Review Article| Volume 355, ISSUE 5, P467-476, May 2018

Antithrombotic Therapy in Nonvalvular Atrial Fibrillation: Consensus and Challenges


      Atrial fibrillation (AF) is associated with high risk of systemic thromboembolism leading to significant morbidity and mortality. Warfarin, previously the mainstay for stroke prevention in AF, requires close monitoring because of multiple food and drug interactions. In recent years, food and drug administration has approved several direct oral anticoagulants (DOACs) for use in patients with nonvalvular AF. These agents have not been studied in patients with valvular AF who are at an even higher risk of systemic thromboembolism. DOACs do not require frequent blood testing or changes in dosage except when renal function deteriorates, however, the lack of established antidotes for many of these agents remains a challenge. Also, currently there is no head-to-head comparison between these agents to guide clinical choice. This article discusses the advantages and disadvantages of currently approved oral antithrombotics in nonvalvular AF, with a special emphasis on the DOACs and their individual characteristics.

      Key Indexing Terms

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of the Medical Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Chugh S.S.
        • Havmoeller R.
        • Narayanan K.
        • et al.
        Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study.
        Circulation. 2014; 129: 837-847
        • Lloyd-Jones D.
        • Wang T.
        • Leip E.
        Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.
        Circulation. 2004; 110: 1042-1046
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • et al.
        2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.
        Circulation. 2014; 130: 2071-2104
        • Wolf P.A.
        Awareness of the role of atrial fibrillation as a cause of ischemic stroke.
        Stroke. 2014; 45: e19-e21
        • Freedman M.D.
        Oral anticoagulants: pharmacodynamics, clinical indications and adverse effects.
        J Clin Pharmacol. 1992; 32: 196-209
        • Group SR in AFW
        Independent predictors of stroke in patients with atrial fibrillation: a systematic review. [Internet].
        Neurology. 2007; 69: 546-554
        • Lip G.Y.H.
        • Nieuwlaat R.
        • Pisters R.
        • et al.
        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: 263-272
        • Odum L.E.
        • Cochran K.A.
        • Aistrope D.S.
        • et al.
        The CHADS2 versus the new CHA2DS2-VASc scoring systems for guiding antithrombotic treatment of patients with atrial fibrillation: review of the literature and recommendations for use.
        Pharmacotherapy. 2012; 32: 285-296
        • Olesen J.B.
        • Lip G.Y.H.
        • Hansen M.L.
        • et al.
        Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.
        Br Med J. 2011; 342: d124
        • Pisters R.
        • Lane D. a
        • Nieuwlaat R.
        • et al.
        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: 1093-1100
        • Apostolakis S.
        • Lane D. a
        • Guo Y.
        • et al.
        Performance of the HEMORR 2HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: The AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial.
        J Am Coll Cardiol. 2012; 60: 861-867
        • Roldán V.
        • Marín F.
        • Manzano-Fernández S.
        • et al.
        The HAS-BLED score has better prediction accuracy for major bleeding than CHADS2 or CHA2DS2-VASc scores in anticoagulated patients with atrial fibrillation.
        J Am Coll Cardiol. 2013; 62: 2199-2204
        • Kiviniemi T.
        • Puurunen M.
        • Schlitt A.
        • et al.
        Performance of bleeding risk-prediction scores in patients with atrial fibrillation undergoing percutaneous coronary intervention.
        Am J Cardiol. 2014; 113: 1995-2001
        • Halperin J.L.
        • Hart R.G.
        Atrial fibrillation and stroke: new ideas, persisting dilemmas.
        Stroke. 1988; 19: 937-941
        • De Caterina R.
        • Camm A.J.
        What is “valvular” atrial fibrillation? A reappraisal. [Internet].
        Eur Heart J. 2014; 35: 3328-3335
        • Avezum A.
        • Lopes R.D.
        • Schulte P.J.
        • et al.
        Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial. [Internet].
        Circulation. 2015; 132: 624-632
        • Limdi N.A.
        • Veenstra D.L.
        Warfarin pharmacogenetics [Internet].
        Pharmacotherapy. 28. 2008: 1084-1097
        • Ebell M.H.
        Evidence-based adjustment of warfarin (Coumadin) doses.
        Am Fam Physician. 2005; 71: 1979-1980
        • Nutescu E.
        • Chuatrisorn I.
        • Hellenbart E.
        Drug and dietary interactions of warfarin and novel oral anticoagulants: an update.
        J Thromb Thrombolysis. 2011; 31: 326-343
        • Thi L.
        • Shaw D.
        • Bird J.
        Warfarin potentiation: a review of the “FAB-4” significant drug interactions.
        Consult Pharm. 2009; 24: 227-230
        • Garcia D.
        • Ageno W.
        • Bussey H.
        • et al.
        Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, Part 1.
        Prevention. 2009; June: 579-583
        • Ageno W.
        • Garcia D.
        • Aguilar M.I.
        • et al.
        Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, part 2: treatment [Internet].
        Am J Hematol. 2009; 84: 584-588
        • Douketis J.D.
        • Spyropoulos A.C.
        • Kaatz S.
        • et al.
        Perioperative bridging anticoagulation in patients with atrial fibrillation [Internet].
        N Engl J Med. 2015; 373: 823-833
        • Morgan C.L.
        • McEwan P.
        • Tukiendorf A.
        • et al.
        Warfarin treatment in patients with atrial fibrillation: observing outcomes associated with varying levels of INR control.
        Thromb Res. 2009; 124: 37-41
        • Eikelboom J.W.
        • Wallentin L.
        • Connolly S.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: 2363-2372
      1. Pradaxa (dabigatran etexilate) [Prescribing information [Internet]. Boehringer Ingelheim Pharm. Inc [date unknown]. Available from:

