19. Evaluation of the influence of statins and proton pump inhibitors on Clopidogrel antiplatelet effect (SPICE) trial
Pierre-Louis Nadeau1, Ugo Déry*1, Mélanie Roy1, Marie-Eve Giguère1, Josep Rodés-Cabau1, Eric Larose1, Stéphane Rinfret1, Onil Gleeton1, Guy Proulx1, Gérald Barbeau1, Bernard Noël1, Louis Roy1, Robert De Larochellière1, Can Mahn Nguyen1, Yohan Bossé1, Pierluigi Tricoci2, Richard C Becker2, Olivier F Bertrand1, Jean-Pierre Déry1. BACKGROUND: Conflicting evidences suggest that proton pump inhibitors (PPI) metabolized by cytochrome P450 (CYP) 2C19 and statins metabolyzed by CYP 3A4 may interfere with clopidogrel biotransformation to its active metabolite. Previous pharmacodynamic studies have demonstrated that omeprazole but not pantoprazole lessens the antiplatelet activity of clopidogrel. It has been suggested that atorvastatin may interfere with clopidogrel effect, but the impact of rosuvastatin, a CYP 2C9 metabolyzed statin, has not been investigated fully. METHODS: SPICE was a prospective randomized open-label with blinded endpoints (PROBE design) trial. The primary objective was to compare the impact of 4 different anti-acid therapies on the antiplatelet effect of clopidogrel. The secondary objective was to determine which factors modulate this drug-drug interaction, including the choice of statin and the presence of 2C19*2 polymorphism. After PCI with stent implantation, 320 treated with clopidogrel 75mg id were recruited and randomized 1:1 to either rosuvastatin 20mg id or atorvastatin 80mg id. Thirty days following PCI, patients underwent platelet function testing. Maximal platelet aggregation (MPA), evaluated with light transmission aggregometry (LTA) after stimulation with 5 µmol/l ADP. Platelet reactivity index (PRI) was evaluated with vasodilator-stimulated phosphoprotein (VASP) phosphorylation (secondary endpoint). At 30 days, patients were randomized again to one of 4 anti-acid treatment groups (omeprazole 20mg id, pantoprazole 40mg id, esomeprazole 40mg id, and ranitidine 300mg id), stratified by statin group and 2C19*2 carrier state. After 30 days of constant therapy, platelet function tests were repeated. Non-responders were defined by MPA >46% (ADP 5 µmol/l). RESULTS: As of August 30th, 303 patients have been recruited. Median age was 61 years. Reason for PCI was ACS for 73% of patients. Thirty-day and 60-day platelet function tests were available for 256 and 227 patients, respectively. After 30 days of anti-acid therapy, MPA increased from 39.2% to 39.7% (p=0.7) in the ranitidine group and from 36.2% to 41.1% (p<0.00001) in the PPI groups combined. Similarly, PRI increased from 44.5% to 46.4% (p=0.2) in ranitidine-treated patients and from 42.5% to 49.2% p<0.00001) in PPI-treated patients. CONCLUSIONS: In patients receiving clopidogrel after PCI, concomitant anti-acid therapy with proton-pump inhibitors decreased the antiplatelet effect of clopidogrel while the H2 receptor blocker ranitidine had not impact on platelet reactivity. The differential effect of each PPI and the role of the choice of statin and 2C19*2 polymorphism on this drug-drug interaction will be presented at the meeting. 1Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, Canada,
2Duke Clinical Research Institute, Durham, USA. No conflict of interest to disclose.
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Langmuir 2009, 25, 3425-3434 Diffusion of an Ionic Drug in Micellar Aqueous Solutions Huixiang Zhang†,‡ and Onofrio Annunziata*,† Department of Chemistry, Texas Christian Uni V ersity, Fort Worth, Texas 76129, and Alcon Research Ltd., Recei V ed No V ember 4, 2008. Re V ised Manuscript Recei V ed December 18, 2008 Supramolecular carriers such as micelles can be used to noncoval