Non-vitamin K oral anticoagulants in atrial fibrillation: Where are we now?

Trends in Cardiovascular Medicine

Volumn 25, Issue 4, 2015, Pages 315-336

  Dzeshka, Mikhail S ^a,b   Lip, Gregory Y H ^a,c  

^a UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^b GRODNO STATE MEDICAL UNIVERSITY   (Belarus)

^c AALBORG UNIVERSITY   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

ANTICOAGULANT AGENT; ANTIVITAMIN K; APIXABAN; DABIGATRAN; EDOXABAN; NON VITAMIN K ORAL ANTICOAGULANT; RIVAROXABAN; UNCLASSIFIED DRUG; WARFARIN; FIBRINOLYTIC AGENT; VITAMIN K GROUP;

ACUTE CORONARY SYNDROME; ANTICOAGULANT THERAPY; ANTICOAGULATION; ATRIAL FIBRILLATION; BLEEDING; CEREBROVASCULAR ACCIDENT; DOSAGE SCHEDULE COMPARISON; DRUG EFFICACY; DRUG SAFETY; HUMAN; INTERNATIONAL NORMALIZED RATIO; PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; THROMBOEMBOLISM; ANTAGONISTS AND INHIBITORS; COMPLICATION; ORAL DRUG ADMINISTRATION; RISK FACTOR; STROKE; TREATMENT OUTCOME;

ADMINISTRATION, ORAL; ANTICOAGULANTS; ATRIAL FIBRILLATION; FIBRINOLYTIC AGENTS; HUMANS; RISK FACTORS; STROKE; THROMBOEMBOLISM; TREATMENT OUTCOME; VITAMIN K;

EID: 84928711401     PISSN: 10501738     EISSN: 18732615     Source Type: Journal    
DOI: 10.1016/j.tcm.2014.10.017     Document Type: Review

References (162)

1. Camm A.J., Lip G.Y., De Caterina R., Savelieva I., Atar D., Hohnloser S.H., et al. ESC Committee for Practice Guidelines-CPG; Document reviewers. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Europace 2012, 14(10):1385-1413.
2. January C.T., Wann L.S., Alpert J.S., Calkins H., Cleveland J.C., Cigarroa J.E., et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014, [Epub ahead of print].
3. Lowres N., Neubeck L., Salkeld G., Krass I., McLachlan A.J., Redfern J., et al. Feasibility and cost-effectiveness of stroke prevention through community screening for atrial fibrillation using iPhone ECG in pharmacies. The SEARCH-AF study. Thromb Haemost 2014, 111(6):1167-1176.
4. Lowres N., Neubeck L., Redfern J., Freedman S.B. Screening to identify unknown atrial fibrillation. A systematic review. Thromb Haemost 2013, 110(2):213-222.
5. De Caterina R., Husted S., Wallentin L., Andreotti F., Arnesen H., Bachmann F., et al. Vitamin K antagonists in heart disease: current status and perspectives (Section III). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013, 110(6):1087-1107.
6. Husted S., de Caterina R., Andreotti F., Arnesen H., Bachmann F., Huber K., et al. Non-vitamin K antagonist oral anticoagulants (NOACs): no longer new or novel. Thromb Haemost 2014, 111:781-782.
7. Heidbuchel H., Verhamme P., Alings M., Antz M., Hacke W., Oldgren J., et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013, 15(5):625-651.
8. Lip G.Y., Nieuwlaat R., Pisters R., Lane D.A., Crijns H.J. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest 2010, 137(2):263-272.
9. Friberg L., Rosenqvist M., Lip G. Net clinical benefit of warfarin in patients with atrial fibrillation: a report from the Swedish Atrial Fibrillation Cohort Study. Circulation 2012, 125(19):2298-2307.
10. Banerjee A., Lane D.A., Torp-Pedersen C., Lip G.Y. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a 'real world' atrial fibrillation population: a modelling analysis based on a nationwide cohort study. Thromb Haemost 2012, 107(3):584-589.
11. Olesen J.B., Lip G.Y., Lindhardsen J., Lane D.A., Ahlehoff O., Hansen M.L., et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a 'real world' nationwide cohort study. Thromb Haemost 2011, 106(4):739-749.
