International normalised ratio normalisation in patients with coumarin-related intracranial haemorrhages - the INCH trial: A randomised controlled multicentre trial to compare safety and preliminary efficacy of fresh frozen plasma and prothrombin complex - study design and protocol

International Journal of Stroke

Volumn 6, Issue 3, 2011, Pages 271-277

  Steiner, Thorsten ^a   Freiberger, Anja ^a   Griebe, Martin ^b   Hüsing, Johannes ^a   Ivandic, Boris ^a   Kollmar, Rainer ^c   Pfefferkorn, Thomas ^d   Wartenberg, Katja E ^e   Weimar, Christian ^f   Hennerici, Michael ^b   Poli, Sven ^a  

^a UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^b UNIVERSITY OF HEIDELBERG   (Germany)

^c UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^d LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^e MARTIN LUTHER UNIVERSITÄT HALLE WITTENBERG   (Germany)

^f UNIVERSITY HOSPITAL ESSEN   (Germany)

Author keywords

Acenocoumarol; Coumarin; Fresh frozen plasma; International normalised ratio; Intracerebral haemorrhage; Phenprocoumon; Prothrombin complex concentrates; Warfarin

Indexed keywords

ANTIVITAMIN K; COUMARIN; FRESH FROZEN PLASMA; PROTHROMBIN COMPLEX;

ADULT; ARTICLE; BRAIN HEMORRHAGE; CLINICAL PROTOCOL; COMPUTER ASSISTED TOMOGRAPHY; CONTROLLED STUDY; DRUG EFFICACY; DRUG SAFETY; HUMAN; INTERNATIONAL NORMALIZED RATIO; MAJOR CLINICAL STUDY; MULTICENTER STUDY (TOPIC); PRIORITY JOURNAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL (TOPIC); STUDY DESIGN; SUBDURAL HEMATOMA; TREATMENT OUTCOME;

ACUTE DISEASE; ADOLESCENT; ADULT; AGED; ANTICOAGULANTS; COUMARINS; ENDPOINT DETERMINATION; FEMALE; HEMATOMA, SUBDURAL; HEMOSTASIS; HUMANS; INTERNATIONAL NORMALIZED RATIO; INTRACRANIAL HEMORRHAGES; MALE; MIDDLE AGED; PLASMA; PROSPECTIVE STUDIES; PROTHROMBIN; RESEARCH DESIGN; RISK ASSESSMENT; TOMOGRAPHY, X-RAY COMPUTED; VITAMIN K; YOUNG ADULT;

EID: 79955750183     PISSN: 17474930     EISSN: 17474949     Source Type: Journal    
DOI: 10.1111/j.1747-4949.2010.00560.x     Document Type: Article

References (79)

