The H 2-receptor antagonist ranitidine interferes with clopidogrel-mediated P2Y 12 inhibition in platelets

Abstract

Background Use of proton-pump inhibitors (PPIs) is common in patients on dual antiplatelet therapy (DAT). Recent warnings about potential interactions of PPIs with clopidogrel metabolism leading to impaired DAT efficacy has prompted the recommendation of substituting PPIs with H 2-receptor antagonists such as ranitidine. We investigated whether ranitidine interacts with P2Y 12 inhibition on the platelet level. Methods Blood was collected from 15 patients with stable coronary artery disease, who had undergone elective coronary intervention. Clopidogrel responsiveness was assessed 24 h after the administration of a 600 mg loading dose using the P2Y 12 specific platelet-reactivity-index (PRI) and light-transmittance aggregometry in the presence and absence of a pharmacologically relevant concentration of the H 2-receptor antagonist ranitidine (400 ng/ml). Results Adding ranitidine enhanced P2Y 12-mediated platelet reactivity to ADP assessed by the PRI (mean PRI ± SEM: before ranitidine 28 ± 5%; after ranitidine 37 ± 5%, p = 0.0025). Similarly, prostaglandin E1 (PGE 1)-mediated inhibition of ADP-induced aggregation was abrogated in the presence of ranitidine (Agg max ± SEM: before PGE 1 41 ± 2%; after PGE 1 29 ± 2%, p < 0.01 vs. before PGE 1; after PGE 1 + ranitidine 42 ± 2%, p < 0.01 vs. after PGE 1). Conclusions Exposition of platelets with ranitidine significantly enhanced their responsiveness to ADP and contributed to impaired P2Y 12 inhibition suggesting that ranitidine interacts with clopidogrel efficacy through adenylyl cyclase inhibition on the platelet level.