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

Figures & data

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):1800–1814.¹⁸ 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.

Table 1 Efficacy and safety end points in the TRACER (at 2 years) trial

TRACER	Vorapaxar (n=6,473)	Placebo (n=6,471)	HR (95% CI)	P-value
Primary efficacy end point (death from cardiovascular causes, MI, stroke, recurrent ischemia with hospitalization, or urgent coronary revascularization)	18.5%	19.9%	0.92 (0.85–1.01)	0.07
Key secondary end point (death from cardiovascular causes, MI, or stroke)	14.7%	16.4%	0.89 (0.81–0.98)	0.02
Death from cardiovascular cause	3.8%	3.8%	1.00 (0.83–1.22)	0.96
MI	11.1%	12.5%	0.88 (0.79–0.98)	0.02
Stroke	1.9%	2.1%	0.93 (0.70–1.23)	0.61
Recurrent ischemia with hospitalization	1.6%	1.5%	1.14 (0.83–1.58)	0.42
Urgent coronary revascularization	3.8%	3.5%	1.07 (0.88–1.31)	0.49
GUSTO moderate or severe bleeding	7.2%	5.2%	1.35 (1.16–1.58)	<0.001
TIMI clinically significant bleeding	20.2%	14.6%	1.43 (1.31–1.57)	<0.001
Fatal bleeding	0.4%	0.2%	1.89 (0.80–4.45)	0.15
Intracranial hemorrhage	1.1%	0.2%	3.39 (1.78–6.45)	<0.001

Abbreviations: HR, hazard ratio; CI, confidence interval; MI, myocardial infarction; TRACER, Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; TIMI, Thrombolysis in Myocardial Infarction.

Table 2 Efficacy and safety end points in the TRA 2°P – TIMI 50 (at 3 years) trial

TRA 2°P-TIMI 50	Vorapaxar (n=13,225)	Placebo (n=13,224)	HR (95% CI)	P-value
Primary efficacy end point (death from cardiovascular causes, MI, stroke, recurrent ischemia leading to urgent coronary revascularization)	11.2%	12.4%	0.88 (0.82–0.95)	0.001
Key secondary end point (death from cardiovascular causes, MI, or stroke)	9.3%	10.5%	0.87 (0.80–0.94)	<0.001
Death from cardiovascular cause	2.7%	3.0%	0.89 (0.76–1.04)	0.15
MI	5.2%	6.1%	0.83 (0.74–0.93)	0.001
Stroke	2.8%	2.8%	0.97 (0.83–1.14)	0.73
Urgent coronary revascularization	2.5%	2.6%	0.88 (0.75–1.03)	0.11
GUSTO moderate or severe bleeding	4.2%	2.5%	1.66 (1.43–1.93)	<0.001
TIMI clinically significant bleeding	15.8%	11.1%	1.46 (1.36–1.57)	<0.001
Fatal bleeding	0.3%	0.2%	1.46 (0.82–2.58)	0.19
Intracranial hemorrhage	1.0%	0.5%	1.94 (1.39–2.70)	<0.001

Abbreviations: HR, hazard ratio; CI, confidence interval; MI, myocardial infarction; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; TIMI, Thrombolysis in Myocardial Infarction.

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, 1317–1324.⁵⁷ 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, 1317–1324.⁵⁷ Copyright © 2012, with permission from Elsevier.
Abbreviations: HR, hazard ratio; CI, confidence interval; TIMI, Thrombolysis in Myocardial Infarction.

CoughlinSRProtease-activated receptors in hemostasis, thrombosis and vascular biologyJ Thromb Haemost2005381800181416102047

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SciricaBMBonacaMPBraunwaldEVorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trialLancet201238098501317132422932716

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