Cardiovascular Drugs and Therapy

, Volume 26, Issue 3, pp 265–271 | Cite as

Novel Oral Anticoagulants After Acute Coronary Syndromes

  • Newton B. Wiggins
  • Christopher B. Granger
  • John H. Alexander
REVIEW ARTICLE
  • 278 Downloads

Abstract

Purpose

A number of novel oral anticoagulants, including direct thrombin inhibitors and direct factor Xa inhibitors, have been developed. This review discusses these agents and their respective clinical trials in patients with acute coronary syndromes.

Methods

This review discusses the results of phase 2 and 3 clinical trials with novel oral anticoagulants.

Results

Phase 2 clinical trials demonstrated that novel oral anticoagulants increase the risk of bleeding in a dose-related fashion, particularly when used in addition to dual antiplatelet therapy. What was less clear is their impact on recurrent ischemic events. In phase 3 trials, rivaroxaban was found to have a benefit on ischemic events and perhaps a greater benefit at the lower dose. The phase 3 trial with apixaban was stopped early due to increased bleeding without a meaningful reduction in ischemic events.

Conclusions

Novel oral anticoagulants represent a promising, potentially beneficial treatment for patients with a recent acute coronary syndrome but come with a risk of bleeding. The benefits and risks of these agents will need to be carefully weighed and may depend on both patient risk and concomitant therapy. Additional research is needed to determine how to best integrate these medications into the care of patients with acute coronary syndromes.

Key words

Anticoagulation Acute coronary syndrome Apixaban Rivaroxaban Dabigatran 

References

  1. 1.
    Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.PubMedCrossRefGoogle Scholar
  2. 2.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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.PubMedCrossRefGoogle Scholar
  3. 3.
    Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.PubMedCrossRefGoogle Scholar
  4. 4.
    Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, 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. Circulation. 2011;123:e426–579.PubMedCrossRefGoogle Scholar
  5. 5.
    Kushner FG, Hand M, Smith Jr SC, King 3rd SB, Anderson JL, Antman EM, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2009;120:2271–306.PubMedCrossRefGoogle Scholar
  6. 6.
    Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–50.PubMedGoogle Scholar
  7. 7.
    Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation. 2002;105:1004–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Weitz JI, Crowther M. Direct thrombin inhibitors. Thromb Res. 2002;106:V275–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:234S–56S.PubMedCrossRefGoogle Scholar
  10. 10.
    Herault JP, Bernat A, Pflieger AM, Lormeau JC, Herbert JM. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharmacol Exp Ther. 1997;283:16–22.PubMedGoogle Scholar
  11. 11.
    Krishnaswamy S, Vlasuk GP, Bergum PW. Assembly of the prothrombinase complex enhances the inhibition of bovine factor Xa by tick anticoagulant peptide. Biochemistry. 1994;33:7897–907.PubMedCrossRefGoogle Scholar
  12. 12.
    Wallentin L, Wilcox RG, Weaver WD, Emanuelsson H, Goodvin A, Nystrom P, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362:789–97.PubMedCrossRefGoogle Scholar
  13. 13.
    Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, 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;32:2781–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, 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;119:2877–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, 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;76:142–54.PubMedCrossRefGoogle Scholar
  18. 18.
    Steg PG, Mehta SR, Jukema JW, Lip GY, Gibson CM, Kovar F, 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;32:2541–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365:699–708.PubMedCrossRefGoogle Scholar
  20. 20.
    Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9–19.PubMedCrossRefGoogle Scholar
  21. 21.
    Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.PubMedCrossRefGoogle Scholar
  23. 23.
    Frost C, Song Y, Barrett YC, Wang J, Li T, LaCreta F, editors. Direct Comparison of the Pharmacokinetics and Pharmacodynamics of Apixaban and Rivaroxaban. XXIII Congress of the International Society on Thrombosis and Haemostasis; Kyoto, Japan: Bristol-Myers Squibb; 2011.Google Scholar
  24. 24.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.PubMedCrossRefGoogle Scholar
  25. 25.
    Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464–76.PubMedCrossRefGoogle Scholar
  26. 26.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Newton B. Wiggins
    • 2
  • Christopher B. Granger
    • 1
    • 2
  • John H. Alexander
    • 1
    • 2
    • 3
  1. 1.Duke Clinical Research InstituteDurhamUSA
  2. 2.Duke University Medical CenterDurhamUSA
  3. 3.Duke Clinical Research Institute, Duke University Medical CenterDurhamUSA

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