Edward P. Sloan, MD, MPH, FACEP ED Hemorrhagic Stroke Patient Management: What Role for Operative...

Edward P. Sloan, MD, MPH, FACEP

ED Hemorrhagic Stroke ED Hemorrhagic Stroke Patient Management:Patient Management:

What Role for Operative What Role for Operative Intervention & Factor VIIa?Intervention & Factor VIIa?

Edward P. Sloan, MD, MPH FACEP

44thth EuSEM Congress EuSEM CongressCrete, GreeceCrete, Greece

October 5-7, 2006October 5-7, 2006



Professor

Department of Emergency MedicineUniversity of Illinois College of Medicine

Chicago, IL


Attending PhysicianEmergency Medicine

University of Illinois HospitalOur Lady of the Resurrection Hospital

Chicago, IL


DisclosuresDisclosures• NovoNordisk, King Pharmaceuticals, UCB NovoNordisk, King Pharmaceuticals, UCB

Pharma Advisory BoardsPharma Advisory Boards• Eisai Speakers’ BureauEisai Speakers’ Bureau

• ACEP Clinical Policies CommitteeACEP Clinical Policies Committee• ACEP Scientific Review CommitteeACEP Scientific Review Committee• Executive Board, Foundation for Education Executive Board, Foundation for Education

and Research in Neurologic Emergenciesand Research in Neurologic Emergencies


Session ObjectivesSession Objectives

• Discuss the potential role for Discuss the potential role for operative intervention given the operative intervention given the results of the STICH trial. results of the STICH trial.

• Determine the optimal protocol for Determine the optimal protocol for treating elevated INR in ICH patients treating elevated INR in ICH patients and the possible role of factor VIIa in and the possible role of factor VIIa in this setting.this setting.


Key Clinical QuestionsKey Clinical Questions

• What is the role of operative intervention in ICH patients given the results of the STICH trial?

• What is the optimal management of anti-coagulated ICH patients and the potential role of factor VIIa?


ED ICH Patients: ED ICH Patients: Key Clinical ConceptsKey Clinical Concepts


ICH Key ConceptsICH Key Concepts

• This is a high morbidity & mortality Dx



• This is a high morbidity and mortality Dx

• Like ischemic stroke (core, penumbra)





• Hemorrhage volume predicts outcome


ICH Volume and OutcomeICH Volume and Outcome

• Broderick: 1993 Stroke• Key Concept: Hemorrhage volume

and GCS predict 30 day mortality• Data: 60 cc blood, GCS < 9, mort 91%• Data: 30 cc blood, GCS > 8, mort 19%• Implications: Simple ED observations

allow for a reasonable outcome assessment




• Like ischemic stroke (core, penumbra)• Hemorrhage volume predicts outcome• Hemorrhage volume increases over

time


ICH Hemorrhage GrowthICH Hemorrhage Growth

• Brott: 1997 Stroke• Key Concept: ICH volume is dynamic,

changes correlate clinically• Data: 26% had 1/3 growth in 1 hour• Data: 1/3 growth = drop in NIHSS, GCS• Implications: Efforts directed at

stabilizing hemorrhage volume may impact patient outcome





• Hemorrhage volume predicts outcome

• Hemorrhage volume increases over time

• Guidelines exist that direct ED acute care


Evidence-Based ICH Evidence-Based ICH Patient ManagementPatient Management

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


ICH Treatment GuidelinesICH Treatment Guidelines

• ASA Council: 1999 Stroke• Key Concept: ICH guidelines exist• Data: Detailed data on disease, epi • Data: BP, ICP Rx recommendations• Implications: The procedures of ICP

and BP management can be uniformly applied by EM physicians



• This is a high morbidity and mortality Dx• Like ischemic stroke (core, penumbra)• Hemorrhage volume predicts outcome• Hemorrhage volume increases over time• Guidelines exist that direct ED acute care• Recent data regarding surgery important


ICH: Surgical ConceptsICH: Surgical Concepts• Remember: Only 4 clinical trials!

• Total of 353 patients studied in all

• Remove clot, reduce pressure

• Manage brain trauma and edema

• Minimize trauma (superficial clots best)

• Minimally invasive approaches now used

• 75-100% mortality in surgical ICH trials


ICH: Surgical IndicationsICH: Surgical Indications• Difficult to specify• Some general principles• Cerebellar hemorrhage: 3 cm or

larger or those that cause mass effect, compression

• ICH related to a surgical lesion• Young patients who deteriorate• Other indications less clear


STITCH ICH Surgical TrialSTITCH ICH Surgical Trial

• Mendelow: 2005 Lancet• Key Concept: Surgery within 24 hours

does not affect 6 month outcome• Data: 25% of pts had a good outcome• Data: Surgery did not change this rate• Implications: ED Rx becomes more

important, given lower likelihood of operative neurosurgical intervention



• Mendelow: 2005 Lancet• 1033 pts, non-US settings• Data: early surgery vs. medical,

surgical• Data: Hemorrhage volume: 40 cc• Data: 81% had GCS 9-15• Data: Surgical time: 30 hrs, 60 hrs• Data: Only 16% had surgery < 12 hrs



• Mendelow: 2005 Lancet• Key concept: This study may not exactly

tell the story of practice that includes rapid identification of optimal surgical candidates and early OR intervention

