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INTRACEREBRAL HEMORRHAGE UPDATE

INTRACEREBRAL HEMORRHAGE UPDATE. Carlos S. Kase, MD Neurology Department Boston Medical Center Boston, MA Department of Medicine Boston Medical Center October 17, 2013. Heart Disease and Stroke Statistics Circulation , 12/15/08. 795,000 strokes/yr in US: 610,000 new, 185,000 recurrent

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INTRACEREBRAL HEMORRHAGE UPDATE

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  1. INTRACEREBRAL HEMORRHAGE UPDATE Carlos S. Kase, MD Neurology Department Boston Medical Center Boston, MA Department of Medicine Boston Medical Center October 17, 2013

  2. Heart Disease and Stroke Statistics Circulation, 12/15/08 • 795,000 strokes/yr in US: 610,000 new, 185,000 recurrent • Subtype distribution: 87% 10% 3%

  3. High Mortality and Poor Recovery following ICH INDEPENDENCE AT 6 MONTHS • ICH: 20% • Ischemic: 60% MORTALITY • 30 days: 37-44% • 6 months: 30-50% • 1-year: 38-58%

  4. Randomized Clinical Trials - STROKECa. 1995Stroke 1999;30:905-15 >315 78 8 Ischemic SAH ICH

  5. Major New Observation about the Early Evolution of ICH 35 min. from onset Volume: 25cc 105 min. from onset Volume: 44cc JP Broderick, TG Brott, T Tomsick, et al. J Neurosurg 1990;72:195-9

  6. Changes in the acute phase of ICH Enlargement of the hematoma In 39/103 pts. (38%) Within 1 hr. from baseline: 26% Within 20 hrs. from baseline: 38% T Brott et al – Stroke 1997;28:1-5 In 41/204 pts. (20%) In 36% of pts. within 3 hrs. In 11% of pts. > 3 hrs. S Kazui et al – Stroke 1996;27:1783-7 AI Qureshi et al. – NEJM 2001;344:1450-60 • Growth of hematoma often associated with neurological deterioration • Risk factors: sustained hypertension?, local coagulation disturbance? • Mechanism: continued bleeding from source or surrounding vessels

  7. Spot-sign in Patient with ICH Baseline Baseline CTA 24 h follow-up Non-contrast CT Spot-sign (+) Non-contrast CT ICH volume: 19.6 ccICH volume: 110.8 cc AM Demchuk et al. – Lancet Neurol 2012;11:307-14

  8. Modified Rankin ScaleDistribution at Day 30 50 15 35 31 23 46 Wada R et al., Stroke 2007;38:1257-62

  9. RISK OF DEATH BY CTA SPOT-SIGN STATUS Spot-sign positive Log-rank test p=0.0006 Spot-sign negative AM Demchuk et al. – Lancet Neurol 2012;11:307-14

  10. Unresolved Issues in the Management of ICH – Progress since 1995 • Management of hypertension in the acute stage of ICH -2 trials of early BP control after ICH • Role of mechanical hematoma removal - 2 small trials of early surgical removal of ICH - 1 major trial of surgical removal of ICH - 1 on-going trial of ICH removal with tPA instillation • Role of hemostatic treatment of ICH - 3 trials of hemostasis in ICH with rFVIIa - 1 trial of hemostasis in warfarin-related ICH

  11. Unresolved Issues in the Management of ICH • Management of hypertension in the acute stage of ICH • Role of mechanical hematoma removal • Role of hemostatic treatment of ICH

  12. Hypertension in the acute stage of ICH • Blood pressure is frequently elevated beyond usual values for patient in setting of ICH • Elevated blood pressure often comes down without treatment • Persistently elevated blood pressure may promote enlargement of the ICH • Lowering of blood pressure may lead to ischemia in the peri-hematoma area

