Impact of Chronic Kidney Disease on Clopidogrel Effects in Diabetes Mellitus

Coronary Artery Disease (CAD) Clinical Trial

Official title:

Impact of Chronic Kidney Disease (CKD) on Pharmacodynamic Profiles of the P2Y12 Receptor Inhibitor Clopidogrel in the Setting of Type 2 Diabetes Mellitus (T2DM) and Coronary Artery Disease (CAD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03774394
• Other study ID #: IRB201801870 -A
• Status: Completed
• Phase: Phase 4
• Start date: August 22, 2019
• Est. completion date: May 31, 2022

Study information

• Verified date: July 2023
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: May 31, 2022
• Est. primary completion date: May 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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
• 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).

Related Conditions & MeSH terms

• Chronic Kidney Disease (CKD)
• Coronary Artery Disease
• Coronary Artery Disease (CAD)
• Coronary Disease
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Kidney Diseases
• Myocardial Ischemia
• Renal Insufficiency, Chronic
• Type 2 Diabetes Mellitus (T2DM)

Intervention

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.
• 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)

Locations

Country	Name	City	State
United States	University of Florida Jacksonville	Jacksonville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Scott R. MacKenzie Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	P2Y12 Reaction Units (PRU) Assessed by VerifyNow. The Cutoff for High Platelet Reactivity is >208.	Comparison of platelet reactivity measured as PRU assessed by VerifyNow after a 600 mg clopidogrel LD between DM patients with and without CKD	6 hours
Other	Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%	Comparison of of platelet reactivity measured as PRI assessed by VASP after incubation with clopidogrel active metabolite between DM patients with and without CKD	Baseline
Primary	Platelet Reactivity Index (PRI) Assessed by VASP. The Cutoff for High Platelet Reactivity is >50%	Comparison of platelet reactivity measured as PRI assessed by VASP after a 600 mg clopidogrel LD between DM patients with and without CKD	6 hours
Secondary	Clopidogrel Active Metabolite Concentration	Comparison of clopidogrel active metabolite plasma concentrations by means of AUC	6 hours