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Published on: May 24, 2024
Protease-activated receptor-1 antagonists in long-term antiplatelet therapy. Current state of evidence and future
I C Moschonas1, J A Goudevenos2, A D Tselepis1
1Atherothrombosis Research Center/Laboratory of Biochemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece.
Insights
Protease-activated receptor-1 (PAR-1) antagonism offers a novel approach to reduce residual cardiovascular risk in atherothrombotic disease. Vorapaxar, a PAR-1 antagonist, has completed Phase 3 trials, showing promise for improved antiplatelet therapy.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Thrombosis Research
Background:
- Atherothrombosis is a major cause of mortality globally.
- Current antiplatelet therapies (aspirin, thienopyridines, ticagrelor) leave residual cardiovascular risk.
- Residual risk is partly attributed to thrombin signaling via protease-activated receptors (PARs), particularly PAR-1.
Purpose of the Study:
- To review the pharmacodynamic and pharmacokinetic properties of PAR-1 antagonists.
- To present the latest clinical data on vorapaxar for atherothrombotic disease treatment.
Main Methods:
- Review of existing literature on PAR-1 antagonists.
- Analysis of clinical trial data for vorapaxar.
Main Results:
- Two selective PAR-1 antagonists, vorapaxar and atopaxar, have been developed.
- Vorapaxar has successfully completed Phase 3 clinical trials.
Conclusions:
- PAR-1 antagonism is a potential therapeutic strategy for atherothrombotic disease.
- Vorapaxar's clinical data warrants further consideration in managing residual cardiovascular risk.
Abstract:
Atherothrombosis and its clinical manifestations are among the leading causes of death in the developed world. The current standard-of-care antiplatelet therapy for the treatment of such events comprises aspirin and a thienopyridine or ticagrelor. However, recurrent ischemic events due to residual cardiovascular risk are a common phenomenon in these patients. It is believed that this residual risk is caused, at least in part, by thrombin, which signals through protease-activated receptors (PARs) and especially PAR-1. Thus, PAR-1 antagonism could represent an effective approach in the treatment of atherothrombotic disease. In this context, two potent and selective agents have been developed, vorapaxar and atopaxar. However, only vorapaxar has completed phase 3 clinical trials. In the present review, the main pharmacodynamic and pharmacokinetic properties of the PAR-1 antagonists are briefly described and the latest clinical data on vorapaxar are presented.
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