Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome

Summary

Acute coronary syndrome (ACS) is a medical emergency. Patients who survive the initial event remain at risk of recurrent cardiovascular events. In most cases, ACS is triggered by thrombosis after rupture of an atherosclerotic plaque. Key to thrombus formation at this site is the generation of thrombin, which not only converts fibrinogen to fibrin but also serves as a potent platelet agonist and induces platelet aggregation at the site of vascular injury. Although dual antiplatelet therapy is more effective for the prevention of recurrent events than aspirin alone after ACS, there remains an approximately 10 % risk of recurrent ischaemic events at one year. Recent studies have evaluated whether the addition of an anticoagulant to antiplatelet therapy reduces the risk of recurrent ischaemia after an ACS event. Rivaroxaban, an oral factor Xa inhibitor, attenuates thrombin generation. When used in conjunction with dual antiplatelet therapy in patients with stabilised ACS, rivaroxaban 2.5 mg twice daily significantly reduced the risk of the composite endpoint of cardiovascular death, myocardial infarction and stroke compared with placebo. Although it increased the risk of bleeding, rivaroxaban was associated with a reduction in mortality; a finding that supports the use of a dual-pathway approach that combines anticoagulant and antiplatelet therapy. This review explores the pathophysiology of ACS to provide perspective on the results of recent clinical trials with novel oral anticoagulants for ACS and to identify their potential role in this setting.

Keywords

Acute coronary syndrome - thrombin - thrombosis - factor Xa - rivaroxaban

• References

• 1 Grech ED, Ramsdale DR. Acute coronary syndrome: unstable angina and nonST segment elevation myocardial infarction. Br Med J 2003; 326: 1259-1261.
• 2 Collinson J, Flather MD, Fox KA. et al. Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective Registry of Acute Ischaemic Syndromes in the UK (PRAISUK). Eur Heart J 2000; 21: 1450-1457.
• 3 Roe MT, Armstrong PW, Fox KA. et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012; 367: 1297-1309.
• 4 Aronow WS. Antiplatelet drug use in patients with non-ST-segment elevation acute coronary syndromes. Postgrad Med 2013; 125: 51-58.
• 5 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045-1057.
• 6 Wiviott SD, Braunwald E, McCabe CH. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
• 7 Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol 2008; 101: 960-966.
• 8 Geeganage CM, Diener HC, Algra A. et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of randomized controlled trials. Stroke 2012; 43: 1058-1066.
• 9 Ardissino D, Merlini PA, Bauer KA. et al. Coagulation activation and long-term outcome in acute coronary syndromes. Blood 2003; 102: 2731-2735.
• 10 Rothberg MB, Celestin C, Fiore LD. et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005; 143: 241-250.
• 11 Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
• 12 Glover CJ, McIntire LV, Leverett LB. et al. Effect of shear stress on clot structure formation. Trans Am Soc Artif Intern Organs 1974; 20B: 463-468.
• 13 Goel MS, Diamond SL. Factor VIIa-mediated tenase function on activated platelets under flow. J Thromb Haemost 2004; 2: 1402-1410.
• 14 Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000; 407: 258-264.
• 15 Monroe DM, Hoffman M, Roberts HR. Platelets and thrombin generation. Arterioscler Thromb Vasc Biol 2002; 22: 1381-1389.
• 16 Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74: 597-607.
• 17 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90: 61-68.
• 18 Fox KA, Carruthers KF, Dunbar DR. et al. Underestimated and under-recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J 2010; 31: 2755-2764.
• 19 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Hae-most 2003; 1: 1504-1514.
• 20 Ansell J. Factor Xa or thrombin: is factor Xa a better target?. J Thromb Haemost 2007; 5 (Suppl. 01) 60-64.
• 21 Wright IS. The use of the anticoagulants in the treatment of diseases of the heart and blood vessels. Ann Intern Med 1949; 30: 80-91.
• 22 Testa L, Zoccai GB, Porto I. et al. Adjusted indirect meta-analysis of aspirin plus warfarin at international normalized ratios 2 to 3 versus aspirin plus clopidogrel after acute coronary syndromes. Am J Cardiol 2007; 99: 1637-1642.
• 23 Oldgren J, Budaj A, Granger CB. 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.
• 24 Steg PG, Mehta SR, Jukema JW. et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur Heart J 2011; 32: 2541-2554.
• 25 Goldstein S, Bates R, Bhatt D. et al. Phase 2 study of TAK-442, an oral factor Xa inhibitor in patients following acute coronary syndrome. Thromb Haemost 2014; 111: 1141-1152.
• 26 Alexander JH, Becker RC, Bhatt DL. et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009; 119: 2877-2885.
• 27 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
• 28 Mega JL, Braunwald E, Mohanavelu S. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009; 374: 29-38.
• 29 Gibson CM, Mega JL, Burton P. et al. Rationale and design of the Anti-Xa Therapy to Lower cardiovascular events in Addition to standard therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS-ACS 2 TIMI 51) trial: A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am Heart J 2011; 161: 815-821.
• 30 Mega JL, Braunwald E, Wiviott SD. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
• 31 Bayer Pharma AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2013. Available at: www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf Accessed May 16, 2014.
• 32 Diener HC, Bogousslavsky J, Brass LM. et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331-337.
• 33 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569-2619.
• 34 Hamm CW, Bassand JP, Agewall S. et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the Management of Acute Coronary Syndromes (ACS) in Patients Presenting without Persistent ST-segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999-3054.
• 35 ClinicalTrials.gov. Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS). Available at: clinicaltrials.gov/ct2/show/NCT01776424 Accessed May 17, 2013.
• 36 Dewilde WJ, Oirbans T, Verheugt FW. et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013; 381: 1107-1115.
• 37 ClinicalTrials.gov. A study exploring two strategies of rivaroxaban and one of oral vitamin K antagonist in patients with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Available at: clinicaltrials.gov/ct2/show/NCT01830543 Accessed May 17, 2013.
• 38 Weitz J. New anticoagulant drugs: the Seventh ACCP Conference on Anti-thrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl. 03) 265S-286S.