Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy.

Abstract

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.

• Authors: 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
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 111 Issue 5 Pg. 883-91 (May 05 2014) ISSN: 2567-689X [Electronic] Germany
• PMID: 24402559 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Inflammation Mediators
• Lactones
• Pyridines
• Receptor, PAR-1
• Receptors, Thrombin
• thienopyridine
• Adenosine Diphosphate
• Aspirin
• vorapaxar

Topics

• Acute Coronary Syndrome (blood, drug therapy)
• Adenosine Diphosphate (metabolism)
• Aged
• Aspirin (administration & dosage, adverse effects)
• Biomarkers (blood)
• Blood Platelets (drug effects, physiology)
• Cells, Cultured
• Europe
• Female
• Follow-Up Studies
• Humans
• Inflammation Mediators (blood)
• Lactones (administration & dosage, adverse effects)
• Male
• Middle Aged
• North America
• Platelet Aggregation (drug effects)
• Pyridines (administration & dosage, adverse effects)
• Receptor, PAR-1 (antagonists & inhibitors)
• Receptors, Thrombin (metabolism)