1. Edward P. Sloan, MD, MPH Optimizing the Management of Emergency Department Intracerebral Hemorrhage Patients FERNE Satellite 2005 ACEP Scientific Assembly Washington, DC 2005

2. Edward P. Sloan, MD, MPH Treating Intracerebral Hemorrhage in the Anti-coagulated Patient

3. Edward P. Sloan, MD, MPH Edward P. Sloan, MD, MPH Professor Department of Emergency Medicine University of Illinois College of Medicine Chicago, IL

4. Edward P. Sloan, MD, MPH Attending Physician Emergency Medicine Attending Physician Emergency Medicine University of Illinois Hospital Our Lady of the Resurrection Hospital Chicago, IL

5. Edward P. Sloan, MD, MPH Andrew Asimos, MD Director of Emergency Stroke Care Neuroscience and Spine Institute Carolinas Medical Center, Charlotte, NC Adjunct Associate Professor, Department of Emergency Medicine University of North Carolina School of Medicine at Chapel Hill

6. Edward P. Sloan, MD, MPH Attending Physician Emergency Medicine Carolinas Medical Center Department of Emergency Medicine Charlotte, NC

7. Edward P. Sloan, MD, MPH CME Disclosure Statement Member of an EM advisory panel for Novo Nordisk® Will be discussing off-label use for rFVIIa

8. Edward P. Sloan, MD, MPH Session Objectives Present a relevant patient case State key clinical questions Outline the procedure and therapeutic options for treating ICH related to anticoagulation

9. Edward P. Sloan, MD, MPH A Clinical Case

10. Edward P. Sloan, MD, MPH Clinical History 66 year old male presents with acute onset of aphasia and right sided weakness while eating at home Initially complained of a headache BP of 220/118 mm Hg Accucheck 316 Initial GCS of 14

11. Edward P. Sloan, MD, MPH Paramedic’s Report Patient less responsive than initially Aphasia and weakness worsening? He is on a “bag o’ meds” –Per family, started an antibiotic a week ago

12. Edward P. Sloan, MD, MPH ED Presentation ED VS –BP 224/124, P 100, RR 16, T 98.8, pulse ox 99% Somnolent, but slowly responds to simple commands Snores a bit when not stimulated Clear lungs and a regular cardiac rate and rhythm Neurological screening exam –Pupils midpoint, equal and reactive –L sided gaze preference –R facial weakness –R upper > lower extremity weakness –Expressive aphasia

13. Edward P. Sloan, MD, MPH Key Clinical Questions What are the key diagnostic issues? What are the potential complicating factors? What guidelines direct potential therapies? What is the urgency of potential interventions? What is the relative availability of those therapies in our institution?

14. Edward P. Sloan, MD, MPH Bag o’ Meds

15. Edward P. Sloan, MD, MPH The Great American Poison

16. Edward P. Sloan, MD, MPH Which of these belong to this patient?

17. Edward P. Sloan, MD, MPH Oral Anticoagulant (OAC) Related ICH: Key Clinical Concepts

18. Edward P. Sloan, MD, MPH OAC Related ICH OAC use increases ICH risk 7-10x –>10 fold risk if over 50 years of age –Increased risk dramatic if INR >4.0 –50-90% OAC-related ICHs with target INR –ICH risk greatest at the start of treatment Punthakee X et al. Thrombosis Research 2003;108:31-36. Butler AC. Tate RC. Blood Reviews 1998;12:35-44 Winzen AR et al. Ann Neurol 1984;16:553-8. Franke CL et al. Stroke 1990;21:726-30. Hylek EM. Singer DE. Ann Int Med 1994;120(11):897-902.

19. Edward P. Sloan, MD, MPH Factors Predicting Worse Outcome in ICH Hematoma Volume –At least 40% of all ICH patients experience early hemorrhage growth of > 33% of baseline volume within 24 hours Depressed Level of Consciousness Hart RG. Neurology 2000:55:907-908. Brott T et al. Stroke 1997;28:1-5.

20. Edward P. Sloan, MD, MPH Early ICH Growth 2 hours after onset 6.5 hours after onset

21. Edward P. Sloan, MD, MPH OAC-Related ICH More frequent progression of bleeding More protracted bleeding Larger hematomas Higher mortality –Hematoma volume correlates with mortality Hematoma volume may be minimized with prompt correction of coagulation Freeman WD et al. Mayo Clin Proc 2004;79(12):1495-1500. Butler AC. Tate RC. Blood Reviews 1998;12:35-44. Flibotte JJ et al. Neurology 2004;63:1059-1064.

