Anticoagulation for Noncardiac Indications in Neurologic Patients: Comparative Use of Non-Vitamin K Oral Anticoagulants, Low-Molecular-Weight Heparins, and Warfarin

Neurologic Manifestations of Systemic Disease (A Pruitt, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neurologic Manifestations of Systemic Disease

Opinion statement

Patients with neurologic disorders may develop a wide variety of thromboembolic events, both as a primary manifestation and as a consequence of their underlying neurologic condition. There are many available options for anticoagulation, ranging from warfarin to the parenteral subcutaneously administered anticoagulants to the non-vitamin K oral anticoagulants (NOACs). Warfarin is orally available, well-studied, and easily reversible in the setting of bleeding, but has a prolonged onset of action, measured in days, and equally slow offset; requires frequent monitoring for dose titration; and has multiple drug-drug and food-drug interactions. Parenteral heparin-based anticoagulants are well-studied and have more predictable pharmacokinetics but are often more expensive, only partially reversible, and require daily injections, which can be difficult for patients to tolerate over long periods of time. The NOACs are easy to administer and have predictable pharmacokinetics but are expensive, not easily reversible, and are not as extensively studied. Specific agents are preferable in some defined neurologic conditions. For acute ischemic stroke, we do not recommend immediate anticoagulation with any agent. For patients with intracranial malignancy (either primary or metastatic), we recommend a low-molecular-weight heparin (LMWH) rather than warfarin or a NOAC. For thromboembolic disease in the setting of spinal cord injury, warfarin, LMWH, or the NOACs are reasonable options. In the setting of VTE or stroke related to antiphospholipid antibody syndrome (APS), we recommend long-term warfarin anticoagulation with an INR goal of 2–3, pending the results of ongoing research involving the NOACs. For cerebral venous sinus thrombosis not related to malignancy or APS, we recommend the use of LMWH in the acute setting, followed by at least three months of warfarin. In this article, we discuss the pharmacology, pathophysiology, and comparative research that served as a basis for our recommendations.


Anticoagulation Venous thromboembolism Ischemic stroke Intracranial malignancy Spinal cord injury Antiphospholipid antibody syndrome Cerebral venous sinus thrombosis 

