Current Cardiology Reports

, Volume 14, Issue 4, pp 450–456 | Cite as

New Anticoagulants in Ischemic Heart Disease

Ischemic Heart Disease (S Brener, Section Editor)


Historically, the use of oral anticoagulants in acute coronary syndromes (ACS) has been controversial. Several prospective trials have shown that vitamin K antagonists (VKAs), such as warfarin or dicoumarol, reduce recurrent ischemic events but with a concomitant increased risk of bleeding. Other trial data have shown a neutral or net negative effect. Regardless, these prior observations are not readily transposable to contemporary practice where many ACS patients receive dual antiplatelet therapy and undergo cardiac catheterization and percutaneous coronary intervention. Because recurrent ischemic events continue to occur following index ACS presentation despite evidence-based practice and knowing the limitations of current oral anticoagulation strategies with VKA, the endeavor continues to find a more effective anticoagulant with predictable, dose-proportional pharmacokinetics, and minimal interactions with food and drugs. We review novel, emerging classes of anticoagulants that focus on specific targets in the coagulation cascade with the aim of improving long-term net clinical outcomes.


Acute coronary syndromes New oral anticoagulants Direct thrombin inhibitors Factor Xa inhibitors Aptamers Ischemic heart disease 



No potential conflicts of interest relevant to this article were reported.


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

  1. 1.
    Yusuf S, Zhao F, Mehta SR, 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(7):494–502.PubMedCrossRefGoogle Scholar
  2. 2.
    Anderson JL, Adams CD, Antman EM, et al. 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/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol. 2007;50(7):e1–157.PubMedCrossRefGoogle Scholar
  3. 3.
    Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51(2):210–47.PubMedCrossRefGoogle Scholar
  4. 4.
    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(4):241–50.PubMedGoogle Scholar
  5. 5.
    Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J. 2006;27(5):519–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999;282(21):2058–67.PubMedCrossRefGoogle Scholar
  7. 7.
    Faxon DP, Eikelboom JW, Berger PB, et al. Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: a North American perspective: executive summary. Circ Cardiovasc Interv. 2011;4(5):522–34.PubMedCrossRefGoogle Scholar
  8. 8.
    Baber U, Kovacic J, Kini AS, et al. How serious a problem is bleeding in patients with acute coronary syndromes? Curr Cardiol Rep. 2011;13(4):312–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114(8):774–82.PubMedCrossRefGoogle Scholar
  10. 10.
    Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: a risk model from the ACUITY trial. Eur Heart J. 2009;30(12):1457–66.PubMedCrossRefGoogle Scholar
  11. 11.
    Eriksson BI, Quinlan DJ, Eikelboom JW. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu Rev Med. 2011;62:41–57.PubMedCrossRefGoogle Scholar
  12. 12.
    Abrams PJ, Emerson CR. Rivaroxaban: a novel, oral, direct factor Xa inhibitor. Pharmacotherapy. 2009;29(2):167–81.PubMedCrossRefGoogle Scholar
  13. 13.
    Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost. 2003;1(7):1504–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59–7939–an oral, direct Factor Xa inhibitor. J Thromb Haemost. 2005;3(3):514–21.PubMedCrossRefGoogle Scholar
  15. 15.
    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(9683):29–38.PubMedCrossRefGoogle Scholar
  16. 16.
    • Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19. Landmark study showing benefit of adding factor Xa inhibitor rivaroxaban to standard dual antiplatelet therapy with aspirin and clopidogrel, at the expense of major bleeding but not fatal bleeding. Lower-dose regimen also revealed mortality benefit..PubMedCrossRefGoogle Scholar
  17. 17.
    Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344–51.PubMedCrossRefGoogle Scholar
  18. 18.
    Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27(6):1238–47.PubMedCrossRefGoogle Scholar
  19. 19.
    Wong PC, Crain EJ, Xin B, et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J Thromb Haemost. 2008;6(5):820–9.PubMedCrossRefGoogle Scholar
  20. 20.
    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
  21. 21.
    Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708.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.
    Cohen M, Bhatt DL, Alexander JH, et al. Randomized, double-blind, dose-ranging study of otamixaban, a novel, parenteral, short-acting direct factor Xa inhibitor, in percutaneous coronary intervention: the SEPIA-PCI trial. Circulation. 2007;115(20):2642–51.PubMedCrossRefGoogle Scholar
  24. 24.
    • Sabatine MS, Antman EM, Widimsky P, et al. Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2009;374(9692):787–95. Otamixaban, an intravenous, direct, selective inhibitor of factor Xa, at intermediate doses in patients presenting with NSTE ACS, may be associated with as much as a 40 % lower risk of ischemic events and a comparable risk of bleeding compared with UFH+GPI..PubMedCrossRefGoogle Scholar
  25. 25.
    Becker RC, Rusconi C, Sullenger B. Nucleic acid aptamers in therapeutic anticoagulation. Technology, development and clinical application. Thromb Haemost. 2005;93(6):1014–20.PubMedGoogle Scholar
  26. 26.
    Becker RC, Povsic T, Cohen MG, et al. Nucleic acid aptamers as antithrombotic agents: opportunities in extracellular therapeutics. Thromb Haemost. 2010;103(3):586–95.PubMedCrossRefGoogle Scholar
  27. 27.
    Dyke CK, Steinhubl SR, Kleiman NS, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation. 2006;114(23):2490–7.PubMedCrossRefGoogle Scholar
  28. 28.
    • Povsic TJ, Cohen MG, Mehran R et al. A randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes: design and rationale of the RADAR Phase IIb trial. Am Heart J. 2011;161(2):261–8. e1-2. REG1, an anticoagulation system consisting of a therapeutic RNA aptamer, pegnivacogin, which is a specific factor IXa inhibitor, and its regulator anivamersen, demonstrated numerically lower rates of ischemic events in patients with ACS undergoing PCI. Higher reversal also corresponded to better safety with less bleeding events. Google Scholar
  29. 29.
    Povsic TJ, Wargin WA, Alexander JH, et al. Pegnivacogin results in near complete FIX inhibition in acute coronary syndrome patients: RADAR pharmacokinetic and pharmacodynamic substudy. Eur Heart J. 2011;32(19):2412–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Steinhubl SR, Moliterno DJ. The role of the platelet in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs. 2005;5(6):399–408.PubMedCrossRefGoogle Scholar
  31. 31.
    Eriksson UG, Bredberg U, Hoffmann KJ, et al. Absorption, distribution, metabolism, and excretion of ximelagatran, an oral direct thrombin inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2003;31(3):294–305.PubMedCrossRefGoogle Scholar
  32. 32.
    Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362(9386):789–97.PubMedCrossRefGoogle Scholar
  33. 33.
    Agnelli G, Eriksson BI, Cohen AT, et al. Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran. Thromb Res. 2009;123(3):488–97.PubMedCrossRefGoogle Scholar
  34. 34.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.PubMedCrossRefGoogle Scholar
  35. 35.
    Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303.PubMedCrossRefGoogle Scholar
  36. 36.
    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(22):2781–9.PubMedCrossRefGoogle Scholar
  37. 37.
    Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001–15.PubMedCrossRefGoogle Scholar
  38. 38.
    Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine, Gill Heart InstituteUniversity of KentuckyLexingtonUSA

Personalised recommendations