andrew w. asimos, md treating cns hemorrhage in the anticoagulated patient

Andrew W. Asimos, MD

Treating CNS Treating CNS Hemorrhage in the Hemorrhage in the

Anticoagulated PatientAnticoagulated Patient


Andrew Asimos, MDAndrew Asimos, MDDirector of Emergency Stroke CareDirector of Emergency Stroke CareNeuroscience and Spine InstituteNeuroscience and Spine Institute

Carolinas Medical Center, Charlotte, NCCarolinas Medical Center, Charlotte, NC

Adjunct Associate Professor, Department of Emergency MedicineAdjunct Associate Professor, Department of Emergency MedicineUniversity of North Carolina School of Medicine at Chapel HillUniversity of North Carolina School of Medicine at Chapel Hill


Attending PhysicianAttending PhysicianEmergency MedicineEmergency Medicine

Carolinas Medical CenterCarolinas Medical CenterDepartment of Emergency MedicineDepartment of Emergency Medicine

Charlotte, NCCharlotte, NC


CME Disclosure StatementCME 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


Session ObjectivesSession Objectives

• Present a relevant patient case

• State key clinical questions

• Outline the procedure and therapeutic options for treating anticoagulation related ICH


A Clinical CaseA Clinical Case


Clinical HistoryClinical 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


Paramedic’s ReportParamedic’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


ED PresentationED 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


Key Clinical QuestionsKey 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?


Bag o’ MedsBag o’ Meds


The Great American PoisonThe Great American Poison


Which of these belong to this patient?Which of these belong to this patient?


Oral Anticoagulant (OAC) Oral Anticoagulant (OAC) Related ICH: Related ICH:

Key Clinical ConceptsKey Clinical Concepts


OAC Related ICHOAC 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;12:35-44Winzen 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.


Factors Predicting Worse Outcome Factors Predicting Worse Outcome in ICHin 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.


Early ICH GrowthEarly ICH Growth

2.0 hours after onset




2 hours2 hoursafter onsetafter onset

6.5 hours6.5 hoursafter onsetafter onset


OAC Related ICHOAC 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.


Risk Factors for Warfarin Related Risk Factors for Warfarin Related ICHICH

• Advanced Age

• Hypertension

• Intensity of Anticoagulation

• Cerebral amyloid angiopathy

Hart RG. Neurology 2000:55:907-908.


Effect of Warfarin on Outcome of Effect of Warfarin on Outcome of ICH:ICH:

Outcome at 3 monthsOutcome at 3 months

Rosand J et al. Arch Intern Med 2004;164:880-884.


WarfarinWarfarin

• Achieves its anticoagulant effect by reducing activity of vitamin K dependent cofactors II, VII, IX, and X

• Considerable drug interactions


Evidence Based Treatment for Evidence Based Treatment for ICHICH

Broderick JP et al. Stroke 1999;30:905-15.


AHA ICH Treatment GuidelinesAHA 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.


Sixth ACCP Recommendations on Sixth ACCP Recommendations on Managing Patients with high INR ValuesManaging Patients with high INR Values

Chest 2001;119(1 Suppl):22S-38S


Sixth ACCP Recommendations on Sixth ACCP Recommendations on Managing Patients with high INR ValuesManaging 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


OAC ICH Rx: Driving PrinciplesOAC ICH Rx: Driving Principles

• Measure INR

• Establish the extent of INR elevation (< 5, 5-9, >9) and presence of bleeding

• Determine if an immediate neurosurgical intervention is needed

• Administer Vitamin K IV

• Order Coagulation Factor Replacement


Elevated INR Therapy: Elevated INR Therapy: The ProcedureThe Procedure


INRINR

• 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


Elevated INR Rx ProcedureElevated INR Rx Procedure

• Vitamin K 10 mg by slow IV infusion


Vitamin KVitamin 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.


Coagulation Factor ReplacementCoagulation 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.


Bedside Realities:Bedside Realities:Can you answer these questions?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?



• Vitamin K 10 mg by slow IV infusion

• Fresh frozen plasma (5-8 ml/kg, 1-2 units, 250-500 cc total)



• 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



• 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

OR


Drawbacks to Reversing OAC with FFPDrawbacks 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.


PCCPCC

• 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.


Onset of Action of PCCOnset 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


Recombinant Factor VIIaRecombinant 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.


Recombinant Factor VIIaRecombinant 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.


INRs Before and After Administration of INRs Before and After Administration of Recombinant factor VIIaRecombinant factor VIIa

Freeman WD et al. Mayo Clin Proc 2004;79(12):1495-1500.


ED Treatment and ED Treatment and Patient OutcomePatient Outcome


ED Patient ManagementED 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


Patient OutcomePatient 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


ED ICH Patient Rx:ED ICH Patient Rx:A RetrospectiveA Retrospective


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


ACCP Guidelines forACCP Guidelines forWarfarin Over-anticogulationWarfarin 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.


Questions??Questions??

[email protected]@ferne.org

andrew w. asimos, md treating cns hemorrhage in the anticoagulated patient

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