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					FERNE: What Role for Operative Intervention & Factor VIIa?                                                          1
Edward P. Sloan, MD, MPH FACEP




          ED Hemorrhagic Stroke
           Patient Management:
          What Role for Operative                                     4th EuSEM Congress
        Intervention & Factor VIIa?                                       Crete, Greece
                                                                        October 5-7, 2006
                                                                                   Edward P. Sloan, MD, MPH FACEP
                             Edward P. Sloan, MD, MPH, FACEP




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




                     Disclosures                                       Session Objectives
         •   NovoNordisk,
             NovoNordisk, King Pharmaceuticals,
             UCB Pharma Advisory Boards                        •   Discuss the potential role for
                                                                   operative intervention given the
         •         Speakers’
             Eisai Speakers’ Bureau
                                                                   results of the STICH trial.
                                                               •   Determine the optimal protocol for
         •   ACEP Clinical Policies Committee                      treating elevated INR in ICH patients
         •   ACEP Scientific Review Committee                      and the possible role of factor VIIa in
         •   Executive Board, Foundation for                       this setting.
             Education and Research in Neurologic
             Emergencies
                           Edward P. Sloan, MD, MPH FACEP                          Edward P. Sloan, MD, MPH FACEP
FERNE: What Role for Operative Intervention & Factor VIIa?                                                      2
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                      ED ICH Patients:
          anti-coagulated ICH patients and                     Key Clinical Concepts
          the potential role of factor VIIa?



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




                ICH Key Concepts                                   ICH Key Concepts
        • This is a high morbidity & mortality Dx           • This is a high morbidity and mortality
                                                              Dx
                                                            • Like ischemic stroke (core,
                                                              penumbra)




                          Edward P. Sloan, MD, MPH, FACEP                     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                     Edward P. Sloan, MD, MPH, FACEP
FERNE: What Role for Operative Intervention & Factor VIIa?                                                                                 3
Edward P. Sloan, MD, MPH FACEP




           ICH Volume and Outcome                                              ICH Key Concepts
         • Broderick: 1993 Stroke                           • This is a high morbidity and mortality
         • Key Concept: Hemorrhage volume                     Dx
           and GCS predict 30 day mortality                 • Like ischemic stroke (core,
         • Data: 60 cc blood, GCS < 9, mort                   penumbra)
           91%
                                                            • Hemorrhage volume predicts
         • Data: 30 cc blood, GCS > 8, mort                   outcome
           19%
         • Implications: Simple ED                          • Hemorrhage volume increases over
           observations allow for a                           time
                          Edward P. Sloan, MD, MPH, FACEP                                                Edward P. Sloan, MD, MPH, FACEP

                   bl    t                  t




                                                                     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
                          Edward P. Sloan, MD, MPH, FACEP
                                                                  stabilizing hemorrhage volume          Edward P. Sloan, MD, MPH, FACEP

                                                                       i     t ti t t




                                                                                  Evidence-
                                                                                  Evidence-Based ICH
                ICH Key Concepts                                                  Patient Management

        • This is a high morbidity and mortality
          Dx
        • Like ischemic stroke (core,
          penumbra)
        • Hemorrhage volume predicts
          outcome
        • Hemorrhage volume increases over
          time                                              Broderick JP et al. Stroke 1999;30:905-15.
                          Edward P. Sloan, MD, MPH, FACEP                                                Edward P. Sloan, MD, MPH, FACEP

          G id li       i t th t di  t ED   t
FERNE: What Role for Operative Intervention & Factor VIIa?                                                       4
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                      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                      Edward P. Sloan, MD, MPH, FACEP

          G id li       i t th t di  t ED   t




             ICH: Surgical Concepts                              ICH: Surgical Indications
         • Remember: Only 4 clinical trials!                • Difficult to specify
         • Total of 353 patients studied in all             • Some general principles
         • Remove clot, reduce pressure                     • Cerebellar hemorrhage: 3 cm or
                                                              larger or those that cause mass
         • Manage brain trauma and edema                      effect, compression
         • Minimize trauma (superficial clots               • ICH related to a surgical lesion
           best)                                            • Young patients who deteriorate
         • Minimally invasive approaches now                • Other indications less clear
           used
                          Edward P. Sloan, MD, MPH, FACEP                      Edward P. Sloan, MD, MPH, FACEP

