Author + information
- Received July 20, 2019
- Revision received July 31, 2019
- Accepted July 31, 2019
- Published online November 25, 2019.
- Francesco Franchi, MDa,
- Fabiana Rollini, MDa,
- Victor Kairouz, MDa,
- Jose Rivas Rios, MDa,
- Andrea Rivas, MDa,
- Malhar Agarwal, MDa,
- Maryuri Briceno, MDa,
- Mustafa Wali, MDa,
- Ahmed Nawaz, MDa,
- Gabriel Silva, MDa,
- Zubair Shaikh, MDa,
- Naji Maaliki, MDa,
- Latonya Been, AASa,
- Jason Piraino, DPMb,
- Andres M. Pineda, MDa,
- Siva Suryadevara, MDa,
- Daniel Soffer, MDa,
- Martin M. Zenni, MDa,
- Lisa K. Jennings, PhDc,
- Theodore A. Bass, MDa and
- Dominick J. Angiolillo, MD, PhDa,∗ ()
- aDivision of Cardiology, Department of Medicine, University of Florida College of Medicine–Jacksonville, Jacksonville, Florida
- bDivision of Foot and Ankle, Department of Orthopaedic Surgery and Rehabilitation, University of Florida College of Medicine–Jacksonville, Jacksonville, Florida
- cCirQuest Labs, Memphis, Tennessee
- ↵∗Address for correspondence:
Dr. Dominick J. Angiolillo, University of Florida College of Medicine–Jacksonville, 655 West 8th Street, Jacksonville, Florida 32209.
• Vorapaxar reduces thrombotic cardiovascular events in patients with atherosclerotic disease, with enhanced effects in those with DM.
• Adjunctive vorapaxar therapy reduces platelet-mediated thrombogenicity without affecting clot kinetics in both patients with and those without DM having prior MI/PAD on dual antiplatelet therapy with aspirin and clopidogrel.
• The pharmacodynamic effects of vorapaxar occur via selective blockade of the PAR-1 on the platelet membrane without apparent interplay with other platelet signaling pathways.
• Aspirin withdrawal, which leaves patients on a background of clopidogrel and vorapaxar, increases markers specific to COX-1–mediated blockade, leading to an increase in platelet-mediated global thrombogenicity, particularly among patients with DM.
Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650)
The present study was investigator-initiated. The study was originally funded by a grant from Merck until transfer of marketing rights of vorapaxar, including grant responsibilities, to Aralez. At the time of transfer, Merck had funded 60% of overall grant costs. Following such transfer, Aralez filed for bankruptcy and did not cover any of the residual grant costs, which was completed using research funds from the Division of Cardiology, University of Florida College of Medicine–Jacksonville. Upon completion of the study, Deerfield acquired marketing rights of vorapaxar and provided a nominal fee for the final phases of investigator-initiated research studies conducted with vorapaxar at our institution (NCT02548650 and NCT02545933). Dr. Franchi has received payment as an individual for consulting fees or honoraria from AstraZeneca and Sanofi. Dr. Rollini has received payment as an individual for consulting fees or honoraria from Chiesi. Dr. Angiolillo has received payment as an individual for consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; participation in review activities from CeloNova and St. Jude Medical; and institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions. Dr. Jennings has received payments as an individual for consulting fees or honoraria from Bayer, Janssen, PhaseBio, and Portola; and institutional payments for grants from Janssen and In Motion Musculoskeletal Institute. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received July 20, 2019.
- Revision received July 31, 2019.
- Accepted July 31, 2019.
- 2019 The Authors