12. Van Staa T.P., Setakis E., Di Tanna G.L., Lane D.A., Lip G.Y. A comparison of risk stratification schemes for stroke in 79,884 atrial fibrillation patients in general practice. J Thromb Haemost 2011, 9(1):39-48.
13. Friberg L., Rosenqvist M., Lip G.Y. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J 2012, 33(12):1500-1510.
14. Olesen J.B., Torp-Pedersen C., Hansen M.L., Lip G.Y. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Thromb Haemost 2012, 107(6):1172-1179.
15. Pisters R., Lane D.A., Nieuwlaat R., de Vos C.B., Crijns H.J., Lip G.Y. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010, 138(5):1093-1100.
16. Lip G.Y. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why?. Eur Heart J 2013, 34(14):1041-1049.
17. Hart R.G., Pearce L.A., Aguilar M.I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007, 146(12):857-867.
18. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S., Pogue J., Hart R., Pfeffer M., Hohnloser S., 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 randomised controlled trial. Lancet 2006, 367(9526):1903-1912.
19. Birman-Deych E., Radford M.J., Nilasena D.S., Gage B.F. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke 2006, 37:1070-1074.
20. Wilke T., Groth A., Mueller S., Pfannkuche M., Verheyen F., Linder R., et al. Oral anticoagulation use by patients with atrial fibrillation in Germany. Adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients. Thromb Haemost 2012, 107(6):1053-1065.
21. Le Heuzey J.Y., Ammentorp B., Darius H., De Caterina R., Schilling R.J., Schmitt J., et al. Differences among western European countries in anticoagulation management of atrial fibrillation. Data from the PREFER IN AF registry. Thromb Haemost 2014, 111(5):833-841.
22. Gallego P., Roldan V., Marín F., Romera M., Valdés M., Vicente V., et al. Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation. Thromb Haemost 2013, 110(6):1189-1198.
23. Gallagher A.M., Setakis E., Plumb J.M., Clemens A., van Staa T.P. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost 2011, 106:968-977.
24. Apostolakis S., Sullivan R.M., Olshansky B., Lip G.Y. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score. Chest 2013, 144(5):1555-1563.
25. Poli D., Antonucci E., Testa S., Lip G.Y. A prospective validation of the SAME-TT2R2 score: how to identify atrial fibrillation patients who will have good anticoagulation control on warfarin. Intern Emerg Med 2014, 9(4):443-447.
26. Lip G.Y., Haguenoer K., Saint-Etienne C., Fauchier L. Relationship of the SAME-TT2R2 score to poor quality anticoagulation, stroke, clinically relevant bleeding and mortality in patients with atrial fibrillation. Chest 2014, 146(3):719-726.
27. De Caterina R., Husted S., Wallentin L., Andreotti F., Arnesen H., Bachmann F., et al. European Society of Cardiology Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. General mechanisms of coagulation and targets of anticoagulants (Section I). Position paper of the ESC Working Group on Thrombosis-Task Force on Anticoagulants in Heart Disease. Thromb Haemost 2013, 109(4):569-579.
28. Esmon C.T. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost 2014, 111(4):625-633.
29. Lip G.Y., Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 2014, 35(28):1844-1855.
30. Connolly S.J., Ezekowitz M.D., Yusuf S., Eikelboom J., Oldgren J., Parekh A., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009, 361(12):1139-1151. RE-LY Steering Committee and Investigators.
31. Connolly S.J., Ezekowitz M.D., Yusuf S., Reilly P.A., Wallentin L. Randomized evaluation of long-term anticoagulation therapy investigators. Newly identified events in the RE-LY trial. N Engl J Med 2010, 363(19):1875-1876.
32. Patel M.R., Mahaffey K.W., Garg J., Pan G., Singer D.E., Hacke W., et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011, 365(10):883-891.
33. Granger C.B., Alexander J.H., McMurray J.J., Lopes R.D., Hylek E.M., Hanna M., et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011, 365(11):981-992. ARISTOTLE Committees and Investigators.
34. Giugliano R.P., Ruff C.T., Braunwald E., Murphy S.A., Wiviott S.D., Halperin J.L., et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013, 369(22):2093-2104. ENGAGE AF-TIMI 48 Investigators.
35. Beyer-Westendorf J., Büller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different?. J Thromb Haemost 2011, 9(11):2153-2158.
