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Journal of Thrombosis and Thrombolysis

, Volume 36, Issue 2, pp 155–162 | Cite as

Target-specific oral anticoagulants in atrial fibrillation: results of phase III trials and comments on sub-analyses

  • Simon ManthaEmail author
Article

Abstract

Dabigatran, rivaroxaban, apixaban and edoxaban administered in fixed doses and without routine laboratory monitoring have been compared to warfarin for the prevention of stoke in patients with nonvalvular atrial fibrillation (AF). Phase III data is currently available for dabigatran, rivaroxaban and apixaban. It is derived from three randomized controlled trials: RE-LY, ROCKET AF and ARISTOTLE. Dabigatran and apixaban appeared to be superior to warfarin for the primary endpoint of stroke or systemic embolism, while rivaroxaban was deemed non-inferior. The risk of major bleeding was modestly decreased overall with the new agents, while the risk of intracranial hemorrhage was substantially reduced. The results of ENGAGE AF-TIMI 48 comparing edoxaban to warfarin are still pending. Large, well designed clinical trials support the use of three new target-specific oral anticoagulants for the prevention of stroke in individuals with nonvalvular AF.

Keywords

Atrial fibrillation Anticoagulation Stroke 

References

  1. 1.
    Haas S, Schellong S (2007) New anticoagulants: from bench to bedside. Hamostaseologie 27(1):41–47PubMedGoogle Scholar
  2. 2.
    Hrebickova L, Nawarskas JJ, Anderson JR (2003) Ximelagatran: a new oral anticoagulant. Heart Dis 5(6):397–408. doi: 10.1097/01.hdx.0000099777.39577.e8 PubMedCrossRefGoogle Scholar
  3. 3.
    Boos CJ, Lip GY (2006) Ximelagatran: an eulogy. Thromb Res 118(3):301–304. doi: 10.1016/j.thromres.2006.02.012 PubMedCrossRefGoogle Scholar
  4. 4.
    Ezekowitz MD, Reilly PA, Nehmiz G, Simmers TA, Nagarakanti R, Parcham-Azad K, Pedersen KE, Lionetti DA, Stangier J, Wallentin L (2007) Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 100(9):1419–1426. doi: 10.1016/j.amjcard.2007.06.034 PubMedCrossRefGoogle Scholar
  5. 5.
    Ezekowitz MD, Connolly S, Parekh A, Reilly PA, Varrone J, Wang S, Oldgren J, Themeles E, Wallentin L, Yusuf S (2009) Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J 157 (5):805–810, 810 e801–802. doi: 10.1016/j.ahj.2009.02.005 Google Scholar
  6. 6.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H-C, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. doi: 10.1056/NEJMoa0905561 PubMedCrossRefGoogle Scholar
  7. 7.
    Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L (2010) Newly identified events in the RE-LY trial. N Engl J Med 363(19):1875–1876. doi: 10.1056/NEJMc1007378 PubMedCrossRefGoogle Scholar
  8. 8.
    Diener HC, Connolly SJ, Ezekowitz MD, Wallentin L, Reilly PA, Yang S, Xavier D, Di Pasquale G, Yusuf S, group R-Ls (2010) Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: a subgroup analysis of the RE-LY trial. Lancet Neurol 9(12):1157–1163. doi: 10.1016/S1474-4422(10)70274-X PubMedCrossRefGoogle Scholar
  9. 9.
    Hori M, Connolly SJ, Ezekowitz MD, Reilly PA, Yusuf S, Wallentin L, Investigators R-L (2011) Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation–sub-analysis in Japanese population in RE-LY trial. Circ J 75(4):800–805PubMedCrossRefGoogle Scholar
  10. 10.
    Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, Themeles E, Heidbuchle H, Avezum A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M, Investigators R-L (2012) Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation 126(3):343–348. doi: 10.1161/CIRCULATIONAHA.111.090464 PubMedCrossRefGoogle Scholar
  11. 11.
    Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH, Flaker G, Brugada J, Kamensky G, Parekh A, Reilly PA, Yusuf S, Connolly SJ (2011) Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 123(2):131–136. doi: 10.1161/CIRCULATIONAHA.110.977546 PubMedCrossRefGoogle Scholar
  12. 12.
    Wallentin L, Yusuf S, Ezekowitz MD, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ, Investigators R-L (2010) Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376(9745):975–983. doi: 10.1016/S0140-6736(10)61194-4 PubMedCrossRefGoogle Scholar
  13. 13.
    Oldgren J, Alings M, Darius H, Diener HC, Eikelboom J, Ezekowitz MD, Kamensky G, Reilly PA, Yang S, Yusuf S, Wallentin L, Connolly SJ, Investigators R-L (2011) Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Ann Intern Med 155(10):660–667. doi: 10.1059/0003-4819-155-10-201111150-00004 W204PubMedCrossRefGoogle Scholar
  14. 14.
    Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, Yang S, Alings M, Kaatz S, Hohnloser SH, Diener HC, Franzosi MG, Huber K, Reilly P, Varrone J, Yusuf S (2011) Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 123(21):2363–2372. doi: 10.1161/CIRCULATIONAHA.110.004747 PubMedCrossRefGoogle Scholar
  15. 15.
    Flaker G, Ezekowitz M, Yusuf S, Wallentin L, Noack H, Brueckmann M, Reilly P, Hohnloser SH, Connolly S (2012) Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation: results from the RE-LY (randomized evaluation of long-term anticoagulation therapy) study. J Am Coll Cardiol 59(9):854–855. doi: 10.1016/j.jacc.2011.10.896 PubMedCrossRefGoogle Scholar
  16. 16.
    Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf S (2012) Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY trial. Stroke 43(6):1511–1517. doi: 10.1161/STROKEAHA.112.650614 PubMedCrossRefGoogle Scholar
  17. 17.
    Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, Eikelboom J, Brueckmann M, Yusuf S, Connolly SJ (2012) Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 125(5):669–676. doi: 10.1161/CIRCULATIONAHA.111.055970 PubMedCrossRefGoogle Scholar
  18. 18.
    Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A (2011) Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 9(11):2168–2175. doi: 10.1111/j.1538-7836.2011.04498.x PubMedCrossRefGoogle Scholar
  19. 19.
    Investigators RAS (2010) Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J 159 (3):340–347, e341. doi: 10.1016/j.ahj.2009.11.025
  20. 20.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. doi: 10.1056/NEJMoa1009638 PubMedCrossRefGoogle Scholar
  21. 21.
    Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W, Investigators RASC (2012) Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 11(4):315–322. doi: 10.1016/S1474-4422(12)70042-X PubMedCrossRefGoogle Scholar
  22. 22.
    Fox KA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM (2011) Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 32(19):2387–2394. doi: 10.1093/eurheartj/ehr342 PubMedCrossRefGoogle Scholar
  23. 23.
    Eikelboom JW, O’Donnell M, Yusuf S, Diaz R, Flaker G, Hart R, Hohnloser S, Joyner C, Lawrence J, Pais P, Pogue J, Synhorst D, Connolly SJ (2010) Rationale and design of AVERROES: apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. Am Heart J 159(3):348–353. doi: 10.1016/j.ahj.2009.08.026 e341PubMedCrossRefGoogle Scholar
  24. 24.
    Connolly SJ, Eikelboom J, Joyner C, Diener H-C, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim K-H, Lewis BS, Van Mieghem W, Lip GYH, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S (2011) Apixaban in patients with atrial fibrillation. N Engl J Med 364(9):806–817. doi: 10.1056/NEJMoa1007432 PubMedCrossRefGoogle Scholar