           75 100%       t lit i     i l ICH
FERNE: What Role for Operative Intervention & Factor VIIa?                                                                                                5
Edward P. Sloan, MD, MPH FACEP




             STITCH ICH Surgical Trial                                                      STITCH ICH Surgical Trial
         • Mendelow: 2005 Lancet                                                       • Mendelow: 2005 Lancet
         • Key Concept: Surgery within 24                                              • 1033 pts, non-US settings
           hours does not affect 6 month                                               • Data: early surgery vs. medical,
           outcome                                                                       surgical
         • Data: 25% of pts had a good                                                 • Data: Hemorrhage volume: 40 cc
           outcome                                                                     • Data: 81% had GCS 9-15
         • Data: Surgery did not change this                                           • Data: Surgical time: 30 hrs, 60 hrs
           rate
                                                                                       • Data: Only 16% had surgery < 12
         • Implications: ED Rx becomes more         Edward P. Sloan, MD, MPH, FACEP
                                                                                         hrs                            Edward P. Sloan, MD, MPH, FACEP

              i     t t i     l     lik lih d




             STITCH ICH Surgical Trial                                                                  ICH Key Concepts
         • Mendelow: 2005 Lancet                                                      • This is a high morbidity and mortality
         • Key concept: This study may not                                              Dx
           exactly tell the story of practice that                                    • Like ischemic stroke (core,
           includes rapid identification of                                             penumbra)
           optimal surgical candidates and                                            • Hemorrhage volume predicts
           early OR intervention                                                        outcome
         • May still need to consider operative                                       • Hemorrhage volume increases over
           intervention, will need to stabilize                                         time
           patients first in the ED                 Edward P. Sloan, MD, MPH, FACEP

                                                                                        G id li       i t th t di  t ED
                                                                                                                        Edward P. Sloan, MD, MPH, FACEP

                                                                                                                          t




               Effect of Warfarin on 3 Month                                                 Sixth ACCP Recommendations on
                   ICH Patient Outcome                                                     Managing Patients with high INR Values




         Rosand J et al. Arch Intern Med 2004;164:880-884.
                                                                                      Chest 2001;119(1 Suppl):22S-38S
                                                    Edward P. Sloan, MD, MPH, FACEP                                     Edward P. Sloan, MD, MPH, FACEP
FERNE: What Role for Operative Intervention & Factor VIIa?                                                                                  6
Edward P. Sloan, MD, MPH FACEP




             6th ACCP INR Recommendations                                                Elevated INR Rx: Key Concepts
                 • Consensus, evidence based                                            • Measure INR
                 • 2001 Chest                                                           • Establish the extent of INR elevation
                 • Key Concept: Guidelines exist                                          (< 5, 5-9, >9) and presence of
                   for managing anticoagulated                                            bleeding
                   patients with serious or life                                        • Determine if an immediate
                   threatening bleeding                                                   neurosurgical intervention is
                 • Grade 2C evidence                                                      needed
                                                                                        • Administer Vitamin K IV
        Chest 2001;119(1 Suppl):22S-38S

                                                                                        • Order Coagulation Factor
                                                    Edward P. Sloan, MD, MPH, FACEP                       Edward P. Sloan, MD, MPH, FACEP




           Elevated INR Rx: ACCP Info


                                                                                          Elevated INR Therapy:
                                                                                              The Procedure


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




            Elevated INR Rx Procedure                                                    Elevated 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)




                                                    Edward P. Sloan, MD, MPH, FACEP                       Edward P. Sloan, MD, MPH, FACEP
FERNE: What Role for Operative Intervention & Factor VIIa?                                                                                 7
Edward P. Sloan, MD, MPH FACEP




            Elevated INR Rx Procedure                                                    Elevated INR Rx Procedure
        • Vitamin K 10 mg by slow IV infusion
                                                                                        • Vitamin K 10 mg subq or IVP
        • Fresh frozen plasma (5-8 ml/kg, 1-2
          units, 250-500 cc total)                                                      • Fresh frozen plasma (5-8 ml/kg)
                         OR                                                                  1-2 units, 250-500 cc total
        • Prothrombin Complex Conc at 25-50                                                           OR
          IU/kg                                                                         • Prothrombin Complex Concentrate
             – Dose based on Factor IX units                                              25-50 IU/kg
             – Alternatively, 500 IU initially followed by                                            OR
               second administration of 500 IU                                          • Recombinant Factor VIIa (40-60
                                 INR value measured
               according to theEdward P. Sloan, MD, MPH, FACEP                            µgr/kg)        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;53:34-39.
        Sorensen B et al. Blood Coagulation and Fibrinolysis
        2003:14:469-477.
        Novoseven [package insert]. Princeton, NJ: Novo Nordisk
        Pharmaceuticals, Inc; 2003.                   Edward P. Sloan, MD, MPH, FACEP                    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
                                                    Edward P. Sloan, MD, MPH, FACEP
                                                                                          therapies in ICH    patients whose
                                                                                                         Edward P. Sloan, MD, MPH, FACEP

