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Thromb Haemost 2014; 111(05): 883-891
DOI: 10.1160/TH13-07-0624
Platelets and Blood Cells
Schattauer GmbH

Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes

The TRACER Pharmacodynamic Substudy
Robert F. Storey   *
1   Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Jayaprakash Kotha   *
2   CirQuest Labs, LLC, Memphis, Tennessee, USA
,
Susan S. Smyth
3   Lexington VA Medical Center and Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA
,
David J. Moliterno
3   Lexington VA Medical Center and Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA
,
Tyrus L. Rorick
4   Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA
,
Tiziano Moccetti
5   Cardiocentro Ticino, Lugano, Switzerland
,
Marco Valgimigli
6   Azienda Ospedaliero-Universitaria Sant’Anna, Ferrara, Italy
,
Jean Pierre Dery
7   Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
,
Jan H. Cornel
8   Medical Center Alkmaar, Alkmaar, The Netherlands
,
Gregory S. Thomas
9   Mission Internal Medical Group, Mission Viejo, California, USA and University of California, Irvine, California, USA
,
Kurt Huber
10   Wilhelminenhospital, Vienna, Austria
,
Robert A. Harrington
4   Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA
,
Edward Hord
2   CirQuest Labs, LLC, Memphis, Tennessee, USA
,
Heather M. Judge
1   Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
,
Edmond Chen
11   Merck & Co., Inc., Whitehouse Station, New Jersey, USA
,
John Strony
11   Merck & Co., Inc., Whitehouse Station, New Jersey, USA
,
Kenneth W. Mahaffey
4   Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA
,
Pierluigi Tricoci
4   Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA
,
Richard C. Becker
4   Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA
,
Lisa K. Jennings
2   CirQuest Labs, LLC, Memphis, Tennessee, USA
12   University of Tennessee Health Science Center, Memphis, Tennessee, USA
› Author Affiliations
Further Information

Publication History

Received: 30 July 2013

Accepted after major revision: 22 January 2013

Publication Date:
01 December 2017 (online)

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Summary

Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study′s objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53–75%) and vorapaxar 3% (2–6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

Keywords

Anti-platelet agents - PAR-1 receptor - pharmacodyamics - vorapaxar - thienopyridines

* Prof. Storey and Dr. Kotha are considered co-first authors of this manuscript.


 

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