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Current Treatment Options in Neurology

Erschienen in:

01.09.2014 | Neurologic Manifestations of Systemic Disease (A Pruitt, Section Editor)

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

verfasst von: Ariela L. Marshall, MD, Jean-Marie Connors, MD

Erschienen in: Current Treatment Options in Neurology | Ausgabe 9/2014

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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.

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.PubMedCrossRef

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.CrossRef

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.CrossRef

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.PubMed

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.PubMedCentralPubMedCrossRef

Hankey GJ, Eikelboom JW, van Bockxmeer FM, et al. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke. 2001;32:1793–9.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

Goldschmidt N, Linetsky E, Shalom E, et al. High incidence of thromboembolism in patients with central nervous system lymphoma. Cancer. 2003;98:1239–42.PubMedCrossRef

10.

Ruff RL, Posner JB. Incidence and treatment of peripheral venous thrombosis in patients with glioma. Ann Neurol. 1983;13:334–6.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

17.

Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer. 1994;73:493–8.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

24.

Kondziolka D, Bernstein M, Resch L, et al. Significance of hemorrhage into brain tumors: clinicopathological study. J Neurosurg. 1987;67:852–7.PubMedCrossRef

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.PubMedCrossRef

26.

Lazio BE, Simard JM. Anticoagulation in neurosurgical patients. Neurosurgery. 1999;45:838–48.PubMedCrossRef

27.

Miranda AR, Hassouna HI. Mechanisms of thrombosis in spinal cord injury. Hematol Oncol Clin N Am. 2000;14:401–16.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

34.

Lim W, Crowther MA. Antiphospholipid antibodies: a critical review of the literature. Curr Opin Hematol. 2007;14:494–9.PubMedCrossRef

35.

Arnson Y, Shoenfeld Y, Alon E, Amital H. The antiphospholipid syndrome as a neurological disease. Semin Arthritis Rheum. 2010;40:97–108.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

39.

http://www.controlled-trials.com/ISRCTN68222801 “RAPS” trial for rivaroxaban in antiphospholipid syndrome. Accessed 6 Jan 2014

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

47.

Reddy P, Atay JK, Selbovitz LG, et al. Dabigatran: a review of clinical and pharmacoeconomic evidence. Crit Pathw Cardiol. 2011;10:117–27.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

49.

Fareed J, Thethi I, Hoppensteadt D. Old versus new oral anticoagulants: focus on pharmacology. Annu Rev Pharmacol Toxicol. 2012;52:79–99.PubMedCrossRef

50.

Streiff MB, Bockenstedt PL, Cataland SR, et al. Venous thromboembolic disease. J Natl Compr Cancer Netw. 2013;11:1402–29.

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.PubMedCentralPubMedCrossRef

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.PubMed

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

55.

Goodnough LT, Shander A. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood. 2011;117:6091–9.PubMedCrossRef

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.PubMed

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.PubMedCentralPubMedCrossRef

58.

Fitzmaurice DA, Blann AD, Lip GY. Bleeding risks of antithrombotic therapy. BMJ. 2002;325:828–31.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

60.

Cosmi B, Palareti G. Old and new heparins. Thromb Res. 2012;129:388–91.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

63.

Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med. 2006;355:809–17.PubMedCrossRef

64.

Mazziotti G, Canalis E, Giustina A. Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med. 2010;123:877–84.PubMedCrossRef

65.

Lindblad B. Protamine sulphate: a review of its effects: hypersensitivity and toxicity. Eur J Vasc Surg. 1989;3:195–201.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

72.

Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet. 2008;47(5):285–95.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

76.

Short NJ, Connors JM. New oral anticoagulants and the cancer patient. Oncologist. 2014;19:82–93.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

Titel: Anticoagulation for Noncardiac Indications in Neurologic Patients: Comparative Use of Non-Vitamin K Oral Anticoagulants, Low-Molecular-Weight Heparins, and Warfarin
verfasst von: Ariela L. Marshall, MD
Jean-Marie Connors, MD
Publikationsdatum: 01.09.2014
Verlag: Springer US
Erschienen in: Current Treatment Options in Neurology / Ausgabe 9/2014
Print ISSN: 1092-8480
Elektronische ISSN: 1534-3138
DOI: https://doi.org/10.1007/s11940-014-0309-2

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