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Recent Developments in the

Acute Treatment of Intracerebral Hemorrhage

Christian Stapf
Tenured Professor of Neurology
Univ Paris Diderot – Sorbonne Paris Cité
APHP - Hôpital Lariboisière, Paris
Neurovascular Unit

Adj. Assist. Professor of Neurology


Stroke Center
Columbia University Medical Center

New York City


21st Annual Stroke Reception
Tuesday, May 20, 2014
Disclosures
Stocks
None
Project Funding
Reference Center for Rare Neurovascular Disorders of the
Brain and Eye (French Ministry of Health)
Trials (< 5 years)
ARUBA ongoing Co-PI (Europe) NIH/NINDS, USA
HeadPost ongoing Co-PI (France) NMHRC, Australia
INTERACT-2 finalized Co-PI (Europe) NMHRC, Australia
Advisory Boards, Panel Member, Speaker Fees (< 3 years)
European Commission, ESC, SFCNS, WFITN
Travels, Accomodation, Admission Fees (< 1year)
AHA/ASA Int. Stroke Conference speaker 2013
AHA/ASA Stroke Reception, NYC speaker 2014
AVM World Conference speaker 2014
Neuroradiologie Aktuell speaker 2013, 2014
ESC speaker 2013, 2014
ESNR speaker 2013
European Stroke Congress speaker 2013, 2014
European Stroke University speaker 2013
French Neurovascular Society speaker 2013
Portuguese Stroke Society speaker 2014
Use of Unlabeled / Unapproved Products
None
Hôpital Lariboisière, Paris (France)
Columbia University Medical Center
Intracerebral Hemorrhage
Recent Developments
Intracerebral Hemorrhage
Recent Developments
The new
generation
is coming…
Intracerebral Hemorrhage
Recent Developments


Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Classification
Ischemic stroke
• Harvard Stroke Registry / NINDS Stroke Databank
• Oxford Community Stroke Project classification (OCSP)
• TOAST (Trial of Org 10172 in Acute Stroke Treatment)
• a-s-C-o classification of stroke
Hemorrhagic stroke
By location:
• Intracerebral / subarachnoid / intraventricular
• Lobar / deep
By etiology:
• Primary versus secondary
• Hypertensive hemorrhage
Intracerebral Hemorrhage
Classification
Ischemic stroke
• Harvard Stroke Registry / NINDS Stroke Databank
• Oxford Community Stroke Project classification (OCSP)
• TOAST (Trial of Org 10172 in Acute Stroke Treatment)
• a-s-C-o classification of stroke
Hemorrhagic stroke
By location:
• Intracerebral / subarachnoid / intraventricular
• Lobar / deep
By etiology:
• Primary versus secondary
• Hypertensive hemorrhage
Intracerebral Hemorrhage
Deep versus lobar
Intracerebral Hemorrhage
Deep versus lobar
78-year old man
Arterial hypertension
Dyslipidemia
Alcohol abuse
Sudden onset left
hemiparesis
Intracerebral Hemorrhage
Deep versus lobar
Intracerebral Hemorrhage
Hemorrhagic infarction
Intracerebral Hemorrhage
Deep versus lobar
72-year old man
Arterial hypertension
Former smoker
Cognitive decline
Sudden onset aphasia
Intracerebral Hemorrhage
Dural arteriovenous fistula
Intracerebral Hemorrhage
Dural arteriovenous fistula
Intracerebral Hemorrhage
Classification
Ischemic stroke
• Harvard Stroke Registry / NINDS Stroke Databank
• Oxford Community Stroke Project classification (OCSP)
• TOAST (Trial of Org 10172 in Acute Stroke Treatment)
• a-s-C-o classification of stroke
Hemorrhagic stroke
By location:
• Intracerebral / subarachnoid / intraventricular
• Lobar / deep
By etiology:
• Primary versus secondary
• Hypertensive hemorrhage
Intracerebral Hemorrhage
Classification
Risk Factors

Underlying Brain
Cause Hemorrhage

Golden Rules:
1) Every intrecerebral hemorrhage has an underlying cause
2) Risk factors may trigger / modify underlying causes
Intracerebral Hemorrhage
Classification
Risk Factors