  25. 25.
    Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD, Gersh BJ, Granger CB, Hanna M, Horowitz J, Hylek EM, McMurray JJ, Verheugt FW, Wallentin L, Investigators A (2010) Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 159(3):331–339. doi: 10.1016/j.ahj.2009.07.035 PubMedCrossRefGoogle Scholar
  26. 26.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L, Committees A, Investigators (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992. doi: 10.1056/NEJMoa1107039 PubMedCrossRefGoogle Scholar
  27. 27.
    Diener HC, Eikelboom J, Connolly SJ, Joyner CD, Hart RG, Lip GY, O’Donnell M, Hohnloser SH, Hankey GJ, Shestakovska O, Yusuf S, Committee AS, Investigators (2012) Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial. Lancet Neurol 11(3):225–231. doi: 10.1016/S1474-4422(12)70017-0 PubMedCrossRefGoogle Scholar
  28. 28.
    Eikelboom JW, Connolly SJ, Gao P, Paolasso E, De Caterina R, Husted S, O’Donnell M, Yusuf S, Hart RG (2012) Stroke risk and efficacy of apixaban in atrial fibrillation patients with moderate chronic kidney disease. J Stroke Cerebrovas Dis 21(6):429–435. doi: 10.1016/j.jstrokecerebrovasdis.2012.05.007 CrossRefGoogle Scholar
  29. 29.
    Flaker GC, Eikelboom JW, Shestakovska O, Connolly SJ, Kaatz S, Budaj A, Husted S, Yusuf S, Lip GY, Hart RG (2012) Bleeding during treatment with aspirin versus apixaban in patients with atrial fibrillation unsuitable for warfarin: the apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment (AVERROES) trial. Stroke. doi: 10.1161/STROKEAHA.112.664144 PubMedGoogle Scholar
  30. 30.
    Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, Keltai M, Lanas F, Lopes RD, Lopez-Sendon J, Granger CB, Wallentin L (2012) Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. doi: 10.1093/eurheartj/ehs274 Google Scholar
  31. 31.
    Easton JD, Lopes RD, Bahit MC, Wojdyla DM, Granger CB, Wallentin L, Alings M, Goto S, Lewis BS, Rosenqvist M, Hanna M, Mohan P, Alexander JH, Diener HC, Committees A, Investigators (2012) Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol 11(6):503–511. doi: 10.1016/S1474-4422(12)70092-3 PubMedCrossRefGoogle Scholar
  32. 32.
    Lopes RD, Al-Khatib SM, Wallentin L, Yang H, Ansell J, Bahit MC, De Caterina R, Dorian P, Easton JD, Erol C, Ezekowitz JA, Gersh BJ, Granger CB, Hohnloser SH, Horowitz J, Hylek EM, McMurray JJ, Mohan P, Vinereanu D, Alexander JH (2012) Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet. doi: 10.1016/S0140-6736(12)60986-6 Google Scholar
  33. 33.
    Weitz JI, Connolly SJ, Patel I, Salazar D, Rohatagi S, Mendell J, Kastrissios H, Jin J, Kunitada S (2010) Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 104(3):633–641. doi: 10.1160/TH10-01-0066 PubMedCrossRefGoogle Scholar
  34. 34.
    Ruff CT, Giugliano RP, Antman EM, Crugnale SE, Bocanegra T, Mercuri M, Hanyok J, Patel I, Shi M, Salazar D, McCabe CH, Braunwald E (2010) Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the effective anticoagulation with factor xA next generation in atrial fibrillation–thrombolysis in myocardial infarction study 48 (ENGAGE AF-TIMI 48). Am Heart J 160(4):635–641. doi: 10.1016/j.ahj.2010.06.042 PubMedCrossRefGoogle Scholar
  35. 35.
    Sankyo D (2010) Daiichi Sankyo completes enrollment of the edoxaban global phase 3 engage af-timi 48 study in patients with atrial fibrillation. http://www.daiichisankyo.com/news/detail/003856.html. Accessed 10 Sept 2012

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of MedicineHematology Service, Memorial Sloan-Kettering Cancer CenterNew York USA

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