Edward P. Sloan, MD, MPH, FACEP ED Hemorrhagic Stroke Patient Management: What Role for Operative Intervention & Factor VIIa?

Edward P. Sloan, MD, MPH FACEP 4 th EuSEM Congress Crete, Greece October 5-7, 2006

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

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

Edward P. Sloan, MD, MPH FACEP Disclosures NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards NovoNordisk, King Pharmaceuticals, UCB Pharma Advisory Boards Eisai Speakers’ Bureau Eisai Speakers’ Bureau ACEP Clinical Policies Committee ACEP Clinical Policies Committee ACEP Scientific Review Committee ACEP Scientific Review Committee Executive Board, Foundation for Education and Research in Neurologic Emergencies Executive Board, Foundation for Education and Research in Neurologic Emergencies

Edward P. Sloan, MD, MPH FACEP Session Objectives Discuss the potential role for operative intervention given the results of the STICH trial. Discuss the potential role for operative intervention given the results of the STICH trial. Determine the optimal protocol for treating elevated INR in ICH patients and the possible role of factor VIIa in this setting. Determine the optimal protocol for treating elevated INR in ICH patients and the possible role of factor VIIa in this setting.

Edward P. Sloan, MD, MPH, FACEP Key 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?

Edward P. Sloan, MD, MPH, FACEP ED ICH Patients: Key Clinical Concepts

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts This is a high morbidity & mortality Dx

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts This is a high morbidity and mortality Dx Like ischemic stroke (core, penumbra)

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts This is a high morbidity and mortality Dx Like ischemic stroke (core, penumbra) Hemorrhage volume predicts outcome

Edward P. Sloan, MD, MPH, FACEP

ICH 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

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts This is a high morbidity and mortality Dx Like ischemic stroke (core, penumbra) Hemorrhage volume predicts outcome Hemorrhage volume increases over time

Edward P. Sloan, MD, MPH, FACEP

ICH 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

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts 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

Edward P. Sloan, MD, MPH, FACEP Evidence-Based ICH Patient Management Broderick JP et al. Stroke 1999;30:

Edward P. Sloan, MD, MPH, FACEP

ICH 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

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts 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

Edward P. Sloan, MD, MPH, FACEP

ICH: 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 % mortality in surgical ICH trials

Edward P. Sloan, MD, MPH, FACEP ICH: 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

Edward P. Sloan, MD, MPH, FACEP STITCH 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

Edward P. Sloan, MD, MPH, FACEP STITCH ICH Surgical Trial 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

Edward P. Sloan, MD, MPH, FACEP STITCH ICH Surgical Trial 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

Edward P. Sloan, MD, MPH, FACEP ICH Key Concepts 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

Edward P. Sloan, MD, MPH, FACEP Effect of Warfarin on 3 Month ICH Patient Outcome Rosand J et al. Arch Intern Med 2004;164:

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

Edward P. Sloan, MD, MPH, FACEP 6 th 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

Edward P. Sloan, MD, MPH, FACEP Elevated INR Rx: Key Concepts 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

Edward P. Sloan, MD, MPH, FACEP Elevated 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):

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

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

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

Edward P. Sloan, MD, MPH, FACEP Elevated INR Rx Procedure Vitamin K 10 mg by slow IV infusion Fresh frozen plasma (5-8 ml/kg, 1-2 units, cc total) OR Prothrombin Complex Conc at 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

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

Edward P. Sloan, MD, MPH, FACEP 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: Sorensen B et al. Blood Coagulation and Fibrinolysis 2003:14: Novoseven [package insert]. Princeton, NJ: Novo Nordisk Pharmaceuticals, Inc; 2003.

Edward P. Sloan, MD, MPH, FACEP

FVIIa 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

Edward P. Sloan, MD, MPH, FACEP FVIIa 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

Edward P. Sloan, MD, MPH, FACEP

FVIIa 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

Edward P. Sloan, MD, MPH, FACEP FVIIa 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

Edward P. Sloan, MD, MPH, FACEP

FVIIa 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

Edward P. Sloan, MD, MPH, FACEP FVIIa Safety, Efficacy in ICH Mayer: 2005 NEJM Key Concept: Optimal patient population Data: GCS 14, NIHSS 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?

Edward P. Sloan, MD, MPH, FACEP FVIIa 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

Edward P. Sloan, MD, MPH, FACEP

FVIIa 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?

Edward P. Sloan, MD, MPH, FACEP FVIIa 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

Edward P. Sloan, MD, MPH FACEPConclusions 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

Edward P. Sloan, MD, MPH FACEPRecommendations 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

Edward P. Sloan, MD, MPH FACEP Questions? ferne_eusem_2006_sloan_ich_100706_finalcd 5/24/2015 1:55 PM