Acute Coronary Syndrome
Conditions
Keywords
Antiplatelet, ticagrelor, clopidogrel, bivalirudin, thrombosis
Brief summary
The purpose of this study is to determine whether treatment with ticagrelor (plus aspirin and bivalirudin) is more effective than treatment with clopidogrel (plus aspirin and bivalirudin).
Detailed description
The HORIZONS-AMI Trial compared the effectiveness of heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) versus bivalirudin in acute myocardial infarction (AMI) patients undergoing stent deployment 1. Overall the data showed benefits associated with the bivalirudin treatment with lower rates of all-cause mortality, cardiac mortality, re-infarction and non-CABG related major bleeding; However, the data seems to indicate a non-significant increase in acute stent thrombosis in the bivalirudin group. This observation seems to suggest the potential benefits of adding an antiplatelet agent to bivalirudin. A study by Dangas G et al found that in the HORIZONS-AMI patients, the group receiving 600 mg loading-dose of clopidogrel had significantly lower 30-day unadjusted rates of mortality, reinfarction and stent thrombosis than the 300 mg loading-dose group, without increase in bleeding rate. Furthermore, even though the benefits of bivalirudin were independent of the clopidogrel loading dose; the 600mg LD was associated with more benefits with both anticoagulation regimens. Similar observations have been reported in the ARMYDA-6 MI study. It is our hypothesis that using ticagrelor instead of clopidogrel, given its more potent and faster activity, would have greater antithrombotic activity and therefore may reduce the rate of acute stent thrombosis when administered in combination with bivalirudin + ASA in AMI patients. To investigate this hypothesis, we will compare the antithrombotic effects of ticagrelor with clopidogrel, when administered in combination with ASA and bivalirudin, in healthy human volunteers using a cross-over study design. The antithrombotic activity will be assessed pre-treatment and 2-hours and 24-hours post treatment, using methodologies including Badimon Perfusion chamber, VerifyNow P2Y12 assay, platelet aggregation with Multiplate Analyzer and Thromboelastography.
Interventions
DRUGTicagrelor + ASA + Bivalirudin
Single loading dose of Ticagrelor (180 mg given as two 90 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.
DRUGClopidogrel + ASA + Bivalirudin
Single loading dose of Clopidogrel (600 mg given as two 300 mg tablets), plus single dose of ASA (one 81 mg tablet) + bivalirudin administered as 0.75 mg/kg IV bolus followed by 1.75 mg/kg/hour for 1 hour.
Sponsors
AstraZeneca
Juan J Badimon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female volunteers between 18 and 65 years old. * Body mass index (BMI) 18 - 30 kg/m2 inclusive. * Healthy as assessed by a detailed medical history and physical examination. * Laboratory est results within the normal range. * Ability to provide signed informed consent.
Exclusion criteria
* History of clinically relevant disease, bleeding, acute infectious disease or signs of acute illness. * Allergy or hypersensitivity to aspirin or thienopyridines, or atopy diagnosed by a physician. * Use of medication within one month prior to study drug administration. * History of drug abuse or alcohol consumption \>20 g/day. * Inability to abstain from intensive muscular effort or sport competition. * Loss of \>400 mL blood or blood donation within 3 months. * Positive serology for hepatitis B (HBs Ag) or hepatitis C. * Conditions associated with hemorrhagic risk. * Positive pregnancy test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | Pre-treatment baseline and 1 hour | Change in thrombus size at 1 hour as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Platelet Reactivity | Pre-treatment baseline | Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition |
| Blood Thrombogenicity | Pre-treatment baseline | Coagulation times, assessed using the ROTEM thromboelastometry |
Countries
United States
Participant flow
Recruitment details
15 healthy volunteers recruited between July 2012 and March 2013
Participants by arm
| Arm | Count |
|---|---|
| Antithrombotic Effects Acute antithrombotic effects of ticagrelor (180 mg + 90 mg) versus clopidogrel (600mg), when coadministered with aspirin (81mg) and bivalirudin (weight-adjusted clinical dose, given as bolus plus 1-hour infusion) using a randomized, two-treatment, two-period, cross-over design in healthy volunteers. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Antithrombotic Effects |
|---|---|
| Age, Continuous | 31.2 years |
| Body mass index | 27.0 kg/m^2 |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Platelet-thrombus Formation in an ex Vivo Model of Thrombosis
Change in thrombus size at 1 hour as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size.
Time frame: Pre-treatment baseline and 1 hour
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | 56.3 percent change |
| Clopidogrel + ASA + Bivalirudin | Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | 35.2 percent change |
Primary
Platelet-thrombus Formation in an ex Vivo Model of Thrombosis
Change in thrombus size at 24 hours as compared to Pre-treatment baseline, where a positive change represents a decrease in thrombus size.
Time frame: Pre-treatment baseline and 24 hrs post treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | 34.1 percent change |
| Clopidogrel + ASA + Bivalirudin | Platelet-thrombus Formation in an ex Vivo Model of Thrombosis | 18.5 percent change |
Secondary
Blood Thrombogenicity
Coagulation times, assessed using the ROTEM thromboelastometry
Time frame: 24-hours post-treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Blood Thrombogenicity | 56.1 seconds |
| Clopidogrel + ASA + Bivalirudin | Blood Thrombogenicity | 54.3 seconds |
Secondary
Blood Thrombogenicity
Coagulation times, assessed using the ROTEM thromboelastometry
Time frame: Pre-treatment baseline
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Blood Thrombogenicity | 53.1 seconds |
| Clopidogrel + ASA + Bivalirudin | Blood Thrombogenicity | 51.1 seconds |
Secondary
Blood Thrombogenicity
Coagulation times, assessed using the ROTEM thromboelastometry
Time frame: 1 hr post-treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Blood Thrombogenicity | 163.1 seconds |
| Clopidogrel + ASA + Bivalirudin | Blood Thrombogenicity | 174.0 seconds |
Secondary
Platelet Reactivity
Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition
Time frame: Pre-treatment baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Platelet Reactivity | 2.9 percent inhibition |
| Clopidogrel + ASA + Bivalirudin | Platelet Reactivity | 3.7 percent inhibition |
Secondary
Platelet Reactivity
Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition
Time frame: 1 hr post-treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Platelet Reactivity | 69.4 percent inhibition |
| Clopidogrel + ASA + Bivalirudin | Platelet Reactivity | 20.1 percent inhibition |
Secondary
Platelet Reactivity
Platelet reactivity measured by VerifyNowP2Y12 assay measuring percent inhibition
Time frame: 24-hours post-treatment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ticagrelor + ASA + Bivalirudin | Platelet Reactivity | 67.4 percent inhibition |
| Clopidogrel + ASA + Bivalirudin | Platelet Reactivity | 53.4 percent inhibition |