36. Furberg C.D., Soliman E.Z. Double-blindness protects scientific validity. J Thromb Haemost 2008, 6:230-231.
37. Juni P., Altman D.G., Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. Br Med J 2001, 323:42-46.
38. Rodriguez R.A., Carrier M., Wells P.S. Non-adherence to new oral anticoagulants: a reason for concern during long-term anticoagulation?. J Thromb Haemost 2013, 11(2):390-394.
39. Kneeland P.P., Fang M.C. Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism. Patient Prefer Adherence 2010, 4:51-60.
40. Platt A.B., Localio A.R., Brensinger C.M., Cruess D.G., Christie J.D., Gross R., et al. Risk factors for nonadherence to warfarin: results from the IN-RANGE study. Pharmacoepidemiol Drug Saf 2008, 17:853-860.
41. Comté L., Vrijens B., Tousset E., Gérard P., Urquhart J. Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics. J Pharmacokinet Pharmacodyn 2007, 34(4):549-558.
42. Chatterjee S., Sardar P., Giri J.S., Ghosh J., Mukherjee D. Treatment discontinuations with new oral agents for long-term anticoagulation: insights from a meta-analysis of 18 randomized trials including 101,801 patients. Mayo Clin Proc 2014, 89(7):896-907.
43. Barker R.V., Lip G.Y., Lane D.A. Best practice for atrial fibrillation patient education. Curr Pharm Des 2014, [Epub ahead of print].
44. Clarkesmith D.E., Pattison H.M., Lane D.A. Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation. Cochrane Database Syst Rev 2013, 6. CD008600.
45. Clarkesmith D.E., Pattison H.M., Lip G.Y., Lane D.A. Educational intervention improves anticoagulation control in atrial fibrillation patients: the TREAT randomised trial. PLoS One 2013, 8(9):e74037.
46. Dale B., Eikelboom J.W., Weitz J.I., Young E., Paikin J.S., Coppens M., et al. Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?. J Thromb Thrombolysis 2013, 35(2):295-301.
47. Adam S.S., McDuffie J.R., Ortel T.L., Williams J.W. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism. Ann Intern Med 2012, 157(11):796-807.
48. Dentali F., Riva N., Crowther M., Turpie A.G., Lip G.Y., Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation. Circulation 2012, 126(20):2381-2391.
49. Lip G.Y.H., Larsen T.B., Skjøth F., Rasmussen L.H. Indirect comparisons of new oral anticoagulants for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol 2012, 60(8):738-746.
50. Ruff C.T., Giugliano R.P., Braunwald E., Hoffman E.B., Deenadayalu N., Ezekowitz M.D., et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014, 383(9921):955-962.
51. Larsen T.B., Rasmussen L.H., Skjøth F., Due K.M., Callréus T., Rosenzweig M., et al. Efficacy and safety of dabigatran etexilate and warfarin in "real-world" patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol 2013, 61(22):2264-2273.
52. Laliberté F., Cloutier M., Nelson W.W., Coleman C.I., Pilon D., Olson W.H., et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin 2014, 30(7):1317-1325.
53. Kreutz R. A clinical and pharmacologic assessment of once-daily versus twice-daily dosing for rivaroxaban. J Thromb Thrombolysis 2014, 38(2):137-149.
54. Mueck W., Lensing A.W., Agnelli G., Decousus H., Prandoni P., Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011, 50:675-686.
55. Weitz J.I., Connolly S.J., Patel I., Salazar D., Rohatagi S., Mendell J., et al. 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 2010, 104:633-641.
56. Salazar D.E., Mendell J., Kastrissios H., Green M., Carrothers T.J., Song S., et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012, 107:925-936.
57. Clemens A., Noack H., Brueckmann M., Lip G.Y. Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria. PLoS One 2014, 9(6):e99276.
58. Douxfils J., Mullier F., Robert S., Chatelain C., Chatelain B., Dogné J.-M. Impact of dabigatran on a large panel of routine or specific coagulation assays. Thromb Haemost 2012, 107(5):985-997.
59. Cohen D. Dabigatran: how the drug company withheld important analyses. Br Med J 2014, 349:g4670.
60. Charlton B., Redberg R. The trouble with dabigatran. Br Med J 2014, 349:g4681.
61. Moore T.J., Cohen M.R., Mattison D.R. Dabigatran, bleeding, and the regulators. Br Med J 2014, 349:g4517.
62. Reilly P.A., Lehr T., Haertter S., Connolly S.J., Yusuf S., Eikelboom J.W., et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014, 63(4):321-328. RE-LY Investigators.