Underlying Brain
Cause Hemorrhage

Golden Rules:
1) Every intrecerebral hemorrhage has an underlying cause
2) Risk factors may trigger / modify underlying causes
3) Do not confound causes and risk factors
Intracerebral Hemorrhage
Classification
Cigarette smoking

Carotid Brain
Stenosis Infarction
embolism

Tabacco infarct…
Primary infarct…
Intracerebral Hemorrhage
Classification
Risk Factors [Arterial Hypertension]

Underlying Brain
Cause Hemorrhage
[Microangiopathy] [deep]
Practical Consequence:
1) Visualize underlying cause
2) Search for risk factors
3) Treat causes and/or risk factors, if modifiable…
Intracerebral Hemorrhage
Classification
Risk Factors [Smoking, Alcohol]

Underlying Brain
Cause Hemorrhage
[Arterial Aneurysm] [+ SAH]
Practical Consequence:
1) Visualize underlying cause
2) Search for risk factors
3) Treat causes and/or risk factors, if modifiable…
Intracerebral Hemorrhage
Classification
Risk Factors

Underlying Brain
Cause Hemorrhage

Do not use:
Primary ICH
Hypertensive Hemorrhage
Intracerebral Hemorrhage
Classification

Cordonnier C, Al Shahi Salman R, Henon H, von Kummer R, Leys D, Stapf C (in preparation)
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Diagnosis

3 countries
F, NL, UK
3 disciplines
NR°, NS, NRO
3 methods
CT, MRI, A°
Stroke 2010;41;685-690
Intracerebral Hemorrhage
Diagnosis

3 countries
F, NL, UK
3 disciplines
NR°, NS, NRO
3 methods
CT, MRI, A°
Stroke 2010;41;685-690
Intracerebral Hemorrhage
Etiological subgroups
Small vessel disease Moyamoya syndrome /
disease
• Arteriolosclerosis / lipohyalinosis
Inflammation
• Amyloid angiopathy
• Vasculitis
• Genetic (Col4A1, CADASIL,…)
• Mycotic aneurysm
Vascular Malformation Malignant disease
• Arteriovenous malformation • Brain tumor
• Cavernous malformation • Cerebral metastasis
Intracranial aneurysm Coagulopathy
Venous disease • Genetic
• Cerebral sinus / venous thrombosis • Acquired / iatrogenic
• Dural arteriovenous fistula Vasoactive drugs

Reversible cerebral Hemorrhagic Infarction


vasoconstriction syndrome Trauma
Al Shahi Salman R, Labovitz DL, Stapf C. Br Med J 2009; 339:b2586
Acute intracerebral hemorrhage
The (un)usual causes
64-year old woman
Arterial hypertension
Active smoker
Sudden onset headache
followed by coma
Acute intracerebral hemorrhage
Aneurysm Rupture
Acute intracerebral hemorrhage
The (un)usual causes
58-year old man
Aterial hypertension
Feeling sick >1 week
Admitted: acute confusion
Temp 38,2°C
CRP 125 mg/dl
Cardiac murmur
Acute intracerebral hemorrhage
Endocarditis & mycotic aneurysms
Acute intracerebral hemorrhage
Endocarditis & mycotic aneurysms
Therapeutic Emergency
1) Antibiotics
2) Embolization
3) Valve replacement
Acute intracerebral hemorrhage
The (un)usual causes
42-year old woman
Thunderclap headache
related to sexual activity
Improving after 2 hours
CT: normal

Day 1
LP: normal
MRI: normal
MRA: normal
Acute intracerebral hemorrhage
Reversible Cerebral Vasoconstriction Syndrome

Day 1 Day 8
Acute intracerebral hemorrhage
Reversible Cerebral Vasoconstriction Syndrome
Clinico-radiological Syndrome
1. Several episodes of sudden onset, severe headaches
2. Intracranial vasoconstriction (after >4 days)
• Transcranial Doppler
• MRA / CT Angio
• Angiography
3. Secondary complications (after 1-14 days)
• Hemorrhagic (ICH, cortical SAH)
• Brain infarction
4. Headaches and vasoconstriction resolve within 1 month

Ducros A (2007) Brain 130:3091


Acute intracerebral hemorrhage
Reversible Cerebral Vasoconstriction Syndrome

Risik:
• Women
• Migraine history

Ducros A (2010) Stroke


Ducros A (2007) Brain 130:3091
Acute intracerebral hemorrhage
The (un)usual causes
48-year old woman
Cigarette smoking
Hormonal contraception
Unusual headaches >2 days
Sec. generalized seizure
Persistent aphasia
Right homonymous hemianopia
Acute intracerebral hemorrhage
The (un)usual causes

MRV T2*
Acute intracerebral hemorrhage
Cerebral venous thrombosis

HEPARIN!!