  13. Effect of Treating Hypertension on CBF Following Acute ICH Powers WJ, et al. Neurology 2001;57:18-24

  14. BLOOD PRESSURE MANAGEMENT AFTER ICH • Gentle lowering of BP by < 20%, to MAP < 130 mmHg • Use of titrable and slow-acting agents (labetalol or nicardipine) • Especially indicated in large or expanding hematomas Avoid: - Fast-acting, unpredictable anti-hypertensive drugs (SL nifedipine, hydralazine) - Lowering MAP below 85 mmHg or > 20%

  15. Trials of BP Management in ICH

  16. P=0.06

  17. Unresolved Issues in the Management of ICH • Management of hypertension in the acute stage of ICH • Role of mechanical hematoma removal • Role of hemostatic treatment of ICH

  18. SURGICAL TREATMENT OF ICH Non-randomized Trials • Various biases introduced into trial design • No clear superiority of surgical v. non-surgical treatment • Possibility of certain sub-groups benefitted by surgical treatment

  19. Lancet 2005;365:387-97 • Study conducted in 83 hospitals in 27 countries • Surgical evacuation of ICH within 4 days v. Conservative Management Surgery 503 • N = 1033 Conservative 530

  20. STICH trialOutcome at 6 Months* 76% 74% % Patients 26% 24% Favorable Unfavorable * Measured by score in eGOS

  21. STICH trialMortality at 6 Months % Mortality 36% 37%

  22. STICH trial: Sub-group Analyses Favors surgery Favors Conservative Treatment

  23. STICH trial: Sub-group Analyses Favors surgery Favors Conservative Treatment

  24. STICH trial Conclusions • No overall benefit from surgery compared to conservative treatment • Superficial location of hematoma may benefit from surgical treatment

  25. SURGICAL TREATMENT OF ICHThe Future New surgical trial: STICH II Eligible Ineligible

  26. Study conducted in 78 hospitals in 27 countries Surgical evacuation of ICH within 12 hours v. Conservative Management Surgery 307 N = 601 Conservative 294

  27. STICH II trialFavorable outcome at 6 Months* P=0.367 % Patients 41% 38% * Measured by score in eGOS

  28. STICH II trialMortality at 6 Months P=0.095 % Mortality 18% 24%

  29. Surgical v. Conservative Management of Lobar ICH

  30. Minimally Invasive (Stereotactic) Surgery + rt-PA for ICH Extraction (MISTIE) A phase II, safety and efficacy study of ICH treatment Sponsored by the NIH/NINDS Surgical Sites & Leadership Daniel F. Hanley MD Stephen Haines, MD Mario Zuccarello, MD Raj Narayan, MD Ross Bullock, MD Joshua Bederson, MD Neal Naff, MD Issam Awad, MD William Broaddus, MD 2006-2012

  31. Stability Post-Surg. Post-Rx Diagnostic MISTIE Hypotheses • Early use of minimally invasive surgery (MIS) + rt-PA is safe for treatment of ICH • Early use of MIS + rt-PA produces clot size reduction compared to medically treated patients Med Rx Surg Rx

  32. Unresolved Issues in the Management of ICH • Management of hypertension in the acute stage of ICH • Role of mechanical hematoma removal • Role of hemostatic treatment of ICH

  33. Recombinant FVIIa controls bleeding at the site of vascular injury Binding of factor VIIa or rFVIIa to TF initiates the coagulation generating small amounts of thrombin  At pharmacological doses rFVIIa binds directly tothe surface of activated platelets resulting in a “thrombin burst”  The thrombin burst leads to the formation of a stable hemostatic plug which controls the bleeding  Adapted from Hoffman M, Monroe DM. Thromb Haemost 2001;85:958–965

  34. Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage Phase II, dose-finding study N = 399 pts. Randomized to 3 doses of rFVIIa (40, 80, 160 μg/kg) v. placebo Treatment given within 4 hours of ICH onset Primary Outcome Measure: % change in ICH volume at 24 hours Clinical Outcomes (mRS, BI, E-GOS, NIHSS) & mortality at 90 days SA Mayer et al. – NEJM 2005:352:777-85

