Anticoagulation during and after acute coronary syndrome

 

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Summary

Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentas-accharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban.

Zusammenfassung

Die derzeitige antithrombotische Therapie bei Patienten mit akutem Koronarsyndrom umfasst Antiplättchen- und antikoagulative The-rapie. Die duale Plättchenhemmung bestehend aus Aspirin sowie einem P2Y12-Inhibitor der dritten Generation (Prasugrel oder Ticagrelor) stellt den Goldstandard dar, während Aspirin zusammen mit einem P2Y12-Inhibitor der zweiten Generation (Clopidogrel) beim Vorhandensein von Kontraindikationen für P2Y12-Inhibitoren der dritten Generation oder aber bei hohem Blutungsrisiko als Alternative eingesetzt wird. In der klassischen anti koagulativen Therapie gilt unfraktioniertes Heparin nach wie vor als Therapiestandard besonders bei Patienten, die interventionell behandelt werden. Neue alternative parenterale Antikoagulationsstrategien umfassen den Einsatz von niedermolekularen Heparinen, z. B. Enoxaparin, und dem synthetischen Pentasaccharid Fondaparinux. Beide Substanzen teilen Vorteile im Vergleich zum unfraktionierten Heparin, besonders bei Patienten mit akutem Koronarsyndrom, die konservativ behandelt werden. Der direkte parenterale Faktor-IIa(Thrombin)-Inhibitor Bivalirudin ist genauso effektiv wie die Kom-bination aus unfraktioniertem Heparin plus Glykoprotein-IIb/IIIa-Inhibitor bei Patienten mit NSTEMI und sogar überlegen zu dem genannten Regime bei STEMI-Patienten, sofern Bivalirudin als einziges Antikoagulanz während der PCI genutzt wird. Der neue Ansatz einer Langezeitbehandlung mit einer niedrigen Dosis des oralen Faktor-Xa-Inhibitors Riva roxaban in der Post-ACS-Phase konnte in der Atlas-II-Studie die kardiovaskuläre Mortalität weiter reduzieren. Allerdings muss sich dieses Konzept in der Klinik in Verbindung mit P2Y12-Inhibitoren der dritten Generation bewähren. Diese Übersichtsarbeit diskutiert ausführlich die etablierten Antikoagulanzien für die Behandlung des akuten Koronarsyndroms sowie neue Ansätze, z. B. Rivaroxaban.

