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Drugs & Aging

, Volume 33, Issue 7, pp 491–500 | Cite as

Minimizing the Risk of Bleeding with NOACs in the Elderly

  • Amartya Kundu
  • Partha Sardar
  • Saurav Chatterjee
  • Wilbert S. Aronow
  • Theophilus Owan
  • John J. Ryan
Review Article

Abstract

Novel oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban have gained a lot of popularity as alternatives to warfarin for anticoagulation in various clinical settings. However, there is conflicting opinion regarding the absolute benefit of NOAC use in elderly patients. Low body mass, altered body composition of fat and muscle, renal impairment and concurrent presence of multiple comorbidities predispose elderly patients to many adverse effects with NOACs that are typically not seen in younger patients. There have been reports that NOAC use, in particular dabigatran, is associated with a higher risk of gastrointestinal bleeding in the elderly. Diagnosis and management of NOAC-associated bleeding in the elderly is difficult due to the absence of commonly available drug-specific antidotes that can rapidly reverse the anticoagulant effects. Moreover, in elderly patients, a number of factors such as the presence of other comorbid medical conditions, renal insufficiency, drug interactions from polypharmacy, risk of falls and dementia need to be considered before prescribing anticoagulation therapy. Elderly patients frequently have compromised renal function, and therefore dose adjustments according to creatinine clearance for NOACs need to be made. As each NOAC comes with its own unique advantages and safety profile, an individualized case by case approach should be adopted to decide on the appropriate anticoagulation regimen for elderly patients after weighing the overall risks and benefits of therapy.

Keywords

Atrial Fibrillation Warfarin International Normalize Ratio Dabigatran Major Bleeding 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Compliance with Ethical Standards

Conflict of interest

All authors declare they have no conflicts of interest that are relevant to the content of this review.

Funding

All authors declare that no sources of funding were used to assist with the preparation of this review.