63. Boehringer Ingelheim. Benefits and safety of Pradaxa® (dabigatran etexilate mesylate) repeatedly confirmed. British Medical Journal publishes biased article regarding PRADAXA. Press Release. Available from: ; 2014 [08.08.2014]. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/07-23-14-benefits-safety-pradaxa-dabigatran-etexilate-mesylate-repeatedly-confirmed.html.
64. Eikelboom J.W., Wallentin L., Connolly S.J., Ezekowitz M., Healey J.S., Oldgren J., et al. 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 2011, 123(21):2363-2372.
65. Halperin J.L., Hankey G.J., Wojdyla D.M., Piccini J.P., Lokhnygina Y., Patel M.R., et al. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014, 130(2):138-146. ROCKET AF Steering Committee and Investigators.
66. Halvorsen S., Atar D., Yang H., De Caterina R., Erol C., Garcia D., et al. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial. Eur Heart J 2014, 35(28):1864-1872.
67. Oldgren J., Alings M., Darius H., Diener H.C., Eikelboom J., Ezekowitz M.D., et al. 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 2011, 155(10). RE-LY Investigators, (660-7, W204).
68. Lopes R.D., Al-Khatib S.M., Wallentin L., Yang H., Ansell J., Bahit M.C., et al. 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 2012, 380(9855):1749-1758.
69. Hijazi Z., Hohnloser S.H., Oldgren J., Andersson U., Connolly S.J., Eikelboom J.W., et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014, 129(9):961-970.
70. Hohnloser S.H., Hijazi Z., Thomas L., Alexander J.H., Amerena J., Hanna M., et al. 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 2012, 33(22):2821-2830.
71. Ferreira J., Ezekowitz M.D., Connolly S.J., Brueckmann M., Fraessdorf M., Reilly P.A., et al. Dabigatran compared with warfarin in patients with atrial fibrillation and symptomatic heart failure: a subgroup analysis of the RE-LY trial. Eur J Heart Fail 2013, 15(9):1053-1061. RE-LY Investigators.
72. McMurray J.J., Ezekowitz J.A., Lewis B.S., Gersh B.J., van Diepen S., Amerena J., et al. Left ventricular systolic dysfunction, heart failure, and the risk of stroke and systemic embolism in patients with atrial fibrillation: insights from the ARISTOTLE trial. Circ Heart Fail 2013, 6(3):451-460. ARISTOTLE Committees and Investigators.
73. Diener H.C., Connolly S.J., Ezekowitz M.D., Wallentin L., Reilly P.A., Yang S., et al. 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 2010, 9(12):1157-1163. RE-LY study group.
74. Hankey G.J., Patel M.R., Stevens S.R., Becker R.C., Breithardt G., Carolei A., et al. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol 2012, 11(4):315-322. ROCKET AF Steering Committee Investigators.
75. Easton J.D., Lopes R.D., Bahit M.C., Wojdyla D.M., Granger C.B., Wallentin L., et al. 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 2012, 11(6):503-511. ARISTOTLE Committees and Investigators.
76. Dans A.L., Connolly S.J., Wallentin L., Yang S., Nakamya J., Brueckmann M., et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013, 127(5):634-640.
77. Alexander J.H., Lopes R.D., Thomas L., Alings M., Atar D., Aylward P., et al. Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2014, 35(4):224-232.
78. Wallentin L., Yusuf S., Ezekowitz M.D., Alings M., Flather M., Franzosi M.G., et al. 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 2010, 376(9745):975-983. RE-LY investigators.
79. Piccini J.P., Hellkamp A.S., Lokhnygina Y., Patel M.R., Harrell F.E., Singer D.E., et al. Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial. J Am Heart Assoc 2014, 3(2):e000521. ROCKET AF Investigators.
80. Wallentin L., Lopes R.D., Hanna M., Thomas L., Hellkamp A., Nepal S., et al. Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Investigators. Efficacy and safety of apixaban compared with warfarin at different levels of predicted international normalized ratio control for stroke prevention in atrial fibrillation. Circulation 2013, 127(22):2166-2176.
