INTRACEREBRAL HEMORRHAGE UPDATE
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Transcript of INTRACEREBRAL HEMORRHAGE UPDATE
INTRACEREBRAL INTRACEREBRAL HEMORRHAGE UPDATEHEMORRHAGE UPDATE
Carlos S. Kase, MDNeurology DepartmentBoston Medical Center
Boston, MA
Department of Medicine Boston Medical Center
October 17, 2013
Heart Disease and Stroke StatisticsHeart Disease and Stroke StatisticsCirculationCirculation, 12/15/08, 12/15/08
• 795,000 strokes/yr in US: 610,000 new, 185,000 recurrent
• Subtype distribution:
0
20
40
60
80
100
Ischemic
ICH
SAH
87%
10%
3%
High Mortality and Poor Recovery High Mortality and Poor Recovery following ICHfollowing ICH
0%
20%
40%
60%
80%
100%
ICH Ischemic
Independent
Dependent
DeadMORTALITY• 30 days: 37-44% • 6 months: 30-50%• 1-year: 38-58%
INDEPENDENCEAT 6 MONTHS
• ICH: 20%• Ischemic: 60%
Randomized Clinical Trials - Randomized Clinical Trials - STROKESTROKECa. 1995
Stroke 1999;30:905-15
0
50
100
150
200
250
300
Ischemic SAH ICH
>315
78
8
Major New Observation about the Major New Observation about the Early Evolution of ICHEarly Evolution of ICH
JP Broderick, TG Brott, T Tomsick, et al. J Neurosurg 1990;72:195-9
35 min. from onsetVolume: 25cc
105 min. from onsetVolume: 44cc
Changes in the acute phase of ICH Changes in the acute phase of ICH Enlargement of the hematomaEnlargement 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;344:1450-60
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
AM Demchuk et al. – Lancet Neurol 2012;11:307-14
Spot-sign in Patient with ICHSpot-sign in Patient with ICH
Baseline Baseline CTA 24 h follow-up Non-contrast CT Spot-sign (+) Non-contrast CTICH volume: 19.6 cc ICH volume: 110.8 cc
Modified Rankin ScaleModified Rankin Scale Distribution at Day 30Distribution at Day 30
0% 20% 40% 60% 80% 100%
Spot (+)
Spot (- )
0 to 2
3 to 5
6
50 35 15
31 46 23
Wada R et al., Stroke 2007;38:1257-62
Spot-sign positive
Spot-sign negative
AM Demchuk et al. – Lancet Neurol 2012;11:307-14
RISK OF DEATH BY CTA SPOT-SIGN STATUSRISK OF DEATH BY CTA SPOT-SIGN STATUS
Log-rank test p=0.0006
Unresolved Issues in the Unresolved Issues in the Management of ICH – Progress Management of ICH – Progress
since 1995since 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
Unresolved Issues in the Unresolved Issues in the Management of ICHManagement of ICH
• Management of hypertension in the acute stage of ICH
• Role of mechanical hematoma removal
• Role of hemostatic treatment of ICH
Hypertension in the acuteacute 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 theperi-hematoma area
Effect of Treating Hypertension on Effect of Treating Hypertension on CBFCBF
Following Acute ICHFollowing Acute ICH
Powers WJ, et al. Neurology 2001;57:18-24
BLOOD PRESSURE MANAGEMENT BLOOD PRESSURE MANAGEMENT AFTER ICHAFTER 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%
ATACH-IIATACH-II INTERACT-2INTERACT-2
Type of trial/Status
Phase III/On-going Phase III/Completed
N 1280 1500
SBP arms Intensive: <140Standard: <180
Intensive: <140Conservative: <180
Primary outcome mRS 4-6 @ 90 d. mRS 3-6 @ 90 d.
