The H2-receptor antagonist ranitidine interferes with clopidogrel-mediated P2Y12 inhibition in platelets

BackgroundUse 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 H2-receptor antagonists such as ranitidine. We investigated whether ranitidine interacts with P2Y12 inhibition on the platelet level.MethodsBlood 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 P2Y12 specific platelet-reactivity-index (PRI) and light-transmittance aggregometry in the presence and absence of a pharmacologically relevant concentration of the H2-receptor antagonist ranitidine (400 ng/ml).ResultsAdding ranitidine enhanced P2Y12-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 (PGE1)-mediated inhibition of ADP-induced aggregation was abrogated in the presence of ranitidine (Aggmax ± SEM: before PGE1 41 ± 2%; after PGE1 29 ± 2%, p < 0.01 vs. before PGE1; after PGE1 + ranitidine 42 ± 2%, p < 0.01 vs. after PGE1).ConclusionsExposition of platelets with ranitidine significantly enhanced their responsiveness to ADP and contributed to impaired P2Y12 inhibition suggesting that ranitidine interacts with clopidogrel efficacy through adenylyl cyclase inhibition on the platelet level.

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