1. INTRACEREBRAL HEMORRHAGE UPDATE
Carlos S. Kase, MD
Neurology Department
Boston Medical Center
Boston, MA
Department of Medicine
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: %
6 months: %
1-year: %

4. Randomized Clinical Trials - STROKE Ca. 1995 Stroke 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: %
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:
AI Qureshi et al. – NEJM 2001;344:
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 h follow-up
Non-contrast CT Spot-sign (+) Non-contrast CT
ICH volume: 19.6 cc ICH volume: cc
AM Demchuk et al. – Lancet Neurol 2012;11:307-14

8. Modified Rankin Scale Distribution at Day 3050 35 15 31 46 23
Wada R et al., Stroke 2007;38:

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
ATACH-II
INTERACT-2
Type of trial/Status
Phase III/On-going
Phase III/Completed N
1280
1500
SBP arms
Intensive: <140
Standard: <180
Conservative: <180
Primary outcome
mRS 90 d.
mRS 90 d.
Hematoma expansion
(CT measurement)
Yes
Trials of BP Management in ICH

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 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. Meta-Analysis of CT era Randomized Trials of Surgical v
Meta-Analysis of CT era Randomized Trials of Surgical v. Non-surgical Treatment of Intracerebral Hemorrhage
Peto OR
(95% CI fixed)
Weight %
Peto OR
(95% CI fixed)
Exp
n/N
Ctrl
n/N
Study 1
Favors Rx Favors control
Fernandes HM, et al. Stroke 2000;31:2511-6

22. Study conducted in 83 hospitals in 27 countries
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

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

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

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

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

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*
P=0.367
% Patients
41%
38%
* Measured by score in eGOS

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

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 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

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
Stability
Post-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 
Hoffmann M, Monroe DM, Thromb Haemost 2001; 85(6): 958–965.
Jurlander B, Semin Thromb Hemost 2001; 27(4): 373–84.
Monroe DM, et al. Br J Haematol 1997; 99: 542–547.
Monroe DM, et al. Blood Coagul Fibrinolysis 1998; 9(Suppl 1): S15–S20.
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.
P=0.01
29%
% Increase ICH Volume
16%
14%
11%
rFVIIa dose (μg/kg)

39. Frequency of Thromboembolic Events in rFVIIa Treatment Group v. Placebo7%
7 AMIs
9 strokes
5 venous
Thromboembolic Events 2%
16 arterial events
(5%)
0 arterial events
(0%)
Mayer SA et al., N Engl J Med 2005;352:777-85

40. 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 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.NS
P=0.0004
26%
% Increase ICH Volume
18%
14%
11%
rFVIIa dose (μg/kg)

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

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

45. 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
1ary outcomes: thromboembolic complications
hematoma 24 h. in 2 groups
N = 184

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

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. K1, 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;67:1272-4
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. Factor VIIa concentrate
Reversal of warfarin-
induced excessive
anticoagulation with
recombinant human
Factor VIIa concentrate
Deveras RAE, Kessler CM - Ann Int Med 2002;137:884-8

54. ORAL-ANTICOAGULANT RELATED ICH Emergency Management - PCC
Prothrombin Complex Concentrate
Main advantages: Rapid reversal INR, small fluid volumes
FE Preston et al., Br J Haematol 2002;116:619-24
Disadvantage: Risk of thromboembolic complications

55. Prothrombin Complex Concentrate
Contains: Factors II, VII, IX, X, Prot C and S
Blood product, virus-inactivated
Dose INR
25 U/kg
35 U/kg
50 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 1
STEP 2
STEP 3
Stop the hemorrhage
Remove the blood
Prevent recurrent bleeding