Coronary Artery Disease
Conditions
Keywords
platelet function, ticagrelor, STEMI
Brief summary
Ticagrelor is a reversible direct acting P2Y12 antagonist, which has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events. Ticagrelor is considered a first line therapy to be administered as soon as possible in ACS patients. However, the pharmacodynamic effects of ticagrelor at the recommended 180mg loading dose are delayed in patients with STEMI undergoing primary PCI. The use of higher loading dose regimens of ticagrelor has therefore been advocated. The proposed investigation will have a prospective, randomized, parallel design in which STEMI patients undergoing primary PCI will be randomized to receive three different loading dose of ticagrelor (180 mg, 270 mg and 360 mg). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that a higher loading dose regiment will achieve more promptly 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). Ticagrelor is a reversible direct acting P2Y12 antagonist, which has shown to be superior to clopidogrel, in adjunct to aspirin, in preventing recurrent ischemic events, including cardiovascular mortality. Ticagrelor was recently approved for clinical use in ACS patients, at a dose of 180 mg loading dose and 90 mg twice/day maintenance dose. Ticagrelor is considered a first line therapy to be administered as soon as possible in ACS patients, including those presenting with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). However, there are discordant data on the onset of its antiplatelet effects in this particular setting. In particular, the pharmacodynamic effects of ticagrelor at the recommended 180mg loading dose are delayed in patients with STEMI undergoing primary PCI. The use of higher loading dose regimens of ticagrelor has therefore been advocated. However, if the administration of a higher ticagrelor loading dose may overcome this limitation is still unknown and represents the aim of our study. The proposed investigation will have a prospective, randomized, parallel design in which STEMI patients undergoing primary PCI will be randomized to receive three different loading dose of ticagrelor (180 mg, 270 mg and 360 mg). Pharmacodynamic testing will be performed at several time points to test our study hypothesis that a higher loading dose regiment will achieve more promptly enhanced platelet inhibitory effects. This study will provide insights on the pharmacodynamic effects of higher ticagrelor loading doses 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
DRUGTicagrelor 180mg
Rndomization to standard or high ticagrelor loading dose regimens
DRUGTicagrelor 270mg
Randomization to standard or high loading dose regimen
DRUGTicagrelor 360mg
Randomization to standrad or high loading dose regimen
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with ST-elevation myocardial infarction undergoing primary PCI. * Age between 18 and 80 years old.
Exclusion criteria
* History of prior intracranial bleeding. * On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor) in past 30 days. * Known allergies to aspirin or ticagrelor. * On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran, rivaroxaban). * 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. * 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 by VerifyNow P2Y12 | 1 hour | The primary end-point of the study was the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 1 hour after administration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 30 min and 2, 4, 8, 24 hours | Secondary outcomes included the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 30 min and 2, 4, 8, 24 hours after ticagrelor loading dose administration |
| Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 30 min and 1, 2, 4, 8, 24 hours | Secondary outcomes included the comparison of the platelet reactivity index (PRI) determined by vasodilator-stimulated phosphoprotein (VASP) at 30 min and 1, 2, 4, 8, 24 hours after ticagrelor loading dose administration |
| Pharmacokinetic Profiles of Ticagrelor (Tmax) | 24 hours | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. |
| Pharmacokinetic Profiles of Ticagrelor (Cmax) | 24 hours | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. |
| Pharmacokinetic Profiles of Ticagrelor (AUC0-t) | 24 hours | Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated. |
Countries
United States
Participant flow
Recruitment details
Between September 2013 and June 2014.
Pre-assignment details
There were a total of 129 STEMI activations; of these, 52 patients provided their written informed consent to participate in the study and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Ticagrelor 180mg Standard ticagrelor 180mg loading dose
Ticagrelor 180mg: Randomization to standard ticagrelor loading dose | 16 |
| Ticagrelor 270mg High ticagrelor 270mg loading dose
Ticagrelor 270mg: Randomization to a high ticagrelor loading dose regimen | 15 |
| Ticagrelor 360mg High ticagrelor 360mg loading dose
Ticagrelor 360mg: Randomization to a high ticagrelor loading dose regimen | 15 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Hemolysis/technical problems | 1 | 2 | 2 |
| Overall Study | Patient vomited pills | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Ticagrelor 180mg | Ticagrelor 270mg | Ticagrelor 360mg | Total |
|---|---|---|---|---|
| Age, Continuous | 60 years STANDARD_DEVIATION 8.6 | 58 years STANDARD_DEVIATION 8.5 | 57 years STANDARD_DEVIATION 12.1 | 58 years STANDARD_DEVIATION 9.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 4 Participants | 12 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 12 Participants | 11 Participants | 34 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 14 Participants | 10 Participants | 8 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 17 | 1 / 17 | 0 / 18 |
| serious Total, serious adverse events | 0 / 17 | 1 / 17 | 1 / 18 |
Outcome results
Primary
Platelet Reactivity by VerifyNow P2Y12
The primary end-point of the study was the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 1 hour after administration
Time frame: 1 hour
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 | 188 PRU | Standard Error 20 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 | 125 PRU | Standard Error 23 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 | 228 PRU | Standard Error 23 |
p-value: 0.017ANCOVA
Secondary
Pharmacokinetic Profiles of Ticagrelor (AUC0-t)
Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated.
