Advertisement

New Oral Anticoagulants in Elderly Patients with Atrial Fibrillation

  • Prakash C. Deedwania
    Correspondence
    Requests for reprints should be addressed to Prakash C. Deedwania, MD, Cardiology Division, University of California at San Francisco, Veterans Affairs Central California Health Care System, E224, 2615 E. Clinton Avenue, Fresno, CA 93703
    Affiliations
    School of Medicine, University of California at San Francisco, Fresno
    Search for articles by this author
Published:January 29, 2013DOI:https://doi.org/10.1016/j.amjmed.2012.10.012

      Abstract

      The prevalence of atrial fibrillation increases with age, augmenting the risk of embolic stroke in elderly individuals. Clinical practice guidelines recommend the long-term use of oral anticoagulation in elderly patients with atrial fibrillation to reduce risk of stroke. Until recently, vitamin K antagonists (eg, warfarin) were the only oral anticoagulants available, but using warfarin in elderly patients can be challenging. Newer oral anticoagulants may offer specific benefits and increased convenience for elderly patients, because they have predictable pharmacologic profiles, a rapid onset of action, a wide therapeutic window, no requirement for routine coagulation monitoring, and fewer and better-defined food and drug interactions compared with warfarin. This review highlights the benefits and challenges of warfarin use in elderly patients with atrial fibrillation and discusses potential efficacy and safety benefits for newer oral agents in these patients. The potential for increased rates of major bleeding in the elderly, particularly those with numerous concomitant medications or renal impairment, also is discussed. Practical considerations for the use of long-term anticoagulation in elderly patients also are discussed.

      Keywords

      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:

