Pharmacodynamic Effect of Prasugrel vs. Ticagrelor in Diabetes

Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Head-to-head comparisons between the two drugs are lacking.

Patients with diabetes mellitus (DM) have an increased risk of adverse atherothrombotic events. This may be in part attributed to the fact that these patients have reduced response to oral antiplatelet medications, in particular the P2Y12 receptor inhibitor clopidogrel, used for secondary prevention of ischemic events. Upregulation of platelet P2Y12 receptor mediated signaling has been shown in DM patients and may contribute to these pharmacodynamic observations, suggesting the need for more potent P2Y12 inhibiting strategies in these patients. Prasugrel and ticagrelor are recently approved P2Y12 receptor inhibitors which, compared with clopidogrel, have more potent antiplatelet effects. Therefore, prasugrel and ticagrelor represent attractive treatment options for patients with DM. This is also supported by the DM sub-group analysis of the pivotal TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) and PLATO (Platelet Inhibition and Patient Outcomes) trials, which have led to approval of prasugrel and ticagrelor, respectively. Although results of these sub-group analysis suggest that prasugrel is associated with an enhanced benefit in DM patients, while ticagrelor effects in DM patients are consistent with the overall study population, only head-to-head comparisons between the two drugs can elucidate if these exert differential effects on platelets from DM patients. However, the pharmacodynamic studies comparing prasugrel with ticagrelor in DM patients are lacking. The ever growing DM population at high risk of recurrent atherothrombotic events underscores the need to define antiplatelet treatment strategies leading to more optimal platelet inhibition in these patients.

Eligibility Criteria:
Inclusion Criteria:

* Patients with known (angiographically documented) CAD.
* On maintenance treatment with aspirin (81 mg per day) for at least 1-month as per standard of care.
* Type 2 DM on treatment with oral hypoglycemic agents and/or insulin.
* Age between 18 and 74 years old.

Exclusion Criteria:

* History of stroke, transient ischemic attack or intracranial bleeding.
* On treatment with a P2Y12 receptor antagonist (ticlopidine, clopidogrel, prasugrel, ticagrelor).
* Known allergies to aspirin, ticlopidine, clopidogrel, prasugrel, ticagrelor.
* Weight \<60kg.
* On treatment with oral anticoagulant (Vitamin K antagonists, dabigatran).
* Blood dyscrasia or bleeding diathesis.
* Platelet count \<80x106/mL.
* Hemoglobin \<10 g/dL.
* Active bleeding or hemodynamic instability.
* Creatinine Clearance \<30 mL/minute.
* Baseline ALT \>2.5 times the upper limit of normal.
* Hb A1c ≥ 10 mg/dL within 3 months.
* Patients with sick sinus syndrome (SSS) or high degree AV block without pacemaker protection.
* Drugs interfering 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.