MRV T2*
Acute intracerebral hemorrhage
The (un)usual causes
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Miller-Fisher C, 2000
Miller-Fisher C, 2000
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Acute intracerebral hemorrhage
Hemorrhagic Infarction
Intracerebral Hemorrhage
Etiological subgroups
Small vessel disease Moyamoya syndrome /
disease
• Arteriolosclerosis / lipohyalinosis
Inflammation
• Amyloid angiopathy
• Vasculitis
• Genetic (Col4A1, CADASIL,…)
• Mycotic aneurysm
Vascular Malformation Malignant disease
• Arteriovenous malformation • Brain tumor
• Cavernous malformation • Cerebral metastasis
Intracranial aneurysm Coagulopathy
Venous disease • Genetic
• Cerebral sinus / venous thrombosis • Acquired / iatrogenic
• Dural arteriovenous fistula Vasoactive drugs

Reversible cerebral Hemorrhagic Infarction


vasoconstriction syndrome Trauma
Al Shahi Salman R, Labovitz DL, Stapf C. Br Med J 2009; 339:b2586
Intracerebral Hemorrhage
Etiological subgroups
Small vessel disease Moyamoya syndrome /
disease
• Arteriolosclerosis / lipohyalinosis
Inflammation
• Amyloid angiopathy
• Vasculitis
• Genetic (Col4A1, CADASIL,…)
• Mycotic aneurysm

!
Vascular Malformation Malignant disease
• Arteriovenous malformation • Brain tumor
• Cavernous malformation • Cerebral metastasis
Intracranial aneurysm Coagulopathy
Venous disease • Genetic
• Cerebral sinus / venous thrombosis • Acquired / iatrogenic
• Dural arteriovenous fistula Vasoactive drugs

Reversible cerebral Hemorrhagic Infarction


vasoconstriction syndrome Trauma
Al Shahi Salman R, Labovitz DL, Stapf C. Br Med J 2009; 339:b2586
Intracerebral Hemorrhage
Diagnostic Work-up
Intracerebral Hemorrhage
Diagnostic Work-up
CT scan

CT angio

MRI/MRA

Angiogram
Intracerebral Hemorrhage
Diagnostic Work-up
CT scan Hem detection ICH, SAH, IVH
Acute f-up Volume

CT angio Arterial/venous find: Aneurysm, spot sign


search: AVM, sinus thrombosis
MRI/MRA Hem detection find: SWD, ven. thrombosis,
hem infarction, CCM
search: AVM, DAVF, RCVS,
moya, aneurysm
Angiogram Vascular imaging find: Aneurysm, AVM,
DAVF, moya, RCVS
search: Vasculitis
Biopsy Brain/meninges find: Vasculitis, tumor, CAA
Intracerebral Hemorrhage
Diagnostic Work-up
CT scan N=152 prospective patients
N=67 (44%) women
Mean age: 63 years (SD +/-12)
CT angio

MRI/MRA

Angiogram
Intracerebral Hemorrhage
Diagnostic Work-up
CT scan N=152 prospective patients
N=2 Small vessel disease
3%
N=2 Sinus thrombosis
CT angio N=73 Small vessel disease
N=9 Hemorrhagic infarcts
MRI/MRA N=4 Cavernous malformation
N=3 Acute RCVS
63%
N=3 Venous thrombosis
N=2 Brain tumor
Angiogram N=4 DAVF / AVM
N=2 Aneurysms
6%
21% acutely N=2 Moya-moya
treatment relevant N=1 Acute RCVS 72%
Intracerebral Hemorrhage
Diagnostic Work-up
CT scan Ancillary studies: normal
(blood lab, retina, LP, genetics, …)

CT angio
Repeat imaging after 3 - 4 months
MRI/MRA

Angiogram

imaging negative Diagnosis (?!)


