Antithrombotic Effects of Ticagrelor Versus Clopidogrel

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.

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.