Impact of Chronic Kidney Disease on the Effects of Ticagrelor in Patients With Diabetes and Coronary Artery Disease

Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events.
Importantly, DM is a key risk factor for the development of chronic kidney disease (CKD),
which further enhances atherothrombotic risk. These observations underscore the importance of
antiplatelet therapy for prevention of atherothrombotic recurrences in these high-risk
patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. However,
despite its clinical benefit, patients with DM and CKD frequently experience recurrent
atherothrombotic events. This may be in part due to the impaired pharmacokinetic (PK) and
pharmacodynamic (PD) effects of clopidogrel in patients with DM and CKD. Since both DM and
CKD represent pandemic public health problems, the prevalence of which will double over the
next 20 years, identifying antiplatelet agents with more favorable PK/PD profiles is of key
importance.

Ticagrelor is an oral, reversible, non-competitive P2Y12 receptor inhibitor with more potent
and consistent platelet inhibition than clopidogrel. In large-scale clinical investigation,
ticagrelor significantly reduced ischemic events to a greater extent than clopidogrel, a
finding that was consistent also among DM patients. In patients with CKD, ticagrelor led to
an even greater relative risk reduction of ischemic events, including cardiovascular
mortality, compared to patients without CKD. However, to date there has been no analysis on
the efficacy of ticagrelor in DM patients according to CKD status. Moreover, although PD
studies showed enhanced platelet inhibition associated with ticagrelor, it is unknown how
this may be affected by CKD status. Ultimately, how PK/PD profiles of different ticagrelor
dosing regimens may be affected by DM and CKD status is also unknown. The proposed study is
aimed to show the impact of CKD status among patients with DM and CAD on PD and PK profiles
of ticagrelor used at 2 doses (90mg bid and 60mg bid) in the setting of a prospective,
randomized, cross-over trial.

Inclusion Criteria:

- Age >18 years.

- Type 2 DM, defined according to World Health Organization (WHO) definition, on
treatment with oral hypoglycemic agents and/or insulin for at least 2 months without
any changes in treatment regimen;

- Angiographically documented CAD.

- On treatment with low-dose aspirin (81mg/day) and clopidogrel (75mg/day) for at least
30 days as part of standard of care.

Exclusion Criteria:

- Patients with end-stage renal disease on hemodialysis.

- Use of any antiplatelet therapy (except aspirin and clopidogrel) in past 30 days.

- Use of parenteral or oral anticoagulation in past 30 day.

- Active pathological bleeding.

- History of intracranial hemorrhage with prior hemorrhage stroke.

- Blood dyscrasia or bleeding diathesis.

- Any active malignancy.

- Platelet count < 80x106/µl.

- Hemoglobin <10 g/dl.

- Known hepatic dysfunction (known moderate and severe hepatic dysfunction).

- Hemodynamic instability.

- Known allergy or hypersensitivity to ticagrelor or any excipients.

- Pregnant / lactating females (women of childbearing age must use reliable birth
control while in the study).

- Strong inhibitors of cytochrome CYP3A4 and potent inducers of cytochrome CYP3A4 (to
avoid interaction with ticagrelor): ketoconazole, itraconazole, voriconazole,
clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir
and telithromycin.

- Patients with sick sinus syndrome (SSS) or high degree atrio-ventricular block without
pacemaker protection.