Hematoma expansion
(CT measurement)
Yes Yes
Trials of BP Management in ICHTrials of BP Management in ICH
P=0.06
Unresolved Issues in the Unresolved Issues in the Management of ICHManagement of ICH
• Management of hypertension in the acute stage of ICH
• Role of mechanical hematoma removal
• Role of hemostatic treatment of ICH
SURGICAL TREATMENT OF ICHSURGICAL TREATMENT OF ICH
Non-randomized TrialsNon-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
• Study conducted in 83 hospitals in 27 countries
• Surgical evacuation of ICH within 4 daysv.
Conservative Management
Surgery 503• N = 1033
Conservative 530
Lancet 2005;365:387-97
STICH trialSTICH trial Outcome at 6 Months*Outcome at 6 Months*
0
20
40
60
80
100
Surgery
Conservative
% P
ati
ents
26% 24%
74% 76%
Favorable Unfavorable
* Measured by score in eGOS
STICH trialSTICH trialMortality at 6 MonthsMortality at 6 Months
0
20
40
60
80
100
Surgery
Conservative
% M
ort
alit
y
36% 37%
Favors surgery Favors Conservative Treatment
STICH trial: Sub-group AnalysesSTICH trial: Sub-group Analyses
Favors surgery Favors Conservative Treatment
STICH trial: Sub-group AnalysesSTICH trial: Sub-group Analyses
STICH trialSTICH trialConclusionsConclusions
No overall benefit from surgery compared to
conservative treatment
Superficial location of hematoma may benefit
from surgical treatment
SURGICAL TREATMENT OF ICHThe Future
New surgical trial: STICH II
Eligible Ineligible
Study conducted in 78 hospitals in 27 countries
Surgical evacuation of ICH within 12 hoursv.
Conservative Management
Surgery 307 N = 601
Conservative 294
STICH II trialSTICH II trial Favorable outcome at 6 Months*Favorable outcome at 6 Months*
0
20
40
60
80
100
Surgery
Conservative
% P
ati
ents
41% 38%
* Measured by score in eGOS
P=0.367
STICH II trialSTICH II trialMortality at 6 MonthsMortality at 6 Months
0
20
40
60
80
100
Surgery
Conservative
% M
ort
alit
y
18% 24%
P=0.095
Surgical v. Conservative Management of Lobar ICH
MMinimally inimally IInvasive nvasive (Stereotactic) (Stereotactic) SSurgery + rurgery + rtt-PA -PA
for for IICH CH EExtraction (MISTIE)xtraction (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, MDMario Zuccarello, MD Raj Narayan, MDRoss Bullock, MD Joshua Bederson, MDNeal Naff, MD Issam Awad, MDWilliam Broaddus, MD
2006-2012
MISTIE HypothesesMISTIE 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
Unresolved Issues in the Unresolved Issues in the Management of ICHManagement of ICH
• Management of hypertension in the acute stage of ICH
• Role of mechanical hematoma removal
• Role of hemostatic treatment of ICH
Recombinant FVIIa controls bleeding Recombinant FVIIa controls bleeding at the site of vascular injuryat 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
Recombinant Activated Factor VII Recombinant Activated Factor VII for Acute Intracerebral Hemorrhagefor 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
Mean % Increase in ICH Volume at 24 Mean % Increase in ICH Volume at 24 h.h.
0
5
10
15
20
25
30
40 80 160 Placebo
rFVIIa dose (μg/kg)
% Incr
ease
IC
H V
olu
me
29%
11%14%
16%
P=0.01
Frequency of Thromboembolic Frequency of Thromboembolic Events in rFVIIa Treatment Group Events in rFVIIa Treatment Group
v. Placebov. Placebo
0%
1%
2%
3%
4%
5%
6%
7%
rFVI I a
Placebo
Th
rom
boem
bolic
Events
7%
2%
Mayer SA et al., N Engl J Med 2005;352:777-85
7 AMIs9 strokes5 venous
0 arterial events(0%)
16 arterial events(5%)
FAST trialFAST 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
FAST trialFAST 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
Mean % Increase in ICH Volume at 24 Mean % Increase in ICH Volume at 24 h.h.