Intracerebral Hemorrhage
2-step diagnosis

Initial MRI: cortical hematoma


Angiography: normal
Intracerebral Hemorrhage
Arteriovenous Malformation

3-month follow-up MRI: negative


3-month follow-up angiography showing L MCA AVM
Intracerebral Hemorrhage
Arteriovenous Malformation

Embolization: AVM occlusion


Intracerebral Hemorrhage
2-step diagnosis

♀ 37 years, left internuclear


ophtalmoplegia, ataxia,
dissociated sensory deficit
Intracerebral Hemorrhage
Cerebral Cavernous Malformation

T1 & gadolinium T2*


Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup

Every ICH has an underlying etiology


- Rule: there is only secondary ICH
- Avoid: “primary ICH”, “hypertensive ICH”, …
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup

Every ICH has an underlying etiology


Add imaging modalities until you visualize the
cause
- Brain imaging (CT, MRI)
- Vascular imaging (CT-A, MRA)
- Acute MRI/MRA soon to be diagnostic standard
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup

Every ICH has an underlying etiology


Add imaging modalities until you visualize the
cause
Some causes require acute treatment decisions
- Arterial disease: aneurysm, hem infarction, …
- Venous disease: thrombosis, DAVF, …
- Systemic disease: endocarditis, vasculitis, …
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup

Every ICH has an underlying etiology


Add imaging modalities until you visualize the
cause
Some causes require acute treatment decisions
All causes have long-term treatment implications
- Remove focal lesion, if possible: Aneurysm,
AVM, CCM, DAVF, …
- Treat risk factors (hypertension, smoking, …)
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup
Intracerebral Hemorrhage
Recent Developments: Diagnostic Workup
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Etiological subgroups = Therapeutic Subgroups
Small vessel disease Moyamoya syndrome /
disease
• Arteriolosclerosis / lipohyalinosis
Inflammation
• Amyloid angiopathy
• Vasculitis
• Genetic (Col4A1, CADASIL,…)
• Mycotic aneurysm
Vascular Malformation Malignant disease
• Arteriovenous malformation • Brain tumor
• Cavernous malformation • Cerebral metastasis
Intracranial aneurysm Coagulopathy
Venous disease • Genetic
• Cerebral sinus / venous thrombosis • Acquired / iatrogenic
• Dural arteriovenous fistula Vasoactive drugs

Reversible cerebral Hemorrhagic Infarction


vasoconstriction syndrome Trauma
Al Shahi Salman R, Labovitz DL, Stapf C. Br Med J 2009; 339:b2586
Intracerebral Hemorrhage
Etiological subgroups = Therapeutic Subgroups
Small vessel disease Moyamoya syndrome /
disease
• Arteriolosclerosis / lipohyalinosis
Inflammation
• Amyloid angiopathy
• Vasculitis
• Genetic (Col4A1, CADASIL,…)
• Mycotic aneurysm
Vascular Malformation Malignant disease
• Arteriovenous malformation • Brain tumor
• Cavernous malformation • Cerebral metastasis
Intracranial aneurysm Coagulopathy
Venous disease • Genetic
• Cerebral sinus / venous thrombosis • Acquired / iatrogenic
• Dural arteriovenous fistula Vasoactive drugs

Reversible cerebral Hemorrhagic Infarction


vasoconstriction syndrome Trauma
Al Shahi Salman R, Labovitz DL, Stapf C. Br Med J 2009; 339:b2586
Acute intracerebral hemorrhage
Acquired small vessel disease
Acute intracerebral hemorrhage
Acquired small vessel disease

Progression Volume increase (mass effect)


Ventricular extension
(24h) Hydrocephalus
Intracranial pressure
Brain stem compression
Acute intracerebral hemorrhage
Acquired small vessel disease

Brain CT (with contrast):

Brain CT Angio-CT Post contrast CT 6h control CT

« Spot – Sign »
Wada R, et al. Stroke 2007;38:1257-1262
Acute intracerebral hemorrhage
Acquired small vessel disease

Prospective, multicenter
N=268, age >18
ICH < 6hrs, <100ml
Spot-sign positive:
N=61 (23%)
Acute intracerebral hemorrhage
Acquired small vessel disease
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes
• Vessel wall rupture
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes
• Vessel wall rupture
• Extravasation
• Hematoma growth
• Tamponating effect
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture
• Extravasation
• Hematoma growth
• Tamponating effect
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture Chapman N, et al. Stroke 2004;35:116-121

