Advances in Therapy

, Volume 26, Issue 12, pp 1058–1071 | Cite as

New pharmacotherapy for stroke prevention in atrial fibrillation: Update 2010

  • Luciana Armaganijan
  • John Eikelboom
  • Jeff S. Healey
  • Carlos A. MorilloEmail author


Atrial fibrillation (AF) is the most commonly encountered arrhythmia in clinical practice and is associated with substantial morbidity and mortality. Its prevalence increases with age, affecting about 1% of patients aged <60 years and almost 10% of patients >80 years. AF is associated with a fivefold increasing risk of embolism or stroke with absolute risk ranging from less than 1% to 20% per year, depending on patient age and the presence of clinical risk factors including congestive heart failure, systemic hypertension, diabetes mellitus and prior history of cardioembolic events. Vitamin K antagonists (VKAs) and acetyl salicylic acid are currently the only licensed antithrombotic therapies for stroke prevention in patients with AF. Anticoagulants are very effective for stroke prevention in patients 0084-8 12 with AF, overall a 64% relative risk reduction. Nonetheless, approximately 50% of patients with AF who have an indication for VKA receive anticoagulant therapy, of which only 50% maintain adequate therapeutic ranges. Furthermore, 50% will discontinue VKAs within 3 to 5 years regardless of appropriate international normalized ratio control. Underutilization of VKAs is related, in part, to their numerous limitations and difficulty in maintaining adequate therapeutic control, prompting the development of new antithrombotic strategies that are equally effective and safer, and easier to manage than VKAs. This review focuses on new antithrombotic therapies for stroke prevention in patients with AF.


