Ticagrelor Versus Clopidogrel in Type 2 Diabetic Patients

The rising prevalence of diabetes mellitus and its associated cardiovascular complications
present a major burden to healthcare providers worldwide. Cardiovascular mortality is much
higher among subjects with Type 2 Diabetes Mellitus (T2DM). Increased platelet reactivity is
considered a potential link between the two diseases. Thus, given the higher blood
thrombogenicity of T2DM with CAD, the availability of more potent antiplatelet drugs should
be associated with improvements in the prevention of cardiovascular events in the diabetic
populations. Ticagrelor has been shown to possess a faster onset of action and more potency
than clopidogrel. Furthermore, the PLATO has shown that these characteristics results in a
significant reduction in Cardiovascular events and even death as compared with Clopidogrel.

We plan to compare the antithrombotic activity of ticagrelor versus clopidogrel in T2DM
patients using a cross-over study design. Each participant will be randomly assigned to
receive ticagrelor/clopidogrel + aspirin as a loading dose followed by 5-7 days of daily
maintenance dosing. After a washout period of 1-2 weeks, each participant will receive the
second treatment (clopidogrel/ticagrelor + aspirin) again as a loading dose followed by 5-7
days of daily dosing. Platelet function will be tested at pre-treatment baseline, two
post-dose time-points on the day of loading dose, and one time-point after the last
maintenance dose on day 5-7. Platelet testing will be carried out using the following
methodologies:

1. Badimon Perfusion Chamber: an ex-vivo model of thrombosis that has been extensively
utilized for evaluation of antithrombotic or prothrombotic effects under various
pathological states. The model involves native blood perfusing over a thrombogenic
substrate, triggering thrombus formation that can be measured by planimetry.

2. Platelet Aggregation - Multiplate Analyzer.

3. Platelet Aggregation - VerifyNow P2Y12 assay.

4. Vasodilator-Stimulated Phosphoprotein (VASP).

Inclusion Criteria:

- Diagnosed with type-2 diabetes being treated with oral or parenteral hypoglycemic
therapy or both.

- Have not had thienopyridine therapy for at least 30 days before the study.

- Are of legal age (at least 18 years of age but less than 75 years of age) and
competent mental condition to provide written informed consent.

- For women of child-bearing potential only test negative for pregnancy at the time of
enrollment.

Exclusion Criteria:

- Have a defined need for thienopyridine therapy.

- Subjects within ≤30 days of coronary artery bypass graft (CABG) surgery or
percutaneous coronary intervention (PCI).

- Known glycosylated hemoglobin (HbA1c) ≥10 mg/dL within last 3 months prior to study
entry.

- Have received fibrinolytic therapy <48 hours prior to randomization.

- Have active internal bleeding or history of bleeding diathesis.

- Have clinical findings that are, in the judgment of the investigator, associated with
an increased risk of bleeding.

- Have history of ischemic or hemorrhagic stroke, transient ischemic attack (TIA) or
intracranial neoplasm, arteriovenous malformation, or aneurysm.

- Have an International Normalized Ratio (INR) known to be >1.5 within 1 week of study
entry.

- Have a known platelet count of <100,000/mm3 within 1 week of study entry.

- Have known anemia (hemoglobin [Hgb] <10 gm/dL) within 1 week of study entry.

- Are receiving or will receive oral anticoagulation or other antiplatelet therapy
(other than ASA) that cannot be safely discontinued for the duration of the trial.

- Are receiving daily treatment with non-steroidal anti-inflammatory drugs (NSAIDS) that
cannot be discontinued.

- Have a concomitant medical illness that in the opinion of the investigator may
interfere with or prevent completion in this study.

- Have known severe hepatic dysfunction (e.g., cirrhosis or portal hypertension).

- Have a history of intolerance or allergy to ASA or approved thienopyridines
(ticlopidine or clopidogrel).