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

Robert F. Storey; Jayaprakash Kotha; Susan S. Smyth; David J. Moliterno; Tyrus L. Rorick; Tiziano Moccetti; Marco Valgimigli; Jean Pierre Dery; Jan H. Cornel; Gregory S. Thomas; Kurt Huber; Robert A. Harrington; Edward Hord; Heather M. Judge; Edmond Chen; John Strony; Kenneth W. Mahaffey; Pierluigi Tricoci; Richard C. Becker; Lisa K. Jennings

doi:10.1160/TH13-07-0624

Thrombosis and Haemostasis, Inhaltsverzeichnis

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^*

¹Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Jayaprakash Kotha^*

²CirQuest Labs, LLC, Memphis, Tennessee, USA

,

Susan S. Smyth

³Lexington VA Medical Center and Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA

,

David J. Moliterno

³Lexington VA Medical Center and Gill Heart Institute, University of Kentucky, Lexington, Kentucky, USA

,

Tyrus L. Rorick

⁴Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA

,

Tiziano Moccetti

⁵Cardiocentro Ticino, Lugano, Switzerland

,

Marco Valgimigli

⁶Azienda Ospedaliero-Universitaria Sant’Anna, Ferrara, Italy

,

Jean Pierre Dery

⁷Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada

,

Jan H. Cornel

⁸Medical Center Alkmaar, Alkmaar, The Netherlands

,

Gregory S. Thomas

⁹Mission Internal Medical Group, Mission Viejo, California, USA and University of California, Irvine, California, USA

,

Kurt Huber

¹⁰Wilhelminenhospital, Vienna, Austria

,

Robert A. Harrington

⁴Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA

,

Edward Hord

²CirQuest Labs, LLC, Memphis, Tennessee, USA

,

Heather M. Judge

¹Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

,

Edmond Chen

¹¹Merck & Co., Inc., Whitehouse Station, New Jersey, USA

,

John Strony

¹¹Merck & Co., Inc., Whitehouse Station, New Jersey, USA

,

Kenneth W. Mahaffey

⁴Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA

,

Pierluigi Tricoci

⁴Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA

,

Richard C. Becker

⁴Duke Clinical Research Institute, Cardiovascular Research, Duke University Medical Center, Durham, North Carolina, USA

,

Lisa K. Jennings

²CirQuest Labs, LLC, Memphis, Tennessee, USA

¹²University of Tennessee Health Science Center, Memphis, Tennessee, USA

› Institutsangaben

Abstract

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

Volltext

Referenzen

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