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Treatment of Warfarin-Associated Intracerebral Hemorrhage: Literature Review and Expert Opinion

2007; Elsevier BV; Volume: 82; Issue: 1 Linguagem: Inglês

10.1016/s0025-6196(11)60970-1

1942-5546

Maria I. Aguilar, Robert G. Hart, Carlos S. Kase, William D. Freeman, Barbara J. Hoeben, Rosa C. García, Jack Ansell, Stephan A. Mayer, Bo Norrving, Jonathan Rosand, Thorsten Steiner, Eelco F. M. Wijdicks, Takenori Yamaguchi, Masahiro Yasaka,

Neurosurgical Procedures and Complications

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence. Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence. The frequent use of long-term oral anticoagulation in elderly patients, particularly to prevent stroke in individuals with atrial fibrillation, has resulted in an increase in warfarin-associated intracerebral hemorrhage (ICH).1Kucher N Castellanos LR Quiroz R Koo S Fanikos J Goldhaber SZ Time trends in warfarin-associated hemorrhage.Am J Cardiol. 2004; 94: 403-406Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 2Flaherty ML Haverbusch M Sekar P et al.The increasing burden of anticoagulant-associated intracerebral hemorrhage [abstract].Stroke. 2006; 37 (Abstract 15.): 623Google Scholar Half of the patients with warfarin-associated ICH die within 30 days, and this uniformly high early mortality rate has remained stable over time3Hart RG Boop BS Anderson DC Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.Stroke. 1995; 26: 1471-1477Crossref PubMed Scopus (484) Google Scholar, 4Neau JP Couderq C Ingrand P Blanchon P Gil R VGP Study Group Intracranial hemorrhage and oral anticoagulant treatment.Cerebrovasc Dis. 2001; 11: 195-200Crossref PubMed Scopus (44) Google Scholar, 5Punthakee X Doobay J Anand SS Oral-anticoagulant-related intracerebral hemorrhage.Thromb Res. 2002; 108: 31-36Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 6Sjoblom L Hardemark HG Lindgren A et al.Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.Stroke. 2001; 32: 2567-2574Crossref PubMed Scopus (186) Google Scholar, 7Rosand J Eckman MH Knudsen KA Singer DE Greenberg SM The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.Arch Intern Med. 2004; 164: 880-884Crossref PubMed Scopus (507) Google Scholar, 8Berwaerts J Robb OJ Jeffers TA Webster J Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.Scott Med J. 2000; 45: 101-104PubMed Google Scholar, 9Steiner T Rosand J Diringer M Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions.Stroke. 2006 Jan; 37 (Epub 2005 Dec 8.): 256-262Crossref PubMed Scopus (268) Google Scholar, 10Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin.Ann Neurol. 1997; 42: 857-865Crossref PubMed Scopus (515) Google Scholar, 11Sjalander A Engstrom G Berntorp E Svensson P Risk of haemorrhagic stroke in patients with oral anticoagulation compared with the general population.J Intern Med. 2003; 254: 434-438Crossref PubMed Scopus (48) Google Scholar, 12Gage BF Waterman AD Shannon W Boechler M Rich MW Radford MJ Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.JAMA. 2001; 285: 2864-2870Crossref PubMed Scopus (4171) Google Scholar (Table 1). Adequate treatment remains to be defined.3Hart RG Boop BS Anderson DC Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.Stroke. 1995; 26: 1471-1477Crossref PubMed Scopus (484) Google Scholar, 4Neau JP Couderq C Ingrand P Blanchon P Gil R VGP Study Group Intracranial hemorrhage and oral anticoagulant treatment.Cerebrovasc Dis. 2001; 11: 195-200Crossref PubMed Scopus (44) Google Scholar, 6Sjoblom L Hardemark HG Lindgren A et al.Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.Stroke. 2001; 32: 2567-2574Crossref PubMed Scopus (186) Google Scholar, 8Berwaerts J Robb OJ Jeffers TA Webster J Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.Scott Med J. 2000; 45: 101-104PubMed Google Scholar No consensus exists about the optimal short-term treatment of this lethal, iatrogenic form of stroke. Randomized trials meaningfully addressing treatment are not available, and current management is based largely on small clinical case series.9Steiner T Rosand J Diringer M Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions.Stroke. 