        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation [Internet].
        N Engl J Med. 2009; 361: 1139-1151
        • Graham D.J.
        • Reichman M.E.
        • Wernecke M.
        • et al.
        Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. [Internet].
        Circulation. 2015; 131: 157-164
        • Kubitza D.
        • Becka M.
        • Mueck W.
        Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor [Internet].
        Br J Clin Pharmacol. 70. 2010: 703-712
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation [Internet].
        N Engl J Med. 2011; 365: 883-891
        • Wang X.
        • Tirucherai G.
        • Marbury T.C.
        • et al.
        Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end-stage renal disease on hemodialysis. [Internet].
        J Clin Pharmacol. 2016; 56: 628-636
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.V.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation [Internet].
        N Engl J Med. 2011; 365: 981-992
      2. Savaysa (edoxaban) [prescribing information]. [date unknown];
        • Ogata K.
        • Mendell-Harary J.
        • Tachibana M.
        • et al.
        Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers.
        J Clin Pharmacol. 2010; 50: 743-753
        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation [Internet].
        N Engl J Med. 2013; 369: 2093-2104
        • Lip G.Y.H.
        • Laroche C.
        • Dan G.A.
        • et al.
        “Real-World” antithrombotic treatment in atrial fibrillation: the eorp-af pilot survey.
        Am J Med. 2014; 127 (e1): 519-529
        • Anderson DC
        • Asinger RW
        • Newburg SM
        • et al.
        Preliminary report of the stroke prevention in atrial fibrillation study.
        N Engl J Med. 1990; 322: 863-868
        • 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: 857-867
        • Connolly S
        • Pogue J
        • Hart R
        • Pfeffer M
        • 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: 1903-1912
        • Connolly SJ
        • Yusuf S
        • Camm J
        • et al.
        Effect of clopidogrel added to aspirin in patients with atrial fibrillation [Internet].
        N Engl J Med. 2009; 360: 2066-2078
        • Connolly S.J.
        • Eikelboom J.
        • Joyner C.
        • et al.
        Apixaban in patients with atrial fibrillation [Internet].
        N Engl J Med. 2011; 364: 806-817
        • Schneeweiss S.
        • Gagne J.J.
        • Patrick A.R.
        • et al.
        Comparative efficacy and safety of new oral anticoagulants in patients with atrial fibrillation. [Internet].
        Circ Cardiovasc Qual Outcomes. 2012; 5: 480-486
        • Lip G.Y.H.
        • Larsen T.B.
        • Skjøth F.
        • et al.
        Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. [Internet].
        J Am Coll Cardiol. 2012; 60: 738-746
        • Tereshchenko L.G.
        • Henrikson C.A.
        • Cigarroa J.
        • et al.
        Comparative effectiveness of interventions for stroke prevention in atrial fibrillation: a network meta-analysis. [Internet].
        J Am Heart Assoc. 2016; 5 (e003206)
        • Eerenberg E.S.