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

      References

        • Chen R.L.
        • Balami J.S.
        • Esiri M.M.
        • et al.
        Ischemic stroke in the elderly: an overview of evidence.
        Nat Rev Neurol. 2010; 6: 256-265
        • Go A.S.
        • Hylek E.M.
        • Phillips K.A.
        • 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
        • Feinberg W.M.
        • Blackshear J.L.
        • Laupacis A.
        • et al.
        Prevalence, age distribution, and gender of patients with atrial fibrillation.
        Arch Intern Med. 1995; 155: 469-473
        • Wolf P.A.
        • Abbott R.D.
        • Kannel W.B.
        Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.
        Stroke. 1991; 22: 983-988
        • Marini C.
        • De Santis F.
        • Sacco S.
        • et al.
        Contribution of atrial fibrillation to incidence and outcome of ischemic stroke: results from a population-based study.
        Stroke. 2005; 36: 1115-1119
        • Roger V.L.
        • Go A.S.
        • Lloyd-Jones D.M.
        • et al.
        Heart disease and stroke statistics—2011 update: a report from the American Heart Association.
        Circulation. 2011; 123: e18-e209
        • Lin H.J.
        • Wolf P.A.
        • Kelly-Hayes M.
        • et al.
        Stroke severity in atrial fibrillation.
        Stroke. 1996; 27: 1760-1764
        • Jorgensen H.S.
        • Nakayama H.
        • Reith J.
        • et al.
        Acute stroke with atrial fibrillation.
        Stroke. 1996; 27: 1765-1769
        • Dulli D.A.
        • Stanko H.
        • Levine R.L.
        Atrial fibrillation is associated with severe acute ischemic stroke.
        Neuroepidemiology. 2003; 22: 118-123
        • Gage B.F.
        • Waterman A.D.
        • Shannon W.
        • et al.
        Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.
        JAMA. 2001; 285: 2864-2870
        • Lip G.Y.
        • 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
        • Camm A.J.
        • Kirchhof P.
        • Lip G.Y.
        • et al.
        Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).
        Eur Heart J. 2010; 31: 2369-2429
        • Cowie C.C.
        • Rust K.F.
        • Ford E.S.
        • et al.
        Full accounting of diabetes and pre-diabetes in the U.S. population in 1988-1994 and 2005-2006.
        Diabetes Care. 2009; 32: 287-294
        • Aronow W.S.
        • Fleg J.L.
        • Pepine C.J.
        • et al.
        ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension.
        J Am Coll Cardiol. 2011; 57: 2037-2114
        • Shih H.
        • Lee B.
        • Lee R.J.
        • Boyle A.J.
        The aging heart and post-infarction left ventricular remodeling.
        J Am Coll Cardiol. 2011; 57: 9-17
        • Fuster V.
        • Ryden L.E.
        • Cannom D.S.
        • et al.
        2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        Circulation. 2011; 123: e269-e367
        • You J.J.
        • Singer D.E.
        • Howard P.A.
        • et al.
        Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
        Chest. 2012; 141: e531S-e575S
        • Wann L.S.
        • Curtis A.B.
        • Ellenbogen K.A.
        • et al.
        2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.
        J Am Coll Cardiol. 2011; 57: 1330-1337
        • 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
        • Lakshminarayan K.
        • Solid C.A.
        • Collins A.J.
        • et al.
        Atrial fibrillation and stroke in the general medicare population: a 10-year perspective (1992 to 2002).
        Stroke. 2006; 37: 1969-1974
        • Mant J.
        • Hobbs F.D.
        • Fletcher K.
        • et al.
        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. 2007; 370: 493-503
        • Singer D.E.
        • Chang Y.
        • Fang M.C.
        • et al.
        Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation?: the ATRIA study.
        Circ Cardiovasc Qual Outcomes. 2009; 2: 297-304
        • Friberg L.
        • Hammar N.
        • Ringh M.
        • et al.
        Stroke prophylaxis in atrial fibrillation: who gets it and who does not?.
        Eur Heart J. 2006; 27: 1954-1964
        • Hylek E.M.
        • D'Antonio J.
        • Evans-Molina C.
        • et al.
        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
        • Gallagher A.M.
        • Rietbrock S.
        • Plumb J.
        • van Staa T.P.
        Initiation and persistence of warfarin or aspirin in patients with chronic atrial fibrillation in general practice: do the appropriate patients receive stroke prophylaxis?.
        J Thromb Haemost. 2008; 6: 1500-1506
        • Quilliam B.J.
        • Lapane K.L.
        Clinical correlates and drug treatment of residents with stroke in long-term care.
        Stroke. 2001; 32: 1385-1393
        • Go A.S.
        • Hylek E.M.
        • Borowsky L.H.
        • et al.
        Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.
        Ann Intern Med. 1999; 131: 927-934
        • Eriksson B.I.
        • Quinlan D.J.
        • Eikelboom J.W.
        Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism.
        Annu Rev Med. 2011; 62: 41-57
        • Ansell J.
        • Hirsh J.
        • Hylek E.
        • et al.
        Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).
        Chest. 2008; 133: 160S-198S
        • Connolly S.J.
        • Eikelboom J.
        • O'Donnell M.
        • et al.
        Challenges of establishing new antithrombotic therapies in atrial fibrillation.
        Circulation. 2007; 116: 449-455
        • Abdel-Latif A.K.
        • Peng X.
        • Messinger-Rapport B.J.
        Predictors of anticoagulation prescription in nursing home residents with atrial fibrillation.
        J Am Med Dir Assoc. 2005; 6: 128-131
        • Lane D.A.
        • Lip G.Y.
        Barriers to anticoagulation in patients with atrial fibrillation: changing physician-related factors.
        Stroke. 2008; 39: 7-9
        • Pugh D.
        • Pugh J.
        • Mead G.E.
        Attitudes of physicians regarding anticoagulation for atrial fibrillation: a systematic review.
        Age Ageing. 2011; 40: 675-683
        • Borosak M.
        • Choo S.
        Warfarin: balancing the benefits and harms.
        Aust Prescr. 2004; 27: 88-92
        • Shepherd A.M.
        • Hewick D.S.
        • Moreland T.A.
        • Stevenson I.H.
        Age as a determinant of sensitivity to warfarin.
        Br J Clin Pharmacol. 1977; 4: 315-320
        • Hylek E.M.
        • Regan S.
        • Go A.S.
        • et al.
        Clinical predictors of prolonged delay in return of the international normalized ratio to within the therapeutic range after excessive anticoagulation with warfarin.
        Ann Intern Med. 2001; 135: 393-400
        • Fleg J.L.
        • Aronow W.S.
        • Frishman W.H.
        Cardiovascular drug therapy in the elderly: benefits and challenges.
        Nat Rev Cardiol. 2011; 8: 13-28
        • Lip G.Y.
        • Agnelli G.
        • Thach A.A.