1. Franke CL, de Jonge J, van Swieten JC, Op de Coul AA, van Gijn J. Intracerebral hematomas during anticoagulant treatment. Stroke 1990; 21:726-30.
2. Rosand 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; 164:880-4.
3. Steiner T, Rosand J, Diringer M. Intracerebral hemorrhage associated with oral anticoagulant therapy: current practices and unresolved questions. Stroke 2006; 37:256-62.
4. Gopinath SP, Robertson CS, Contant CF, Hayes C, Feldman Z, Narayan RK, Grossman RG. Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry 1994; 57:717-23.
5. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. 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; 285:2370-5.
6. Walker ID, Machin S, Baglin TP et al. Guidelines on oral anticoagulation: third edition. Br J Haematol 1998; 101:374-87.
7. Ansell J, Hirsh J, American College of Chest Physicians, et al. Pharmacology and management of the vitamin k antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133:160S-98S.
8. Baglin TP, Keeling DM, Watson HG, British Committee for Standards in Haematology. Guidelines on oral anticoagulation (warfarin): third edition - 2005 update. Br J Haematol 2006; 132:277-85.
9. Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery 1999; 45:1113-8; discussion 1118-19.
10. Butler AC, Tait RC. Management of oral anticoagulant-induced intracranial haemorrhage. Blood Rev 1998; 12:35-44.
11. Fewel ME, Park P. The emerging role of recombinant-activated factor VII in neurocritical care. Neurocrit Care 2004; 1:19-29.
12. Freeman WD, Brott TG, Barrett KM, Castillo PR, Deen HG Jr, Czervionke LF, Meschia JF. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc 2004; 79:1495-500.
13. Freeman WD, Aguilar MI. Management of warfarin-related intracerebral hemorrhage. Expert Rev Neurother 2008; 8:271-90.
14. Kessler CM. Urgent reversal of warfarin with prothrombin complex concentrate: where are the evidence-based data? J Thromb Haemost 2006; 4:963-6.
15. Flaherty ML, Tao H, Haverbusch M et al. Warfarin use leads to larger intracerebral hematomas. Neurology 2008; 71:1084-9.
16. Goldstein JN, Thomas SH, Frontiero V et al. Timing of fresh frozen plasma administration and rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006; 37:151-5.
17. Steiner T, Griebe M, Hennerici M et al. Multicenter, prospective randomized trial on the use of prothrombin complex and fresh frozen plasma in patients with intracerebral hemorrhage related to vitamin k antagonists. Available at (accessed 20 December 2009).
18. Steiner T, Walter-Sack I, Taupitz J, Hacke W, Strowitzki T. Ethical and legal aspects of including patients unable to consent in acute therapy studies. Example of a medication study for the treatment of intracerebral hemorrhage - the Heidelberg procedure. Dtsch Med Wochenschr 2008; 133:787-92.
19. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke 1988; 19:604-7.
20. Brott T, Adams HP Jr, Olinger CP et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989; 20:864-70.
21. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965; 14:61-5.
22. Wilson JT, Pettigrew LE, Teasdale GM. Structured interviews for the glasgow outcome scale and the extended glasgow outcome scale: guidelines for their use. J Neurotrauma 1998; 15:573-85.
23. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy 1990; 16:199-208.
24. Snow V, Qaseem A, Barry P et al. Management of venous thromboembolism: a clinical practice guideline from the American college of physicians and the American academy of family physicians. Ann Intern Med 2007; 146:204-10.
25. Thygesen K, Alpert JS, White HD et al. Universal definition of myocardial infarction. Circulation 2007; 116:2634-53.
26. Toni D, Chamorro A, Kaste M, EUSI Executive Committee; EUSI Writing Committee, et al. Acute treatment of ischaemic stroke. European Stroke Initiative. Cerebrovasc Dis 2004; 17 (Suppl. 2): 30-46.
27. Torbicki A, Perrier A, Konstantinides S et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the european society of cardiology (ESC). Eur Heart J 2008; 29:2276-315.
28. Flibotte JJ, Hagan N, O'Donnell J, Greenberg SM, Rosand J. Warfarin, hematoma expansion, and outcome of intracerebral hemorrhage. Neurology 2004; 63:1059-64.
29. Fredriksson K, Norrving B, Strömblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke 1992; 23:972-7.
30. Huttner HB, Schellinger PD, Hartmann M et al. Hematoma growth and outcome in treated neurocritical care patients with intracerebral hemorrhage related to oral anticoagulant therapy: comparison of acute treatment strategies using vitamin k, fresh frozen plasma, and prothrombin complex concentrates. Stroke 2006; 37:1465-70.
31. Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost 2006; 4:967-70.
32. Broderick J, Connolly S, Feldmann E et al. Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the american heart association/american stroke association stroke council, high blood pressure research council, and the quality of care and outcomes in research interdisciplinary working group. Stroke 2007; 38:2001-23.
33. Steiner T, Kaste M, Forsting M et al. Recommendations for the management of intracranial haemorrhage - part 1: spontaneous intracerebral haemorrhage. The European stroke initiative writing committee and the writing committee for the EUSI executive committee. Cerebrovasc Dis 2006; 22:294-316.
34. Söhngen D, Kretschmer V, Franke K, Pelzer H, Walker WH. Thawing of fresh-frozen plasma with a new microwave oven. Transfusion 1988; 28:576-80.
35. Hirsch J, Bach R, Menzebach A, Welters ID, Dietrich GV, Hempelmann G. Temperature course and distribution during plasma heating with a microwave device. Anaesthesia 2003; 58:444-7.
36. White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122:40-2.
37. Pabinger I, Brenner B, Kalina U, Beriplex P/N Anticoagulation Reversal Study Group, et al. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost 2008; 6:622-31.
38. Kalina M, Tinkoff G, Gbadebo A, Veneri P, Fulda G. A protocol for the rapid normalization of INR in trauma patients with intracranial hemorrhage on prescribed warfarin therapy. Am Surg 2008; 74:858-61.
