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DOI: 10.5482/HAMO-12-05-0009
Atopaxar
A novel player in antiplatelet therapy?AtopaxarEin neuer Mitspieler der antithrombozytären Therapie?Publication History
received:
25 May 2012
accepted:
19 June 2012
Publication Date:
28 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034925/201203/lookinside/thumbnails/10-5482-hamo-12-05-0009_de-1.jpg)
Summary
Atopaxar, also known as E 5555 is a novel reversible protease-activated receptor-1 (PAR-1) thrombin receptor antagonist. To date, Atopaxar has been investigated in phase II trials with focus on safety and tolerability in patients with acute coronary syndromes or stable coronary artery disease on top of standard antiplatelet therapy. Atopaxar was generally well tolerated, however a rise in liver enzymes and prolongation of the QTcF interval were observed. The data suggest, that atopaxar administration may promote some minor bleeding complications, but does not seem to significantly increase the risk of major bleeding. Although not powered for efficacy, the currently available data suggest potential benefits in patients at high risk for recurrent ischemic events on top of standard antiplatelet therapy. In conclusion, more studies (e.g. phase III) are needed to evaluate efficacy and safety of atopaxar.
Zusammenfassung
Atopaxar, auch bekannt als E 5555 ist ein neuer, reversibler Antagonist des Thrombin Protease-aktivierten Rezeptors-1 (PAR-1). Atopaxar wurde bisher in Phase-II-Studien in Hinblick auf Sicherheit und Verträglichkeit bei Patienten mit akutem Koronarsyndrom oder stabiler koronarer Herzkrankheit zusätzlich zur antithrombozytären Standardtherapie untersucht. Atopaxar wurde im Allgemeinen gut vertragen, jedoch waren eine Erhöhung der Leberenzyme und eine Verlängerung der QTZeit auffällig. Die zusätzliche Einnahme von Atopaxar scheint zu einer Zunahme leichter Blutungskomplikationen zu führen, jedoch ohne das Auftreten schwerwiegender Blutungskomplikationen relevant zu erhöhen. Obwohl bisherige Studien nicht primär die Wirksamkeit von Atopaxar untersuchten, gibt es Hinweise dafür dass Patienten mit hohem Risiko für das Auftreten ischämischer Ereignisse von der zusätzlichen Einnahme von Atopaxar profítieren. Weitere (Phase-III-)Studien sind nötig, die Wirksamkeit und Sicherheit von Atopaxar untersuchen.
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References
- 1 Lopez AD. et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747-1757.
- 2 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-1234.
- 3 Massberg S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.
- 4 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
- 5 Sabatine MS. et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005; 352: 1179-1189.
- 6 Yusuf S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
- 7 Steinhubl SR. et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411-2420.
- 8 Serebruany VL. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
- 9 Matetzky S. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
- 10 Geisler T. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
- 11 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
- 12 Wallentin L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
- 13 Mega JL. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
- 14 Alexander JH. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
- 15 Oldgren J. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J 2011; 32: 2781-2789.
- 16 Wallentin L. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789-797.
- 17 May AE, Seizer P, Gawaz M. Platelets: inflammatory firebugs of vascular walls. Arterioscler Thromb Vasc Biol 2008; 28: s5-s10.
- 18 Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115: 3378-3384.
- 19 Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 2005; 03: 1800-1814.
- 20 Brummel KE. et al. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002; 100: 148-152.
- 21 Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006; 99: 1293-1304.
- 22 Leonardi S, Tricoci P, Becker RC. Thrombin receptor antagonists for the treatment of atherothrombosis: therapeutic potential of vorapaxar and E-5555. Drugs 2010; 70: 1771-1783.
- 23 Leger AJ. et al. Blocking the protease-activated receptor 1–4 heterodimer in platelet-mediated thrombosis. Circulation 2006; 113: 1244-1254.
- 24 Martorell L. et al. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb Haemost 2008; 99: 305-315.
- 25 Leger AJ, Covic L, Kuliopulos A. Protease-activated receptors in cardiovascular diseases. Circulation 2006; 114: 1070-1077.
- 26 Martin K. et al. Thrombin stimulates smooth muscle cell differentiation from peripheral blood mononuclear cells via protease-activated receptor-1, RhoA, and myocardin. Circ Res 2009; 105: 214-218.
- 27 Pawlinski R. et al. Protease-activated receptor-1 contributes to cardiac remodeling and hypertrophy. Circulation 2007; 116: 2298-2306.
- 28 Serebruany VL. et al. Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). Am J Cardiol 2006; 97: 1332-1336.
- 29 Shi X. et al. Protease-activated receptors (PAR1 and PAR2) contribute to tumor cell motility and metastasis. Mol Cancer Res 2004; 02: 395-402.
- 30 Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010; 31: 17-28.
- 31 Eikelboom JW. et al. Clopidogrel does not suppress blood markers of coagulation activation in aspirintreated patients with non-ST-elevation acute coronary syndromes. Eur Heart J 2002; 23: 1771-1779.
- 32 Kogushi M. et al. The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs. Eur J Pharmacol 2011; 657: 131-137.
- 33 Serebruany VL. et al. The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb Haemost 2009; 102: 111-119.
- 34 Kogushi M. et al. Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats. Eur J Pharmacol 2011; 666: 158-164.
- 35 O’Donoghue ML. et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of Thrombin-Acute Coronary Syndromes Trial. Circulation 2011; 123: 1843-1853.
- 36 Wiviott SD. et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation 2011; 123: 1854-1863.
- 37 Goto S. et al. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J 2010; 31: 2601-2613.
- 38 Peters RJ. et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108: 1682-1687.
- 39 Chesebro JH. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987; 76: 142-154.
- 40 Tricoci P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012; 366: 20-33.