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

Phase 4

Completed

Conditions: Diabetes Mellitus
Coronary Artery Disease

Interventions: Drug: ticagrelor

Registration Number: NCT02539160

Lead Sponsor: University of Florida

Brief 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 101

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
CKD - Ticagrelor 90	ticagrelor	Patients with chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.
CKD - Ticagrelor 60	ticagrelor	Patients with chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.
Non-CKD - Ticagrelor 90	ticagrelor	Patients without chronic kidney disease will receive ticagrelor 90mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 60mg twice/daily for 7-10 days.
Non-CKD - Ticagrelor 60	ticagrelor	Patients without chronic kidney disease will receive ticagrelor 60mg twice/daily for 7-10 days. Then patients will cross over to ticagrelor 90mg twice/daily for 7-10 days.

Primary Outcome Measures

Name	Time	Method
Platelet Reactivity Measured by Vasodilator Stimulated Phosphoprotein (VASP) Platelet Reactivity Index (PRI %)	7 days	The primary end point of the study was platelet reactivity assessed by VASP-PRI following treatment with ticagrelor 90mg between DM-CKD and DM-non-CKD cohorts. PRI % is a measure of platelet reactivity, where higher PRI levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRI greater than 50% represents inadequate response to antiplatelet medications.

Secondary Outcome Measures

Name	Time	Method
Platelet Reactivity Measured by VerifyNow P2Y12	7 days	Platelet reactivity assessed by VerifyNow P2Y12 following treatment with ticagrelor 90mg or 60 mg between DM-CKD and DM-non-CKD cohorts. Results are expressed in P2Y12 reaction units (PRU). PRU is a measure of platelet reactivity, where higher PRU levels represent higher platelet reactivity and lower effect of antiplatelet medications. PRU greater than 208 represents inadequate response to antiplatelet medications.