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

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Presentation on theme: "INTRACEREBRAL HEMORRHAGE UPDATE Carlos S. Kase, MD Neurology Department Boston Medical Center Boston, MA Department of Medicine Boston Medical Center October."— Presentation transcript:

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 MORTALITY 30 days: 37-44% 6 months: 30-50% 1-year: 38-58% INDEPENDENCE AT 6 MONTHS ICH: 20% Ischemic: 60%

4 Randomized Clinical Trials - STROKE Randomized Clinical Trials - STROKE Ca Stroke 1999;30: Ischemic SAH ICH >

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

6 Changes in the acute phase of ICH Enlargement of the hematoma Enlargement of the hematoma Growth of hematoma often associated with neurological deterioration Risk factors: sustained hypertension?, local coagulation disturbance? Mechanism: continued bleeding from source or surrounding vessels AI Qureshi et al. – NEJM 2001;344: 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:

7 AM Demchuk et al. – Lancet Neurol 2012;11: 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 cc ICH volume: cc

8 Modified Rankin Scale Distribution at Day Wada R et al., Stroke 2007;38:

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

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 acute 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 ATACH-IIINTERACT-2 Type of trial/Status Phase III/On-goingPhase III/Completed N SBP armsIntensive: <140 Standard: <180 Intensive: <140 Conservative: <180 Primary outcomemRS 90 d.mRS 90 d. Hematoma expansion (CT measurement) Yes Trials of BP Management in ICH

16

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18 P=0.06

19 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

20 SURGICAL TREATMENT OF ICH 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

21 Fernandes HM, et al. Stroke 2000;31: Meta-Analysis of CT era Randomized Trials of Surgical v. Non-surgical Treatment of Intracerebral Hemorrhage Study Exp n/N Ctrl n/N Peto OR (95% CI fixed) Peto OR (95% CI fixed) Weight % 1 Favors Rx Favors control

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

23 STICH trial Outcome at 6 Months* % Patients 26% 24% 74% 76% FavorableUnfavorable * Measured by score in eGOS

24 STICH trial Mortality at 6 Months % Mortality 36%37%

25 Favors surgery Favors Conservative Treatment STICH trial: Sub-group Analyses

26 Favors surgery Favors Conservative Treatment STICH trial: Sub-group Analyses

27 STICH trial Conclusions  No overall benefit from surgery compared to conservative treatment  Superficial location of hematoma may benefit from surgical treatment

28 SURGICAL TREATMENT OF ICH The Future New surgical trial: STICH II Eligible Ineligible

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

30 STICH II trial Favorable outcome at 6 Months* % Patients 41%38% * Measured by score in eGOS P=0.367

31 STICH II trial Mortality at 6 Months % Mortality 18%24% P=0.095

32 Surgical v. Conservative Management of Lobar ICH

33 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 MDStephen Haines, MD Mario Zuccarello, MDRaj Narayan, MD Ross Bullock, MDJoshua Bederson, MD Neal Naff, MDIssam Awad, MD William Broaddus, MD

34 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 Diagnostic StabilityPost-Surg.Post-Rx Med Rx Surg Rx

35 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

36 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 to the 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

37 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

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

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

40 FAST trial FAST trial rFVIIa 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:

41 FAST trial FAST trial rFVIIa 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

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

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

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

45 FAST trial FAST trial Conclusions 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

46 HEMOSTATIC TREATMENT OF ICH The 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 1 ary outcomes: thromboembolic complications hematoma 24 h. in 2 groups N =

47 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

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

49 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

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

51 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

52 ORAL-ANTICOAGULANT RELATED ICH Emergency Management - FFP  Lee et al., Neurology 2006;67: INR correction Average 30 h. ( h.) 5 units FFP (± 2.1) Median time presentation-FPP: 3 h. ( h.) Median time completion FPP infusion: 9.25 h. ( h.)

53 Deveras RAE, Kessler CM - Ann Int Med 2002;137:884-8 Reversal of warfarin- induced excessive anticoagulation with recombinant human Factor VIIa concentrate

54 ORAL-ANTICOAGULANT RELATED ICH Emergency Management - PCC FE Preston et al., Br J Haematol 2002;116: Prothrombin Complex Concentrate  Main advantages: Rapid reversal INR, small fluid volumes  Disadvantage: Risk of thromboembolic complications

55 Prothrombin Complex Concentrate  Contains: Factors II, VII, IX, X, Prot C and S  Blood product, virus-inactivated  DoseINR 25 U/kg U/kg U/kg > 6.0  Slow IV administration over minutes  Repeated doses avoided b/o thromboembolic risk

56 Prothrombin Complex Concentrate

57 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  Uncertain impact of arresting ICH growth on clinical outcome  Future studies: comparison of FFP, PCC, rFVIIa in terms of ability to arrest ICH growth, mortality and functional outcome

58 Key Assumptions to Organize Research Regarding ICH Treatment STEP 1STEP 1 STEP 2STEP 2 STEP 3STEP 3 Stop the hemorrhageStop the hemorrhage Remove the bloodRemove the blood Prevent recurrent bleedingPrevent recurrent bleeding


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