Transcription

1 Anticoagulation related Intracranial hemorrhage Tamer Abdelhak, MD Senior Staff NeuroCritical Care Program Director NeuroCritical Care Fellowship Departments Of Neurology and Neurosurgery Henry Ford Health System 5/9/2012 1

2 Disclosure None 5/9/2012 2

3 Objectives Clotting pathways refresher. Anticoagulation Associated ICH Epidemiology, i Mortality. AC reversal guidelines n Protocols New Agents. 5/9/2012 3

4 5/9/2012 4

5 5/9/2012 5

6 5/9/2012 6

7 5/9/ Hoffman 2003, 2005, J Thromb Thrombolysis

8 Every bleeding eventually stops but how? Activation of Platelets leading to Platelet clot. Activation of clotting cascade leading to Fibrin clot formation. 5/9/2012 8

9 5/9/2012 9

10 Clotting factors 1- Natural deficiency: Hemophiliacs, liver disease. 2-Acquired: Drugs e.g warfarin, heparin etc 5/9/

11 5/9/

12 5/9/

13 5/9/

14 5/9/

15 So is anticoagulation a problem for us??? 5/9/

16 5/9/

17 Bleeding mechanical heart valves (1 8.3%), atrial fibrillation (0 6.6%), coronary heart disease ( %), venous thromboembolism (0 16.7%), ischemic cerebrovascular disease (2 13%) The most frequent complication of OAC is gastrointestinal bleeding, intracranial hemorrhage (ICH) is the main cause of fatal bleeding. 5/9/

18 Epidemiology % of the population is currently receiving OAC with vitamin K antagonists. (Schurgers, Blood 2004) 5 12% of ICH is related to OAC. (Flaherty&Broderick Neurology 2007) Rate of OAC-ICH is about 2 9 per 100,000 /y, an incidence 7- to 10- fold higher than in the untreated population(steiner et al Stroke 2006) 5/9/

19 Epidemiology The incidence of anticoagulant-associated associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage. h (Flaherty&Broderick Neurology 2007) 5/9/

20 Annual incidence rates for intracerebral hemorrhage (ICH), anticoagulant associated intracerebral hemorrhage (AAICH), and ischemic stroke in the Greater Cincinnati/Northern Kentucky area The increasing incidence of anticoagulant associated intracerebral hemorrhage. Flaherty, M; Kissela, B; Woo, D; Kleindorfer, D; Alwell, K; Sekar, P;Moomaw, C; Haverbusch, M; Broderick, J Neurology. 68(2): , January 9, /9/

21 Flood is coming 5/9/

22 5/9/

23 5/9/

24 Why is OAC ICH increasing problem?? larger number of elderly patients that receive OAC for cardiovascular reasons. The increased use of combined anticoagulant regimens The addition of antiplatelets the expanded use of OAC for secondary stroke prevention. Smith et Al 1999 Arch IM 5/9/

25 5/9/

26 5/9/

27 Is outcome any different between AA ICH and non AA ICH??? 5/9/

28 Answer Patients with OAT-related ICH have a mortality rate approaching 60%, compared to about 40% for their non-anticoagulated counterparts ( Hart Stroke 1995, Lavoie J Trauma 2004, Mina J Trauma 2003) 5/9/

29 New Data 299 ICHs. Use of warfarin was associated with a higher mortality from ICH (OR, 1.62; 95% CI, ). INRs >3 increased the odds of dying of ICH by fold (95% CI, ). (Fang( et al Stroke 2012) 5/9/

30 New data Re LY trial 2.0 years of follow-up (18,113 pts) 154 intracranial i hemorrhages h occurred in 153 participants i 46% intracerebral (49% mortality), 45% subdural (24% mortality), and 8% subarachnoid (31% mortality). The rates of intracranial hemorrhage were 0.76%, 0.31%, per year among those assigned to warfarin, dabigatran 150 mg respectively (P<0.001) Independent predictors of intracranial hemorrhage were assignment to warfarin (relative risk, 2.9; P<0.001), aspirin use (relative risk, 1.6; P=0.01), 01) age (relative risk, per year; P<0.001), and previous stroke/transient ischemic attack (relative risk, 1.8; P=0.001). (Hart et al, Stroke, april 2012) 5/9/