81. Garcia D.A., Wallentin L., Lopes R.D., Thomas L., Alexander J.H., Hylek E.M., et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J 2013, 166(3):549-558.
82. Ng K.H., Hart R.G., Eikelboom J.W. Anticoagulation in patients aged ≥75 years with atrial fibrillation: role of novel oral anticoagulants. Cardiol Ther 2013, 2(2):135-149.
83. Sardar P., Chatterjee S., Chaudhari S., Lip G.Y. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc 2014, 62(5):857-864.
84. Nagarakanti R., Ezekowitz M.D., Oldgren J., Yang S., Chernick M., Aikens T.H., et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011, 123(2):131-136.
85. Piccini J.P., Stevens S.R., Lokhnygina Y., Patel M.R., Halperin J.L., Singer D.E., et al. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 2013, 61(19):1998-2006. ROCKET AF Steering Committee & Investigators.
86. Flaker G., Lopes R.D., Al-Khatib S.M., Hermosillo A.G., Hohnloser S.H., Tinga B., et al. Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 2014, 63(11):1082-1087. ARISTOTLE Committees and Investigators.
87. Bernard A., Fauchier L., Pellegrin C., Clementy N., Saint Etienne C., Banerjee A., et al. Anticoagulation in patients with atrial fibrillation undergoing coronary stent implantation. Thromb Haemost 2013, 110(3):560-568.
88. Lip G.Y., Windecker S., Huber K., Kirchhof P., Marin F., Ten Berg J.M., et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary or valve interventions: a joint consensus document of the European Society of Cardiology Working Group on Thrombosis, European Heart Rhythm Association (EHRA), European Association of Percutaneous Cardiovascular Interventions (EAPCI) and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS) and Asia-Pacific Heart Rhythm Society (APHRS). Eur Heart J 2014, Task Force Members, [Epub ahead of print].
89. Lamberts M., Gislason G.H., Lip G.Y., Lassen J.F., Olesen J.B., Mikkelsen A.P., et al. Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. Circulation 2014, 129(15):1577-1585.
90. Depta J.P., Bhatt D.L. Atherothrombosis and atrial fibrillation: important and often overlapping clinical syndromes. Thromb Haemost 2010, 104(4):657-663.
91. Wysokinski W.E., Owen W.G., Fass D.N., Patrzalek D.D., Murphy L., McBane R.D. Atrial fibrillation and thrombosis: immunohistochemical differences between insitu and embolized thrombi. J Thromb Haemost 2004, 2(9):1637-1644.
92. Lip G.Y., Huber K., Andreotti F., Arnesen H., Airaksinen K.J., Cuisset T., et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost 2010, 103(1):13-28. European Society of Cardiology Working Group on Thrombosis.
93. Hawn M.T., Graham L.A., Richman J.S., Itani K.M., Henderson W.G., Maddox T.M. Risk of major adverse cardiac events following noncardiac surgery in patients with coronary stents. J Am Med Assoc 2013, 310:1462-1472.
94. Mehran R., Baber U., Steg P.G., Ariti C., Weisz G., Witzenbichler B., et al. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013, 382:1714-1722.
95. Mega J.L., Braunwald E., Wiviott S.D., Bassand J.P., Bhatt D.L., Bode C., et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012, 366(1):9-19. ATLAS ACS 2-TIMI 51 Investigators.
96. Mega J.L., 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(9683):29-38. ATLAS ACS-TIMI 46 study group.
97. Alexander J.H., Becker R.C., Bhatt D.L., Cools F., Crea F., 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):2877-2885. APPRAISE Steering Committee and Investigators.
98. Alexander J.H., Lopes R.D., James S., Kilaru R., He Y., Mohan P., et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011, 365(8):699-708. APPRAISE-2 Investigators.
99. Oldgren J., Budaj A., Granger C.B., 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(22):2781-2789. RE-DEEM Investigators.
100. Oldgren J., Wallentin L., Alexander J.H., James S., Jönelid B., Steg G., et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013, 34(22):1670-1680.
101. Douketis J.D., Spyropoulos A.C., Spencer F.A., Mayr M., Jaffer A.K., Eckman M.H. American College of Chest Physicians. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141(2 Suppl):e326S-e350S.