Time frame: 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ticagrelor 180mg | Pharmacokinetic Profiles of Ticagrelor (AUC0-t) | 7893 ng*hr/mL |
| Ticagrelor 270mg | Pharmacokinetic Profiles of Ticagrelor (AUC0-t) | 12379 ng*hr/mL |
| Ticagrelor 360mg | Pharmacokinetic Profiles of Ticagrelor (AUC0-t) | 12381 ng*hr/mL |
Secondary
Pharmacokinetic Profiles of Ticagrelor (Cmax)
Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated.
Time frame: 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ticagrelor 180mg | Pharmacokinetic Profiles of Ticagrelor (Cmax) | 789 ng/mL |
| Ticagrelor 270mg | Pharmacokinetic Profiles of Ticagrelor (Cmax) | 1208 ng/mL |
| Ticagrelor 360mg | Pharmacokinetic Profiles of Ticagrelor (Cmax) | 1208 ng/mL |
Secondary
Pharmacokinetic Profiles of Ticagrelor (Tmax)
Pharmacokinetic assessments included determination of plasma concentration of ticagrelor. Time for the maximum plasma concentration (Tmax), maximum observed plasma concentration (Cmax) and the area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) were calculated.
Time frame: 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Ticagrelor 180mg | Pharmacokinetic Profiles of Ticagrelor (Tmax) | 3.9 hours |
| Ticagrelor 270mg | Pharmacokinetic Profiles of Ticagrelor (Tmax) | 5.0 hours |
| Ticagrelor 360mg | Pharmacokinetic Profiles of Ticagrelor (Tmax) | 7.4 hours |
Secondary
Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points
Secondary outcomes included the comparison of the platelet reactivity index (PRI) determined by vasodilator-stimulated phosphoprotein (VASP) at 30 min and 1, 2, 4, 8, 24 hours after ticagrelor loading dose administration
Time frame: 30 min and 1, 2, 4, 8, 24 hours
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 2 hours | 41 PRI | Standard Error 9 |
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 8 hours | 25 PRI | Standard Error 5 |
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 4 hours | 35 PRI | Standard Error 6 |
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 1 hour | 56 PRI | Standard Error 7 |
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 30 min | 76 PRI | Standard Error 6 |
| Ticagrelor 180mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 24 hours | 27 PRI | Standard Error 4 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 2 hours | 39 PRI | Standard Error 10 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 30 min | 81 PRI | Standard Error 6 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 1 hour | 51 PRI | Standard Error 8 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 4 hours | 30 PRI | Standard Error 7 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 8 hours | 30 PRI | Standard Error 5 |
| Ticagrelor 270mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 24 hours | 30 PRI | Standard Error 5 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 24 hours | 28 PRI | Standard Error 5 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 8 hours | 23 PRI | Standard Error 5 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 1 hour | 78 PRI | Standard Error 8 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 30 min | 78 PRI | Standard Error 6 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 4 hours | 21 PRI | Standard Error 7 |
| Ticagrelor 360mg | Platelet Reactivity by Vasodilator-stimulated Phosphoprotein (VASP) at All Time Points | 2 hours | 48 PRI | Standard Error 10 |
Secondary
Platelet Reactivity by VerifyNow P2Y12 at Other Time Points
Secondary outcomes included the comparison of the P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 30 min and 2, 4, 8, 24 hours after ticagrelor loading dose administration
Time frame: 30 min and 2, 4, 8, 24 hours
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 8 hours | 60 PRU | Standard Error 18 |
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 4 hours | 75 PRU | Standard Error 19 |
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 30 min | 231 PRU | Standard Error 15 |
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 2 hours | 90 PRU | Standard Error 28 |
| Ticagrelor 180mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 24 hours | 39 PRU | Standard Error 13 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 4 hours | 46 PRU | Standard Error 22 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 30 min | 225 PRU | Standard Error 17 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 2 hours | 83 PRU | Standard Error 31 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 8 hours | 44 PRU | Standard Error 21 |
| Ticagrelor 270mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 24 hours | 41 PRU | Standard Error 14 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 24 hours | 72 PRU | Standard Error 14 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 8 hours | 78 PRU | Standard Error 21 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 30 min | 249 PRU | Standard Error 17 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 4 hours | 69 PRU | Standard Error 22 |
| Ticagrelor 360mg | Platelet Reactivity by VerifyNow P2Y12 at Other Time Points | 2 hours | 148 PRU | Standard Error 31 |