Impact of Chronic Kidney Disease on the Effects of Ticagrelor in Patients With Diabetes and Coronary Artery Disease
Condition: Coronary Artery Disease; Diabetes Mellitus
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Diabetes Mellitus
Intervention: ticagrelor
Intervention description: Diabetic patients with or without chronic kidney disease will be randomized 1:1 to either (A) standard dose (90mg twice daily of ticagrelor) for 7-10 days and then cross-over to low dose (60mg twice daily of ticagrelor) for 7-10 days; (B) low dose (60mg twice daily of ticagrelor) for 7-10 days (phase 1) and then cross-over to standard dose (90mg twice daily of ticagrelor) for 7-10 days (phase 2).
Intervention MeSH terms: Ticagrelor
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 101.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: coronary artery disease; diabetes mellitus; chronic kidney disease; ticagrelor

Summary:

      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. 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. 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. To date there has been no analysis on the efficacy of ticagrelor in DM
      patients according to CKD status. Moreover, although pharmacodynamic (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 coronary artery disease) 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.
    

Eligibility criteria:

        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.