102. Beyer-Westendorf J., Gelbricht V., Förster K., Ebertz F., Kohler C., Werth S., et al. Peri-interventional management of novel oral anticoagulants in daily care: results from the prospective Dresden NOAC registry. Eur Heart J 2014, 35(28):1888-1896.
103. Healey J.S., Eikelboom J., Douketis J., Wallentin L., Oldgren J., Yang S., et al. 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 2012, 126(3):343-348. RE-LY Investigators.
104. Sherwood M.W., Douketis J.D., Patel M.R., Piccini J.P., Hellkamp A.S., Lokhnygina Y., et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation 2014, 129(18):1850-1859. ROCKET AF Investigators.
105. Lopes R.D., Garcia D.A., Wojdyla D., Dorian P., Alexander J.H., Wallentin L., et al. Use of apixaban and warfarin in patients undergoing invasive procedures: insights from Aristotle. Can J Cardiol 2013, 29(10, Suppl):S232-S233.
106. Dickneite G., Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence?. Thromb Haemost 2014, 111(2):189-198.
107. Miesbach W., Seifried E. New direct oral anticoagulants-current therapeutic options and treatment recommendations for bleeding complications. Thromb Haemost 2012, 108(4):625-632.
108. Singh T., Maw T.T., Henry B.L., et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013, 8(9):1533-1539.
109. Chang D.N., Dager W.E., Chin A.I. Removal of dabigatran by hemodialysis. Am J Kidney Dis 2013, 61(3):487-489.
110. Khadzhynov D., Wagner F., Formella S., Wiegert E., Moschetti V., Slowinski T., et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease. Thromb Haemost 2013, 109(4):596-605.
111. Lip G.Y., Frison L., Halperin J.L., Lane D.A. Identifying patients at high risk for stroke despite anticoagulation: a comparison of contemporary stroke risk stratification schemes in an anticoagulated atrial fibrillation cohort. Stroke 2010, 41(12):2731-2738.
112. Strazzullo P., D'Elia L., Cairella G., Garbagnati F., Cappucio F.P., Scalfi L. Excess body weight and incidence of stroke: meta-analysis of prospective studies with 2 million participants. Stroke 2010, 41(5):e418-e426.
113. Overvad T.F., Rasmussen L.H., Skjøth F., Overvad K., Lip G.Y., Larsen T.B. Body mass index and adverse events in patients with incident atrial fibrillation. Am J Med 2013, 126(7):640.e9-640.e17.
114. Albertsen I.E., Rasmussen L.H., Lane D.A., Overvad T.F., Skjoth F., Overvad K., et al. The impact of smoking on thromboembolism and mortality in patients with incident atrial fibrillation: insights from the Danish Diet, Cancer and Health study. Chest 2014, 145(3):559-566.
115. Overvad T.F., Rasmussen L.H., Skjøth F., Overvad K., Albertsen I.E., Lane D.A., et al. Alcohol intake and prognosis of atrial fibrillation. Heart 2013, 99(15):1093-1099.
116. Schaefer J.K., McBane R.D., Black D.F., Williams L.N., Moder K.G., Wysokinski W.E. Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients. Thromb Haemost 2014, 112(5). [Epub ahead of print].
117. Kernan W.N., Ovbiagele B., Black H.R., Bravata D.M., Chimowitz M.I., Ezekowitz M.D., et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014, 45(7):2160-2236.
118. Paré G., Eriksson N., Lehr T., Connolly S., Eikelboom J., Ezekowitz M.D., et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation 2013, 127(13):1404-1412.
119. Sargento-Freitas J., Silva F., Pego J., Duque C., Cordeiro G., Cunha L. Cardioembolic stroke in a patient taking dabigatran etexilate: the first case report of clinical and pharmacologic resistance. J Neurol Sci 2014, [Epub ahead of print].
120. Paciaroni M., Agnelli G. Should oral anticoagulants be restarted after warfarin-associated cerebral haemorrhage in patients with atrial fibrillation?. Thromb Haemost 2014, 111(1):14-18.
121. Yung D., Kapral M.K., Asllani E., Fang J., Lee D.S. Reinitiation of anticoagulation after warfarin-associated intracranial hemorrhage and mortality risk: the Best Practice for Reinitiating Anticoagulation Therapy After Intracranial Bleeding (BRAIN) study. Can J Cardiol 2012, 28:33-39. Investigators of the Registry of the Canadian Stroke Network.