31 Reversal is indicated HOW???? 5/9/

32 5/9/

33 AHA Patients with a severe coagulation factor deficiency or severe thrombocytopenia should receive appropriate factor replacement therapy or platelets, respectively (Class I; Level of Evidence: C). (New recommendation) 2. Patients with ICH whose INR is elevated due to OACs should have their warfarin withheld, receive therapy to replace vitamin i K dependent factors and correct the INR, and receive intravenous vitamin K (Class I; Level of Evidence: C). PCCs have not shown improved outcome compared with FFP but may have fewer complications compared with FFP and are reasonable to consider as an alternative to FFP (Class IIa; Level of Evidence: B). rfviia does not replace all clotting factors, and although h the INR may be lowered, clotting may not be restored in vivo; therefore, rfviia is not routinely recommended as a sole agent for OAC reversal in ICH (Class III; Level of Evidence: C). (Revised from the previous guideline). 5/9/

34 AHA Although rfviia can limit the extent of hematoma expansion in noncoagulopathic ICH patients, there is an increase in thromboembolic risk with rfviia and no clear clinical benefit in unselected patients. Thus rfviia is not recommended in unselected patients. (Class III; Level of Evidence: A). (New recommendation) Further research to determine whether any selected group of patients may benefit from this therapy is needed before any recommendation for its use can be made. 5/9/

35 Vitamin K slowly reverts INR to its normal values, needing 2 24 h to be effective. All patients with OAC-ICH must be given vitamin K. Otherwise, INR will not be corrected completely and a rebound coagulopathy might develop should be administered IV as the effect is too slow using the oral route. ( Dentali et al J Thrombosis Hemostasis 2006) 5/9/

36 Fresh Frozen Plasma IV at a dose of ml/kg requires the concomitant administration of vitamin K. Delays due to thawing and preparation. volume overload has to be considered in older patients small risk of viral transmission,thrombocytopenia, anaphylactoid reactions,septicemia (Goldstein Stroke 2006) 5/9/

37 Prothrombin Concentrate Complex PCC Is a mixture of clotting factors II, VII, IX, X, and protein C and S, derived from large donor plasma pools by ion-exchange chromatography and cryoprecipitation (Bershad & Suarez NCC 2009) 5/9/

38 PCC Bebulin (US) 3 F Profilnine (US)3 F Proplex-Ta Preconativ Beriplex P/N Kaskadil Octaplex Cofact PPSB-HT Nichiyaku Konyne Prothrombinex-HT 5/9/

39 Comparison Blood type matching Thawing time PCC No No FFP Yes Yes Infection risk Y Y Thrombosis risk Y Y Clotting factor concentration High Low Infusion volume <200ml Speed of INR correction Expensive Availability Quicker Yes limited Slower Moderate yes 5/9/

