Vorapaxar as an Add-On Antiplatelet Therapy in Patients With and Without Diabetes Mellitus

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor, more frequently
clopidogrel, represents the standard of care for the long-term secondary prevention of
atherothrombotic events in patients with myocardial infarction (MI) or peripheral arterial
disease (PAD). However, rates of ischemic recurrences remain high, in part due to the fact
that other platelet signaling pathways, such as thrombin-induced platelet aggregation,
continue to be activated. Vorapaxar is a novel, orally active, competitive and slowly
reversible protease-activated receptor (PAR)-1 inhibitor, which exerts potent inhibition of
thrombin-mediated platelet aggregation. It is approved for clinical use by the Food and Drug
Administration for the reduction of thrombotic cardiovascular events in patients with a
history of MI or with peripheral arterial disease. Patients with DM are known to be at
increased risk of recurrent atherothrombotic events, which translates into worse outcomes,
despite the use of standard of care therapy. This is in part due to the hyperreactive
platelet phenotype, which characterizes DM patients, and to inadequate response to oral
antiplatelet agents, including clopidogrel. Importantly, in DM patients with prior MI
included in the TRA 2P trial, vorapaxar reduced the primary composite end point at 3 years by
27% and led to a greater absolute risk reduction compared with those without DM. Therefore,
vorapaxar is an attractive treatment option for DM patients with a prior MI. However, to date
the PD effects of vorapaxar in DM patients and how these may differentiate from non-DM
patients has not been explored. Further, current trends in clinical practice are seeing many
patients discontinue aspirin and maintain clopidogrel. Hence, the role of vorapaxar as part
of a dual antithrombotic treatment regimen combined with clopidogrel (and stopping aspirin)
represents another important area of clinical interest, in order to maximize ischemic
protection while reducing the risk of bleeding. The proposed prospective, parallel-design
study conducted in patients post-MI or with PAD with and without DM will aim the assess the
pharmacodynamic effects of vorapaxar in addition to standard DAPT with aspirin and
clopidogrel as well as in combination with clopidogrel only following aspirin withdrawal.
Pharmacodynamic assessments will be performed at multiple time point, with different assays
exploring multiple pathways of platelet aggregation.

Inclusion criteria:

1. Patients with a prior MI between 2 weeks and 24 months or with PAD.

2. On DAPT with low-dose aspirin (81mg od) and clopidogrel (75mg od) as per
standard-of-care for at least 14 days.

3. Age ≥ 18 years old.

Exclusion criteria:

1. History of acute coronary syndrome in the previous 2 weeks.

2. History of stroke, transient ischemic attack, or intracranial hemorrhage.

3. Active pathological bleeding, history of bleeding events or increased risk of
bleeding.

4. Known severe hepatic impairment.

5. Use of strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole, itraconazole,
posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir,
indinavir, boceprevir, telaprevir, telithromycin and conivaptan) or inducers (e.g.,
rifampin, carbamazepine, St. John's Wort and phenytoin).

6. On treatment with any oral anticoagulant (vitamin K antagonists, dabigatran,
rivaroxaban, apixaban, edoxaban).

7. On treatment with any antiplatelet agent other than aspirin and clopidogrel in the
past 14 days.

8. Creatinine clearance <30 mL/minute.

9. Platelet count <80x106/mL

10. Hemoglobin <10g/dL

11. Hemodynamic instability

12. Pregnant females