BP lowering by 80% less


10 mmHg systolic  ICH
5 mmHg diastolic over 5 years!
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture
• Extravasation Local Hemostasis
• Hematoma growth
Acute intracerebral hemorrhage
Acquired small vessel disease

N=841 patients
<4h after onset

Primary Endpointt:
Rankin 5 or 6
Follow-up: 30 days
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture Local Hemostasis
• Extravasation  Factor VIIa: no benefit!
• Hematoma growth
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture Local Hemostasis
• Extravasation  - STOP-IT (USA)
• Hematoma growth - SPOTLIGHT (CA)
- TICH (UK) - STOP-AUST (AU)
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture
• Extravasation  Local Hemostasis
• Hematoma growth  Surgical evacuation
Acute intracerebral hemorrhage
Surgical Evacuation

Cerebellar Hematoma
Acute intracerebral hemorrhage
Surgical Evacuation

Cerebellar Hematoma
Acute intracerebral hemorrhage
Surgical Evacuation

Cerebral Hematoma
Acute intracerebral hemorrhage
Surgical Evacuation

N=1033 patients
Supratentorial hemorrhage <72h
Surgical evacuation versus non invasive management
Surgery < 24h post randomisation
Acute intracerebral hemorrhage
Surgical Evacuation
Primary endpoint:
Glasgow Outcome
Scale
Follow-up : 6 months
Acute intracerebral hemorrhage
Surgical Evacuation
Inclusion:
n=597
Lobar ICH (CT)
AND </=1cm from cortical surface
AND volume: 10-100 ml

Comparison:
Early surgery (evacuation <12h) versus initial
conservative management

But: 25% crossover


46% randomized >21h
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture
• Extravasation  Local Hemostasis
• Hematoma growth  Surgical intervention
MISTIE, SWITCH, …
Acute intracerebral hemorrhage
Acquired small vessel disease

Lenticulostriate artery

• Degenerative changes  Risk Factor Control


• Vessel wall rupture
• Extravasation  Local Hemostasis
• Hematoma growth  Acute blood pressure
• Tamponating effect lowering therapy
Acute intracerebral hemorrhage
Acquired small vessel disease

High arterial BP Low arterial BP

!
Management of Hypertension in Acute Stroke
Once upon a time…
Management of Hypertension in Acute Stroke
Once upon a time…
Zhang et al. J Hypertension 2008; 26: 1446-52.
6 hospital registries: Mongolia, China, 2003-2005
Cerebral infarction (n=2178) Intracerebral hemorrhage (n=1760)
Management of Hypertension in Acute Stroke
Once upon a time…
Management of Hypertension in Acute Stroke
A complex relationship...

Distribution of syst BP before and immediately after stroke (n=636, OXVASC)

Fischer U et al Lancet Neurology 2014;13:374-384


Management of Hypertension in Acute Stroke
A complex relationship...

Distribution of maximum syst BP before and 3h after stroke (n=636, OXVASC)

Fischer U et al Lancet Neurology 2014;13:374-384


Feasibility, efficacy, safety
Acute intracerebral hemorrhage
INTERACT Pilot Trial
Relative hematoma growth

Time from onset Relative growth P for


Reduction
Favors Favors
In
to treatment Intensive Guideline trend
intensive guideline volume

<2.9h -10% 10% 21% 0.02

2.9-3.6h 16% 31% 15%

3.7-4.8h -6% 1% 7%

≥4.9h 19% 22% 4%

30 20 10 0 -10
Reduction in hematoma growth over 72h (%)

Anderson C, et al. INTERACT Lancet Neurol 2008;7:391-399


Acute intracerebral hemorrhage
Blood pressure therapy

‘The pressure is now back to normal…’


Acute intracerebral hemorrhage
INTERACT 2
Acute intracerebral hemorrhage
INTERACT 2

Acute spontaneous ICH


onset < 6 hours
SBP ≥150 and ≤220 mmHg
No definite indications or contraindications to treatment
Able to be actively managed
Non comatous, no emergency evacuation

