1. Andrew W. Asimos, MD Treating CNS Hemorrhage in the Anticoagulated Patient

2. Andrew W. Asimos, MD 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

3. Andrew W. Asimos, MD Attending Physician Emergency Medicine Carolinas Medical Center Department of Emergency Medicine Charlotte, NC

4. Andrew W. Asimos, MD

5. CME Disclosure Statement Member of an EM advisory panel for Novo Nordisk® and an investigator in a NovoSeven® Phase 3a Trial Will be discussing off-label use for rFVIIa

6. Andrew W. Asimos, MD Session Objectives Present a relevant patient case State key clinical questions Outline the procedure and therapeutic options for treating anticoagulation related ICH

7. Andrew W. Asimos, MD A Clinical Case

8. Andrew W. Asimos, MD 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

9. Andrew W. Asimos, MD Paramedic’s Report Patient seems less responsive than initially Aphasia and weakness may be worsening He is on a “bag o’ meds” –Per family, started on an antibiotic a week ago

10. Andrew W. Asimos, MD 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 Neuro screening exam –Pupils midpoint, equal and reactive –L sided gaze preference –R facial weakness –R upper > lower extremity weakness –Expressive aphasia

11. Andrew W. Asimos, MD 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?

12. Andrew W. Asimos, MD Bag o’ Meds

13. Andrew W. Asimos, MD The Great American Poison

14. Andrew W. Asimos, MD Which of these belong to this patient?

15. Andrew W. Asimos, MD Oral Anticoagulant (OAC) Related ICH: Key Clinical Concepts

16. Andrew W. Asimos, MD OAC Related ICH OAC use increases ICH risk 7-10 times –>10 fold risk if over 50 years of age –Increased risk dramatic if INR >4.0 50-90% OAC-related ICHs occur while INR in the target range –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.

17. Andrew W. Asimos, MD 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.

18. Andrew W. Asimos, MD Early ICH Growth 2 hours after onset 6.5 hours after onset

19. Andrew W. Asimos, MD OAC Related ICH More frequent progession of bleeding –Hematoma volume may be minimized with prompt correction of coagulation More protracted bleeding Larger hematomas Higher mortality –Hematoma volume correlates with mortality 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.

20. Andrew W. Asimos, MD Risk Factors for Warfarin Related ICH Advanced Age Hypertension Intensity of Anticoagulation Cerebral amyloid angiopathy Hart RG. Neurology 2000:55:907-908.

21. Andrew W. Asimos, MD Effect of Warfarin on Outcome of ICH: Outcome at 3 months Rosand J et al. Arch Intern Med 2004;164:880-884.

22. Andrew W. Asimos, MD Warfarin Achieves its anticoagulant effect by reducing activity of vitamin K dependent cofactors II, VII, IX, and X Considerable drug interactions

23. Andrew W. Asimos, MD Evidence Based Treatment for ICH Broderick JP et al. Stroke 1999;30:905-15.

24. Andrew W. Asimos, MD 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.

25. Andrew W. Asimos, MD Sixth ACCP Recommendations on Managing Patients with high INR Values Chest 2001;119(1 Suppl):22S-38S

26. Andrew W. Asimos, MD 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

27. Andrew W. Asimos, MD 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

28. Andrew W. Asimos, MD Elevated INR Therapy: The Procedure

29. Andrew W. Asimos, MD 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

30. Andrew W. Asimos, MD Elevated INR Rx Procedure Vitamin K 10 mg by slow IV infusion

31. Andrew W. Asimos, MD 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.

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

33. Andrew W. Asimos, MD Bedside Realities: Can you answer these 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?

34. Andrew W. Asimos, MD 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)

35. Andrew W. Asimos, MD 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

36. Andrew W. Asimos, MD 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

37. Andrew W. Asimos, MD Drawbacks to Reversing OAC with FFP 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.

38. Andrew W. Asimos, MD 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.

39. Andrew W. Asimos, MD 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

40. Andrew W. Asimos, MD Recombinant Factor VIIa Rapid onset of action –Almost immediate Clinically apparent hemostasis within 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.

41. Andrew W. Asimos, MD

42. Recombinant Factor VIIa Up to 7% risk of associated thromboembolic events –AMI –PE –Cerebral infarction –DIC Published small case series demonstrate its efficacy 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.

43. Andrew W. Asimos, MD INRs Before and After Administration of Recombinant factor VIIa Freeman WD et al. Mayo Clin Proc 2004;79(12):1495-1500.

44. Andrew W. Asimos, MD ED Treatment and Patient Outcome

45. Andrew W. Asimos, MD ED Patient Management The BP treated with IV labetalol The INR was noted to be 5.6 Vitamin K administered 2 units FFP administered The pt was admitted to the neurosurgical ICU

46. Andrew W. Asimos, MD 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

47. Andrew W. Asimos, MD ED ICH Patient Rx: A Retrospective

48. Andrew W. Asimos, MD 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

49. Andrew W. Asimos, MD ACCP Guidelines for Warfarin Over-anticogulation Derived from Chest 2001;119(1 Suppl):22S-38S, courtesy of Wjasow C, McNamara R. J Emerg Med 2003;24(2):169-72.

50. Andrew W. Asimos, MD Questions?? www.ferne.org ferne@ferne.org www.ferne.org