Pharmacogenetic and Pharmacokinetic Study of Clopidogrel

Coronary Artery Disease

coronary stent implantation; clopidogrel low response

This registration study aims to investigate the associations of the pharmacogenetic and pharmacokinetic factors with clopidogrel low response and clinical outcome in patients with coronary artery disease, and provide new pharmacogenetic and pharmacokinetic targets for the individualized anti-platelet treatment.

Associations of the Pharmacogenetic and Pharmacokinetic Factors With Clopidogrel Low Response and Clinical Outcome in Patients With Coronary Stent Implantation: a Registration Study Published data linking clopidogrel non-responsiveness to adverse ischaemic events lead to the suggestion that the magnitude of platelet inhibition by clopidogrel can be monitored and individually adjusted. This has been tested in randomised clinical trials (ARCTIC, GRAVITAS and TRIGGER-PCI), but despite reducing platelet reactivity, a strategy of therapy adjustment based on platelet function monitoring did not reduce the incidence of cardiac ischaemic events1, which indicates that most pharmacodynamical tests monitored anti-platelet treatment failed so far. We accordingly performed this registration study to investigate whether the pharmacogenetic and pharmacokinetic factors are associated with clopidogrel low response as well as clinical outcome, and aimed to provide new targets for the individualized anti-platelet treatment. Inclusion criteria: 1. Successively recruit all patients who receive stent implantation and take aspirin 100 mg and clopidogrel 75 mg once daily (7:00 a.m.) for more than 5 days. 2. Patient aged \>18 years; 3. Signed inform consent. Exclusion criteria: 1. intolerant with aspirin or clopidogrel treatment (e.g. allergic reactions or gastrointestinal bleeding); 2. taking medication that could interfere with the antiplatelet efficacy of clopidogrel (e.g. vitamin K antagonists, direct oral anticoagulants or nonsteroidal anti-inflammatory drugs); 3. with myelodysplastic syndrome or abnormal baseline platelet counts of \< 80 × 10∧9/L or \> 450 × 10∧9/L; 4. hemoglobin \< 90g/L; 5. with a history of cerebral hemorrhage within 1 year; 6. in pregnancy. Clinical data collection: 1. Patients basic characteristics. 2. Diagnosis and complicated diseases. 3. Medical treatment and interventional treatment. Methods: Blood samples are collected 5 days after the patients' taking clopidogrel to perform the genetic testing and determine the light transmittancy aggregation (LTA) and the serum levels of the parent clopidogrel, intermediate and active metabolites of clopidogrel. LTA is to re-determined 1 month after clopidogrel consumption. Clopidogrel low response is defined as the inhibition of platelet aggregation (IPA) in response to 5μM ADP is more than 40%. Clinical follow-up will be performed 1month, 6month, and 1year after the patients' included. Major adverse cardiovascular events (MACE) is set as death, non-fatal myocardial infarction (MI), ischemic stroke. Associations of the pharmacogenetic and pharmacokinetic factors with clopidogrel low response and clinical outcome will be analyzed. Tests: 1. ADP-induced platelet aggregation: LTA in response to 5μM ADP. 2. Arachidonic acid (AA)-induced platelet aggregation: LTA in response to 1mM AA. 3. Simultaneous detection of clopidogrel, 2-oxo-clopidogrel and its thiol metabolite in human plasma by the high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. 4. GWAS scan or genotyping of ABCB1,CYP2C19, paraoxonase 1 (PON1), CYP3A5, P2RY12. Sample size: We plan to recruit 1800 patients. Clinical follow-up: 1 month, 6 month, and 1 year after the patients' included. Major adverse cardiovascular events (MACE): Death, non-fatal MI, ischemic stroke. Minor adverse cardiovascular events: Hospitalization, revascularization, stent thrombosis (ARC definition) and minor, moderate, and major bleeding (TIMI definition).

None listed

China