Treating CNS Hemorrhage in the Anticoagulated Patient

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Treating CNS Hemorrhage in the Anticoagulated
Patient
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Andrew Asimos, MDDirector of Emergency Stroke
CareNeuroscience and Spine InstituteCarolinas
Medical Center, Charlotte, NCAdjunct Associate
Professor, Department of Emergency
MedicineUniversity of North Carolina School of
Medicine at Chapel Hill
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Attending PhysicianEmergency MedicineCarolinas
Medical CenterDepartment of Emergency
MedicineCharlotte, NC
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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

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Session Objectives

• Present a relevant patient case
• State key clinical questions
• Outline the procedure and therapeutic options for
  treating anticoagulation related ICH

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A Clinical Case
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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

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Paramedics 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

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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 gt lower extremity weakness
• Expressive aphasia

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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?

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Bag o Meds
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The Great American Poison
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Which of these belong to this patient?
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Oral Anticoagulant (OAC) Related ICH Key
Clinical Concepts
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OAC Related ICH

• OAC use increases ICH risk 7-10 times
• gt10 fold risk if over 50 years of age
• Increased risk dramatic if INR gt4.0
• 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
200310831-36. Butler AC. Tate RC. Blood Reviews
19981235-44 Winzen AR et al. Ann Neurol
198416553-8. Franke CL et al. Stroke
199021726-30. Hylek EM. Singer DE. Ann Int Med
1994120(11)897-902.
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Factors Predicting Worse Outcome in ICH

• Hematoma Volume
• At least 40 of all ICH patients experience early
  hemorrhage growth of gt 33 of baseline volume
  within 24 hours
• Depressed Level of Consciousness

Hart RG. Neurology 200055907-908. Brott T et
al. Stroke 1997281-5.
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Early ICH Growth
2 hours after onset
6.5 hours after onset
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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
200479(12)1495-1500. Butler AC. Tate RC. Blood
Reviews 19981235-44. Flibotte JJ et al.
Neurology 2004631059-1064.
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Risk Factors for Warfarin Related ICH

• Advanced Age
• Hypertension
• Intensity of Anticoagulation
• Cerebral amyloid angiopathy

Hart RG. Neurology 200055907-908.
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Effect of Warfarin on Outcome of ICHOutcome at
3 months
Rosand J et al. Arch Intern Med 2004164880-884.
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Warfarin

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

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Evidence Based Treatment for ICH
Broderick JP et al. Stroke 199930905-15.
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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 199930905-15.
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Sixth ACCP Recommendations on Managing Patients
with high INR Values
Chest 2001119(1 Suppl)22S-38S
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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 2001119(1 Suppl)22S-38S
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OAC ICH Rx Driving Principles

• Measure INR
• Establish the extent of INR elevation
  (lt 5, 5-9, gt9) and presence of bleeding
• Determine if an immediate neurosurgical
  intervention is needed
• Administer Vitamin K IV
• Order Coagulation Factor Replacement

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Elevated INR Therapy The Procedure
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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

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Elevated INR Rx Procedure

• Vitamin K 10 mg by slow IV infusion

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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
200324(2)169-72. Fiore LD et al. J Thrombosis
Thrombolysis 200111(2)175-83.
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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 199223972-977. Makri
s M et al. Thromb Haemostasis 199777477-480.
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Bedside RealitiesCan 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?

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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)

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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
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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
OR
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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 11,900,000
• Hepatitis C 11,000,000
• Hepatitis B 1137,000

Makris M et al. Thromb Haemostasis
199777477-480.
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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
1987641327-37. Sorensen B et al. Blood
Coagulation and Fibrinolysis 200314469-477.
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Onset of Action of PCC
PCC dose7-27 IU/kg, Vit K dose 10 mg
Yasaka M et al. Thrombosis Research
200310825-30.
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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 20035334-39. Sorensen
B et al. Blood Coagulation and Fibrinolysis
200314469-477. Novoseven package insert.
Princeton, NJ Novo Nordisk Pharmaceuticals, Inc
2003.
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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 20035334-39. Mayer
SA et al. N Eng J Med 2005352777-85. Sorensen B
et al. Blood Coagulation and Fibrinolysis
200314469-477. Freeman WD et al. Mayo Clin Proc
200479(12)1495-1500.
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INRs Before and After Administration of
Recombinant factor VIIa
Freeman WD et al. Mayo Clin Proc
200479(12)1495-1500.
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ED Treatment and Patient Outcome
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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

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Patient Outcome

• The hemorrhage size increased slightly on CT with
  slight intraventricular extension
• The patients clinical condition slightly
  improved gradually
• Discharged to rehab 10 days after admission

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ED ICH Patient RxA Retrospective
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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

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ACCP Guidelines forWarfarin Over-anticogulation
Derived from Chest 2001119(1 Suppl)22S-38S,
courtesy of Wjasow C, McNamara R. J Emerg Med
200324(2)169-72.
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