Low Maintenance Dose Ticagrelor Versus Clopidogrel in Diabetes Patients Undergoing PCI

Patients with diabetes mellitus (DM) are characterized by platelet hyperreactivity and
reduced pharmacodynamic (PD) effects to several oral antiplatelet agents, including
clopidogrel. In addition to the hyperreactive platelet phenotype, impaired drug metabolism as
well as increased platelet turnover rates may contributed to impaired clopidogrel-induced
antiplatelet effects in DM patients. These observations may contribute to the higher ischemic
event rates, including stent thrombosis, observed in DM patients compared with non-DM
patients treated with clopidogrel.

Ticagrelor is characterized by more prompt, potent and predictable antiplatelet effects
compared with clopidogrel and lower ischemic events in patients with an acute coronary
syndrome (ACS) on a background of aspirin therapy. In patients who experienced a prior (1-3
years) myocardial infarction (MI), compared with placebo, ticagrelor 60 mg bid on a
background of aspirin therapy also reduced long-term ischemic events, with a mortality
benefit observed in DM patients.

To date the PD effects of ticagrelor versus clopidogrel in DM largely derive from post-hoc
assessments or in stabilized patients (e.g. >30 days after PCI), and have not been
prospectively evaluated in the context of elective PCI procedures. Moreover, PD studies with
the ticagrelor 60 mg bid regimen are limited. Therefore, the aim of this investigation will
be to compare the PD effects of a ticagrelor 60 mg bid versus clopidogrel 75 mg od MD regimen
in DM patients without a prior major CV event undergoing elective PCI.

Inclusion criteria:

1. Provision of informed consent prior to any study specific procedures

2. Men or women ≥18 years of age

3. Diagnosed with type 2 DM defined by ongoing glucose lowering drug (oral medications
and / or insulin) treatment for at least 1 month

4. Presence of CAD undergoing elective PCI* * Patients will need to be cardiac
enzyme-negative prior to undergoing coronary angiography. Patient will need to be on a
background of aspirin therapy (treated with a 325 mg LD prior to coronary angiography
unless already on chronic low-dose aspirin therapy). Patients on maintenance
clopidogrel 75 mg therapy for at least 1 week due to a prior vascular intervention
will also be eligible. However, patients on clopidogrel, ticagrelor or prasugrel due
to a prior acute major cardiovascular event (MI or stroke) will not be eligible.

Exclusion criteria:

1. Previous MI (with the exception of definite non-type 1 MI [eg, due to coronary
revascularization procedure, profound hypotension, hypertensive emergency,
tachycardia, or profound anemia])

2. Previous stroke (transient ischemic attack [TIA] is not included in the stroke
definition)

3. Use of an intravenous antiplatelet therapy (i.e., cangrelor or GPI) during PCI

4. On treatment with clopidogrel, prasugrel, or ticagrelor due to a prior acute major CV
event (MI or stroke) (on treatment with clopidogrel due to prior vascular intervention
not secondary to a major CV event is allowed)

5. Planned use of aspirin treatment at doses >100 mg od

6. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4
(CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot
be stopped for the course of the study:

- Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin,
clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir,
saquinavir, nelfinavir, indinavir, atanazavir

- CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses
>40 mg daily or lovastatin at doses >40 mg daily

7. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin
(at venous thrombosis treatment not prophylaxis doses)

8. Patients with known bleeding diathesis or coagulation disorder

9. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed
within the past 6 months prior to randomization, or major surgery within 30 days prior
to randomization

10. Active pathological bleeding

11. Hypersensitivity to ticagrelor and clopidogrel or any of the excipients

12. Increased risk of bradycardic events (eg, known sick sinus syndrome, second or third
degree AV block or previous documented syncope suspected to be due to bradycardia)
unless treated with a pacemaker

13. Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy)

14. Renal failure requiring dialysis

15. Known platelet count <80x106/mL

16. Known hemoglobin <9 g/dL

17. Women of child-bearing potential (ie, those who are not chemically or surgically
sterilized or who are not post-menopause) who are not willing to use a medically
accepted method of contraception that is considered reliable in the judgment of the
investigator OR who have a positive pregnancy test at enrolment or randomization OR
women who are breast-feeding. If a subject becomes pregnant during the course of the
study the investigational product should be discontinued immediately [the outcome of
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy,
normal birth or congenital abnormality) will be followed up and documented even if the
subject was discontinued from the study].

18. Inability of the patient to understand and/or comply with study procedures and/or
follow up, in the opinion of the investigator, OR any conditions that, in the opinion
of the investigator, may render the patient unable to complete the study

19. Life expectancy of less than 1 month based on investigator's judgement

20. Participation in another clinical study with an investigational (defined as non-FDA
approved) product within 28 days prior to enrolment

21. Previous randomization in the present study