2006 Jan; 37 (Epub 2005 Dec 8.): 256-262Crossref PubMed Scopus (268) Google ScholarTABLE 1Early Mortality in Anticoagulant-Associated Intracranial HemorrhageReferenceMethodNo. of central nervous bleeds% (No.) of 30-day mortalityHart et al,3Hart RG Boop BS Anderson DC Oral anticoagulants and intracranial hemorrhage: facts and hypotheses.Stroke. 1995; 26: 1471-1477Crossref PubMed Scopus (484) Google Scholar 1995Literature review, 15 studies, 1982-199445460 (272)Neau et al,4Neau JP Couderq C Ingrand P Blanchon P Gil R VGP Study Group Intracranial hemorrhage and oral anticoagulant treatment.Cerebrovasc Dis. 2001; 11: 195-200Crossref PubMed Scopus (44) Google Scholar 2001Case series7944 (35)Sjoblom et al,6Sjoblom L Hardemark HG Lindgren A et al.Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.Stroke. 2001; 32: 2567-2574Crossref PubMed Scopus (186) Google Scholar 2001Medical record review15154 (82)Rosand et al,7Rosand J Eckman MH Knudsen KA Singer DE Greenberg SM The effect of warfarin and intensity of anticoagulation on outcome of intracerebral hemorrhage.Arch Intern Med. 2004; 164: 880-884Crossref PubMed Scopus (507) Google Scholar 2004Prospective case series10252*Three-month mortality.(53)Berwaerts et al,8Berwaerts J Robb OJ Jeffers TA Webster J Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.Scott Med J. 2000; 45: 101-104PubMed Google Scholar 2000Case series4244 (35)SPIRIT trial,10Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin.Ann Neurol. 1997; 42: 857-865Crossref PubMed Scopus (515) Google Scholar 1997Randomized trial2743 (18)Sjalander et al,11Sjalander A Engstrom G Berntorp E Svensson P Risk of haemorrhagic stroke in patients with oral anticoagulation compared with the general population.J Intern Med. 2003; 254: 434-438Crossref PubMed Scopus (48) Google Scholar 2003Case series4844 (21)Gage et al,12Gage BF Waterman AD Shannon W Boechler M Rich MW Radford MJ Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.JAMA. 2001; 285: 2864-2870Crossref PubMed Scopus (4171) Google Scholar 2001Medicare cohort∼20052 (104)Pooled data110353†SD ± 7. (602)* Three-month mortality.† SD ± 7. Open table in a new tab In the absence of well-designed clinical trials, treatment based on the opinions of experts in clinical stroke, neurologic intensive care, and hematology and coagulation is likely the best available evidence. In this article, current treatment options for warfarin-associated ICH and management recommendations solicited independently from 7 international experts are reviewed. A computerized search of the OVID database from January 1996 to January 2006 combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage was undertaken. The reference lists from recent review articles were also examined. From the elicited sources, 4 of the coauthors (R.G.H., C.S.K., M.I.A., and W.D.F.) drafted the narrative review of the recent literature. Because information about the practical clinical pharmacology of prothrombin complex concentrates (PCCs) is not readily accessible, 2 coauthors (B.J.H. and R.C.G.) prepared a structured pharmacological summary of these drugs (Appendix 113Factor IX complex (human). Lexi-Comp Drug Reference. Lexi-Comp Online.Available at: www.lexi.com/web/index.jspDate: 2006Google Scholar, 14Prothrombin complex concentrates (PCC) content of factors II, VII, IX and X. Bebulin [package insert]. Baxter, Deerfield, Ill2004Available at: www.hemophiliagalaxy.com/pdfs/therapies/BebulinPI.PDFGoogle Scholar, 15Cohen HE 2003 Drug Topics Red Book. Thompson Healthcare, Montvale, NJ2003Google Scholar). Seven experts in clinical stroke (B.N., T.S., and T.Y. or M.Y.), neurological intensive care (J.R., S.A.M., and E.F.M.W.), and hematology and coagulation (J.E.A.) were asked to independently address the following 3 questions: 1.How should anticoagulation be reversed in