• References

• 1 Gerdes N, Zirlik A. Co-stimulatory molecules in and beyond co-stimulation – tipping the balance in atherosclerosis?. Thromb Haemost 2011; 106: 804-813.
  Article in Thieme ConnectPubMedGoogle Scholar
• 2 Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med 2013; 368: 2004-2013.
  CrossrefPubMedGoogle Scholar
• 3 Brambilla M, Camera M, Colnago D. et al. Tissue factor in patients with acute coronary syndromes: expression in platelets, leukocytes, and plateletleukocyte aggregates. Arteriosc, Thromb Vasc Biol 2008; 28: 947-953.
  CrossrefPubMedGoogle Scholar
• 4 Viles-Gonzalez JF, Badimon JJ. Atherothrombosis: the role of tissue factor. Int J Biochem Cell Biol 2004; 36: 25-30.
  CrossrefPubMedGoogle Scholar
• 5 Cimmino G, Golino P, Badimon JJ. Pathophysiological role of blood-borne tissue factor: should the old paradigm be revisited?. Int Emerg Med 2011; 06: 29-34.
  PubMedGoogle Scholar
• 6 Edgington TS, Ruf W, Rehemtulla A, Mackman N. The molecular biology of initiation of coagulation by tissue factor. Current studies in hematology and blood transfusion 1991; 58: 15-21.
  PubMedGoogle Scholar
• 7 Kopp CW, Gremmel T, Steiner S. et al. Plateletmonocyte cross talk and tissue factor expression in stable angina vs. unstable angina/non ST-elevation myocardial infarction. Platelets 2011; 22: 530-536.
  CrossrefPubMedGoogle Scholar
• 8 Morange PE, Blankenberg S, Alessi MC. et al. Prognostic value of plasma tissue factor and tissue factor pathway inhibitor for cardiovascular death in patients with coronary artery disease: the Athero-Gene study. J Thromb Haemost 2007; 05: 475-482.
  CrossrefPubMedGoogle Scholar
• 9 Eikelboom JW, Mehta SR, Anand SS. et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774-782.
  CrossrefPubMedGoogle Scholar
• 10 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. Eur Heart J 2011; 32: 2999-3054.
  CrossrefPubMedGoogle Scholar
• 11 Ahrens I, Smith BK, Bode C, Peter K. Direct thrombin inhibition with bivalirudin as an antithrombotic strategy in general and interventional cardiology. Expert opinion on drug metabolism & toxicology 2007; 03: 609-620.
  CrossrefPubMedGoogle Scholar
• 12 Höchtl T, Farhan S, Wojta J, Huber K. New anticoagulant agents in acute coronary syndromes. Heart 2011; 97: 244-252.
  CrossrefPubMedGoogle Scholar
• 13 Wijns W, Kolh P, Danchin N. et al. Guidelines on myocardial revascularization. Eur Heart J 2010; 31: 2501-2555.
  CrossrefPubMedGoogle Scholar
• 14 Chalmers TC, Matta RJ, Smith Jr H, Kunzler AM. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977; 297: 1091-1096.
  CrossrefPubMedGoogle Scholar
• 15 Magee KD, Campbell SG, Moher D, Rowe BH. Heparin versus placebo for acute coronary syndromes. The Cochrane database of systematic reviews 2008; CD003462.
  PubMedGoogle Scholar
• 16 Gray E, Hogwood J, Mulloy B. The anticoagulant and antithrombotic mechanisms of heparin. Handbook of experimental pharmacology 2012; 207: 43-61.
  PubMedGoogle Scholar
• 17 Chew DP, Bhatt DL, Lincoff AM. et al. Defining the optimal activated clotting time during percutaneous coronary intervention: aggregate results from 6 randomized, controlled trials. Circulation 2001; 103: 961-966.
  CrossrefPubMedGoogle Scholar
• 18 Tolleson TR, O’Shea JC, Bittl JA. et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. J Am Coll Cardiol 2003; 41: 386-393.
  PubMedGoogle Scholar
• 19 Montalescot G, Zeymer U, Silvain J. et al. Intravenous enoxaparin or unfractionated heparin in primary percutaneous coronary intervention for ST-elevation myocardial infarction: the international randomised open-label ATOLL trial. Lancet 2011; 378: 693-703.
  CrossrefPubMedGoogle Scholar
• 20 Navarese EP, De Luca G, Castriota F. et al. Lowmolecular-weight heparins vs. unfractionated heparin in the setting of percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis. J Thromb Haemost 2011; 09: 1902-1915.
  CrossrefPubMedGoogle Scholar
• 21 Murphy SA, Gibson CM, Morrow DA. et al. Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis. Eur Heart J 2007; 28: 2077-2086.
  CrossrefPubMedGoogle Scholar
• 22 Steg PG, James SK, Atar D. et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012; 33: 2569-2619.
  CrossrefPubMedGoogle Scholar
• 23 Silvain J, Beygui F, Barthelemy O. et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ 2012; 344: e553.
  CrossrefPubMedGoogle Scholar
• 24 Mehta SR, Boden WE, Eikelboom JW. et al. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008; 118: 2038-2046.
  CrossrefPubMedGoogle Scholar
• 25 Montalescot G, Walenga JM. Catheter-related thrombosis: biological and clinical evidence for risk with currently available anticoagulants. Clin Appl Thromb Hemost 2009; 15: 183-196.
  PubMedGoogle Scholar
• 26 Steg PG, Jolly SS, Mehta SR. et al. Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial. JAMA 2010; 304: 1339-1349.
  CrossrefPubMedGoogle Scholar
• 27 Stone GW, McLaurin BT, Cox DA. et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203-2216.
  CrossrefPubMedGoogle Scholar
• 28 Stone GW, Witzenbichler B, Guagliumi G. et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218-2230.
  CrossrefPubMedGoogle Scholar
• 29 Stone GW, Witzenbichler B, Guagliumi G. et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 2011; 377: 2193-2204.
  CrossrefPubMedGoogle Scholar
• 30 Meijer A, Verheugt FW, Werter CJ. et al. Aspirin versus coumadin in the prevention of reocclusion and recurrent ischemia after successful thrombolysis: a prospective placebo-controlled angiographic study. Results of the APRICOT Study. Circulation 1993; 87: 1524-1530.
  CrossrefPubMedGoogle Scholar
• 31 Ahrens I, Lip GY, Peter K. New oral anticoagulant drugs in cardiovascular disease. Thromb Haemost 2010; 104: 49-60.
  Article in Thieme ConnectPubMedGoogle Scholar
• 32 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
  CrossrefPubMedGoogle Scholar
• 33 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.
  CrossrefPubMedGoogle Scholar
• 34 Stoll P, Bassler N, Hagemeyer CE. et al. Targeting ligand-induced binding sites on GPIIb/IIIa via single-chain antibody allows effective anticoagulation without bleeding time prolongation. Arterioscl Thromb Vascul Biol 2007; 27: 1206-1212.
  PubMedGoogle Scholar
• 35 Schwarz M, Meade G, Stoll P. et al. Conformationspecific blockade of the integrin GPIIb/IIIa: a novel antiplatelet strategy that selectively targets activated platelets. Circulation Res 2006; 99: 25-33.
  CrossrefPubMedGoogle Scholar
• 36 Ahrens I, Bode C. New parenteral anticoagulants: focus on factor Xa and thrombin inhibitors. Current drug discovery technologies 2012; 09: 129-136.
  CrossrefPubMedGoogle Scholar
• 37 Povsic TJ, Vavalle JP, Aberle LH. et al. A Phase 2, randomized, partially blinded, active-controlled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J. 2013 ::::::::::((VOLUME; SEITEN ODER DOI; AUTOR BITTE ERGÄNZEN)).
  PubMedGoogle Scholar
• 38 Regado, Biosciences, press, release. New Investor Leads Round to Fund Phase 3 Development of REG1. wwwregadobiocom/indexphp/2012/12/regado-biosciences-inc-secures-51-million-series-e-financing/. 2012 December 17.
  PubMedGoogle Scholar