Vorapaxar: A novel protease-activated receptor-1 inhibitor

Paul A. Gurbel, Young Hoon Jeong, Udaya S. Tantry

Research output: Contribution to journalArticle

Abstract

Introduction: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. Areas covered: Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y12 receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombinprotease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations vorapaxar and atopaxar. In preclinical and Phase I II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. Expert opinion: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.

Original languageEnglish (US)
Pages (from-to)1445-1453
Number of pages9
JournalExpert Opinion on Investigational Drugs
Volume20
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

PAR-1 Receptor
clopidogrel
Platelet Activation
Hemorrhage
Numbers Needed To Treat
Fibrinolytic Agents
Intracranial Hemorrhages
Expert Testimony
Percutaneous Coronary Intervention
Therapeutics
Acute Coronary Syndrome
Thrombin
Aspirin
Blood Platelets
Stroke
vorapaxar
Liver
E 5555

Keywords

  • PAR-1 receptor
  • Platelet
  • Thrombosis
  • Vorapaxar

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Vorapaxar : A novel protease-activated receptor-1 inhibitor. / Gurbel, Paul A.; Jeong, Young Hoon; Tantry, Udaya S.

In: Expert Opinion on Investigational Drugs, Vol. 20, No. 10, 10.2011, p. 1445-1453.

Research output: Contribution to journalArticle

Gurbel, Paul A. ; Jeong, Young Hoon ; Tantry, Udaya S. / Vorapaxar : A novel protease-activated receptor-1 inhibitor. In: Expert Opinion on Investigational Drugs. 2011 ; Vol. 20, No. 10. pp. 1445-1453.
@article{09d7687704e242c5bc5cd50cc735837e,
title = "Vorapaxar: A novel protease-activated receptor-1 inhibitor",
abstract = "Introduction: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. Areas covered: Only 20{\%} relative risk (∼ 2{\%} absolute risk) reduction associated with newer P2Y12 receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombinprotease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations vorapaxar and atopaxar. In preclinical and Phase I II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. Expert opinion: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.",
keywords = "PAR-1 receptor, Platelet, Thrombosis, Vorapaxar",
author = "Gurbel, {Paul A.} and Jeong, {Young Hoon} and Tantry, {Udaya S.}",
year = "2011",
month = "10",
doi = "10.1517/13543784.2011.606809",
language = "English (US)",
volume = "20",
pages = "1445--1453",
journal = "Expert Opinion on Investigational Drugs",
issn = "1354-3784",
publisher = "Taylor and Francis Ltd.",
number = "10",

}

TY - JOUR

T1 - Vorapaxar

T2 - A novel protease-activated receptor-1 inhibitor

AU - Gurbel, Paul A.

AU - Jeong, Young Hoon

AU - Tantry, Udaya S.

PY - 2011/10

Y1 - 2011/10

N2 - Introduction: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. Areas covered: Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y12 receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombinprotease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations vorapaxar and atopaxar. In preclinical and Phase I II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. Expert opinion: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.

AB - Introduction: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. Areas covered: Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y12 receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombinprotease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations vorapaxar and atopaxar. In preclinical and Phase I II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. Expert opinion: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.

KW - PAR-1 receptor

KW - Platelet

KW - Thrombosis

KW - Vorapaxar

UR - http://www.scopus.com/inward/record.url?scp=80052751010&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052751010&partnerID=8YFLogxK

U2 - 10.1517/13543784.2011.606809

DO - 10.1517/13543784.2011.606809

M3 - Article

C2 - 21819272

AN - SCOPUS:80052751010

VL - 20

SP - 1445

EP - 1453

JO - Expert Opinion on Investigational Drugs

JF - Expert Opinion on Investigational Drugs

SN - 1354-3784

IS - 10

ER -