Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus
Study Details
Study Description
Brief Summary
Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its benefits, many patients still experience recurrent atherothrombotic events. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
Detailed Description
Patients with diabetes mellitus (DM) and coexisting chronic kidney disease (CKD) are at increased risk of atherothrombotic events, underscoring the importance of secondary prevention antiplatelet therapy in these high-risk patients. Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor in patients with coronary artery disease (CAD). However, despite its clinical benefits, many patients still experience recurrent atherothrombotic events. This is in part due to the impaired effects of clopidogrel in DM patients, particularly among those with coexisting CKD. However, underlying mechanism(s) leading to magnification of impaired clopidogrel response among DM patients with CKD remain unexplored. The ever growing prevalence of CKD in patients with DM and their high risk of recurrent events underscores the need to define such mechanism(s) as this may set the basis for identifying treatment regimens leading to more effective platelet inhibition and cardiovascular protection in these high-risk patients. The proposed study will test the central hypothesis that in DM patients the presence of CKD reduces clopidogrel-mediated P2Y12 inhibitory effects through synergistic mechanisms, which include upregulation of the P2Y12 signaling pathway and impaired clopidogrel metabolism. Comprehensive pharmacokinetic and pharmacodynamic assessments, including ex vivo and in vitro experiments, evaluating the impact of CKD on antiplatelet drug response in DM patients are proposed.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Diabetes Mellitus patients with Chronic Kidney Disease Patients with CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite. |
Drug: Clopidogrel
Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.
Other Names:
Drug: Clopidogrel active metabolite
In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)
Other Names:
|
| Active Comparator: Diabetes Mellitus patients without Chronic Kidney Disease Patients without CKD will be administered a 600-mg LD of Clopidogrel followed by a single 75-mg MD administered after 24 hours. Blood samples collected at baseline will be incubated with clopidogrel active metabolite. |
Drug: Clopidogrel
Both CKD and Non-CKD patients will be administered a 600-mg LD of clopidogrel followed by a single 75-mg MD administered after 24 hours.
Other Names:
Drug: Clopidogrel active metabolite
In both CKD and Non-CKD patients, blood samples collected at baseline only (before clopidogrel LD administration) will be incubated with escalating concentrations of clopidogrel active metabolite (1, 3 and 10 μM)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Platelet reactivity index (PRI) [6 hours]
Comparison of of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD
Secondary Outcome Measures
- Clopidogrel active metabolite concentration [6 hours]
Comparison of clopidogrel active metabolite plasma concentrations, Tmax, Cmax and AUC
Other Outcome Measures
- P2Y12 reaction units (PRU) [6 hours]
Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD
- Platelet reactivity index (PRI) [baseline]
Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Type 2 DM, defined according to ADA definition, on treatment with oral hypoglycemic agents and/or insulin
-
Angiographically documented CAD
-
On treatment with low-dose aspirin (81mg/day) for ≥30 days as part of standard of care.
Exclusion Criteria:
-
Use of any antiplatelet therapy (except aspirin) in prior 30 days
-
Use of parenteral or oral anticoagulation
-
Active bleeding
-
High risk of bleeding
-
Clinical indication to be on a P2Y12 receptor inhibitor
-
End-stage renal disease on hemodialysis
-
Any active malignancy
-
Platelet count < 100x106/µl
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Hemoglobin <9 g/dl
-
Severe known liver disease
-
Hemodynamic instability
-
Known allergy to clopidogrel
-
Pregnant / lactating females (women of childbearing age must use reliable birth control).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Florida Jacksonville | Jacksonville | Florida | United States | 32209 |
Sponsors and Collaborators
- University of Florida
- Scott R. MacKenzie Foundation
Investigators
- Principal Investigator: Francesco Franchi, MD, University of Florida
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB201801870 -A