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Drugs & Aging

, Volume 23, Issue 1, pp 13–25 | Cite as

Haemorrhagic Complications of Vitamin K Antagonists in the Elderly

Risk Factors and Management
  • Eric Pautas
  • Isabelle Gouin-Thibault
  • Matthieu Debray
  • Pascale Gaussem
  • Virginie Siguret
Review Article

Abstract

In patients >75 years of age, the two main indications for oral anticoagulant therapy with vitamin K antagonists (VKAs) are treatment of venous thromboembolic disease and prevention of systemic embolism in patients with nonvalvular atrial fibrillation. In both indications, a target International Normalized Ratio of 2.5 (range 2.0–3.0) is recommended. Bleeding is the adverse effect feared by physicians that most limits the use of VKAs in older frail patients. In this paper, we discuss (i) the risk of VKA-related bleeding with advancing age; (ii) the severity of bleeding complications and particularly the risk of intracranial haemorrhage in older patients; (iii) the risk factors for bleeding related to patient characteristics; and (iv) the risk factors or determinants for bleeding related to treatment variables (warfarin induction and maintenance administration, instability of anticoagulation, poor compliance and patient’s education level, and concomitant use of drugs). Avoiding over-anticoagulation and/or reducing periods of overdosing in the course of oral anticoagulant treatment with tailored monitoring may help to minimise the risk of bleeding in older patients.

Keywords

Atrial Fibrillation Warfarin International Normalize Ratio Major Bleeding Cerebral Amyloid Angiopathy 
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