R
Standard Standard BP management Intensive BP lowering
best
practice AHA/EUSI Guideline-based Target systolic BP 140 mmHg
& (treatment if systolic BP >180 mmHg) within 1 hour and for 24+ hrs
stroke unit
care

Repeat CT scans at 24 hrs in selected sites


Vital signs and BP over 7 days
28 day and 90 day month follow-up
Acute intracerebral hemorrhage
INTERACT 2 vs. published trials

Trial Date Duration Centres Sponsor Patients Average Average


(months) recruitment recruitment
rate per by site
month
STICH2 2007-2012 67 129 MRC 601 9 5

INTERACT2 2008-2012 47 144 NHMRC 2839 60 20

INTERACT1 2005-2007 18 44 NHMRC 404 22 9

STICH 1995-2003 156 107 MRC 1033 7 10

FAST 2005-2007 40 122 NovoNordisk 841 21 7

CHANT 2003-2005 29 133 AstraZeneca 607 21 5

NovoSeven 2002-2004 20 73 NovoNordisk 399 20 6


Acute intracerebral hemorrhage
INTERACT 2 recruitment

Europe (64 sites)


Germany (9 sites)
Austria (3 sites)
Belgium (3 sites)
Spain (3 sites)
Finland (1 site)
France (13 sites)
Italia (5 sites)
Norway (3 sites)
US (1 site) Netherlands (1 site)
Portugal (2 sites)
UK (20) China (47 sites)
Switzerland (1)
Pakistan (1 site)

India (9 sites)

Brazil (5 sites)
Australia (10 sites)

Chile (5 sites)
Argentina (2 sites)
Acute intracerebral hemorrhage
INTERACT 2 recruitment
• 2839 patients between Octobre 2008 et August 2012
Acute intracerebral hemorrhage
INTERACT 2 recruitment

1926
Patient Flow – 2839 patients recruited October
2008 to August 2012
28,829 Total estimated screened Reasons for exclusion (n=3572)
39% Outside time window
16% Judged unlikely to benefit
6411 Screening logs completed 11% BP outside criteria
8% Planned early surgery
5% Refused
2839 Randomised 21% Other reasons

1403 Intensive BP lowering 1436 Standard BP lowering

3 no consent 5 no consent
1 missing baseline data 1 missing baseline data
2 lost to follow-up 5 lost to follow-up
3 withdrew consent 4 withdrew consent
12 alive without mRS data 9 alive without mRS data

1382 (98.5%) for primary outcome 1412 (98.3%) for primary outcome
INTERACT 2
Baseline variables
Intensive Standard
Variable
(N=1399) (N=1430)
Time to randomisation, mean(SD) 3.8(1.2) 3.8(1.2)
Age, mean(SD), yr 63(13) 64 (13)
Male 64% 62%
Chinese 68% 68%
BP (mmHg) 179/101 179/101
History of hypertension 72% 73%
NIHSS median (iqr) score 10 (6-15) 11 (6-16)
GCS median (iqr) score 14 (12-15) 14 (12-15)
ICH volume median (iqr) mL 11 (6-19) 11 (6-20)
Deep location 83% 83%
Intraventricular extension 29% 28%
*all non-significant
INTERACT 2
Systolic BP control, median time (iqr) to treatment
Intensive group to target (<140mmHg) Systolic BP time trends
462 (33%) at 1 hour 1 hour - Δ14 mmHg (P<0.0001)
200 731 (53%) at 6 hours 6 hour - Δ14 mmHg (P<0.0001)
Mean Systolic Blood Pressure (mm Hg)

190 Standard
Intensive
180

170
164
160
153
150 150

140
Target level 139
130

120

110 P<0.0001
beyond 15mins
0 // //
am pm am pm am pm am pm am pm am pm
R 15 30 45 60 6 12 18 24 2 3 4 5 6 7
Minutes Hours Days / Time
Intensive Standard
Variable (N=1399) (N=1430)
Any intravenous treatment 90% 43%*
Combination bolus + infusion 30% 18%*
Multiple agents 26% 8%*
*P<0.001

80%

%
INTERACT 2
Death or major disability (mRS 3-6) at 90 days
Odds ratio 0.87 (95%CI 0.75 to 1.01) P=0.06