• May still need to consider operative intervention, will need to stabilize patients first in the ED



• This is a high morbidity and mortality Dx• Like ischemic stroke (core, penumbra)• Hemorrhage volume predicts outcome• Hemorrhage volume increases over time• Guidelines exist that direct ED acute care• Recent data regarding surgery important• Need to treat elevated INR in ICH setting


Effect of Warfarin on 3 Month Effect of Warfarin on 3 Month ICH Patient OutcomeICH Patient Outcome

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


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


66thth ACCP INR Recommendations ACCP INR Recommendations

• 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


Elevated INR Rx: Key ConceptsElevated INR Rx: Key Concepts

• 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 Rx: ACCP InfoElevated INR Rx: ACCP Info

Derived from Chest 2001;119(1 Suppl):22S-38S, courtesy of Wjasow C, McNamara R. J Emerg Med 2003;24(2):169-72.


Elevated INR Therapy: Elevated INR Therapy: The ProcedureThe Procedure


Elevated INR Rx ProcedureElevated INR Rx Procedure

• Vitamin K 10 mg by slow IV infusion



• Vitamin K 10 mg by slow IV infusion

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


Elevated INR Rx ProcedureElevated 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)OR

• Prothrombin Complex Conc at 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



• Vitamin K 10 mg subq or IVP• Fresh frozen plasma (5-8 ml/kg)

1-2 units, 250-500 cc totalOR

• Prothrombin Complex Concentrate 25-50 IU/kg

OR• Recombinant Factor VIIa (40-60 µgr/kg)–Usually 3-4 mg total


Recombinant Factor VIIaRecombinant 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.


FVIIa in Warfarin-Related ICHFVIIa in Warfarin-Related ICH

• Freeman: 2004 Mayo Clin Proc• Key Concept: Warfarin-related ICH can

be treated successfully with rec FVIIa

• Data: 62 micrograms/kg Factor VIIa• Data: INR decreased from 2.7 to 1.1• Implications: This therapy used today

as an adjunct to blood therapies in ICH patients whose bleed is INR-related


FVIIa in Warfarin-Related ICHFVIIa in Warfarin-Related ICH

• Freeman: 2004 Mayo Clin Proc

• Data: 12-28% growth by 24 hours

• Data: INR normalized within 2 hours

• Implications: May facilitate craniotomy for patients who are surgical candidates


FVIIa Safety in ICHFVIIa Safety in ICH

• Mayer: 2005 Stroke• Key Concept: FVIIa is safe when given

within 3 hours of presentation• Data: 36 patients, 6 doses tested• Data: No safety issues preclude phase

III• Implications: Larger study is justified,

given data on hemorrhage volume growth and outcome


FVIIa Safety in ICHFVIIa Safety in ICH

• Mayer: 2005 Stroke• Key Concept: Careful with

thromboembolic events • Data: 2 Significant AEs• Data: DVT at 72 hours, Angina at 29

days• Implications: Careful pt selection may

allow for minimal complications to occur


FVIIa Safety, Efficacy in ICHFVIIa Safety, Efficacy in ICH• Mayer: 2005 NEJM• Key Concept: FVIIa is safe when given

within 3 hours of presentation• Data: 399 pts, 3 doses, ICH growth, 90-day• Data: Less ICH growth, improved outcome• Data: Thromboembolic events noted• Implications: Larger study is critical in

order to establish clear benefit, safety


FVIIa Safety, Efficacy in ICHFVIIa Safety, Efficacy in ICH• Mayer: 2005 NEJM• Key Concept: Optimal patient population• Data: GCS 14, NIHSS 12-15• Data: 24 cc hemorrhage volume• Data: 180 minutes to treatment• Implications: Good population for

surgical Rx, fits with ED paradigm of stabilization

• Role in larger population of ICH pts?


FVIIa Safety, Efficacy in ICHFVIIa Safety, Efficacy in ICH• Mayer: 2005 NEJM• Key Concept: Good outcome, limited

AEs• Data: 47 vs. 31 % favorable outcome• Data: NIHSS 6 vs. 12• Data: 7 cardiac ischemia, 9 CVAs, 1 AMI• Implications: May represent a favorable

risk/benefit profile


FVIIa in ICH: CommentaryFVIIa in ICH: Commentary

• Brown: 2005 NEJM• Key Concept: Editorial provides

perspective on Mayer study• Data: How should data be interpreted?• Data: What can be learned from study?• Implications: What are the implications

of this study? What do we do now?


FVIIa in ICH: CommentaryFVIIa in ICH: Commentary

• Brown: 2005 NEJM• Key Concept: Many unknowns persist• Data: BP and ICH management

unclear• Data: Surgical Rx indications variable• Implications: Use it for good surgical

candidate, related to elevated INR, in pt not at high risk for thromboembolic event


ConclusionsConclusions• ICH is a bad disease

• Literature defines pathology and acute treatment options

• Surgical intervention enhances outcome

• Reversal of elevated INR a critical skill

• Await the confirmatory study of FVIIa in ICH patients


RecommendationsRecommendations

• Learn about the disease state

• Aggressively define extent of ICH

• Know how to manage ICH patients

• Know what the guidelines suggest

• Look for the upcoming trial results

• Continue to explore best approaches


Questions?Questions?

www.FERNE.org

[email protected] 312 413 7490

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