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Kniffin Jr WD, Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154(8): 861–6PubMedCrossRefGoogle Scholar
  2. 2.
    Aronow WS, Ahn C, Gutstein H. Prevalence of atrial fibrillation and association of atrial fibrillation with prior and new thromboembolic stroke in older patients. J Am Geriatr Soc 1996; 44(5): 521–3PubMedGoogle Scholar
  3. 3.
    Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl.): 204S–33SPubMedCrossRefGoogle Scholar
  4. 4.
    Guideline AGS. The use of oral anticoagulants (warfarin) in older people. J Am Geriatr Soc 2002; 50: 1439–45CrossRefGoogle Scholar
  5. 5.
    Devereaux PJ, Anderson DR, Gardner MJ, et al. Differences between perspectives of physicians and patients on anticoagu-lation in patients with atrial fibrillation: observational study. BMJ 2001; 323(7323): 1218–22PubMedCrossRefGoogle Scholar
  6. 6.
    Gross CP, Vogel EW, Dhond AJ, et al. Factors influencing physicians’ reported use of anticoagulation therapy in nonvalvular atrial fibrillation: a cross-sectional survey. Clin Ther 2003; 25(6): 1750–64PubMedCrossRefGoogle Scholar
  7. 7.
    Monette J, Gurwitz JH, Rochon PA, et al. Physician attitudes concerning warfarin for stroke prevention in atrial fibrillation: results of a survey of long-term care practitioners. J Am Geriatr Soc 1997; 45(9): 1060–5PubMedGoogle Scholar
  8. 8.
    Hajjar ER, Hanlon JT, Artz MB, et al. Adverse drug reaction risk factors in older outpatients. Am J Geriatr Pharmacother 2003; 1(2): 82–9PubMedCrossRefGoogle Scholar
  9. 9.
    White RH, McBurnie MA, Manolio T, et al. Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med 1999; 106(2): 165–71PubMedCrossRefGoogle Scholar
  10. 10.
    Lau E, Bungard TJ, Tsuyuki RT. Stroke prophylaxis in institutionalized elderly patients with atrial fibrillation. J Am Geriatr Soc 2004; 52(3): 428–33PubMedCrossRefGoogle Scholar
  11. 11.
    Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87(2): 144–52PubMedCrossRefGoogle Scholar
  12. 12.
    Launbjerg J, Egeblad H, Heaf J, et al. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients. J Intern Med 1991; 229(4): 351–5PubMedCrossRefGoogle Scholar
  13. 13.
    van der Meer FJ, Rosendaal FR, Vandenbroucke JP, et al. Bleeding complications in oral anticoagulant therapy: an analysis of risk factors. Arch Intern Med 1993; 153(13): 1557–62PubMedCrossRefGoogle Scholar
  14. 14.
    The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995; 333: 5–10CrossRefGoogle Scholar
  15. 15.
    Hutten BA, Lensing AW, Kraaijenhagen RA, et al. Safety of treatment with oral anticoagulants in the elderly: a systematic review. Drugs Aging 1999; 14(4): 303–12PubMedCrossRefGoogle Scholar
  16. 16.
    Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 Suppl.): 287S–310SPubMedCrossRefGoogle Scholar
  17. 17.
    Schulman S. Clinical practice: care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003; 349(7): 675–83PubMedCrossRefGoogle Scholar
  18. 18.
    Bleeding during antithrombotic therapy in patients with atrial fibrillation: the Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996; 156(4): 409–16Google Scholar
  19. 19.
    Palareti G, Hirsh J, Legnani C, et al. Oral anticoagulation treatment in the elderly: a nested, prospective, case-control study. Arch Intern Med 2000; 160(4): 470–8PubMedCrossRefGoogle Scholar
  20. 20.
    Pengo V, Legnani C, Noventa F, et al. Oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and risk of bleeding: a Multicenter Inception Cohort Study. Thromb Haemost 2001; 85(3): 418–22PubMedGoogle Scholar
  21. 21.
    Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation. Arch Intern Med 2001; 161(17): 2125–8PubMedCrossRefGoogle Scholar
  22. 22.
    Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet 1994; 343(8899): 687–91Google Scholar
  23. 23.
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3(4): 692–4PubMedCrossRefGoogle Scholar
  24. 24.
    Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med 1993; 95(3): 315–28PubMedCrossRefGoogle Scholar
  25. 25.
    Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290(20): 2685–92PubMedCrossRefGoogle Scholar
  26. 26.
    White RH, Beyth RJ, Zhou H, et al. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 1999; 107(5): 414–24PubMedCrossRefGoogle Scholar
  27. 27.
    Kagansky N, Knobler H, Rimon E, et al. Safety of anticoagulation therapy in well-informed older patients. Arch Intern Med 2004; 164(18): 2044–50PubMedCrossRefGoogle Scholar
  28. 28.
    Johnson CE, Lim WK, Workman BS. People aged over 75 in atrial fibrillation on warfarin: the rate of major hemorrhage and stroke in more than 500 patient-years of follow-up. J Am Geriatr Soc 2005; 53(4): 655–9PubMedCrossRefGoogle Scholar
  29. 29.