                                                                                          bl d i INR l t d
FERNE: What Role for Operative Intervention & Factor VIIa?                                                        8
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                     Edward P. Sloan, MD, MPH, FACEP




                  FVIIa Safety in ICH                                FVIIa Safety in ICH
         • Mayer: 2005 Stroke                                 • Mayer: 2005 Stroke
         • Key Concept: FVIIa is safe when                    • Key Concept: Careful with
           given within 3 hours of presentation                 thromboembolic events
         • Data: 36 patients, 6 doses tested                  • Data: 2 Significant AEs
         • Data: No safety issues preclude
           phase III                                          • Data: DVT at 72 hours, Angina at 29
                                                                days
         • Implications: Larger study is
           justified, given data on hemorrhage                • Implications: Careful pt selection
           volume     growth and outcome
                            Edward P. Sloan, MD, MPH, FACEP
                                                                may allow for minimal complications
                                                                                Edward P. Sloan, MD, MPH, FACEP

                                                                t




                                                               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
                            Edward P. Sloan, MD, MPH, FACEP
                                                                in order to establish clear benefit
                                                                                Edward P. Sloan, MD, MPH, FACEP
FERNE: What Role for Operative Intervention & Factor VIIa?                                                        9
Edward P. Sloan, MD, MPH FACEP




         FVIIa Safety, Efficacy in ICH                       FVIIa Safety, Efficacy in ICH
        • Mayer: 2005 NEJM                                  • Mayer: 2005 NEJM
        • Key Concept: Optimal patient                      • Key Concept: Good outcome, limited
          population                                          AEs
        • Data: GCS 14, NIHSS 12-15                         • Data: 47 vs. 31 % favorable outcome
        • Data: 24 cc hemorrhage volume
                                                            • Data: NIHSS 6 vs. 12
        • Data: 180 minutes to treatment
                                                            • Data: 7 cardiac ischemia, 9 CVAs, 1
        • Implications: Good population for
          surgical Rx, fits with ED paradigm of               AMI
          stabilization                                     • Implications: May represent a
                          Edward P. Sloan, MD, MPH, FACEP
        • Role in larger population of ICH pts?               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?
                          Edward P. Sloan, MD, MPH, FACEP
                                                            • Implications: What are the
                                                                                Edward P. Sloan, MD, MPH, FACEP

                                                              i li ti         f thi t d ? Wh t




          FVIIa in ICH: Commentary                                    Conclusions
                                                            • ICH is a bad disease
         • Brown: 2005 NEJM                                 • Literature defines pathology and acute
         • Key Concept: Many unknowns                         treatment options
           persist                                          • Surgical intervention enhances
         • Data: BP and ICH management                        outcome
           unclear                                          • Reversal of elevated INR a critical skill
         • Data: Surgical Rx indications                    • Await the confirmatory study of FVIIa in
           variable                                           ICH patients
         • Implications: Use it for good
           surgical candidate, related to
                          Edward P. Sloan, MD, MPH, FACEP
                                                                              Edward P. Sloan, MD, MPH FACEP


            l   t d INR i       t t t hi h
FERNE: What Role for Operative Intervention & Factor VIIa?                                                                           10
Edward P. Sloan, MD, MPH FACEP




               Recommendations
         •   Learn about the disease state                                         Questions?
         •   Aggressively define extent of ICH
         •   Know how to manage ICH patients                          www.FERNE.org
         •   Know what the guidelines suggest
         •   Look for the upcoming trial results                      edsloan@uic.edu
         •   Continue to explore best approaches                      312 413 7490

                                                            ferne_eusem_2006_sloan_ich_100706_finalcd
                                                            11/7/2006 8:20 PM
                           Edward P. Sloan, MD, MPH FACEP                                           Edward P. Sloan, MD, MPH FACEP

				
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