Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar

Abstract

Platelet activation with subsequent aggregation is a complex process leading to thrombus formation, which remains a key component for atherothrombotic manifestations, in particular myocardial infarction. Therefore, antiplatelet therapies are pivotal for the treatment of these patients. Current oral antiplatelet therapies used for secondary prevention of ischemic recurrences include aspirin and adenosine diphosphate P2Y12 platelet-receptor antagonists. However, despite these therapies, patients who have experienced a myocardial infarction remain at risk for ischemic recurrences. Therefore, more aggressive secondary prevention measures have been an area of research, including identifying additional targets modulating platelet-activation and -aggregation processes. Among these, thrombin-mediated platelet activation via protease-activated receptors (PARs) has been subject to extensive clinical investigation. Several PAR-1 receptor antagonists have been developed. However, vorapaxar is the only one that has completed large-scale clinical investigation. The present manuscript will provide an overview on the role of thrombin-mediated signaling, the impact of PAR-1 blockade with vorapaxar on ischemic and bleeding outcomes, and the potential role for vorapaxar in clinical practice.

Vorapaxar: The Current Role and Future Directions of a Novel Protease-Activated Receptor Antagonist for Risk Reduction in Atherosclerotic Disease

“…Of those, over 75% have atherothrombosis as an underlying pathophysiology: 7.3 million due to ischemic heart disease and 6.2 million due to strokes. Even with early revascularization and potent dual antiplatelet therapy, residual mortality remains high [ 2 ]. As a result, assessment of new antiplatelet agents is an expanding research area.…”

Vorapaxar: A novel agent to be considered in the secondary prevention of myocardial infarction

“…[ 7 ] Before now, the ADP receptors and TXA2 have been the major targets of antiplatelet used as standard of care and this includes clopidogrel, prasugrel, ticagrelor (ADP receptor antagonist), and aspirin (TXA2 inhibitor). [ 8 ] The discovery of the protease-activated receptor-1 (PAR-1) and its novel antagonist, vorapaxar, presents an opportunity for additional option to be considered in the management of MI through the inhibition of thrombin-mediated platelet activation. Vorapaxar (formerly called SCH 530348) is a synthetic tricyclic 3-phenylpyridine structurally similar to himbacine, and it is a selective antagonist of PAR-1 which is the major thrombin receptor found on the surface of human platelets cell.…”