References

  1. 1.
    Robert-Ebadi H, Le Gal G, Righini M. Use of anticoagulants in elderly patients: practical recommendations. Clin Interv Aging. 2009;4:165–77.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Spyropoulos AC, Merli G. Management of venous thromboembolism in the elderly. Drugs Aging. 2006;23:651–71.CrossRefPubMedGoogle Scholar
  3. 3.
    Deedwania PC. New oral anticoagulants in elderly patients with atrial fibrillation. Am J Med. 2013;126:289–96.CrossRefPubMedGoogle Scholar
  4. 4.
    Engbers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost. 2010;8:2105–12.CrossRefPubMedGoogle Scholar
  5. 5.
    Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, et al. Full accounting of diabetes and pre-diabetes in the US population in 1988–1994 and 2005–2006. Diabetes Care. 2009;32:287–94.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost. 2007;5:692–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–47.CrossRefPubMedGoogle Scholar
  8. 8.
    Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, 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(18):2370–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Lane DA, Lip GY. Use of the CHA(2)DS(2)-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation. 2012;126(7):860–5.CrossRefPubMedGoogle Scholar
  10. 10.
    van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke. 2009;40:1410–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–67.CrossRefPubMedGoogle Scholar
  13. 13.
    Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, 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 randomized controlled trial. Lancet. 2007;370:493–503.CrossRefPubMedGoogle Scholar
  14. 14.
    Sen P, Kundu A, Sardar P, Chatterjee S, Nairooz R, Amin H, et al. Outcomes after cardioversion in atrial fibrillation patients treated with non-vitamin K antagonist oral anticoagulants (NOACs): insights from a meta-analysis. Am J Cardiovasc Drugs. 2016;16(1):33–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Ogata K, Mendell-Harary J, Tachibana M, Masumoto H, Oguma T, Kojima M, et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol. 2010;50(7):743–53.CrossRefPubMedGoogle Scholar
  16. 16.
    Sardar P, Chatterjee S, Chaudhari S, Lip GY. New oral anticoagulants in elderly adults: evidence from a meta-analysis of randomized trials. J Am Geriatr Soc. 2014;62(5):857–64.CrossRefPubMedGoogle Scholar
  17. 17.
    Roehrig S, Straub A, Pohlmann J, Lampe T, Pernerstorfer J, Schlemmer KH, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl} methyl)thiophene-2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005;48(19):5900–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. A once-daily, oral, direct factor Xa inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement. Circulation. 2006;114(22):2374–81.CrossRefPubMedGoogle Scholar
  19. 19.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.CrossRefPubMedGoogle Scholar
  20. 20.
    Halperin JL, Hankey GJ, Wojdyla DM, Piccini JP, Lokhnygina Y, Patel MR, 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):138–46.CrossRefPubMedGoogle Scholar
  21. 21.
    EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499–510.CrossRefGoogle Scholar
  22. 22.
    EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287–97.CrossRefGoogle Scholar
  23. 23.
    Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN–DVT and PE randomized studies. Thromb J. 2013;11(1):21.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121(13):1523–32.CrossRefPubMedGoogle Scholar
  25. 25.
    Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, et al. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806–17.CrossRefPubMedGoogle Scholar
  26. 26.
    Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban vs warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.CrossRefPubMedGoogle Scholar
  27. 27.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369(9):799–808.CrossRefPubMedGoogle Scholar
  28. 28.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.CrossRefPubMedGoogle Scholar
  29. 29.
    Investigators Hokusai-VTE, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406–15.CrossRefGoogle Scholar
  30. 30.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A. Dabigatran vs warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.CrossRefPubMedGoogle Scholar
  31. 31.
    Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, 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;123:2363–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Coppens M, Eikelboom J, Ezekowitz M, Clemens A, Healy J, Wallentin L, et al. Dabigatran versus warfarin in very elderly patients with atrial fibrillation: results from the RE-LY trial. Circulation. 2012;126:A15l537.Google Scholar
  33. 33.
    Sharma M, Cornelius VR, Patel JP, Davies JG, Molokhia M. Efficacy and harms of direct oral anticoagulants in the elderly for stroke prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and meta-analysis. Circulation. 2015;132(3):194–204.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zarraga IG, Kron J. Oral anticoagulation in elderly adults with atrial fibrillation: integrating new options with old concepts. J Am Geriatr Soc. 2013;61(1):143–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Strate LL. Lower GI bleeding: epidemiology and diagnosis. Gastroenterol Clin North Am. 2005;34(4):643–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Kundu A, Sen P, Sardar P, Chatterjee S, Kapoor A, McManus DD. Intracranial hemorrhage with target specific oral anticoagulants in patients with atrial fibrillation: an updated meta-analysis of randomized controlled trials. Int J Cardiol. 2016;203:1000–2.CrossRefPubMedGoogle Scholar
  37. 37.
    Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76:455–66.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Marchetti S, Mazzanti R, Beijnen JH, Schellens JH. Concise review: clinical relevance of drug–drug and herb–drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist. 2007;12(8):927–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Rosenman MB, Baker L, Jing Y, Makenbaeva D, Meissner B, Simon TA, et al. Why is warfarin underused for stroke prevention in atrial fibrillation? A detailed review of electronic medical records. Curr Med Res Opin. 2012;28:1407–14.CrossRefPubMedGoogle Scholar
  40. 40.
    Sanders NA, Ganguly JA, Jetter TL, Daccarett M, Wasmund SL, Brignole M, et al. Atrial fibrillation: an independent risk factor for nonaccidental falls in older patients. Pacing Clin Electrophysiol. 2012;35:973–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Mani H, Rohde G, Stratmann G, Hesse C, Herth N, Schwers S, et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost. 2012;108(1):191–8.CrossRefPubMedGoogle Scholar
  42. 42.
    Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost. 2013;11(8):1493–502.CrossRefPubMedGoogle Scholar
  43. 43.
    Levi M, Moore KT, Castillejos CF, Kubitza D, Berkowitz SD, Goldhaber SZ, et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12(9):1428–36.CrossRefPubMedGoogle Scholar
  44. 44.
    Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–20.CrossRefPubMedGoogle Scholar
  45. 45.
    Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–24.CrossRefPubMedGoogle Scholar
  46. 46.
    Stöllberger C, Finsterer J. Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation. Drugs Aging. 2013;30(12):949–58.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Amartya Kundu
    • 1
  • Partha Sardar
    • 2
  • Saurav Chatterjee
    • 3
  • Wilbert S. Aronow
    • 4
  • Theophilus Owan
    • 2
  • John J. Ryan
    • 2
  1. 1.Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  2. 2.Division of Cardiovascular Medicine, University of Utah Health Science CenterUniversity of UtahSalt Lake CityUSA
  3. 3.Division of CardiologySt. Luke’s-Roosevelt Hospital of the Mount Sinai Health SystemNew YorkUSA
  4. 4.Division of CardiologyNew York Medical CollegeValhallaUSA

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