        • Kamphuisen P.W.
        • Sijpkens M.K.
        • et al.
        Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects.
        Circulation. 2011; 124: 1573-1579
        • Levi M.
        • Moore K.T.
        • Castillejos C.F.
        • et al.
        Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers [Internet].
        J Thromb Haemost. 12. 2014: 1428-1436
        • Wang X.
        • Mondal S.
        • Wang J.
        • et al.
        Effect of activated charcoal on apixaban pharmacokinetics in healthy subjects.
        Am J Cardiovasc Drugs. 2014; 14: 147-154
        • Escolar G.
        • Fernandez-Gallego V.
        • Arellano-Rodrigo E.
        • et al.
        Reversal of apixaban induced alterations in hemostasis by different coagulation factor concentrates: Significance of studies In Vitro with circulating human blood.
        PLoS One. 2013; 8 (e78696)
        • Lee F.M.H.
        • Chan A.K.C.
        • Lau K.K.
        • Chan H.H.
        Reversal of new, factor-specific oral anticoagulants by rFVIIa, prothrombin complex concentrate and activated prothrombin complex concentrate: a review of animal and human studies.
        Thromb Res. 2014; 133: 705-713
        • Schiele F.
        • Van Ryn J.
        • Canada K.
        • et al.
        A specific antidote for dabigatran: functional and structural characterization.
        Blood. 2013; 121: 3554-3562
        • Pollack C.V.
        • Reilly P.A.
        • Eikelboom J.
        • et al.
        Idarucizumab for dabigatran reversal [Internet].
        N Engl J Med. 2015; 373: 511-520
        • Lu G.
        • DeGuzman F.R.
        • Hollenbach S.J.
        • et al.
        A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. [Internet].
        Nat Med. 2013; 19: 446-451
        • Ansell J.E.
        • Bakhru S.H.
        • Laulicht B.E.
        • et al.
        Use of PER977 to reverse the anticoagulant effect of edoxaban [Internet].
        N Engl J Med. 2014; 371: 2141-2142
      3. Comparison of ATI-5923, a Novel Vitamin K Antagonist, With Warfarin in Patients Requiring Chronic Anticoagulation (EmbraceAC). [date unknown]
        • Ellis D.J.
        • Usman M.H.
        • Milner P.G.
        • et al.
        The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation.
        Circulation. 2009; 120: 1029-1035
        • Connolly S.J.
        • Eikelboom J.
        • Dorian P.
        • et al.
        Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (explore-Xa) [Internet].
        . 2013; 34 (em8, 8006263): 1498-1505
        • Palladino M.
        • Merli G.
        • Thomson L.
        Evaluation of the oral direct factor Xa inhibitor—betrixaban.
        Expert Opin Investig Drugs. 2013; 22: 1465-1472
        • Lip G.Y.H.
        • Halperin J.L.
        • Petersen P.
        • et al.
        Safety and tolerability of the oral factor Xa inhibitor, {YM150} vs. warfarin in 1297 patients with nonvalvular atrial fibrillation: A dose confirmation study ({OPAL-2)} [Internet]. 2011; 9: 748
        • Harrington A.R.
        • Armstrong E.P.
        • Nolan P.E.
        • et al.
        Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation.
        Stroke. 2013; 44: 1676-1681