22. Edward P. Sloan, MD, MPH Warfarin-Related ICH Risk Factors Advanced Age Hypertension Intensity of Anticoagulation Cerebral amyloid angiopathy Hart RG. Neurology 2000:55:907-908.

23. Edward P. Sloan, MD, MPH Effect of Warfarin on Outcome of ICH: Outcome at 3 months Rosand J et al. Arch Intern Med 2004;164:880-884.

24. Edward P. Sloan, MD, MPH Warfarin Achieves its anticoagulant effect by reducing activity of vitamin K dependent cofactors II, VII, IX, and X Considerable drug interactions

25. Edward P. Sloan, MD, MPH Evidence Based Intracerebral Hemorrhage Patient Treatments Broderick JP et al. Stroke 1999;30:905-15.

26. Edward P. Sloan, MD, MPH AHA ICH Treatment Guidelines AHA Stroke Council: 1999 Stroke Key Concept: General ICH guidelines exist –Detailed data on disease, epidemiology, BP management, ICP Rx recommendations Lack any recommendations regarding ICH in the setting of anticoagulation Almost seven years without revision Broderick JP et al. Stroke 1999;30:905-15.

27. Edward P. Sloan, MD, MPH Sixth ACCP Recommendations on Managing Patients with high INR Values Chest 2001;119(1 Suppl):22S-38S

28. Edward P. Sloan, MD, MPH Sixth ACCP Recommendations on Managing Patients with high INR Values Consensus, evidence based 2001 Chest Key Concept: Guidelines exist for managing anticoagulated patients with serious or life threatening bleeding Grade 2C evidence Chest 2001;119(1 Suppl):22S-38S

29. Edward P. Sloan, MD, MPH OAC ICH Rx: Driving Principles Measure INR Establish the extent of INR elevation ( 9) and presence of bleeding Determine if an immediate neurosurgical intervention is needed Administer Vitamin K IV Order Coagulation Factor Replacement

30. Edward P. Sloan, MD, MPH ACCP Guidelines for Warfarin-related Elevated Anti-coagulation Derived from Chest 2001;119(1 Suppl):22S-38S, courtesy of Wjasow C, McNamara R. J Emerg Med 2003;24(2):169-72.

31. Edward P. Sloan, MD, MPH Elevated INR Therapy: The Procedure

32. Edward P. Sloan, MD, MPH INR Based on the Prothrombin time test Sensitive to reductions of Vitamin-K dependent clotting factors II, VII, and X –Not factor IX Designed specifically for stably anticoagulated patients –May be inappropriate test following replacement therapy with either plasma or clotting factor concentrates

33. Edward P. Sloan, MD, MPH Elevated INR Rx Procedure Vitamin K 10 mg by slow IV infusion

34. Edward P. Sloan, MD, MPH Vitamin K Necessary to achieve more than a temporary reversal of anticoagulation Adequate response requires at least 2-6 and up to 24 hours Anaphylactic or anaphylactoid reactions rarely associated with IV administration Safest and most rapidly acting route of administration unclear Wjasow C, McNamara R. J Emerg Med 2003;24(2):169-72. Fiore LD et al. J Thrombosis & Thrombolysis 2001;11(2):175-83.

35. Edward P. Sloan, MD, MPH Coagulation Factor Replacement Options include –FFP –Prothrombin Complex Concentrates (PCC) –Recombinant Factor VIIa Normal coagulation achieved more rapidly with PCC, rFVIIa than with FFP Fredriksson K et al. Stroke 1992;23:972-977. Makris M et al. Thromb Haemostasis 1997;77:477-480.

36. Edward P. Sloan, MD, MPH Bedside Realities: Can you answer these process questions? Is thawed FFP immediately available from your blood bank? How long will it take your blood bank to get it to you? Does your hospital blood bank or inpatient pharmacy store PCC and rFVIIa? What is the relative rapidity of response of each of these agents?