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

  1. 1.
    Coull BM, Williams LS, Goldstein LB, et al. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a Division of the American Heart Association). Neurology. 2002;59:13–22.PubMedCrossRefGoogle Scholar
  2. 2.
    International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet. 1997;349:1569–81.CrossRefGoogle Scholar
  3. 3.
    Therapy of Patients with Acute Stroke (TOPAS) Investigators. Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the TOPAS trial. Stroke. 2001;32:22–9.CrossRefGoogle Scholar
  4. 4.
    De Schryver EL, Algra A, Kappelle LJ, van Gijn J, Koudstaal PJ. Vitamin K antagonists versus antiplatelet therapy after transient ischaemic attack or minor ischaemic stroke of presumed arterial origin. Cochrane Database Syst Rev. 2012;9, CD001342.PubMedGoogle Scholar
  5. 5.
    Lansberg MG, O'Donnell JM, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke. Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e601S–36.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Hankey GJ, Eikelboom JW, van Bockxmeer FM, et al. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke. 2001;32:1793–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Cheruku R, Tapazoglou E, Ensley J, et al. The incidence and significance of thromboembolic complications in patients with high-grade gliomas. Cancer. 1991;68:2621–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Sawaya R, Zuccarello M, El-Kalliny M, Nishiyama H. Postoperative venous thromboembolism and brain tumors: Part I. Clinical Profile. J Neurooncol. 1992;14:119–25.PubMedGoogle Scholar
  9. 9.
    Goldschmidt N, Linetsky E, Shalom E, et al. High incidence of thromboembolism in patients with central nervous system lymphoma. Cancer. 2003;98:1239–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol. 1983;13:334–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Simanek R, Vormittag R, Hassler M, et al. Venous thromboembolism and survival in patients with high-grade glioma. Neuro Oncol. 2007;9:89–95.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors. Neurology. 1993;43:1111–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Olin JW, Young JR, Graor RA, et al. Treatment of deep vein thrombosis and pulmonary emboli in patients with primary and metastatic brain tumors. Anticoagulants or inferior vena cava filter? Arch Intern Med. 1987;147:2177–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Choucair AK, Silver P, Levin VA. Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism. J Neurosurg. 1987;66:357–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Altschuler E, Moosa H, Selker RG, Vertosick Jr FT. The risk and efficacy of anticoagulant therapy in the treatment of thromboembolic complications in patients with primary malignant brain tumors. Neurosurgery. 1990;27:74–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Schmidt F, Faul C, Dichgans J, Weller M. Low molecular weight heparin for deep vein thrombosis in glioma patients. J Neurol. 2002;249:1409–12.PubMedCrossRefGoogle Scholar
  17. 17.
    Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer. 1994;73:493–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a Coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146–53.PubMedCrossRefGoogle Scholar
  19. 19.
    Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med. 1996;100:269–77.PubMedCrossRefGoogle Scholar
  20. 20.
    Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1999;130:800–9.PubMedGoogle Scholar
  21. 21.
    Farge D, Debourdeau P, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost. 2013;11:56–70.PubMedCrossRefGoogle Scholar
  22. 22.
    Büller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695–702.PubMedCrossRefGoogle Scholar
  23. 23.
    Büller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140:867–73.PubMedGoogle Scholar
  24. 24.
    Kondziolka D, Bernstein M, Resch L, et al. Significance of hemorrhage into brain tumors: clinicopathological study. J Neurosurg. 1987;67:852–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Wakai S, Yamakawa K, Manaka S, et al. Spontaneous intracranial hemorrhage caused by brain tumor: its incidence and clinical significance. Neurosurgery. 1982;10:437–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Lazio BE, Simard JM. Anticoagulation in neurosurgical patients. Neurosurgery. 1999;45:838–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Miranda AR, Hassouna HI. Mechanisms of thrombosis in spinal cord injury. Hematol Oncol Clin N Am. 2000;14:401–16.CrossRefGoogle Scholar
  28. 28.
    Chung SB, Lee SH, Kim ES, Eoh W. Incidence of deep vein thrombosis after spinal cord injury: a prospective study in 37 consecutive patients with traumatic or nontraumatic spinal cord injury treated by mechanical prophylaxis. J Trauma. 2011;71(4):867–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Maung AA, Schuster KM, Kaplan LJ, et al. Risk of venous thromboembolism after spinal cord injury: not all levels are the same. J Trauma. 2011;71:1241–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Giorgi PM, Donadini MP, Dentali F, et al. The short- and long-term risk of venous thromboembolism in patients with acute spinal cord injury: a prospective cohort study. Thromb Haemost. 2013;109:34–8.CrossRefGoogle Scholar
  31. 31.
    Chen HL, Wang XD. Heparin for venous thromboembolism prophylaxis in patients with acute spinal cord injury: a systematic review and meta-analysis. Spinal Cord. 2013;51:596–602.PubMedCrossRefGoogle Scholar
  32. 32.
    Ageno W, Agnelli G, Checchia G. Italian Society for Haemostasis and Thrombosis. Prevention of venous thromboembolism in immobilized neurological patients: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2009;124:e26–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Lim AC, Roth EJ, Green D. Lower limb paralysis: its effect on the recanalization of deep-vein thrombosis. Arch Phys Med Rehabil. 1992;73:331–3.PubMedCrossRefGoogle Scholar
  34. 34.
    Lim W, Crowther MA. Antiphospholipid antibodies: a critical review of the literature. Curr Opin Hematol. 2007;14:494–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Arnson Y, Shoenfeld Y, Alon E, Amital H. The antiphospholipid syndrome as a neurological disease. Semin Arthritis Rheum. 2010;40:97–108.PubMedCrossRefGoogle Scholar
  36. 36.•
    Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133–8. One of two well-designed randomized controlled trials demonstrating that a higher INR target was not associated with fewer recurrent thromboses (and was associated with a higher risk of bleeding) in antiphospholipid syndrome.PubMedCrossRefGoogle Scholar
  37. 37.•
    Finazzi G, Marchioli R, Brancaccio V, et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848–53. The second of two well-designed randomized controlled trials demonstrating that a higher INR target was not associated with fewer recurrent thromboses (and was associated with a higher risk of bleeding) in antiphospholipid syndrome.PubMedCrossRefGoogle Scholar