40 EBM for use of PCC Sandler SG, Rath CE, Ruder A. Prothrombin complex concentrates Yasaka M, Oomura M, Ikeno K, Naritomi H, Minematsu K. in acquired hypoprothrombinemia. Ann Intern Med. Effect of prothrombin complex concentrate on INR and blood 1973;79(4): coagulation system in emergency patients treated with warfarin Josic D, Hoffer L, Buchacher A, Schwinn H, Frenzel W, Biesert L, overdose. Ann Hematol. 2003;82(2): et al. Manufacturing of a prothrombin complex concentrate aiming van Aart L, Eijkhout HW, Kamphuis JS, Dam M, Schattenkerk at low thrombogenicity. Thromb Res. 2000;100(5): ME, Schouten TJ, et al. Individualized dosing regimen for Hellstern P. Production and composition of prothrombin complex prothrombin concentrates: correlation between composition and therapeutic complex concentrate more effective than standard efficiency. Thromb Res. 1999;95(4 Suppl 1):S7 12. treatment in the reversal of oral anticoagulant therapy: an open, McQuillan AM, Eikelboom JW, Hankey GJ, Baker R, Thom J, Staton J, et al. Protein Z in ischemic stroke and its etiologic subtypes. Stroke. 2003;34(10): Lubetsky A, Hoffman R, Zimlichman R, Eldor A, Zvi J, Kostenko V, et al. Efficacy and safety of a prothrombin complex concentrate (Octaplex) for rapid reversal of oral anticoagulation. Thromb Res. 2004;113(6): Evans G, Luddington R, Baglin T. Beriplex P/N reverses severe warfarin-induced overanticoagulation immediately and completely in patients presenting with major bleeding. Br J Haematol. 2001;115(4): Ostermann H, Haertel S, Knaub S, Kalina U, Jung K, Pabinger I. Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers. Thromb Haemost. 2007;98(4): Boulis NM, Bobek MP, Schmaier A, Hoff JT. Use of factor IX complex in warfarin-related intracranial hemorrhage. Neurosurgery. 1999;45(5): discussion Cartmill M, Dolan G, Byrne JL, Byrne PO. Prothrombin complex concentrate for oral anticoagulant reversal in neurosurgical emergencies. Br J Neurosurg. 2000;14(5): Fredriksson K, Norrving B, Stromblad LG. Emergency reversal of anticoagulation after intracerebral hemorrhage. Stroke. 1992; 23(7): Lankiewicz MW, Hays J, Friedman KD, Tinkoff G, Blatt PM. Urgent reversal of warfarin with prothrombin complex concentrate. J Thromb Haemost. 2006;4(5): Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann H. Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6(4): Preston FE, Laidlaw ST, Sampson B, Kitchen S. Rapid reversal of oral anticoagulation with warfarin by a prothrombin complex concentrate (Beriplex): efficacy and safety in 42 patients. Br J Haematol. 2002;116(3): Vigue B, Ract C, Tremey B, Engrand N, Leblanc PE, Decaux A, prospective randomized d controlled trial. Thromb Res. 2006; 118(3): Bruce D, Nokes TJ. Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital. Crit Care. 2008;12(4):R105. Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005;115(6): Hellstern P, Halbmayer WM, Kohler M, Seitz R, Muller-Berghaus G. Prothrombin complex concentrates: indications, contraindications, and risks: a task force summary. Thromb Res. 1999;95(4 Suppl 1):S3 6. Schulman S, Bijsterveld NR. Anticoagulants and their reversal. Transfus Med Rev. 2007;21(1): Pindur G, Morsdorf S. The use of prothrombin complex concentrates in the treatment of hemorrhages induced by oral anticoagulation. Thromb Res. 1999;95(4 Suppl 1):S Makris M, Watson HG. The management of coumarin-induced over-anticoagulation Annotation. Br J Haematol. 2001;114(2): Crawford JH, Augustson BM. Prothrombinex use for the reversal of warfarin: is fresh frozen plasma needed? Med J Aust. 2006; 184(7): Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49(6): Blatt PM, Lundblad RL, Kingdon HS, McLean G, Roberts HR. Thrombogenic materials in prothrombin complex concentrates. Ann Intern Med. 1974;81(6): /9/ et al. Ultra-rapid management of oral anticoagulant therapyrelated surgical intracranial hemorrhage. Intensive Care Med. 2007;33(4): Schimpf K, Zeltsch C, Zeltsch P. Myocardial infarction complicating activated prothrombin complex concentrate substitution in patient with hemophilia A. Lancet. 1982;2(8306):1043. Hampton KK, Preston FE, Lowe GD, Walker ID, Sampson B. Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate. Br J Haematol. 1993;84(2): Aledort LM. Factor IX and thrombosis. Scand J Haematol Suppl.

