Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y12 Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study.

Abstract

Background Vorapaxar as an adjunct to dual antiplatelet therapy (DAPT) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y12 inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA-PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor) study. Methods and Results Post-myocardial infarction patients (n=130) on standard DAPT (aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3) DAPT: aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen-ADP-TRAP)-induced platelet aggregation, a marker of platelet-mediated global thrombogenicity (triple therapy versus DAPT at 30 days: mean difference=-27; 95% CI,-35 to -19; P<0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus DAPT at 30 days: mean difference=-15; 95% CI,-23 to -7; P<0.001; between-group comparisons, P<0.05). Vorapaxar abolished TRAP-induced aggregation (P<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y12 reactivity. Markers sensitive to aspirin-induced effects increased (P<0.001) in the dual-therapy arm. Conclusions In post-myocardial infarction patients treated with potent P2Y12 inhibitors, vorapaxar reduces platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y12 reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02545933.

• Authors: Francesco Franchi, Fabiana Rollini, Gabriel Faz, Jose Ramon Rivas, Andrea Rivas, Malhar Agarwal, Maryuri Briceno, Mustafa Wali, Ahmed Nawaz, Gabriel Silva, Zubair Shaikh, Naji Maaliki, Kerolos Fahmi, Latonya Been, Andres M Pineda, Siva Suryadevara, Daniel Soffer, Martin M Zenni, Usman Baber, Roxana Mehran, Lisa K Jennings, Theodore A Bass, Dominick J Angiolillo
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 9 Issue 8 Pg. e015865 (04 21 2020) ISSN: 2047-9980 [Electronic] England
• PMID: 32306797 (Publication Type: Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Lactones
• Platelet Aggregation Inhibitors
• Purinergic P2Y Receptor Antagonists
• Pyridines
• Prasugrel Hydrochloride
• Ticagrelor
• Aspirin
• vorapaxar

Topics

• Aged
• Aspirin (adverse effects, therapeutic use)
• Dual Anti-Platelet Therapy (adverse effects, mortality)
• Female
• Florida
• Hemorrhage (chemically induced)
• Humans
• Lactones (adverse effects, therapeutic use)
• Male
• Middle Aged
• Myocardial Infarction (blood, drug therapy, mortality)
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (adverse effects, therapeutic use)
• Prasugrel Hydrochloride (adverse effects, therapeutic use)
• Prospective Studies
• Purinergic P2Y Receptor Antagonists (adverse effects, therapeutic use)
• Pyridines (adverse effects, therapeutic use)
• Thrombosis (blood, etiology, prevention & control)
• Ticagrelor (adverse effects, therapeutic use)
• Time Factors
• Treatment Outcome