Monitoring Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention Breet, N.J. 2011-06-15 Doctoral Thesis

Dual antiplatelet therapy with aspirin and thienopyridines is the cornerstone in the treatment of patients with acute coronary syndrome (ACS) and in those undergoing PCI with stent-implantation.However, the magnitude of on-treatment platelet reactivity is not uniform among individuals, due to a multifactorial origin including clinical, pharmacologic and genetic factors. Clopidogrel is a prodrug that requires conversion by hepatic P450 isoenzymes to its active metabolite. Most of the clopidogrel (85%) is hydrolyzed by carboxylase to an inactive carboxylic acid metabolite, whereas the remaining 15% is transformed rapidly into its active metabolite that is able to exert its antiplatelet response by irreversibly inhibiting the binding of adenosinediphosphate (ADP) to the P2Y12 receptor. Recently, paraoxonase-1 (PON1) was identified as the crucial enzyme in clopidogrel bioactivation. Consistent findings across multiple investigations support the association between a lower degree of platelet inhibition, i.e. a high on-treatment platelet reactivity (HPR), and an increased risk for the occurrence of thrombo-ischemic events (Table 1).9-14,14,15,15-27 Multiple factors have been associated with high on-treatment platelet reactivity, among which genetic polymorphisms of cytochrome P450 and of the P2Y12 receptor as well as and drug-drug interactions. Consequently, the monitoring of the magnitude of platelet reactivity has gained widespread attention.

http://repub.eur.nl/res/pub/25658/110615_Breet_Nicoline%20Jantine.pdf