122. Majeed A., Kim Y.K., Roberts R.S., Holmstrom M., Schulman S. Optimal timing of resumption of warfarin after intracranial hemorrhage. Stroke 2010, 41:2860-2866.
123. Poli D., Antonucci E., Dentali F., Erba N., Testa S., Tiraferri E., Palareti G. Italian Federation of Anticoagulation Clinics (FCSA). Recurrence of ICH after resumption of anticoagulation with VK antagonists: CHIRONE study. Neurology 2014, 82(12):1020-1026.
124. Eckman M.H., Rosand J., Knudsen K.A., Singer D.E., Greenberg S.M. Can patients be anticoagulated after intracerebral hemorrhage? A decision analysis. Stroke 2003, 34:1710-1716.
125. Viswanathan A., Rakich S.M., Engel C., Snider R., Rosand J., Greenberg S.M., et al. Antiplatelet use after intracerebral hemorrhage. Neurology 2006, 66(2):206-209.
126. Bailey R.D., Hart R.G., Benavente O., Pearce L.A. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology 2001, 56(6):773-777.
127. Morgenstern L.B., Hemphill J.C., Anderson C., Becker K., Broderick J.P., Connolly E.S., et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2010, 41(9):2108-2129.
128. Steiner T., Al-Shahi Salman R., Beer R., Christensen H., Cordonnier C., Csiba L., et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014, 9(7):840-855.
129. Zhang R., Wang X., Tang Z., Liu J., Yang S., Zhang Y., et al. Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies. Lipids Health Dis 2014, 13:47.
130. van Etten E.S., Auriel E., Haley K.E., Ayres A.M., Vashkevich A., Schwab K.M., et al. Incidence of symptomatic hemorrhage in patients with lobar microbleeds. Stroke 2014, 45(8):2280-2285.
131. Barkun A.N., Bardou M., Kuipers E.J., Sung J., Hunt R.H., Martel M., et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2010, 152(2):101-113.
132. Qureshi W., Mittal C., Patsias I., Garikapati K., Kuchipudi A., Cheema G., et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol 2014, 113(4):662-668.
133. Witt D.M., Delate T., Garcia D.A., Clark N.P., Hylek E.M., Ageno W., et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med 2012, 172:1484-1491.
134. Clemens A., Strack A., Noack H., Konstantinides S., Brueckmann M., Lip G.Y. Anticoagulant-related gastrointestinal bleeding-could this facilitate early detection of benign or malignant gastrointestinal lesions?. Ann Med 2014, 1-7. [Epub ahead of print].
135. Skjøth F., Larsen T.B., Rasmussen L.H. Indirect comparison studies-are they useful? Insights from the novel oral anticoagulants for stroke prevention in atrial fibrillation. Thromb Haemost 2012, 108(3):405-406.
136. Mantha S., Ansell J. An indirect comparison of dabigatran, rivaroxaban, and apixaban for atrial fibrillation. Thromb Haemost 2012, 108(3):476-484.
137. Rasmussen L.H., Larsen T.B., Graungaard T., Skjøth F., Lip G.Y. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis. Br Med J 2012, 345:e7097. 10.1136/bmj.e7097.
138. Skjøth F., Larsen T.B., Rasmussen L.H., Lip G.Y. Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. An indirect comparison analysis. Thromb Haemost 2014, 111(5):981-988.
139. Verdecchia P., Angeli F., Lip G.Y., Reboldi G. Edoxaban in the evolving scenario of non vitamin K antagonist oral anticoagulants imputed placebo analysis and multiple treatment comparisons. PLoS One 2014, 9(6):e100478.
140. Ezekowitz M.D., Cappato R., Klein A.L., Camm A.J., Ma C.S., Le Heuzey J.Y., et al. Rationale and design of the eXplore the efficacy and safety of once-daily oral riVaroxaban for the prEvention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion trial: A comparison of oral rivaroxaban once daily with dose-adjusted vitamin K antagonists in patients with nonvalvular atrial fibrillation undergoing elective cardioversion. Am Heart J 2014, 167(5):646-652.
141. John H. Stroger Hospital. Anticoagulation with rivaroxaban in cardioversion-The ARC study. NLM Identifier: NCT01747746. Available from ; 2012 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01747746.
