysfunction * Acute or severe bronchial asthma or upper airway obstruction. * 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 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 | 2 hours | The primary end point of the study will be the non-inferiority in P2Y12 reaction units (PRU) measured by VerifyNow after discontinuation of cangrelor vs. placebo |
Countries
United States
Participant flow
Pre-assignment details
22 patients were consented and enrolled in the study: 2 patients were eligible for randomization due to the presence of exclusion criteria. A total of 20 patients were randomized and exposed to at least one dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Whole Study Population Using a computer-based randomization system, patients were randomly assigned in a 1:1 fashion to 1 of the following treatment arms: 1) ticagrelor loading dose (LD) followed after 1 hour by cangrelor bolus and infusion; or 2) ticagrelor LD followed after 1 hour by placebo bolus and infusion. Ticagrelor was administered as a 180-mg LD and cangrelor as a 30-μg/kg bolus followed by 4-μg/kg/min infusion. Cangrelor/placebo infusion was continued for a duration of 2 hours. After completing the first phase of the study, patients underwent a 1- to 4-week washout period and then crossed over to the alternative treatment in the second phase (ie, patients assigned to treatment with cangrelor in the first phase were assigned to placebo in the second phase and vice versa). | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Whole Study Population |
|---|---|
| Age, Continuous | 68.4 years STANDARD_DEVIATION 8 |
| Prior myocardial infatction | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 9 / 20 | 9 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
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) measured by VerifyNow after discontinuation of cangrelor vs. placebo
Time frame: 2 hours
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cangrelor | Platelet Reactivity Measured by VerifyNow | 16.9 P2Y12 reaction units |
| Placebo | Platelet Reactivity Measured by VerifyNow | 12.6 P2Y12 reaction units |