Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Novel oral anticoagulants to prevent stroke in atrial fibrillation

Nature Reviews Cardiology volume 7, pages 149–154 (2010)Cite this article

Subjects

Abstract

Warfarin reduces the risk of stroke in atrial fibrillation by around 60%, while antiplatelet therapy is much less effective. Bleeding is, however, a notable adverse effect with warfarin. Another major drawback of warfarin is the need for frequent clotting assessment. Oral agents have been developed that directly inhibit the activity of thrombin (factor IIa), as well as drugs that directly block activated factor X (factor Xa), which is the first enzyme in the final common pathway to the activation of thrombin. These drugs have fast onset and offset of action and anticoagulation does not seem to need monitoring. These new agents for stroke prevention in atrial fibrillation are being investigated in ongoing phase III trials. In one of these trials an oral thrombin blocker has so far shown superiority to warfarin in efficacy and safety. In this Review, I address the potential of modern oral anticoagulants to improve stroke prevention in atrial fibrillation.

Key Points

  • Warfarin therapy to achieve a target International Normalized Ratio (INR) score of between 2.0 and 3.0 is the cornerstone for stroke prevention in patients with atrial fibrillation

  • Less than two-thirds of patients taking warfarin achieve and maintain INR scores within the therapeutic range

  • Warfarin is associated with severe bleeding episodes, at a rate of ≥1% per year

  • The new oral direct thrombin blockers and oral direct factor Xa inhibitors are yielding promising results for the prevention of venous and arterial thromboembolism

  • These agents have fast onset and offset of action and anticoagulation do not need to be monitored, but some preparations need to be taken twice daily

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Simplified schema of the coagulation cascade.

Similar content being viewed by others

References

  1. Wolf, P. A., Abbott, R. D. & Kannel, W. B. Atrial fibrillation: a major contributor to stroke. The Framingham study. Arch. Intern. Med. 147, 1561–1564 (1987).

    Article  CAS  Google Scholar 

  2. Kopecky, S. L. et al. The natural history of lone atrial fibrillation. A population-based study over three decades. N. Engl. J. Med. 317, 669–674 (1987).

    Article  CAS  Google Scholar 

  3. Brouwer, M. A. & Verheugt, F. W. Oral anticoagulants in acute coronary syndromes. Circulation 105, 1270–1274 (2002).

    Article  Google Scholar 

  4. Lip, G. Y., Hart, R. G. & Conway, D. S. Antithrombotic therapy for atrial fibrillation. BMJ 325, 1022–1025 (2002).

    Article  Google Scholar 

  5. Olsen, S. B. for the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 362, 1691–1698 (2003).

    Article  Google Scholar 

  6. Gage, B. F. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 285, 2864–2870 (2001).

    Article  CAS  Google Scholar 

  7. De Caterina, R. et al. Anticoagulants in heart disease: current status and perspectives. Eur. Heart J. 28, 880–913 (2007).

    Article  CAS  Google Scholar 

  8. Azar, J. A. et al. Optimal intensity of oral anticoagulant therapy after myocardial infarction. J. Am. Coll. Cardiol. 27, 1349–1355 (1996).

    Article  CAS  Google Scholar 

  9. Hurlen, M., Abdelnoor, M., Smith, P., Erikssen, J. & Arnesen, H. Warfarin, aspirin, or both after myocardial infarction. N. Engl. J. Med. 347, 969–974 (2002).

    Article  CAS  Google Scholar 

  10. Eikelboom, J. W. et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet 355, 1936–1942 (2000).

    Article  CAS  Google Scholar 

  11. Sabatine, M. S. 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 374, 787–795 (2009).

    Article  CAS  Google Scholar 

  12. Van Es, R. F., Jonker, J. J., Verheugt, F. W., Deckers, J. W. & Grobbee, D. E. for the Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 360, 109–113 (2002).

    Article  CAS  Google Scholar 

  13. Hylek, E. M. et al. Effect of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N. Engl. J. Med. 349, 1019–1026 (2003).

    Article  CAS  Google Scholar 

  14. Wysowski, D. K., Nourjah, P. & Swartz, L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch. Intern. Med. 167, 1414–1419 (2007).

    Article  Google Scholar 

  15. Hayden, M., Pignone, M., Phillips, C. & Mulrow, C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the, U. S. Preventive Services Task Force. Ann. Intern. Med. 136, 161–172 (2002).