  38. 38.
    Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of anticoagulation study group. Am J Med. 1998;104:332–8.PubMedCrossRefGoogle Scholar
  39. 39. “RAPS” trial for rivaroxaban in antiphospholipid syndrome. Accessed 6 Jan 2014
  40. 40.
    Einhäupl KM, Villringer A, Meister W, Mehraein S, Garner C, Pellkofer M, et al. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597–600.PubMedCrossRefGoogle Scholar
  41. 41.
    de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular weight heparin for cerebral sinus thrombosis. Stroke. 1999;30:484–8.PubMedCrossRefGoogle Scholar
  42. 42.•
    Coutinho J, de Bruijn SF, Deveber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database Syst Rev. 2011;8, CD002005. A recent comprehensive review of the literature regarding anticoagulation for cerebral venous sinus thrombosis.PubMedGoogle Scholar
  43. 43.
    Misra UK, Kalita J, Chandra S, et al. Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial. Eur J Neurol. 2012;19:1030–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Kernan WN, Ovbiagele B, Black HR, 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):2160–236.Google Scholar
  45. 45.
    Kansal AR, Sorensen SV, 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;98:573–8.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Chang AM, Ho JC, Yan BP, et al. Cost-effectiveness of dabigatran compared with warfarin for stroke prevention in patients with atrial fibrillation—a real patient data analysis in a Hong Kong teaching hospital. Clin Cardiol. 2013;36:280–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Reddy P, Atay JK, Selbovitz LG, et al. Dabigatran: a review of clinical and pharmacoeconomic evidence. Crit Pathw Cardiol. 2011;10:117–27.PubMedCrossRefGoogle Scholar
  48. 48.
    Wisloff T, Hagen G, Klemp M. Economic evaluation of warfarin, dabigatran, rivaroxaban, and apixaban for stroke prevention in atrial fibrillation. Pharmacoeconomics. 2014;32:601–12.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Fareed J, Thethi I, Hoppensteadt D. Old versus new oral anticoagulants: focus on pharmacology. Annu Rev Pharmacol Toxicol. 2012;52:79–99.PubMedCrossRefGoogle Scholar
  50. 50.
    Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. J Natl Compr Cancer Netw. 2013;11:1402–29.Google Scholar
  51. 51.••
    Guyatt GH, Akl EA, Crowther M, American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: american college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):7S–47. The most updated version of a highly regarded summary and evidence-based recommendation for treatment of thrombotic disease.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Visser LE, Penning-van Bees FJ, Kasbergen AA, et al. Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants. Thromb Haemost. 2002;88:705–10.PubMedGoogle Scholar
  53. 53.
    Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ. 2007;177:347–51.PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Schelleman H, Bilker WB, Brensinger CM, et al. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med. 2010;123(2):151–7.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood. 2011;117:6091–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Sarode R, Milling Jr TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate inpatients on vitamin K antagonists presenting with major bleeding: a randomized, plasma-controlled, phase IIIb study. Circulation. 2013;128:1234–43.PubMedGoogle Scholar
  57. 57.
    Limdi NA, Beasley TM, Baird MF, et al. Kidney function influences warfarin responsiveness and hemorrhagic complications. J Am Soc Nephrol. 2009;20:912–21.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Fitzmaurice DA, Blann AD, Lip GY. Bleeding risks of antithrombotic therapy. BMJ. 2002;325:828–31.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS One. 2012;7(8):e44064.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Cosmi B, Palareti G. Old and new heparins. Thromb Res. 2012;129:388–91.PubMedCrossRefGoogle Scholar
  61. 61.
    Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest. 2001;119:64S–94.PubMedCrossRefGoogle Scholar
  62. 62.
    Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. A randomized controlled trial. Ann Intern Med. 1993;119:874–81.PubMedGoogle Scholar
  63. 63.
    Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809–17.PubMedCrossRefGoogle Scholar
  64. 64.
    Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med. 2010;123:877–84.PubMedCrossRefGoogle Scholar
  65. 65.
    Lindblad B. Protamine sulphate: a review of its effects: hypersensitivity and toxicity. Eur J Vasc Surg. 1989;3:195–201.PubMedCrossRefGoogle Scholar
  66. 66.
    Crowther MA, Warkentin TE. Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood. 2008;111:4871–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA consensus conference on neuraxial anesthesia and anticoagulation). Reg Anesth Pain Med. 2003;28:172–97.PubMedGoogle Scholar
  68. 68.
    Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002;51 Suppl 2:1–9.CrossRefGoogle Scholar
  69. 69.
    Bijsterveld NR, Moons AH, Boekholdt SM, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–4.PubMedCrossRefGoogle Scholar
  70. 70.
    Schulman S, Kearon C, Kakkar AK, RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–52.PubMedCrossRefGoogle Scholar
  71. 71.
    Connolly SJ, Ezekowitz MD, Yusuf S. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.PubMedCrossRefGoogle Scholar
  72. 72.
    Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.PubMedCrossRefGoogle Scholar
  73. 73.
    Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol. 2013;8:1533–9.PubMedCrossRefGoogle Scholar
  74. 74.•
    Siegal DM, Garcia DA, Crowther MA. How I treat target-specific oral anticoagulant-associated bleeding. Blood. 2014;123:1152–8. An expert-derived algorithm for the management of bleeding associated with the non-vitamin K oral anticoagulants.PubMedCrossRefGoogle Scholar
  75. 75.
    Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis. 2011;31:326–43.PubMedCrossRefGoogle Scholar
  76. 76.
    Short NJ, Connors JM. New oral anticoagulants and the cancer patient. Oncologist. 2014;19:82–93.PubMedCrossRefGoogle Scholar
  77. 77.
    EINSTEIN-PE Investigators, Büller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97.PubMedCrossRefGoogle Scholar
  78. 78.
    EINSTEIN Investigators Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–510.PubMedCrossRefGoogle Scholar
  79. 79.
    Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1563–79.CrossRefGoogle Scholar
  80. 80.
    Agnelli G, Büller HR, Cohen A. AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799–808.PubMedCrossRefGoogle Scholar
  81. 81.
    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.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Hematology and Medical OncologyDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of HematologyBrigham and Women’s HospitalBostonUSA

Personalised recommendations