142. Pfizer. Study of the blood thinner, apixaban, for patients who have an abnormal heart rhythm (atrial fibrillation) and expected to have treatment to put them back into a normal heart rhythm (Cardioversion) (EMANATE). NLM Identifier: NCT02100228. Available from ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02100228.
143. Daiichi Sankyo Inc. Edoxaban vs. warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF). NLM Identifier: NCT02072434. Available from ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02072434.
144. Skanes A. DAPPAR A.F. Dabigatran for peri procedural anticoagulation during radiofrequency ablation of atrial fibrillation (DAPPARAF). NLM Identifier: NCT01468155. Available from: ; 2011 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01468155.
145. Nickenig G. Prevention of silent cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation (ODIn-AF). NLM Identifier: NCT02067182. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02067182.
146. Vanderbilt University. Use of dabigatran etexilate to prevent stroke and thromboembolism. NLM Identifier: NCT01976507. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01976507.
147. Naccarelli G.V., Cappato R., Hohnloser S.H., Marchlinski F.E., Wilber D.J., Xiang J., et al. Rationale and design of VENTURE-AF: a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial fibrillation. J Interv Card Electrophysiol 2014, 41(2):107-116. on behalf of the VENTURE-AF Investigators.
148. University of Ottawa Heart Institute. Optimal Anticoagulation for higher risk patients post-catheter ablation for atrial fibrillation trial (OCEAN). NLM Identifier: NCT02168829. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02168829.
149. Bayer. Exploring the efficacy of once daily oral rivaroxaban for treatment of thrombus in left atrial/left atrial appendage in subjects with nonvalvular atrial fibrillation or atrial flutter (X-TRA). NLM Identifier: NCT01839357. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01839357.
150. Boehringer Ingelheim. Evaluation of dual therapy with dabigatran vs. triple therapy with warfarin in patients with AF that undergo a PCI with stenting (REDUAL-PCI). NLM Identifier: NCT02164864. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02164864.
151. Janssen Scientific Affairs, LLC. A study exploring two strategies of rivaroxaban (JNJ39039039; BAY-59-7939) and one of oral vitamin K antagonist in patients with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). NLM Identifier: NCT01830543. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01830543.
152. Fujita Health University. Registry for estimation of warfarin and rivaroxaban in atrial fibrillation patients with coronary stent implantation (REWRAPS). NLM Identifier: NCT02024230. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02024230.
153. Japan Cardiovascular Research Foundation. RELAXED: recurrent embolism lessened by rivaroxaban for acute ischemic stroke. NLM Identifier: NCT02129920. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02129920.
154. Asan Medical Center. Rivaroxaban versus warfarin in acute ischemic stroke with atrial fibrillation (TripleAXEL). NLM Identifier: NCT02042534. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02042534.
155. Boehringer Ingelheim. Pradaxa study in non-valvular atrial fibrillation patients with severely impaired renal function. NLM Identifier: NCT01896297. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01896297.
156. Eikelboom J.W., Connolly S.J., Brueckmann M., Granger C.B., Kappetein A.P., Mack M.J., et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013, 369(13):1206-1214. RE-ALIGN Investigators.
157. Hospital Ana Nery. Dabigatran versus warfarin after mitral and/or aortic bioprosthesis replacement and atrial fibrillation postoperatively (DAWA). NLM Identifier: NCT01868243. Available from: ; 2013 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT01868243.
158. Lévy S. Newer clinically available antithrombotics and their antidotes. J Interv Card Electrophysiol 2014, 40(3):269-275.
159. Boehringer Ingelheim. Reversal of dabigatran anticoagulant effect with idarucizumab. NLM Identifier: NCT02104947. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/show/NCT02104947.
160. Lu G., DeGuzman F.R., Hollenbach S.J., Karbarz M.J., Abe K., Lee G., et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013, 19(4):446-451.
161. Portola Pharmaceuticals. A study in older subject to evaluate the safety and ability of andexanet alfa to reverse the anticoagulation effect of rivaroxaban. NLM Identifier: NCT02220725. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02220725.
162. Portola Pharmaceuticals. A study in older subject to evaluate the safety and ability of andexanet alfa to reverse the anticoagulation effect of rivaroxaban. NLM Identifier: NCT02207725. Available from: ; 2014 [accessed 20.08.14]. http://clinicaltrials.gov/ct2/show/NCT02207725.