37. Edward P. Sloan, MD, MPH Elevated INR Rx Procedure Vitamin K 10 mg by slow IV infusion Fresh frozen plasma (5-8 ml/kg, 1-2 units, 250-500 cc total)

38. Edward P. Sloan, MD, MPH Elevated INR Rx Procedure Vitamin K 10 mg by slow IV infusion Fresh frozen plasma (5-8 ml/kg, 1-2 units, 250-500 cc total) Prothrombin Complex Concentrate 25-50 IU/kg –Dose based on Factor IX units –Alternatively, 500 IU initially followed by second administration of 500 IU according to the INR value measured just after the first administration OR

39. Edward P. Sloan, MD, MPH Elevated INR Rx Procedure Vitamin K 10 mg subq or IVP Fresh frozen plasma (5-8 ml/kg) 1-2 units, 250-500 cc total Prothrombin Complex Concentrate 25-50 IU/kg Recombinant Factor VIIa (40-60 µgr/kg) –Usually 3-4 mg total OR

40. Edward P. Sloan, MD, MPH Drawbacks to FFP Reversing OAC Time-consuming? –Can delay neurosurgical evacuation May require clinically substantial IV fluid volumes Contains a variable content of Vitamin K- dependent clotting factors May not completely correct INR –May not adequately correct for factor IX Risk of viral transmission –Not pooled HIV≈ 1:1,900,000 Hepatitis C≈ 1:1,000,000 Hepatitis B ≈ 1:137,000 Makris M et al. Thromb Haemostasis 1997;77:477-480.

41. Edward P. Sloan, MD, MPH PCC Prepared from pooled plasma of thousands of blood donors –Less viral transmission risk than FFP Contains vitamin K-dependent procoagulant and factors Infused over 15 minutes Relative thromboembolic risk unclear Acquisition cost of usual adult dose ≈ $450 Abe et al. Rinsho to Kenkyu [in Japanese] 1987;64:1327-37. Sorensen B et al. Blood Coagulation and Fibrinolysis 2003:14:469-477.

42. Edward P. Sloan, MD, MPH Onset of Action of PCC Yasaka M et al. Thrombosis Research 2003;108:25-30. PCC dose=7-27 IU/kg, Vit K dose 10 mg

43. Edward P. Sloan, MD, MPH Recombinant Factor VIIa Rapid onset of action –Almost immediate Clinically apparent hemostasis in 10 minutes Short half life (2.3 hours) Relatively high acquisition cost –≈ $2,500-$3,500 for 3-4 gm dose Park p et al. Neurosurgery 2003;53:34-39. Sorensen B et al. Blood Coagulation and Fibrinolysis 2003:14:469-477. Novoseven [package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc; 2003.

44. Edward P. Sloan, MD, MPH

45. Recombinant Factor VIIa Up to 7% risk of thromboembolic events –AMI –PE –Cerebral infarction –DIC Demonstrated OAC efficacy in case series Phase IIB trial demonstrates effectiveness Park P et al. Neurosurgery 2003;53:34-39. Mayer SA et al. N Eng J Med 2005:352:777-85. Sorensen B et al. Blood Coagulation and Fibrinolysis 2003:14:469-477. Freeman WD et al. Mayo Clin Proc 2004;79(12):1495-1500.

46. Edward P. Sloan, MD, MPH INR Following Recombinant Factor VIIa Administration Freeman WD et al. Mayo Clin Proc 2004;79(12):1495-1500.

47. Edward P. Sloan, MD, MPH ED Treatment and Patient Outcome

48. Edward P. Sloan, MD, MPH ED Patient Management The BP treated with IV labetalol The INR was noted to be 5.6 Vitamin K administered 2 units FFP administered Pt admitted to the neurosurgical ICU

49. Edward P. Sloan, MD, MPH Patient Outcome The hemorrhage size increased slightly on CT with slight intraventricular extension The patient’s clinical condition slightly improved gradually Discharged to rehab 10 days after admission

50. Edward P. Sloan, MD, MPH ED ICH Patient Rx: A Retrospective

51. Edward P. Sloan, MD, MPH OAC Related ICH Know the treatment guidelines Know the relative availability at your institution of different coagulation factor replacements Communicate with neurosurgical consultants regarding a potential indication for PCC or rFVIIa use

52. Edward P. Sloan, MD, MPH Thank you!! www.ferne.org ferne@ferne.org Edward P. Sloan, MD, MPH 312 413 7490 Thank you!! www.ferne.org ferne@ferne.org Edward P. Sloan, MD, MPH edsloan@uic.edu 312 413 7490 www.ferne.org ferne_acep_2005_ich_sloan_anticoag_notes_100206