    Article  CAS  Google Scholar 

  16. Yusuf, S. et al. for the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502 (2001).

    Article  CAS  Google Scholar 

  17. Bhatt, D. L. et al. for the Charisma Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N. Engl. J. Med. 354, 1706–1717 (2006).

    Article  CAS  Google Scholar 

  18. Connolly, S. et al. for the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 367, 1903–1912 (2006).

    Article  CAS  Google Scholar 

  19. Verheugt, F. W. Good old warfarin for stroke prevention in atrial fibrillation. Lancet 367, 1877–1878 (2006).

    Article  Google Scholar 

  20. Connolly, S. J. et al. for the ACTIVE Investigators. Effect of clopidogrel added to aspirin in atrial fibrillation. N. Engl. J. Med. 360, 2066–2078 (2009).

    Article  Google Scholar 

  21. Hellemons, B. S. et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ 319, 958–964 (1999).

    Article  CAS  Google Scholar 

  22. Garcia, D. & Hylek, E. Stroke prevention in elderly patients with atrial fibrillation. Lancet 3 70, 460–461 (2007).

    Article  Google Scholar 

  23. Mant, J. et al. for the BAFTA Investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet 370, 493–503 (2007).

    Article  CAS  Google Scholar 

  24. Ansell, J. et al. Pharmacology and management of the vitamin K antagonists. American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 133, 160S–198S (2008).

    Article  CAS  Google Scholar 

  25. Fiessinger, J. N. et al. for the THRIVE Treatment Study Investigators. Ximelagatran vs low-molecular weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 293, 681–689 (2005).

    Article  CAS  Google Scholar 

  26. Shulman, S., Wählander, K., Lundström, T., Billing Clason, S. & Eriksson, H. for the THRIVE III Investigators. Secondary prevention of venous thromboembolism with the direct thrombin inhibitor ximelagatran. N. Engl. J. Med. 349, 1713–1721 (2003).

    Article  Google Scholar 

  27. Wallentin, L. et al. for the ESTEEM Investigators. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 362, 789–797 (2003).

    Article  CAS  Google Scholar 

  28. Albers, G. W. et al. and the SPORTIF Executive Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 293, 690–698 (2005).

    Article  Google Scholar 

  29. Connolly, S. J. et al. for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    Article  CAS  Google Scholar 

  30. Agnelli, G. et al. for the ODIXa-DVT Investigators. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59–7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59–7939 in Patients With Acute Symptomatic Deep-Vein Thrombosis) study. Circulation 116, 180–187 (2007).

    Article  CAS  Google Scholar 

  31. Eriksson, B. I. et al. for the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N. Engl. J. Med. 358, 2765–2775 (2008).

    Article  CAS  Google Scholar 

  32. Kakkar, A. K. et al. for the RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet 372, 31–29 (2008).

    Article  CAS  Google Scholar 

  33. Lassen, M. R. et al. for the RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N. Engl. J. Med. 358, 2776–2786 (2008).

    Article  CAS  Google Scholar 

  34. Turpie, A. G. et al. for the RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4). Lancet 373, 1673–1680 (2009).

    Article  CAS  Google Scholar 

  35. Hylek, E. M., Frison, L., Henault, L. E. & Cupples, A. Disparate stroke rates on warfarin among contemporaneous cohorts with atrial fibrillation: potential insights into risk from a comparative analysis of SPORTIF-III versus SPORTIF.-V. Stroke 39, 3009–3014 (2008).

    Article  CAS  Google Scholar 

  36. Ezekowitz, M. D. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am. J. Cardiol. 100, 1419–1426 (2007).

    Article  CAS  Google Scholar 

  37. Mega, J. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29–38 (2009).

    Article  CAS  Google Scholar 

  38. Alexander, J. H. for the APPRAISE Steering Committee and Investigators. Apixaban, an oral direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Ischemic and Safety events (APPRAISE) Trial. Circulation 119, 2877–2885 (2009).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Onze Lieve Vrouwe Gasthuis, Oosterpark 9, Amsterdam, 1091, AC, The Netherlands

    Freek W. A. Verheugt

Authors
  1. Freek W. A. Verheugt
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

F. W. A. Verheugt has received speaker's bureau honoraria from AstraZeneca, Bristol-Myers Squibb, and Pfizer. He has acted as a consultant for Sanofi-Aventis and has received research support from Pfizer and Sanofi-Aventis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verheugt, F. Novel oral anticoagulants to prevent stroke in atrial fibrillation. Nat Rev Cardiol 7, 149–154 (2010). https://doi.org/10.1038/nrcardio.2009.235

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2009.235

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing