Current Cardiology Reports

, Volume 14, Issue 4, pp 493–501 | Cite as

Which Antithrombin for Whom? Identifying the Patient Population that Benefits Most from Novel Antithrombin Agents

  • David A. Burke
  • Haider J. Warraich
  • Duane S. PintoEmail author
Management of Acute Coronary Syndromes (R Mehran, Section Editor)


Anticoagulation has proven to be a key component in the management of acute coronary syndromes (ACS). Pharmacological agents with various modes of action are utilized to reduce thrombus development by impairing thrombin formation, platelet activation, and platelet aggregation. The optimal management of these patients is to achieve maximal anti-ischemic benefit while avoiding bleeding complications. Synthetic “novel” agents have been developed to specifically target factor Xa or thrombin to achieve this goal. A growing amount of data show that these agents provide a net clinical benefit in the setting of stable ischemic heart disease, unstable angina, non-ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI).


Anticoagulation Factor Xa inhibitor Thrombin inhibitor Heparin Fondaparinux Apixaban Rivaroxaban Bivalirudin Argatroban Unstable angina NSTEMI STEMI Antithrombin 



Conflicts of interest: D.A. Burke: none; H.J. Warraich: none; D.S. Pinto: has been a consultant for Medicines Company, Janssen, AstraZeneca, Merck, and Genentech.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365–72.PubMedCrossRefGoogle Scholar
  2. 2.
    Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844–50.PubMedCrossRefGoogle Scholar
  3. 3.
    Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost. 2006;32 Suppl 1:3–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258–64.PubMedCrossRefGoogle Scholar
  5. 5.
    Rao SV, Ohman EM. Anticoagulant therapy for percutaneous coronary intervention. Circ Cardiovasc Interv. 2010;3:80–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Weitz JI, Leslie B, Hudoba M. Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation. 1998;97:544–52.PubMedCrossRefGoogle Scholar
  7. 7.
    Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e24S–43S.PubMedCrossRefGoogle Scholar
  8. 8.
    Fox KA, Antman EM, Cohen M, et al. Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-ST-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention. ESSENCE/TIMI 11B Investigators. Am J Cardiol. 2002;90(5):477–82.PubMedCrossRefGoogle Scholar
  9. 9.
    Cohen M, Demers C, Gurfinkel EP, et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: the ESSENCE trial. Efficacy and Safety of Subcutaneous Enoxaparin versus intravenous unfractionated heparin, in non-Q-wave Coronary Events. Am J Cardiol. 1998;82(5B):19L–24L.PubMedCrossRefGoogle Scholar
  10. 10.
    Peterson JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292(1):89–96.CrossRefGoogle Scholar
  11. 11.
    Antman EM, Cohen M, McCabe C, et al. Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE. Eur Heart J. 2002;23(4):308–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Spinler SA, Inverso SM, Cohen M, et al. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J. 2003;146(1):33–41.PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen M, Mahaffey KW, Pieper K, et al. A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol. 2006;48(7):1346–54.PubMedCrossRefGoogle Scholar
  14. 14.
    White HD, Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J. 2006;152(6):1042–50.PubMedCrossRefGoogle Scholar
  15. 15.
    Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol. 2007;50(18):1742–51.PubMedCrossRefGoogle Scholar
  16. 16.
    Simoons ML, Bobbink IW, Boland J, et al. A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: the Pentasaccharide in unstable Angina (PENTUA) study. J Am Coll Cardiol. 2004;43(12):2183–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of Fondaparinux on mortality and reinfarcation in patients with acute ST-segment elevation myocardial infarction. The OASIS-6 Randomized Trial. JAMA. 2006;295(13):1519–30.PubMedCrossRefGoogle Scholar
  18. 18.
    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(22):2877–85.PubMedCrossRefGoogle Scholar
  19. 19.
    Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. APPRAISE-2 Investigators. N Engl J Med. 2011;365(8):699–708.PubMedCrossRefGoogle Scholar
