Genotype and Platelet Reactivity in Patients on Hemodialysis

Study Overview
=================
Brief Summary
-----------------
Patients with end stage renal disease (ESRD) on hemodialysis (HD) exhibited higher platelet reactivity to clopidogrel than did those with normal renal function. We recently reported platelet inhibition by ticagrelor was faster and markedly greater than by clopidogrel with onset dosing regimen in patients with ESRD on HD. However, few studies have been conducted genetic influence in high platelet reactivity in patients with ESRD on HD.

Detailed Description
-----------------
Chronic kidney disease (CKD) is a strong risk factor for cardiovascular morbidity and mortality, and confers an increasing risk of stent thrombosis even when dual antiplatelet therapy (clopidogrel and aspirin) is administered. Patients with severe CKD or end stage renal disease (ESRD) on hemodialysis (HD) exhibited higher platelet reactivity to clopidogrel than did those with normal renal function. We recently reported platelet inhibition by ticagrelor was markedly greater than by clopidogrel in patients with ESRD on HD. But exact mechanism of high platelet reactivity in ESRD patients was not fully evaluated. A possible postulation would be genetic influence. To investigate this issue, we will evaluate genetic polymorphism in patients with normal kidney function and ESRD on HD according to different doses of clopidogrel and ticagrelor. Genetic test will be assessed polymorphism of ABCB1, PON1, CYP2C19, CYP2C9 and P2Y12.

Official Title
-----------------
The Relationship Between Genotype and Platelet Reactivity in Patients Treated With Ticagrelor Versus Clopidogrel: PIANO Genotype Study

Conditions
-----------------
Chronic Kidney Disease

Intervention / Treatment
-----------------
* Drug: Ticagrelor
* Drug: Clopidogrel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ESRD patients undergoing regular (≥ 6 months) maintenance HD Matching patients with normal kidney function documented coronary artery disease or high risk (Framingham heart risk score ≥ 20%) of coronary artery disease Exclusion Criteria: known allergies to aspirin, clopidogrel, or ticagrelor concomitant use of other antithrombotic drugs (oral anticoagulants, dipyridamole) thrombocytopenia (platelet count <100,000/mm3) hematocrit <25% uncontrolled hyperglycemia (hemoglobin A1c >10%) liver disease (bilirubin level >2 mg/dl) symptomatic severe pulmonary disease active bleeding or bleeding diathesis gastrointestinal bleeding within the last 6 months hemodynamic instability acute coronary or cerebrovascular event within the last 3 months pregnancy any malignancy concomitant use of a cytochrome P450 inhibitor or nonsteroidal anti-inflammatory drug recent treatment (<30 days) with a glycoprotein IIb/IIIa antagonist

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor 180mg in ESRD patients<br>After randomization, ESRD patients on HD will be treated by an initial loading dose of ticagrelor (180 mg) and maintenance doses (ticagrelor 90 mg twice daily) for 14 days. Platelet reactivity and genetic polymorphism will be assessed. | Drug: Ticagrelor<br>* Patients with normal kidney function and ESRD on hemodialysis will be treated by ticagrelor 90mg twice a day for 14 days. After then, platelet reactivity will be assessed by light aggregometry and VerifyNow assay.<br>* Other names: Brilinta;|
| Active Comparator: Clopidogrel 75mg in ESRD patients<br>After randomization, ESRD patients on HD will be treated by an initial loading dose of clopidogrel 300 mg) and maintenance doses (clopidogrel 75 mg once a day) for 14 days. Platelet reactivity and genetic polymorphism will be assessed. | Drug: Clopidogrel<br>* Patients with normal kidney function and ESRD on hemodialysis will be treated by clopidogrel 75mg or 150mg once a day for 14 days. After then, platelet reactivity will be assessed by light aggregometry and VerifyNow assay.<br>* Other names: Plavix;|
| Active Comparator: Clopidogrel 150mg in ESRD patients<br>After randomization, ESRD patients on HD will be treated by an initial loading dose of clopidogrel 300 mg) and maintenance doses (clopidogrel 150 mg once a day) for 14 days. Platelet reactivity and genetic polymorphism will be assessed. | Drug: Clopidogrel<br>* Patients with normal kidney function and ESRD on hemodialysis will be treated by clopidogrel 75mg or 150mg once a day for 14 days. After then, platelet reactivity will be assessed by light aggregometry and VerifyNow assay.<br>* Other names: Plavix;|
| Active Comparator: Ticagrelor 180mg in normal kidney<br>After randomization, patients with normal kidney function will be treated by an initial loading dose of ticagrelor (180 mg) and maintenance doses (ticagrelor 90 mg twice daily) for 14 days. Platelet reactivity and genetic polymorphism will be assessed | Drug: Ticagrelor<br>* Patients with normal kidney function and ESRD on hemodialysis will be treated by ticagrelor 90mg twice a day for 14 days. After then, platelet reactivity will be assessed by light aggregometry and VerifyNow assay.<br>* Other names: Brilinta;|
| Active Comparator: Clopidogrel 75mg in normal kidney<br>After randomization, patients with normal kidney function will be treated by an initial loading dose of clopidogrel 300 mg) and maintenance doses (clopidogrel 75 mg once a day) for 14 days. Platelet reactivity and genetic polymorphism will be assessed. | Drug: Clopidogrel<br>* Patients with normal kidney function and ESRD on hemodialysis will be treated by clopidogrel 75mg or 150mg once a day for 14 days. After then, platelet reactivity will be assessed by light aggregometry and VerifyNow assay.<br>* Other names: Plavix;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference of antiplatelet effects according to genotype | The difference of P2Y12 reaction units (PRUs) according to genotype | 14 days after study drug treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The difference of antiplatelet effects according to kidney function | The difference of P2Y12 reaction units (PRUs) according to kidney function | 14 days after study drug treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
platelet, ticagrelor, clopidogrel, end stage renal disease, hemodialysis, genetics