Pharmacodynamic Comparison of Omeprazole Versus Pantoprazole on Platelet Reactivity in Patients With Acute Coronary Syndromes on Dual Antiplatelet Therapy With New P2Y12 Inhibitors -Trial dOPPLER-

Coronary Artery Disease

Clopidogrel and Prasugrel are pro-drug necessitating conversion in active metabolites through CYP 450 system (CYP), particularly CYP3A and CYP2C19 isoforms. These drugs are platelet purinergic receptor antagonists, known as P2Y12. The link between active metabolite of Clopidogrel and Prasugrel to P2Y12 receptor prevents ADP receptor activation and inhibits several events leading to conformational change of platelets, therefore facilitating their activation and aggregation, that is the basis of acute coronary syndromes. Proton pump inhibitors (PPI) are actually considered principal agents reducing gastroenteric bleeding risk associated to antiplatelet therapy. Nevertheless the interaction between PPI and antiplatelet therapy has been object of interest. Several studies demonstrated PPI reduce efficacy of clopidogrel on platelet reactivity. Only few data about Prasugrel are available showing a minor effect of PPI on its antiplatelet activity than clopidogrel. Differing from prasugrel and clopidogrel, ticagrelor is a direct inhibitor of P2Y12, not necessitating biotransformation in the liver; therefore its interaction with PPI remains unclear. Interaction between omeprazole and clopidogrel seems related to high inhibitory activity of PPI on CYP2C19, interfering with the conversion of clopidogrel in its active metabolite.

Clopidogrel and Prasugrel are pro-drug necessitating conversion in active metabolites through CYP 450 system (CYP), particularly CYP3A and CYP2C19 isoforms. These drugs are platelet purinergic receptor antagonists, known as P2Y12. The link between active metabolite of Clopidogrel and Prasugrel to P2Y12 receptor prevents ADP receptor activation and inhibits several events leading to conformational change of platelets, therefore facilitating their activation and aggregation, that is the basis of acute coronary syndromes. Despite double antiplatelet drugs are the principle therapy for the treatment and the prevention of atherothrombotic events in cardiovascular diseases, they are the most important cause of bleeding peptic ulcer. Proton pump inhibitors (PPI) are actually considered principal agents reducing gastroenteric bleeding risk associated to antiplatelet therapy. Nevertheless the interaction between PPI and antiplatelet therapy has been object of interest. Several studies demonstrated PPI reduce efficacy of clopidogrel on platelet reactivity, probably through the inhibition of its metabolism, increasing the risk of cardiovascular events. Only few data about Prasugrel are available showing a minor effect of PPI on its antiplatelet activity than clopidogrel. Differing from prasugrel and clopidogrel, ticagrelor is a direct inhibitor of P2Y12, not necessitating biotransformation in the liver; therefore its interaction with PPI remains unclear. Nevertheless actual studies considered only clinical outcomes (MACEs), such as a subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial, showing a higher rate of MACEs in clopidogrel and Ticagrelor patients undergone PPI therapy, especially omeprazole treatment. Interaction between omeprazole and clopidogrel seems related to high inhibitory activity of PPI on CYP2C19, interfering with the conversion of clopidogrel in its active metabolite. It is yet unclear the higher rate of MACEs in the ticagrelor group, similarly to clopidogrel, despite it hasn't a hepatic metabolism.

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