39. Bundesärztekammer. Leitlinien zur therapie mit blutkomponenten und plasmaderivaten. Köln: Deutscher Ärzte-Verlag, 2003.
40. Octapharma. Fachinformation Octaplex 500 (humaner prothrombinkomplex, ppsb). Berlin: Rote Liste Service GmbH, 2009.
41. Schulman S. Clinical practice. Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003; 349:675-83.
42. Steiner T, Bösel J. Options to restrict hematoma expansion after spontaneous intracerebral hemorrhage. Stroke 2010; 41:402-9.
43. Brott T, Broderick J, Kothari R et al. Early hemorrhage growth in patients with intracerebral hemorrhage. Stroke 1997; 28:1-5.
44. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993; 24:987-93.
45. Davis SM, Broderick J, Hennerici M et al. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage. Neurology 2006; 66:1175-81.
46. Mayer SA, Brun NC, Begtrup K et al. Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med 2005; 352:777-85.
47. Mayer SA, Brun NC, Begtrup K et al. Randomised, placebo-controlled, double-blind phase III study to assess rFVIIa efficacy in acute intracerebral hemorrhage: the FAST trial, XVI European Stroke Conference, Glasgow, 2007.
48. Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker J. Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 1990; 72:195-9.
49. Zimmerman RD, Maldjian JA, Brun NC, Horvath B, Skolnick BE. Radiologic estimation of hematoma volume in intracerebral hemorrhage trial by CT scan. Am J Neuroradiol 2006; 27:666-70.
50. Steiner T, Kaste M, Forsting M et al. Recommendations for the management of intracranial haemorrhage - part 1: spontaneous intracerebral haemorrhage. The European stroke initiative writing committee and the writing committee for the EUSI executive committee. Cerebrovasc Dis 2006; 22:294-316.
51. Anderson CS, Huang Y, Wang JG et al. Intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT): a randomised pilot trial. Lancet Neurol 2008; 7:391-9.
52. Qureshi AI. Antihypertensive treatment of acute cerebral hemorrhage (ATACH): rationale and design. Neurocrit Care 2007; 6:56-66.
53. Levine JM, Snider R, Finkelstein D et al. Early edema in warfarin-related intracerebral hemorrhage. Neurocrit Care 2007; 7:58-63.
54. Sansing LH, Kaznatcheeva EA, Perkins CJ, Komaroff E, Gutman FB, Newman GC. Edema after intracerebral hemorrhage: correlations with coagulation parameters and treatment. J Neurosurg 2003; 98:985-92.
55. Ansell J, Hirsh J, Dalen J et al. Managing oral anticoagulant therapy. Chest 2001; 119:22S-38S.
56. Beeck H, Hellstern P. In vitro characterization of solvent/detergent-treated human plasma and of quarantine fresh frozen plasma. Vox Sang 1998; 74 (Suppl. 1): 219-23.
57. Hanley JP. Warfarin reversal. J Clin Pathol 2004; 57:1132-9.
58. Yasaka M, Minematsu K, Naritomi H, Sakata T, Yamaguchi T. Predisposing factors for enlargement of intracerebral hemorrhage in patients treated with warfarin. Thromb Haemost 2003; 89:278-83.
59. Makris M, Greaves M, Phillips WS, Kitchen S, Rosendaal FR, Preston EF. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997; 77:477-80.
60. Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol 2001; 114:271-80.
61. Hellstern P, Muntean W, Schramm W, Seifried E, Solheim BG. Practical guidelines for the clinical use of plasma. Thromb Res 2002; 107 (Suppl. 1): S53-7.
62. O'Shaughnessy DF, Atterbury C, Bolton Maggs P et al. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126:11-28.
63. Pindur G, Mörsdorf S, Schenk JF, Krischek B, Heinrich W, Wenzel E. The overdosed patient and bleedings with oral anticoagulation. Semin Thromb Hemost 1999; 25:85-8.
64. Brody DL, Aiyagari V, Shackleford AM, Diringer MN. Use of recombinant factor VIIa in patients with warfarin-associated intracranial hemorrhage. Neurocrit Care 2005; 2:263-7.
65. Frazee LA, Bourguet CC, Gutierrez W, Elder-Arrington J, Elackattu AE, Haller NA. Retrospective evaluation of a method to predict fresh-frozen plasma dosage in anticoagulated patients. Am J Ther 2008; 15:111-18.
66. Butler AC, Tait RC. Restarting anticoagulation in prosthetic heart valve patients after intracranial haemorrhage: a 2-year follow-up. Br J Haematol 1998; 103:1064-6.
67. Phan TG, Koh M, Wijdicks EF. Safety of discontinuation of anticoagulation in patients with intracranial hemorrhage at high thromboembolic risk. Arch Neurol 2000; 57:1710-3.
68. Wijdicks EF, Schievink WI, Brown RD, Mullany CJ. The dilemma of discontinuation of anticoagulation therapy for patients with intracranial hemorrhage and mechanical heart valves. Neurosurgery 1998; 42:769-73.
69. Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko V, Brenner B. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thromb Res 2004; 113:371-8.
70. Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res 2007; 121:9-16.
71. Vigué B, Ract C, Tremey B et al. Ultra-rapid management of oral anticoagulant therapy-related surgical intracranial hemorrhage. Intensive Care Med 2007; 33:721-5.
72. Bertram M, Bonsanto M, Hacke W, Schwab S. Managing the therapeutic dilemma: patients with spontaneous intracerebral hemorrhage and urgent need for anticoagulation. J Neurol 2000; 247:209-14.
73. Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg 2000; 14:458-61.
74. Sjoblom L, Hårdemark HG, Lindgren A et al. Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a swedish multicenter study. Stroke 2001; 32:2567-74.
75. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008; 83:137-43.
76. Committee for Medicinal Products For Human Use (CMPH). Core spc for Human Prothrombin Complex Products (CPMP/BPWG/3735/02). London: EMEA - European Medicines Agency (Human Medicines Evaluation Unit), 2004.
77. Fiore LD, Scola MA, Cantillon CE, Brophy MT. Anaphylactoid reactions to vitamin k. J Thromb Thrombolysis 2001; 11:175-83.
78. Riegert-Johnson DL, Volcheck GW. The incidence of anaphylaxis following intravenous phytonadione (vitamin K1): a 5-year retrospective review. Ann Allergy Asthma Immunol 2002; 89:400-6.
79. Raj G, Kumar R, McKinney WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Arch Intern Med 1999; 159:2721-4.