    Tsivgoulis G, Spengos K, Zakopoulos N, et al. Efficacy of anticoagulation for secondary stroke prevention in older people with non-valvular atrial fibrillation: a prospective case series study. Age Ageing 2005; 34(1): 35–40PubMedCrossRefGoogle Scholar
  30. 30.
    Fihn SD, Callahan CM, Martin DC, et al. The risk for and severity of bleeding complications in elderly patients treated with warfarin: the National Consortium of Anticoagulation Clinics. Ann Intern Med 1996; 124(11): 970–9PubMedGoogle Scholar
  31. 31.
    Lane D, Lip GY. Anti-thrombotic therapy for atrial fibrillation and patients’ preferences for treatment. Age Ageing 2005; 34(1): 1–3PubMedCrossRefGoogle Scholar
  32. 32.
    Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120(11): 897–902PubMedGoogle Scholar
  33. 33.
    Fang MC, Chang Y, Hylek EM, et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141(10): 745–52PubMedGoogle Scholar
  34. 34.
    A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin: the Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol 1997; 42(6): 857–65Google Scholar
  35. 35.
    Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139(11): 893–900PubMedGoogle Scholar
  36. 36.
    Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105(2): 91–9PubMedCrossRefGoogle Scholar
  37. 37.
    Kuijer PM, Hutten BA, Prins MH, et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159(5): 457–60PubMedCrossRefGoogle Scholar
  38. 38.
    Bond AJ, Molnar FJ, Li M, et al. The risk of hemorrhagic complications in hospital in-patients who fall while receiving antithrombotic therapy. Thromb J 2005; 3(1): 1–6PubMedCrossRefGoogle Scholar
  39. 39.
    Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118: 612–7PubMedCrossRefGoogle Scholar
  40. 40.
    Man-Son-Hing M, Nichol G, Lau A, et al. Choosing antithrombotic therapy for elderly patients with atrial fibrillation who are at risk for falls. Arch Intern Med 1999; 159(7): 677–85PubMedCrossRefGoogle Scholar
  41. 41.
    Moroney JT, Tseng CL, Paik MC, et al. Treatment for the secondary prevention of stroke in older patients: the influence of dementia status. J Am Geriatr Soc 1999; 47(7): 824–9PubMedGoogle Scholar
  42. 42.
    Gage BF, Fihn SD, White RH. Warfarin therapy for an octogenarian who has atrial fibrillation. Ann Intern Med 2001; 134(6): 465–74PubMedGoogle Scholar
  43. 43.
    Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation: a multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118(7): 511–20PubMedGoogle Scholar
  44. 44.
    Palareti G, Leali N, Coccheri S, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 1996; 348(9025): 423–8PubMedCrossRefGoogle Scholar
  45. 45.
    Fitzmaurice DA, Blann AD, Lip GY. Bleeding risks of antithrombotic therapy. BMJ 2002; 325(7368): 828–31PubMedCrossRefGoogle Scholar
  46. 46.
    Hylek EM. Oral anticoagulants: pharmacologic issues for use in the elderly. Clin Geriatr Med 2001; 17(1): 1–13PubMedCrossRefGoogle Scholar
  47. 47.
    Barrett J, Scott A, Galvani D. Anticoagulation of older patients [letter]. Age Ageing 2000; 29(5): 457PubMedCrossRefGoogle Scholar
  48. 48.
    Cooper MW, Hendra TJ. Prospective evaluation of a modified Fennerty regimen for anticoagulating elderly people. Age Ageing 1998; 27(5): 655–6PubMedCrossRefGoogle Scholar
  49. 49.
    Gedge J, Orme S, Hampton KK, et al. A comparison of a low-dose warfarin induction regimen with the modified Fennerty regimen in elderly inpatients. Age Ageing 2000; 29(1): 31–4PubMedCrossRefGoogle Scholar
  50. 50.
    O’Connell MB, Kowal PR, Allivato CJ, et al. Evaluation of warfarin initiation regimens in elderly inpatients. Pharmacotherapy 2000; 20(8): 923–30PubMedCrossRefGoogle Scholar
  51. 51.
    Roberts GW, Druskeit T, Jorgensen LE, et al. Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty’s protocol. Aust N Z J Med 1999; 29(5): 731–6PubMedCrossRefGoogle Scholar
  52. 52.
    Siguret V, Gouin I, Debray M, et al. Initiation of warfarin therapy in elderly medical inpatients: a safe and accurate regimen. Am J Med 2005; 118: 137–42PubMedCrossRefGoogle Scholar
  53. 53.
    Chatap G, Chaibi P, Giraud K, et al. Oral anticoagulation in older patients. Establishment and validation of a new posologic warfarin regimen [in French]. Presse Med 2001; 30(10): 475–80PubMedGoogle Scholar
  54. 54.
    Redwood M, Taylor C, Bain BJ, et al. The association of age with dosage requirement for warfarin. Age Ageing 1991; 20(3): 217–20PubMedCrossRefGoogle Scholar
  55. 55.
    Gurwitz JH, Avorn J, Ross-Degnan D, et al. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992; 116(11): 901–4PubMedGoogle Scholar
  56. 56.
    Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91(1): 87–94PubMedGoogle Scholar
  57. 57.