  20. 20.
    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. The Lancet 374(9683):29–38.Google Scholar
  21. 21.
    Mega JL, Braunwald EM, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.PubMedCrossRefGoogle Scholar
  22. 22.
    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(20):2541–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Stone GW, McLaurin BT, Cox D, et al. Bivalirudin for patients with acute coronary syndromes. New Engl J Med 355(21):2203–16.Google Scholar
  24. 24.
    Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA: J Am Med Assoc 289(7):853–63.Google Scholar
  25. 25.
    Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218–30.PubMedCrossRefGoogle Scholar
  26. 26.
    Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. ISAR-REACT 3 Trial Investigators. N Engl J Med. 2008;359(7):688–96.PubMedCrossRefGoogle Scholar
  27. 27.
    Schulz S, Mehilli J, Ndrepepa G, et al. Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Heart J. 2010;31(5):582–7.PubMedCrossRefGoogle Scholar
  28. 28.
    • Kastrati A, Neumann FJ, Schulz S, et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. ISAR-REACT 4 Trial Investigators. N Engl J Med. 2011;365(21):1980–9. This article shows patients with NSTEMI randomized to bivalirudin or abciximab, with reduced bleeding rates in the bivalirudin group and no ischemic benefit of GPI over bivalirudin once the patient was pretreated with a clopidogrel loading dose of 600 mg.PubMedCrossRefGoogle Scholar
  29. 29.
    Mehran R, Lansky AJ, Witzenbichler B, et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. The Lancet 374(9696):1149–59.Google Scholar
  30. 30.
    • 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, randomized controlled trial. The Lancet. 2011;377(9784):2193–204. At 3-year follow-up of the HORIZONS-AMI trial, major bleeding and reinfarction were reduced in the bivalirudin group compared with heparin plus GPI, with nonsignificantly different rates of target vessel revascularization and stroke.CrossRefGoogle Scholar
  31. 31.
    • Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;57:e215–367. This is the most recent guideline report of the American College of Cardiology Foundation, the American Heart Association Task Force on Practice Guidelines, and the Society for Cardiovascular Angiography and Interventions on all aspects of PCI.PubMedCrossRefGoogle Scholar
  32. 32.
    Kohl P, Danchin N, DiMario C, et al. Guidelines of myocardial revascularization. The task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2010;31:2501–55.CrossRefGoogle Scholar
  33. 33.
    Singh M, Peterson ED, Milford-Beland S, et al. Validation of the Mayo clinic risk score for in-hospital mortality after percutaneous coronary interventions using the national cardiovascular data registry. Circ Cardiovasc Interv. 2008;1(1):36–44.PubMedCrossRefGoogle Scholar
  34. 34.
    Mehran R, Pocock SJ, Nikolsky E, et al. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol. 2010;55(23):2556–66.PubMedCrossRefGoogle Scholar
  35. 35.
    Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004;44(7):1393–9.PubMedGoogle Scholar
  36. 36.
    Pinto DS, Stone GW, Shi C, Dunn ES, Reynolds MR, York M, Walczak, Berezin RH, Mehran R, McLaurin BT, Cox DA, Ohman EM, Lincoff AM, Cohen DJ. Economic evaluation of bivalirudin with or without glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for early invasive management of acute coronary syndromes. J Am Coll Cardiol. 2008;52:1758–68.PubMedCrossRefGoogle Scholar
  37. 37.
    Pinto DS, Ogbonnaya A, Sherman S, Tung P, Normand SL. Bivalirudin Therapy is Associated with Improved Clinical and Economic Outcomes in STEMI patients undergoing percutaneous coronary intervention: results from an observational database. Circulation: quality and outcomes. Circ Cardiovasc Qual Outcomes. 2012;5:52–61.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • David A. Burke
    • 1
  • Haider J. Warraich
    • 1
  • Duane S. Pinto
    • 1
    • 2
    Email author
  1. 1.Beth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  2. 2.Division of CardiologyBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations