Prasugrel but not high dose clopidogrel overcomes the lansoprazole neutralizing effect of P2Y12 inhibition: Results of the randomized DOSAPI study

• Published in: European journal of clinical pharmacology Vol. 70; no. 9; pp. 1049 - 1057
• Main Authors: Collet, Jean-Philippe, Hulot, Jean-Sébastien, Abtan, Jérémie, Anzaha, Ghalia, Kerneis, Mathieu, Silvain, Johanne, Cayla, Guillaume, O’Connor, Stephen A., Barthélémy, Olivier, Beygui, Farzin, Galier, Sophie, Brugier, Delphine, Stanek, Eric J., Charland, Scott L., Gallois, Vanessa, Montalescot, Gilles
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2014; Springer
• Subjects: Adult; Aged; Anti-Ulcer Agents - administration & dosage; Aspirin - administration & dosage; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cardiology. Vascular system; Clinical Trial; Coronary Artery Disease - drug therapy; Coronary heart disease; Double-Blind Method; Drug Interactions; Female; Heart; Humans; Lansoprazole - administration & dosage; Male; Medical sciences; Middle Aged; Pharmacology. Drug treatments; Pharmacology/Toxicology; Piperazines - administration & dosage; Platelet Activation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists - administration & dosage; Receptors, Purinergic P2Y12; Thiophenes - administration & dosage; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Thienopyridine; Platelet reactivity; Coronary artery disease; Proton pump inhibitor; H; Cardiovascular disease; Antiulcer agent; K; Result; Randomization; Antisecretory agent; Antithrombotic agent; High dose; Human; P2Y12 purinergic receptor; Enzyme; Enzyme inhibitor; Coronary heart disease; Antiplatelet agent; Prasugrel; Platelet; Reactivity; Benzimidazole derivatives; exchanging ATPase; Hydrolases; Clopidogrel; Thienopyridine derivative; Lansoprazole
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-014-1710-1

Aims The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction. Method and results In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA 14day -RPA baseline )/RPA baseline ]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (−53.6±48.4 % versus +0.8±53.7 % without and with lansoprazole, respectively, p  = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (−81.8 %±24.8 % vs. −72.9 %±32.9 % without and with lansoprazole, respectively, p  = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups. Conclusion The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.