Abstract 16420: Impact of Potent Oral P2Y12 Inhibiting Therapies on Multiple Platelet Signaling Pathways: Results of a Prospective Ex vivo Pharmacodynamic Investigation
Background: Although pharmacodynamic (PD) studies have compared the effects of the P2Y12 receptor inhibitors prasugrel and ticagrelor on adenosine (ADP) mediated platelet aggregation showing enhanced effects compared with clopidogrel, to date there are no studies assessing how these agents affect other platelet signaling pathways. The aim of this study was to assess the PD effects on multiple platelet signaling pathways after switching clopidogrel treated patients to prasugrel or ticagrelor.
Methods: In this prospective PD study, clopidogrel (75mg/qd) treated patients (n=110) with coronary artery disease (CAD) were randomized to switch to prasugrel (60mg loading dose/10mg maintenance dose qd) or ticagrelor (180mg loading dose /90mg maintenance dose bid) for 1 week. PD assessments were performed to evaluate the acute (baseline and 30 min, 2 hrs, 24 hrs after LD) and chronic (1 week) effects of therapy using Multiple Electrode Aggregometry following stimuli with multiple agonists: arachidonic acid (AA), ADP (with and without PGE1), collagen and TRAP.
Results: There were no differences in baseline (on-clopidogrel) platelet reactivity. Switching to prasugrel and ticagrelor led to a reduction in platelet reactivity stimulated by ADP (with and without PGE1) as early as 30 min and sustained up to 1 week (p<0.05 for all time points compared with clopidogrel). Switching to prasugrel or ticagrelor was not associated with further platelet inhibitory effects following AA and collagen stimuli. However, compared with clopidogrel, both prasugrel (p=0.006) and ticagrelor (p<0.001) reduced platelet aggregation stimulated by TRAP as assessed by analysis of variance. This was driven by the acute effects of more potent P2Y12 inhibition. No PD differences were found between prasugrel and ticagrelor with all agonists.
Conclusions: In CAD patients on maintenance clopidogrel therapy, in addition to exerting prompt and enhanced inhibition of ADP mediated platelet aggregation, switching to either prasugrel or ticagrelor is also associated with diminished thrombin-induced platelet aggregation. These ex vivo results support an interplay between the ADP P2Y12 and the thrombin platelet signaling pathways previously reported in in vitro experimental models.
Author Disclosures: F. Franchi: None. J. Cho: None. F. Rollini: None. M. Bhatti: None. C. DeGroat: None. A. Muniz-Lozano: None. M. Taha: None. R. Patel: None. E.C. Dunn: None. E. Ferrante: None. M.M. Zenni: None. L.A. Guzman: None. T.A. Bass: None. D.J. Angiolillo: Research Grant; Significant; Bristol Myers Squibb, Sanofi-Aventis, Glaxo Smith Kline, Otsuka, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva, and Gilead. Honoraria; Significant; Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular, Bayer, and PLx Pharma. Consultant/Advisory Board; Significant; Johnson & Johnson, St. Jude, Sunovion, and CeloNova.
- © 2014 by American Heart Association, Inc.