Clopidogrel Use in End‐Stage Kidney Disease

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.

Prevention and treatment of stroke in patients with chronic kidney disease: an overview of evidence and current guidelines

“…25 CKD and end-stage kidney disease (ESKD) are independent risk factors for clopidogrel resistance; 50% to 80% of patients with ESKD have high on-treatment residual platelet reactivity (resistance) when treated with clopidogrel. 26 However, it has been suggested that the high burden of comorbidities in patients with CKD may account for this observation rather than CKD itself. 27 Overall, the current guideline recommendations to generally avoid primary prevention with aspirin in patients with CKD are reasonable in the context of recent randomized trials (ASPirin in Reducing Events in the Elderly study, Aspirin to Reduce Risk of Initial Vascular Events study, and A Study of Cardiovascular Events iN Diabetes) 28-30 that did not find aspirin to be beneficial for stroke prevention in other atrisk groups (elderly, moderate cardiovascular risk, and diabetes, respectively) ( Table 1).…”

Clopidogrel Drug Interactions and Serious Bleeding: Generating Real‐World Evidence via Automated High‐Throughput Pharmacoepidemiologic Screening

“…Use of these precipitants may portend worsening renal function and/or dialysis. Advanced CKD and end‐stage kidney disease increase one's risk of bleeding due to platelet dysfunction and heightened risk of angioectasias (i.e., thin‐walled, dilated, ectatic blood vessels), which may be exacerbated in the setting of clopidogrel treatment . Cinacalcet, lanthanum, paricalcitol, and sevelamer are used almost exclusively in the treatment of abhorrent bone and mineral metabolism in persons with advanced CKD and end‐stage kidney disease.…”

“…Advanced CKD and end-stage kidney disease increase one's risk of bleeding due to platelet dysfunction 12 and heightened risk of angioectasias (i.e., thin-walled, dilated, ectatic blood vessels), 13 which may be exacerbated in the setting of clopidogrel treatment. 5,14,15 Cinacalcet, lanthanum, paricalcitol, and sevelamer are used almost exclusively in the treatment of abhorrent bone and mineral metabolism in persons with advanced CKD and end-stage kidney disease. These disorders of bone and mineral metabolism can lead to gastrointestinal mucosal calcinosis and calciphylaxis, 16 which may increase the risk of bleeding.…”

Emerging Factors Implicated in Fibrotic Organ–Associated Thrombosis: The Case of Two Organs

“…51 52 Despite a hyperthrombotic phenotype, not all CKD patients respond effectively to clopidogrel, an inhibitor of platelet ADP receptor, and a commonly used antiplatelet medication. 49 50 53 54 This is important since poor response to clopidogrel has been associated with increased risk of death, MI, and stent thrombosis in patients undergoing PCI. 55 The antiplatelet effects of aspirin have also been reported to be reduced in patients with CKD, 56 although some studies reported no difference in platelet aggregation in CKD patients compared with non-CKD.…”