Effect van genetische variaties op de effectiviteit van clopidogrel

OBJECTIVE: To assess how platelet reactivity and the occurrence of stent thrombosis in patients undergoing percutaneous coronary interventions (PCI) on dual antiplatelet therapy is influenced by genetic variants affecting clopidogrel's absorption (ASCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C9*2 or *3, CYP2C19*2 or *3, CYP3A4*1B and CYP3A5*3) and pharmacodynamics (P2Y1 A1622G). Clopidogrel plays an important role in the prevention of thrombotic events in patients undergoing PCI. However, a substantial number of atherothrombotic events, including stent thrombosis, still occurs. METHODS: In the first study, platelet function was assessed by two platelet function tests in 428 consecutive patients undergoing elective PCI. Patients were on Clopidogrel maintenance therapy for > 5 days prior to PCI ('75 mg group') or received a 300 mg clopidogrel loading dose 1-5 days prior to PCI ('300 mg group'). In a second study, logistic regression analysis was used to analyse the impact of genetic variations in 176 subjects who developed stent thrombosis while on dual antiplatelet therapy and in 420 control subjects who did not develop atherothrombotic events, including stent thrombosis, within one year post-PCI. RESULTS: In both the 75 mg group and the 300 mg group in the first study, CYP2C19*2 was associated with higher platelet reactivity (p < 0.001) and poor-responder status: OR_adj 3.8 (CI95 2.0-7.2) and OR_adj 4.1 (CI95 1.6-10.4), respectively. In the 300 mg group, CYP2C9*3 was associated with higher platelet reactivity (p < 0.05) and poor-responder status: OR_adj 4.0 (CI95 1.2-13.8). In the second study, CYP2C19*2 and CYP2C9*3 were associated with stent thrombosis: OR_adj 1.7 (CI95 1.0-2.6) and OR_adj 2.4 (CI95 1.1-5.5), respectively. CONCLUSIONS: Carriage of CYP2C19*2 and CYPC9*3 is associated with heightened platelet reactivity and an increased risk of stent thrombosis after PCI.