  35. Mean % Increase in ICH Volume at 24 h. P=0.01 29% % Increase ICH Volume 16% 14% 11% rFVIIa dose (μg/kg)

  36. 7% Frequency of Thromboembolic Events in rFVIIa Treatment Group v. Placebo 7 AMIs 9 strokes 5 venous Thromboembolic Events 2% 0 arterial events (0%) 16 arterial events (5%) Mayer SA et al., N Engl J Med 2005;352:777-85

  37. FAST trialrFVIIa in Acute Haemorrhagic Stroke Treatment Phase III International trial rFVIIa, 20 μg/kg, 80 μg/kg v. placebo Window: 4 hours SA Mayer et al. NEJM 2008;358:2127-37

  38. FAST trialrFVIIa in Acute Haemorrhagic Stroke Treatment Efficacy endpoints • Primary efficacy endpoint: mRS 5-6 on d. 90 • Secondary efficacy endpoints: • Absolute and % change in ICH volume by CT from prior to dosing to 24 hours after the baseline scan • Barthel Index at d. 15 and d. 90 • Mortality

  39. Mean % Increase in ICH Volume at 24 h. NS P=0.0004 26% % Increase ICH Volume 18% 14% 11% rFVIIa dose (μg/kg)

  40. mRS 5-6 at 90 days % with mRS 5-6 at 90 days 26% 29% 24% rFVIIa dose (μg/kg)

  41. Thromboembolic Complications – 90 d. 13% 11% 11% Arterial 10% % with TE complications Arterial 6% Arterial 5% P=0.041 rFVIIa dose (μg/kg)

  42. FAST trialConclusions • Despite similar reduction in ICH growth as in the Phase IIB trial, negative results x primary outcome • Groups with poor outcome: Age >70 Low baseline GCS IVH >5 ml baseline Volume ICH > 60 ml Infratentorial ICH

  43. HEMOSTATIC TREATMENT OF ICHThe Future The Spot Sign for Predicting and Treating ICH Growth Study (STOP-IT) A phase II, safety and efficacy study of ICH treatment Sponsored by the NIH/NINDS Design: rFVIIa v. placebo in pts. with ICH and “Spot Sign” Treatment within 5 h. from ICH onset 1ary outcomes: thromboembolic complications hematoma growth @ 24 h. in 2 groups N = 184 2008-2013

  44. Unresolved Issues in the Management of ICH – Areas of Remaining Uncertainty • Management of anticoagulant-related ICH • A devastating type of ICH, with mortality up to 60% • High frequency of continuing hematoma enlargement

  45. Gradual Enlargement of Hematoma Patient on Coumadin - Initial INR=4.8 1:48 AM 3:36 AM 5:52 AM ICH volume: 4.25 cc ICH volume: 43 cc ICH volume: 73.7 cc NIHSS: 3 NIHSS: 14 NIHSS: >20

  46. Unresolved Issues in the Management of ICH – Areas of Remaining Uncertainty • Management of anticoagulant-related ICH • A devastating type of ICH, with mortality up to 60% • High frequency of continuing hematoma enlargement • Inadequate options for timely INR reversal

  47. ORAL-ANTICOAGULANT RELATED ICH Emergency Management - FFP • CALL BLOOD BANK, ORDER 6 UNITS FFP !! • Vit. K1, 10 mg slow IV injection (over ~ 30 min.) (Only achieves ~ 70% correction of INR after 8 h.) • FFP, 15-25 ml/kg (~ 1000-1750 ml) • Infuse FFP every 45 min - 1 hour • Check INR at least every 4 hours

  48. ORAL-ANTICOAGULANT RELATED ICH Emergency Management - FFP • Fresh frozen plasma • Main advantage: Availability • Disadvantages: -Time spent thawing - Need for large volumes of infusion - Risk of CHF in elderly, renal failure - Low amounts of factor IX, variability among batches - Need for blood group typing, not virus-inactivated - Long time (hours) spent before INR reversal

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