0
5
10
15
20
25
30
20 80 Placebo
rFVIIa dose (μg/kg)
% Incr
ease
IC
H V
olu
me
26%
11%14%
18%
P=0.0004NS
mRS 5-6 at 90 daysmRS 5-6 at 90 days
0
5
10
15
20
25
30
20 80 Placebo
rFVIIa dose (μg/kg)
% w
ith m
RS 5
-6 a
t 9
0 d
ays
24%29%26%
Thromboembolic Complications – 90 Thromboembolic Complications – 90 d.d.
0
5
10
15
20
20 80 Placebo
rFVIIa dose (μg/kg)
% w
ith T
E c
om
plic
ati
ons
11%
13%
11%
P=0.041 Arterial
6% Arterial5%
Arterial 10%
FAST trialFAST 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
HEMOSTATIC TREATMENT OF ICHHEMOSTATIC TREATMENT OF ICHThe FutureThe Future
The Spot Sign for Predicting and Treating The Spot Sign for Predicting and Treating ICH Growth Study (STOP-IT)ICH Growth Study (STOP-IT)
A phase II, safety and efficacy study of ICH treatmentSponsored 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 = 1842008-2013
Unresolved Issues in the Unresolved Issues in the Management of ICH – Areas of Management of ICH – Areas of
Remaining UncertaintyRemaining Uncertainty
• Management of anticoagulant-related ICH
A devastating type of ICH, with mortality up to 60%
High frequency of continuing hematoma enlargement
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
Gradual Enlargement of HematomaGradual Enlargement of HematomaPatient on Coumadin - Initial INR=4.8 Patient on Coumadin - Initial INR=4.8
Unresolved Issues in the Unresolved Issues in the Management of ICH – Areas of Management of ICH – Areas of
Remaining UncertaintyRemaining 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
ORAL-ANTICOAGULANT RELATED ORAL-ANTICOAGULANT RELATED ICHICH
Emergency Management - FFPEmergency 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
ORAL-ANTICOAGULANT RELATED ORAL-ANTICOAGULANT RELATED ICHICH
Emergency Management - FFPEmergency 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
ORAL-ANTICOAGULANT RELATED ORAL-ANTICOAGULANT RELATED ICHICH
Emergency Management - FFPEmergency Management - FFP
Lee et al., Neurology 2006;67:1272-4
• INR correction
Average 30 h. (14-49.5 h.)
5 units FFP (± 2.1)
Median time presentation-FPP: 3 h. (1.5-4.5 h.)
Median time completion FPP infusion: 9.25 h. (5-11.75 h.)
Deveras RAE, Kessler CM - Ann Int Med 2002;137:884-8
Reversal of warfarin-induced excessiveanticoagulation withrecombinant humanFactor VIIa concentrate
ORAL-ANTICOAGULANT RELATED ORAL-ANTICOAGULANT RELATED ICHICH
Emergency Management - PCCEmergency Management - PCC
FE Preston et al., Br J Haematol 2002;116:619-24
Prothrombin Complex Concentrate
Main advantages: Rapid reversal INR, small fluid volumes
Disadvantage: Risk of thromboembolic complications
Prothrombin Complex Concentrate
Contains: Factors II, VII, IX, X, Prot C and S
Blood product, virus-inactivated
Dose INR 25 U/kg 2-3.9
35 U/kg 4-6.0
50 U/kg > 6.0
Slow IV administration over 10-15 minutes
Repeated doses avoided b/o thromboembolic risk
Unresolved Issues in the Unresolved Issues in the Management of ICH – Areas of Management of ICH – Areas of
Remaining UncertaintyRemaining 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
Key Assumptions to OrganizeKey Assumptions to OrganizeResearch Regarding ICH Research Regarding ICH
TreatmentTreatment
• STEP 1STEP 1
• STEP 2STEP 2
• STEP 3STEP 3
• Stop the hemorrhageStop the hemorrhage
• Remove the bloodRemove the blood
• Prevent recurrent Prevent recurrent bleedingbleeding