41 EBM Prothrombin Complex Concentrates for Oral Anticoagulant Therapy- Related Intracranial Hemorrhage: A Review of the Literature Bershad & Suarez, NCC, /9/

42 INCH Trial INR Normalization in Coumarin associated intracerebral Haemorrhage Steiner Thorsten University Hospitals: Halle, Mannheim, Erlangen, München, Heidelberg, Germany Randomized, open label, parallel groups, multicenter. 5/9/

43 INCH inclusion Spontaneous intracerebral and subdural hematoma diagnosed by CT within 12 hours after onset of symptoms Patient receiving oral anticoagulation w INR 2 Age 18 years 5/9/

44 INCH outcome 1ry: INR <1.2 in 3 hrs. 2ry Percentage of ICH volume increase within 24 hours NIHSS, mrs, BI, GOS, EQ-5D at dischargeand 90 days Safety 5/9/

45 Factor VII Still in use in many places Single factor replacement. Activated t Falling out of favor for expense and side effects after FAST Trial (Mayer et al 2005 NEJM). 5/9/

46 Protocols How can we be practical? We have an ICH in ER and high INR!!!!! Tell me what should I do now??? 5/9/

47 5/9/

48 AAFP 5/9/

49 October 4-7, 2012 Sheraton Denver Downtown Hotel Denver, Colorado, USA 5/9/

50 5/9/

51 HFHS Anticoagulation Reversal Protocol These guidelines are supported by latest literature from AHA, ACCP and published articles and expert consultation. Let me share our background data 5/9/

52 HFH NCCU CoRICH Trial 2971 pts with intracranial bleeds. 122 were identified on warfarin (4.1%). Mean admission GCS was 10 (3-15), mean pre-therapy INR 4.20 ( ) 18.78) and mean INR post therapy 1.25 ( ). Mean time elapsed before a post therapy repeat INR check was 155 minutes ( min). Reversal agents used included: vitamin K in 36 patients (87.8%), FFP in 34 patients (82.9%), activated factor 7 in 19 patients (46.3%) and prothrombin concentrate complex in 20 patients (48.7%). 5/9/

53 CoRICH data When looking at outcomes of these patients, average ICU length of stay was 12.5 days, There was a 39% mortality. Thromboembolic events were encountered in 4 patients (10%). Anticoagulation was resumed in 12 patients. The mean return to anticoagulation 15.6 days (range 2-58 days) (Abdelhak et al 2012 SCCM) 5/9/

54 HFHS Warfarin reversal protocol INR 1.7-3: for ICH 2011/2012 Profilnine 20 u/kg+factor VII 10 mcg/kg. INR >3: Profilnine 20 u/kg+factor VII 20 mcg/kg. 5/9/

55 Follow up INR minutes after administration of reversal then q 4 hours. If first INR unsatisfactory may give FFP. 5/9/

56 Heparin et al Protamine sulphate. 1 mg for each 100 units heparin IV. 1 mg for each 1 mg enoxparin <8h. 0.5mg for each 1 mg enoxparin >8h. 5/9/

57 Direct X inhibitors Dabigatran (2009, BI, Pradaxa) Rivaroxaban (2011, Janssen&Bayer, Xarelto) Apixaban (Not FDA approved yet, Pfizer&BM, Eliquis) i 5/9/

58 5/9/

59 5/9/

60 5/9/

61 The new arrivals Direct thrombin inhibitor. Oral once or twice daily. Safer and more expensive than warfarin. No need for INR monitoring Renal excreted. Reversal : Help us GOD. 5/9/

62 A, Effect of rivaroxaban followed by prothrombin complex concentrate (PCC) or placebo on the prothrombin time (PT; mean±sd). Eerenberg E S et al. Circulation 2011;124: Copyright American Heart Association

63 A, Effect of dabigatran followed by prothrombin complex concentrate (PCC) or placebo on the activated partial thromboplastin time (aptt; mean ±SD). Eerenberg E S et al. Circulation 2011;124: Copyright American Heart Association

64 Seriousely We don t know. PCC 50 u/kg +/- Factor VII 50 mcg/kg +/- FFP Dialysis i if possible on the way to the. 5/9/

65 Summary AA ICH is an increasing problem with high mortality. Urgent Clotting factor replacement is highly recommended. Follow up INR important. t New agents reversal is not available. 5/9/

66 5/9/

67 Henry Ford NeuroICU Team 04/05/2012 5/9/

68 5/9/

69 Thank you 04/05/2012 5/9/