atrial fibrillation anticoagulation thrombin vitamin K antagonists 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ostrander LD Jr., Brandt RL, Kjelsberg MO, Epstein FH. Electrocardiographic findings among the adult population of a total natural community, Tecumseh, Michigan. Circulation. 1965;31:888–898.PubMedGoogle Scholar
  2. 2.
    Flegel KM, Shipley MJ, Rose G. Risk of stroke in nonrheumatic atrial fibrillation. Lancet. 1987;1:526–529.CrossRefPubMedGoogle Scholar
  3. 3.
    Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham study. Stroke. 1991;22:983–988.PubMedGoogle Scholar
  4. 4.
    Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol. 1994;74:236–241.CrossRefPubMedGoogle Scholar
  5. 5.
    Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. JAMA. 2001;285:2370–2375.CrossRefPubMedGoogle Scholar
  6. 6.
    Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110:2287–2292.CrossRefPubMedGoogle Scholar
  7. 7.
    Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867.PubMedGoogle Scholar
  8. 8.
    Nieuwlatt R, Capucci A, Lip GYH, et al. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2006;27:3018–3026.CrossRefGoogle Scholar
  9. 9.
    Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke. 2006;37:1075–1080.CrossRefPubMedGoogle Scholar
  10. 10.
    Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in medicare beneficiaries with atrial fibrillation. Stroke. 2006;37:1070–1074.CrossRefPubMedGoogle Scholar
  11. 11.
    Waldo AL, Becker RC, Tapson VF, Colgan KJ, for the NABOR Steering Committee. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardio. 2005;46:1729–1736.CrossRefGoogle Scholar
  12. 12.
    Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with non-valvular atrial fibrillation: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Ann Intern Med. 1999;131:927–934.PubMedGoogle Scholar
  13. 13.
    Bungard TJ, Ghali WA, Teo KK, McAlister FA, Tsuyuki RT. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med. 2000;160:41–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Bradley BC, Perdue KS, Tisdel KA, Gilligan DM. Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center. Am J Cardiol. 2000;85:568–572.CrossRefPubMedGoogle Scholar
  15. 15.
    Connolly SJ, Eikelboom J, O’Donnell M, Pogue J. Yusuf S. Challenges of establishing new antithrombotic therapies in atrial fibrillation. Circulation 2007;116:449–455.CrossRefPubMedGoogle Scholar
  16. 16.
    Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE. Antithrmbotic therapy in atrial fibrillation. Chest. 2001;119:194S–1206S.CrossRefPubMedGoogle Scholar
  17. 17.
    Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with non-rheumatic atrial fibrillation. N Engl J Med. 1996;335:540–546.CrossRefPubMedGoogle Scholar
  18. 18.
    Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527–533.CrossRefPubMedGoogle Scholar
  19. 19.
    Active Steering Committee, ACTIVE Investigators, Connolly S, et al. Rationale and design of ACTIVE: the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events. Am Heart J. 2006;151:1187–1193.CrossRefPubMedGoogle Scholar
  20. 20.
    ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al. 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 randomized controlled trial. Lancet. 2006;367:1903–1912.CrossRefPubMedGoogle Scholar
  21. 21.
    ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066–2078.CrossRefPubMedGoogle Scholar
  22. 22.
    Sobieraj-Teague M, O’Donnell M, Eikelboom J. New anticoagulants for atrial fibrillation. Semin Thromb Hemost. 2009;35:515–524.CrossRefPubMedGoogle Scholar
  23. 23.
    Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178–2185.CrossRefPubMedGoogle Scholar
  24. 24.
    AMADEUS Investigators. Bousser MG, Bouthier J, et al. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial. Lancet. 2008;371:315–321.CrossRefPubMedGoogle Scholar
  25. 25.
    Olsson SB, Executive Steering Committee of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with nonvalvular atrial fibrillation (SPORTIF III): randomized controlled trial. Lancet. 2003;362:1691–1698.CrossRefPubMedGoogle Scholar
  26. 26.
    Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293:690–698.CrossRefPubMedGoogle Scholar
  27. 27.
    Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949–956.CrossRefPubMedGoogle Scholar
  28. 28.
    RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1–9.PubMedGoogle Scholar
  29. 29.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.CrossRefPubMedGoogle Scholar
  30. 30.
    Lip GY, Rasmussen LH, Olsson SB, et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized doseguiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists. Eur Heart J. 2009;30:2897–2907.CrossRefPubMedGoogle Scholar
  31. 31.
    Finsterer J, Stöllberger C. Strategies for primary and secondary stroke prevention in atrial fibrillation. Neth J Med. 2008;66:327–333.PubMedGoogle Scholar
  32. 32.
    Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs. 2006;15:843–855.CrossRefPubMedGoogle Scholar
  33. 33.
    Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J. 2008;29:155–165.CrossRefPubMedGoogle Scholar
  34. 34.
    Koopman MMW, Büller HR. Short- and longacting synthetic pentasaccharides. J Intern Med. 2003;254:335–342.CrossRefPubMedGoogle Scholar
  35. 35.
    Bijsterveld NR, Vink R, van Aken BE, et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol. 2004;124:653–658.CrossRefPubMedGoogle Scholar
  36. 36.
    Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106:2550–2554.CrossRefPubMedGoogle Scholar
  37. 37.
    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;3:514–521.CrossRefPubMedGoogle Scholar
  38. 38.
    Mueck W, Becka M, Kubitza D, Voith B, Zuehlsdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban — an oral, direct factor xa inhibitor — in healthy subjects. Int J Clin Pharmacol Ther. 2007;45:335–344.PubMedGoogle Scholar
  39. 39.
    Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 — an oral, direct Factor Xa inhibitor — after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873–880.CrossRefPubMedGoogle Scholar
  40. 40.
    Haas S. New oral Xa and IIa inhibitors: updates on clinical trials results. J ThrombThrombolysis. 2008;25:52–60.CrossRefGoogle Scholar
  41. 41.
    Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31–39.CrossRefPubMedGoogle Scholar
  42. 42.
    Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776–2786.CrossRefPubMedGoogle Scholar
  43. 43.
    Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765–2775CrossRefPubMedGoogle Scholar
  44. 44.
    Pinto DJ, Orwat MJ, Koch S, et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c] pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J Med Chem. 2007;50:5339–5356.CrossRefPubMedGoogle Scholar
  45. 45.
    Lassen MR, Gallus AS, Pineo GF, Raskob GE, and the ADVANCE-1 Investigators. Randomized doubleblind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: The ADVANCE-1 trial. Paper presented at: The American Society of Hematology 50th Annual Meeting and Exposition;December 6–9, 2008; San Francisco, CA, USA.Google Scholar
  46. 46.
    Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development. Clin Pharmacokinet. 2009;48:1–22.CrossRefPubMedGoogle Scholar
  47. 47.
    Weitz JI, Connolly SJ, Kunitada S, Jin J, Patel I. Randomized, parallel group, multicenter, multinational study evaluating safety of DU-176b compared with warfarin in subjects with non-valvular atrial fibrillation. Paper presented at: American Society of Hematology 50th Annual Meeting and Exposition; December 6–9, 2008; San Francisco, CA, USA.Google Scholar

Copyright information

© Springer Healthcare 2010

Authors and Affiliations

  • Luciana Armaganijan
    • 1
  • John Eikelboom
    • 2
  • Jeff S. Healey
    • 1
  • Carlos A. Morillo
    • 1
    Email author
  1. 1.Department of Medicine, Cardiology Division, Arrhythmia ServiceMcMaster University, HHSCHamiltonCanada
  2. 2.Department of Medicine, Thrombosis ServiceMcMaster UniversityHamiltonCanada

Personalised recommendations