Coronary Artery Disease
Conditions
Keywords
coronary artery disease, platelet function, ticagrelor, cangrelor
Brief summary
Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing stent procedures who have not been pretreated with clopidogrel. In vitro investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the effects on platelet function achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor.
Detailed description
A higher degree of platelet inhibition remains the goal in the peri-interventional period in patients undergoing percutaneous coronary interventions (PCI) as this is associated with a lower rate of adverse ischemic events. Ticagrelor and prasugrel are novel and potent generation oral P2Y12 receptor inhibitors associated with a greater reduction in ischemic events compared with clopidogrel. However, both prasugrel and ticagrelor have recently showed variability in pharmacodynamic (PD) response, particularly in patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI, exposing these patients to an increased risk of thrombotic complications. These findings support the need for intravenous agents with more rapid platelet inhibiting effects. Cangrelor is a potent intravenous P2Y12 receptor inhibitor with rapid onset and offset of action associated with a greater reduction in ischemic events, including stent thrombosis, in patients undergoing PCI who have not been pretreated with clopidogrel. In vitro PD investigations have shown cangrelor to be associated with more rapid, potent, and consistent platelet inhibition in patients on maintenance prasugrel therapy exposed to a re-loading dose of prasugrel. However, if cangrelor exerts similar effects in ticagrelor treated patients remain unknown. The aim of the present study is to evaluate the PD effects achieved after in vitro incubation with cangrelor in patients on ticagrelor maintenance dose who receive a loading dose of ticagrelor. The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. PD assessments will be done before and after incubation with cangrelor at 3 time-points. The study hypothesis is that in vitro incubation with cangrelor will lead to incremental P2Y12 receptor blockade, the extent of which will be inversely related to dose of ticagrelor.
Interventions
DRUGTicagrelor 180mg
The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.
DRUGTicagrelor 90mg
The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor.
Sponsors
The Medicines Company
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with angiographically documented coronary artery disease. 2. Age between 18 to 80 years 3. On treatment per standard of care with ticagrelor 90mg/b.i.d. and aspirin \<100mg/day for at least 14 days.
Exclusion criteria
1. History of intracranial bleeding 2. Known severe hepatic dysfunction 3. Known hypersensitivy 4. Active bleeding or propensity to bleed 5. Platelet count \<80x106/mL 6. Hemodynamic instability 7. Serum creatinine \<30 mL/min 8. Use of oral anticoagulants (Vitamin K antagonist, dabigatran, rivaroxaban, apixaban) 9. Recent (\<14 days) antiplatelet treatment with a glycoprotein IIb/IIIa inhibitor 10. Blood dyscrasia 11. Patients with sick sinus syndrome (SSS) or II or III degree AV block without pacemaker 12. Drugs interfering CYP3A4 metabolism (to avoid interaction with Ticagrelor): Ketoconazole, itraconazole, voriconazole, clarithromicin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir and telithromizycin 13. Hemoglobin \< 10g/dL 14. 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 Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) | Baseline | PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PRI Measured by VASP | 1 hour | PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from October 2014 to October 2015. Patients were screened and recruited in the Cardiology clinics of the Division of Cardiology of University of Florida Jacksonville.
Pre-assignment details
64 patients were consented for the study. Of these, 3 withdrew from the study before being randomized, 1 had an exclusion criteria. A total of 60 patients were randomized to receive study medications.
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor 180mg The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor. | 30 |
| Ticagrelor 90mg The proposed study will have a prospective, randomized, parallel design in which patients on chronic ticagrelor therapy will be assigned to receive a reloading dose of 90 or 180 mg ticagrelor. Platelet function assays will be done following in vitro incubation with and without 500 nM cangrelor. | 30 |
| Total | 60 |
Baseline characteristics
| Characteristic | Ticagrelor 90mg | Total | Ticagrelor 180mg |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 8 | 58 years STANDARD_DEVIATION 9 | 58 years STANDARD_DEVIATION 9 |
| 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 | 6 Participants | 15 Participants | 9 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 | 24 Participants | 45 Participants | 21 Participants |
| Sex: Female, Male Female | 9 Participants | 20 Participants | 11 Participants |
| Sex: Female, Male Male | 21 Participants | 40 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP)
PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment
Time frame: Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor 180mg | Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) | Without cangrelor | 30 %PRI | Standard Error 3.6 |
| Ticagrelor 180mg | Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) | With cangrelor | 18 %PRI | Standard Error 1.7 |
| Ticagrelor 90mg | Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) | Without cangrelor | 30 %PRI | Standard Error 4 |
| Ticagrelor 90mg | Platelet Reactivity Index (PRI) Determined by Whole Blood Vasodilator-stimulated Phosphoprotein (VASP) | With cangrelor | 17 %PRI | Standard Error 1.8 |
Secondary
PRI Measured by VASP
PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment
Time frame: 1 hour
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor 180mg | PRI Measured by VASP | Without cangrelor | 20 %PRI | Standard Error 2.4 |
| Ticagrelor 180mg | PRI Measured by VASP | With cangrelor | 12 %PRI | Standard Error 1.6 |
| Ticagrelor 90mg | PRI Measured by VASP | Without cangrelor | 29 %PRI | Standard Error 3.4 |
| Ticagrelor 90mg | PRI Measured by VASP | With cangrelor | 16 %PRI | Standard Error 1.5 |
Secondary
PRI Measured by VASP
PRI determined by VASP between before and after incubation with 500 nM Cangrelor in each arm of treatment
Time frame: 4 hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor 180mg | PRI Measured by VASP | Without cangrelor | 22 %PRI | Standard Error 2.4 |
| Ticagrelor 180mg | PRI Measured by VASP | With cangrelor | 14 %PRI | Standard Error 1.2 |
| Ticagrelor 90mg | PRI Measured by VASP | Without cangrelor | 22 %PRI | Standard Error 2 |
| Ticagrelor 90mg | PRI Measured by VASP | With cangrelor | 17 %PRI | Standard Error 1.9 |