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

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

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

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


% 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


% 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


% 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






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


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


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


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






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

intracerebral hemorrhage update

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