a patient with acute (within 6 hours of symptom onset) warfarin-associated ICH with an international normalized ratio (INR) of 2.5? What are the roles of recombinant factor VIIa (rFVIIa) and PCCs?When should anticoagulation (warfarin) be restarted in survivors of warfarin-associated ICH with mechanical prosthetic heart valves?Under what circumstances (if any) should anticoagulation be resumed in a patient with chronic nonvalvular atrial fibrillation who experienced an ICH during warfarin therapy? Does it matter whether the INR was 1.8 or 3.5 at the time of the hemorrhage? An expert was defined as someone with involvement with one or more publications on the specific topic or who had personal experience treating warfarin-associated ICH. The selection of experts was also based on geographic location to reflect an international perspective (United States, Japan, Germany, and Sweden). No pharmaceutical company participated in the development of this article or in the selection of the experts. The experts were provided with the literature review, Appendix 1, and access to all sources cited in the reference list. Rather than attempting to reach a consensus, individual responses were collated and summarized (Table 2). Full answers provided by the experts are available online at www.mayoclinicproceedings.com linked to this article. Experts did not have access to each other's responses.TABLE 2Expert Recommendations for the Management of Warfarin-Associated ICH: Responses to 3 Specific Questions*See text for complete statement of the questions. Complete responses available online at www.mayoclinicproceedings.com linked to this article. FFP = fresh frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCCs = prothrombin complex concentrates; rFVIIa = recombinant activated factor VIIa.QuestionExpert 1Expert 2Expert 3†Expert has served as consultant for NovoNordisk.Expert 4†Expert has served as consultant for NovoNordisk.Expert 5†Expert has served as consultant for NovoNordisk.Expert 6Expert 7 1.How can anticoagulation best be reversed (INR=2.5)?rFVIIa and vitamin KrFVIIa if deteriorating; FFP and vitamin K otherwiserFVIIa, FFP, and vitamin KFFP or PCCs and vitamin KPCCs and vitamin KPCCs and vitamin KPCCs and vitamin K 2.When should anticoagulation with prosthetic cardiac valve be restarted?>7 d in most patients‡If patient was older than 80 years and if moderate to severe leukoaraiosis was absent.>7 d if computed tomogram stable5-10 dLow-dose heparin as early as 48 h10-14 d§Low-dose heparin as early as 24 hours after normalization of INR (<1.5).1-3 d7 d 3.Should warfarin therapy be restarted for atrial fibrillation?With reluctanceIf prior ischemic strokeProbably neverIf ICH is deep (ie, nonlobar)If ICH is deep (ie, nonlobar)If ICH is deep (ie, nonlobar)In secondary* See text for complete statement of the questions. Complete responses available online at www.mayoclinicproceedings.com linked to this article. FFP = fresh frozen plasma; ICH = intracerebral hemorrhage; INR = international normalized ratio; PCCs = prothrombin complex concentrates; rFVIIa = recombinant activated factor VIIa.† Expert has served as consultant for NovoNordisk.‡ If patient was older than 80 years and if moderate to severe leukoaraiosis was absent.§ Low-dose heparin as early as 24 hours after normalization of INR ( 50 mL), intraventricular extension, and shift of midline structures are associated with poorer outcome.4Neau JP Couderq C Ingrand P Blanchon P Gil R VGP Study Group Intracranial hemorrhage and oral anticoagulant treatment.Cerebrovasc Dis. 2001; 11: 195-200Crossref PubMed Scopus (44) Google Scholar, 6Sjoblom L Hardemark HG Lindgren A et al.Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.Stroke. 