        • et al.
        Oral anticoagulation in atrial fibrillation: A pan-European patient survey.
        Eur J Intern Med. 2007; 18: 202-208
        • Gage B.F.
        • Yan Y.
        • Milligan P.E.
        • et al.
        Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF).
        Am Heart J. 2006; 151: 713-719
        • 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
        • Fang M.C.
        • Go A.S.
        • Chang Y.
        • et al.
        A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.
        J Am Coll Cardiol. 2011; 58: 395-401
        • Lane D.A.
        • Lip G.Y.
        Barriers to anticoagulation in patients with atrial fibrillation: changing physician-related factors.
        Stroke. 2008; 39: 7-9
        • Man-Son-Hing M.
        • Laupacis A.
        Anticoagulant-related bleeding in older persons with atrial fibrillation: physicians' fears often unfounded.
        Arch Intern Med. 2003; 163: 1580-1586
        • Granger C.B.
        • Armaganijan L.V.
        Newer oral anticoagulants should be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism.
        Circulation. 2012; 125: 159-164
        • Ahmad Y.
        • Lip G.Y.
        Stroke prevention in atrial fibrillation: where are we now?.
        Clin Med Insights Cardiol. 2012; 6: 65-78
        • US Food and Drug Administration
        Pradaxa (dabigatran etexilate mesylate) [package insert].
        Boehringer Ingelheim Pharmaceuticals Inc., 2011 (Accessed June 18, 2012)
        • US Food and Drug Administration
        Xarelto (rivaroxaban) [package insert].
        Janssen Pharmaceuticals Inc., 2011 (Accessed June 18, 2012)
        • Bristol-Myers Squibb
        FDA accepts Eliquis (apixaban) new drug application for review for the prevention of stroke and systemic embolism in patients with atrial fibrillation (press release).
        November 29, 2011 (Accessed June 18, 2012)
        • Lip G.Y.
        • Rasmussen L.H.
        • Olsson S.B.
        • et al.
        Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a Phase II study of AZD0837 in patients who are appropriate for but unable or unwilling to take vitamin K antagonist therapy.
        Thromb Res. 2011; 127: 91-99
        • Ruff C.T.
        • Giugliano R.P.
        • Antman E.M.
        • et al.
        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 x.
        Am Heart J. 2010; 160: 635-641
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • 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
        • Bristol-Myers Squibb, Pfizer EEIG
        Eliquis (apixaban) summary of product characteristics.
        2011 (Accessed June 18, 2012)
        • Boehringer Ingelheim International GmbH
        Pradaxa (dabigatran etexilate) summary of product characteristics.
        2011 (Accessed June 18, 2012)
        • Bayer HealthCare AG
        Xarelto (rivaroxaban) summary of product characteristics.
        2012 (Accessed June 18, 2012)
        • Wyatt C.M.
        • Kim M.C.
        • Winston J.A.
        Therapy insight: how changes in renal function with increasing age affect cardiovascular drug prescribing.
        Nat Clin Pract Cardiovasc Med. 2006; 3: 102-109
        • Eriksson B.I.
        • Quinlan D.J.
        • Weitz J.I.
        Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development.
        Clin Pharmacokinet. 2009; 48: 1-22
        • Stangier J.
        Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.
        Clin Pharmacokinet. 2008; 47: 285-295
        • Stangier J.
        • Rathgen K.
        • Stahle H.
        • Mazur D.
        Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.
        Clin Pharmacokinet. 2010; 49: 259-268
        • Wychowski M.K.
        • Kouides P.A.
        Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment.
        Ann Pharmacother. 2012; 46 (Epub 2012 Apr 10): e10
        • Legrand M.
        • Mateo J.
        • Aribaud A.
        • et al.
        The use of dabigatran in elderly patients.
        Arch Intern Med. 2011; 171: 1285-1286
        • Harper P.
        • Young L.
        • Merriman E.
        Bleeding risk with dabigatran in the frail elderly.
        N Engl J Med. 2012; 366: 864-866
        • Kubitza D.
        • Becka M.
        • Mueck W.
        • et al.
        Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor.
        Br J Clin Pharmacol. 2010; 70: 703-712
        • Mueck W.
        • Lensing A.W.
        • Agnelli G.
        • et al.
        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
        • Fox K.A.
        • Piccini J.P.
        • Wojdyla D.
        • et al.
        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. 2011; 32: 2387-2394
        • Leil T.A.
        • Feng Y.
        • Zhang L.
        • et al.
        Quantification of apixaban's therapeutic utility in prevention of venous thromboembolism: selection of phase III trial dose.
        Clin Pharmacol Ther. 2010; 88: 375-382
        • Shah S.V.
        • Gage B.F.
        Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation.
        Circulation. 2011; 123: 2562-2570
        • Sorensen S.V.
        • Kansal A.R.
        • Connolly S.
        • et al.
        Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: A Canadian payer perspective.
        Thromb Haemost. 2011; 105: 908-919
        • Adcock A.K.
        • Lee-Iannotti J.K.
        • Aguilar M.I.
        • et al.
        Is dabigatran cost effective compared with warfarin for stroke prevention in atrial fibrillation?: a critically appraised topic.
        Neurologist. 2012; 18: 102-107
        • Kamel H.
        • Johnston S.C.
        • Easton J.D.
        • Kim A.S.
        Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack.
        Stroke. 2012; 43: 881-883
        • Langkilde L.K.
        • Bergholdt A.M.
        • Overgaard M.
        Cost-effectiveness of dabigatran etexilate for stroke prevention in non-valvular atrial fibrillation.
        J Med Econ. 2012; 15: 695-703
        • Kansal A.R.
        • Sorensen S.V.
        • Gani R.
        • et al.
        Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation.
        Heart. 2012; 98: 573-578
        • Freeman J.V.
        • Zhu R.P.
        • Owens D.K.
        • et al.
        Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in atrial fibrillation.
        Ann Intern Med. 2011; 154: 1-11
        • Pink J.
        • Lane S.
        • Pirmohamed M.
        • Hughes D.A.
        Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses.
        BMJ. 2011; 343: d6333
        • Ali A.
        • Bailey C.
        • Abdelhafiz A.H.
        Stroke prophylaxis with warfarin or dabigatran for patients with non-valvular atrial fibrillation-cost analysis.
        Age Ageing. 2012; 41: 681-684
        • Deitelzweig S.
        • Amin A.
        • Jing Y.
        • et al.
        Medical cost reductions associated with the usage of novel oral anticoagulants vs. warfarin among atrial fibrillation patients, based on the RE-LY, ROCKET-AF and ARISTOTLE trials.
        J Med Econ. 2012; 15: 776-785