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.

Keywords: antiplatelet agent; platelet aggregation; protease-activated receptor 1; vorapaxar.

Figure 1

Pathways of platelet protease-activated receptor (PAR)-1 activation. Notes: Activated PAR-1 can signal through the G_α12/13, G_αq, and G_αi/z families. The α-subunits of G₁₂ and G₁₃ bind Rho GEFs and induce Rho-mediated cytoskeletal responses, leading to changes in platelet shape. The G_αq binds phospholipase Cβ to generate IP3, which promotes calcium mobilization and protein kinase C activation. This then activates pathways leading to granule secretion, as PAR-1-stimulated G_αq-coupled adenosine diphosphate release is especially important for thrombin-mediated platelet activation. The G_βγ subunits can activate PI3-kinase and other lipid-modifying enzymes, protein kinases, and channels. The PI3-kinase modifies the inner leaflet of the plasma membrane to provide molecular docking sites. Activation of PAR-1 can also activate growth-factor shedding and activation of receptor tyrosine kinases involved in cell growth and differentiation. Reproduced with permission from John Wiley and Sons. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3(8):1800–1814. Copyright © 2005, John Wiley and Sons. Abbreviations: GEFs, guanine nucleotide exchange factors; IP3, inositol trisphosphate 3; PI3-kinase, phosphoinositide-3 kinase; MAP, mitogen activated kinase; DAG, diacylglycerol; WASP, Wiskott–Aldrich syndrome protein; SRE, serum response element; MLC, myosin light chain; PHD, prolyl hydroxylase domain.

Figure 2

Chemical structure of vorapaxar.

Figure 3

Kaplan–Meier curve of estimated occurrence of cardiovascular death, myocardial infarction, or stroke in TRA 2°P – TIMI 50 prior myocardial infarction cohort. Note: Reprinted from The Lancet, Vol 380, Scirica BM, Bonaca MP, Braunwald E, et al, Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial, 1317–1324. Copyright © 2012, with permission from Elsevier. Abbreviations: HR, hazard ratio; CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction.

Figure 4

Kaplan–Meier estimates of cardiovascular death, myocardial infarction, or stroke according to time from qualifying myocardial infarction to randomization: <3 months (A), 3–6 months (B), and >6 months (C) in the TRA 2°P–TIMI 50 prior myocardial infarction cohort. Note: Reprinted from The Lancet, Vol 380, Scirica BM, Bonaca MP, Braunwald E, et al, Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial, 1317–1324. Copyright © 2012, with permission from Elsevier. Abbreviations: HR, hazard ratio; CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction.