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Clopidogrel use in end-stage kidney disease
Bassem Y Tanios1, Houssam S Itani, Deborah L Zimmerman
1Nephrology Department, Paris Sud University, Le Kremlin Bicêtre, France.
Insights
Clopidogrel may not benefit patients with end-stage kidney disease (ESKD) and may increase bleeding risks. Further research is needed to determine its role and explore alternatives like prasugrel or ticagrelor for this population.
Area of Science:
- Cardiology
- Pharmacology
- Nephrology
Background:
- Clopidogrel, a P2Y12 inhibitor, prevents cardiovascular events but requires hepatic conversion and is subject to genetic variations affecting efficacy.
- Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are linked to clopidogrel resistance, with 50-80% of ESKD patients showing high residual platelet reactivity.
- Suboptimal outcomes post-coronary intervention in kidney disease patients may be due to clopidogrel resistance.
Purpose of the Study:
- To evaluate the efficacy and safety of clopidogrel in patients with end-stage kidney disease (ESKD).
- To investigate the role of platelet function assays in guiding clopidogrel therapy for ESKD patients.
- To explore alternative antiplatelet agents for ESKD patients with high on-treatment residual platelet reactivity.
Main Methods:
- Review of existing clinical trial data, including reanalysis of CURE and CREDO trials for CKD populations.
- Assessment of clopidogrel's association with adverse outcomes, including mortality and bleeding events, in ESKD patients.
- Discussion of the utility of various platelet reactivity assays in the context of ESKD treatment.
Main Results:
- Reanalysis of trials showed reduced or no benefit of clopidogrel in CKD patients (eGFR <60 ml/minute).
- ESKD patients were largely excluded from major clopidogrel trials, limiting evidence for their specific benefit.
- Clopidogrel use in ESKD is associated with increased risks of death, bleeding-related death, and hospitalization for bleeding.
Conclusions:
- Current evidence suggests ESKD patients may not benefit from clopidogrel as much as the general population and may experience harm.
- The effectiveness of platelet function assays in tailoring clopidogrel therapy for ESKD remains unclear.
- Further well-designed studies are required to establish clopidogrel's role in ESKD and evaluate alternatives like prasugrel and ticagrelor.
Abstract:
Clopidogrel irreversibly binds to the P2Y12 platelet receptor and acts as a potent inhibitor of platelet activation and aggregation. It is currently recommended for the prevention of cardiovascular events in patients with acute coronary syndromes, recent ischemic stroke, and peripheral arterial disease. Clopidogrel is a prodrug requiring hepatic conversion into its active metabolite. In the general population, genetic polymorphisms in the CYP2C19 gene interfering with hepatic conversion and the ABCB1 gene interfering with gut absorption of clopidogrel, account for the large interindividual response to clopidogrel and clopidogrel resistance. Chronic kidney disease (CKD) and ESKD are independent risk factors for clopidogrel resistance; 50-80% of patients with ESKD have high on-treatment residual platelet reactivity when treated with clopidogrel. This may partially explain the abysmal outcomes for patients with kidney disease post coronary intervention. Several assays are used to determine residual on-treatment platelet reactivity; however, their use in tailoring the suitability of clopidogrel treatment in patients with ESKD is unclear. Although clopidogrel decreased cardiovascular events in the general population after acute coronary syndromes and percutaneous intervention in the CURE and CREDO trials, a reanalysis of these studies in patients with CKD (eGFR <60 ml/minute) showed either a reduced or no benefit from clopidogrel treatment. ESKD patients were not represented in these two large trials; this is true for most of the trials that established clopidogrel as an integral part of the therapeutic armamentarium for cardiovascular disease. Furthermore, clopidogrel has been associated with an increased risk of death, death from bleeding, and hospitalization for bleeding in patients with ESKD. In conclusion, current evidence suggests that ESKD patients may not derive the same benefits from clopidogrel therapy as the general population and this therapy may be associated with harm. Properly designed observational studies and randomized controlled trials are needed to establish the role of clopidogrel in patients with ESKD, the use of platelet assays to tailor therapy, and the role of other antiplatelet agents such as prasugrel or ticagrelor in patients who exhibit high on-treatment residual platelet reactivity.