2001; 32: 2567-2574Crossref PubMed Scopus (186) Google Scholar, 8Berwaerts J Robb OJ Jeffers TA Webster J Intracerebral haemorrhages and oral anticoagulation in the north of Scotland.Scott Med J. 2000; 45: 101-104PubMed Google Scholar Warfarin-associated ICH should prompt emergent correction of anticoagulation. Even small hematomas in patients who have undergone anticoagulation therapy can expand during the initial 24 to 48 hours, particularly if the INR is greater than 3.0, and anticoagulation should be reversed without delay. Several options exist for achieving this goal (Table 3). No randomized trials assessing clinical outcomes were found on treatment of warfarin-associated ICH. The existing literature consists mainly of small case series, often retrospective and potentially biased by selection. In the absence of meaningful evidence, the management of these patients varies widely.TABLE 3Reversing Anticoagulation in Warfarin-Associated Intracerebral Hemorrhage*INR = international normalized ratio.Management optionTime to anticoagulation reversalComments and cautionsDiscontinuing warfarin therapy5-14 dVitamin K†A total of 10 mg intravenously by slow infusion throughout 10 minutes.6-24 h to correct the INR Replacement of factors IX and X takes longer than 24 hours, risk of anaphylaxis with intravenous injection, warfarin resistance in higher doses up to 1 wkFresh frozen plasma3-6 h for infusion, typically 12-32 h for reversalVolume (2-4 L to normalize INR) can be prohibitiveProthrombin complex concentrate15 min after 10-min to 1-h infusionLimited availability, cost, variable cofactor content based on manufacturer, potentially prothromboticFactor VIIa concentrate15 min after bolus infusionShort half-life, cost, potentially prothrombotic, uncertain safety* INR = international normalized ratio.† A total of 10 mg intravenously by slow infusion throughout 10 minutes. Open table in a new tab Vitamin K and fresh frozen plasma (FFP) are standard therapies to reverse warfarin anticoagulation, but neither agent is ideal for emergency anticoagulation reversal. Both vitamin K and FFP take several hours to reduce the INR and have a potential for adverse reactions.27Manno EM Atkinson JLD Fulgham JR Wijdicks EFM Emerging medical and surgical management strategies in the evaluation and treatment of intracerebral hemorrhage.Mayo Clin Proc. 2005; 80: 420-433Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Administration of vitamin K (10 mg intravenously) does not normalize the INR for 6 to 24 hours. A dose of 5 to 10 mg may be repeated every 12 hours, up to a total dose of 25 mg.28Fredriksson K Norrving B Stromblad LG Emergency reversal of anticoagulation after intracerebral hemorrhage.Stroke. 1992; 23: 972-977Crossref PubMed Scopus (264) Google Scholar, 29Ansell J Hirsh J Dalen J et al.Managing oral anticoagulant therapy.Chest. 2001; 119: 22S-38SCrossref PubMed Scopus (537) Google Scholar, 30Yasaka M Sakata T Minematsu K Naritomi H Correction of INR by prothrombin complex concentrate and vitamin K in patients with warfarin related hemorrhagic complication.Thromb Res. 2002; 108: 25-30Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 31Lacy CF Armstrong LL Goldman MP Lance LL Drug Information Handbook. 11th ed. Lexi-Comp, Hudson, Ohio2003-2004Google Scholar The infusion rate is 1 mg/min, and it can be diluted in dextrose 5% in water or dextrose 5% in normal saline.31Lacy CF Armstrong LL Goldman MP Lance LL Drug Information Handbook. 11th ed. Lexi-Comp, Hudson, Ohio2003-2004Google Scholar Subcutaneous administration may be safer, but the effect is even slower and less reliable.32Bianco C Choice of human plasma preparations for transfusion.Transfus Med Rev. 1999; 13: 84-88Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 33Fiore LD Scola MA Cantillon CE Brophy MT Anaphylactoid reactions to vitamin K.J Thromb Thrombolysis. 2001; 11: 175-183Crossref PubMed Scopus (98) Google Scholar The volume of FFP required to reverse fully the coagulation defect (often 2-4 L if the INR is greatly prolonged) is an important limiting factor in this critically ill population. A rapid infusion is also required to increase the plasma protein levels significantly, increasing the risk of circulatory overload.34Hellstern P Muntean W Schramm W Seifried