    Siguret V, Gouin I, Golmard JL, et al. Cytochrome P450 2C9 polymorphisms (CYP2C9) and warfarin maintenance dose in elderly patients [in French]. Rev Med Interne 2004; 25(4): 271–4PubMedCrossRefGoogle Scholar
  58. 58.
    D’Andrea G, D’Ambrosio RL, Di Perna P, et al. A polymorphism in VKORC1 gene is associated with an inter-individual variability in the dose-anticoagulant effect of warfarin. Blood. 2005; 105(2): 645–9PubMedCrossRefGoogle Scholar
  59. 59.
    Rieder MJ, Reiner AP, Gage BF, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352(22): 2285–93PubMedCrossRefGoogle Scholar
  60. 60.
    Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106(7): 2329–33PubMedCrossRefGoogle Scholar
  61. 61.
    Froom P, Miron E, Barak M. Oral anticoagulants in the elderly. Br J Haematol 2003; 120(3): 526–8PubMedCrossRefGoogle Scholar
  62. 62.
    Siguret V, Esquirol C, Debray M, et al. Excess antivitamin K in elderly hospitalised patients aged over 70: a one-year prospective survey [in French]. Presse Med 2003; 32(21): 972–7PubMedGoogle Scholar
  63. 63.
    Panneerselvam S, Baglin C, Lefort W, et al. Analysis of risk factors for over-anticoagulation in patients receiving long-term warfarin. Br J Haematol 1998; 103(2): 422–4PubMedCrossRefGoogle Scholar
  64. 64.
    Hylek EM, Chang YC, Skates SJ, et al. Prospective study of the outcomes of ambulatory patients with excessive warfarin an-ticoagulation. Arch Intern Med 2000; 160(11): 1612–7PubMedCrossRefGoogle Scholar
  65. 65.
    Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized, controlled trial. Ann Intern Med 2002; 137(4): 251–4PubMedGoogle Scholar
  66. 66.
    Hylek EM, Skates SJ, Sheehan MA, et al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996; 335(8): 540–6PubMedCrossRefGoogle Scholar
  67. 67.
    Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med 2001; 135 (8 Pt 2): 703–10PubMedGoogle Scholar
  68. 68.
    Penning-van Beest FJ, van Meegen E, Rosendaal FR, et al. Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost 2001; 86(2): 569–74PubMedGoogle Scholar
  69. 69.
    van der Meer FJ, Briet E, Vandenbroucke JP, et al. The role of compliance as a cause of instability in oral anticoagulant therapy. Br J Haematol 1997; 98(4): 893–900PubMedCrossRefGoogle Scholar
  70. 70.
    Arnsten JH, Gelfand JM, Singer DE. Determinants of compliance with anticoagulation: a case-control study. Am J Med 1997; 103(1): 11–7PubMedCrossRefGoogle Scholar
  71. 71.
    Waterman AD, Milligan PE, Bayer L, et al. Effect of warfarin nonadherence on control of the International Normalized Ratio. Am J Health Syst Pharm 2004; 61(12): 1258–64PubMedGoogle Scholar
  72. 72.
    Chiquette E, Amato MG, Bussey HI. Comparison of an anticoagulation clinic with usual medical care: anticoagulation control, patient outcomes, and health care costs. Arch Intern Med 1998; 158(15): 1641–7PubMedCrossRefGoogle Scholar
  73. 73.
    Poller L, Shiach CR, MacCallum PK, et al. Multicentre randomised study of computerised anticoagulant dosage: European Concerted Action on Anticoagulation. Lancet 1998; 352(9139): 1505–9PubMedCrossRefGoogle Scholar
  74. 74.
    Beyth RJ, Quinn L, Landefeld CS. A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin: a randomized, controlled trial. Ann Intern Med 2000; 133(9): 687–95PubMedGoogle Scholar
  75. 75.
    Heidinger KS, Bernardo A, Taborski U, et al. Clinical outcome of self-management of oral anticoagulation in patients with atrial fibrillation or deep vein thrombosis. Thromb Res 2000; 98(4): 287–93PubMedCrossRefGoogle Scholar
  76. 76.
    Khan TI, Kamali F, Kesteven P, et al. The value of education and self-monitoring in the management of warfarin therapy in older patients with unstable control of anticoagulation. Br J Haematol 2004; 126(4): 557–64PubMedCrossRefGoogle Scholar
  77. 77.
    Wehinger C, Stollberger C, Langer T, et al. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation. Stroke 2001; 32(10): 2246–52PubMedCrossRefGoogle Scholar
  78. 78.
    Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165(10): 1095–106PubMedCrossRefGoogle Scholar
  79. 79.
    Shireman TI, Howard PA, Kresowik TF, et al. Combined anti-coagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke 2004; 35: 2362–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Eric Pautas
    • 1
  • Isabelle Gouin-Thibault
    • 2
  • Matthieu Debray
    • 3
  • Pascale Gaussem
    • 4
    • 5
  • Virginie Siguret
    • 2
    • 5
  1. 1.Unité de Gériatrie AiguëHôpital Charles Foix (AP-HP)Ivry/SeineFrance
  2. 2.Laboratoire d’HématologieHôpital Charles Foix (AP-HP)Ivry-sur-Seine cedexFrance
  3. 3.Service de GériatrieCentre Hospitalier Régional d’AnnecyAnnecyFrance
  4. 4.Service d’Hématologie biologiqueHôpital Européen Georges PompidouParisFrance
  5. 5.INSERM U.765 - Université Paris VParisFrance

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