60 55.6%
52.0%
50

40 Major Among survivors


Odds Ratio 0.85
% 40,0
Disability 43,6 (95%IC 0.73-0.99)
30 (mRS 3-5) P=0.049

20

10
12.0 Death 12,0
0
Intensive Standard
(N=1399) (N=1430)
INTERACT 2
Ordinal shift in mRS scores (0-6) at 90 days

Odds ratio 0.87 (95%CI 0.77 to 1.00); P=0.04

0 1 2 3 4 5 6

\
Intensive 8.1% 21.1% 18.7% 15.9% 18.1% 6.0% 12.0%

Standard 7.6% 18.0% 18.8% 16.6% 19.0% 8.0% 12.0%

Disability but independent Major disability Death


INTERACT 2
Health-related Quality of Life (EuroQoL EQ-5D)
% with problems
P=0.13 P=0.01

Health utility - 0.6 intensive vs 0.55 standard groups; P=0.002


INTERACT 2
Safety: cause-specific morbidity, n (%)
Intensive Standard
Serious Adverse Event (N=1399) (N=1430) P
Direct effects of primary ICH event 47 (3.4) 55 (3.8) 0.49
Cardiovascular disease 37 (2.6) 41 (2.9) 0.72
ICH 4 (0.3) 4 (0.3)
Ischaemic/undifferentiated stroke 8 (0.6) 8 (0.6)
Acute MI/coronary event/other 5 (0.4) 5 (0.3)
Other vascular disease 13 (0.9) 14 (1.0)
Other cardiac disease 9 (0.6) 12 (0.8)
Non-cardiovascular disease 160 (11.4) 152 (10.6) 0.49
Renal failure 5 (0.4) 7 (0.5)
Severe hypotension 7 (0.5) 8 (0.6) 0.83
Respiratory infections 48 (3.4) 53 (3.7)
Sepsis (includes other infections) 21 (1.5) 20 (1.4)
Non-vascular medical /injury 132 (9.4) 125 (8.7)
128
Management of Hypertension in Acute ICH
Post hoc analysis: INTERACT2

Correlation between Hematoma Volume, Death and Disability (mRS>2)


100

90
Death or
80 Disability
Event rate (%)

70

60

50

40 Death
30

20

10

0
0 10 20 30 40 50
Decile of ICH volume (ml)
Management of Hypertension in Acute ICH
Number of target systolic BP reached (<140mmHg)

Blood Pressure Variability and Outcome (mRS>2)

Manning et al Lancet Neurol 2014;13:364-373


Management of Hypertension in Acute ICH
Practical Implications
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- Predefined treatment protocol
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- Predefined treatment protocol
- IV line (continuous)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- Predefined treatment protocol
- IV line (continuous)
- BP monitoring (every 15min over 1h)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- Stroke alert: ‘thrombolysis’ type attitude
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- Stroke alert: ‘thrombolysis’ type attitude
- Avoid any delays (imaging  unit, iv line, …)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- Stroke alert: ‘thrombolysis’ type attitude
- Avoid any delays (imaging  unit, iv line, …)
- Team approach / training (Drs, nurses)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- SUSTAINED (>24h and beyond)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- SUSTAINED (>24h and beyond)
- Benefit for hyperacute (<24h) phase
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- SUSTAINED (>24h and beyond)
- Benefit for hyperacute (<24h) phase
- Benefit for postacute (<7 days) phase
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- SUSTAINED (>24h and beyond)
- Benefit for hyperacute (<24h) phase
- Benefit for postacute (<7 days) phase
- Long-term benefit (lifetime prevention)
Management of Hypertension in Acute ICH
Practical Implications

Acute BP lowering therapy is beneficial, if


- INTENSE (systolic target <140mmHg )
- FAST (<60 min)
- SUSTAINED (>24h and beyond)

Updated AHA/ASA Recommendations


- upcoming soon -
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Uncertainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Primary Hemorrhage Prevention by
Interventional Lesion Eradication

Proportion of unruptured or asymptomatic status


at diagnosis increases for:
• Arterial aneurysms
• Cerebral cavernous malformations (CCM)
• Arteriovenous malformations (AVM)
Primary Hemorrhage Prevention by
Interventional Lesion Eradication

Canada UK Russie
France
Australie
Chine
Suisse
Costa Rica
USA
Pays-Bas
Chili
Espagne
Italie Trial on endovascular Norvège
Allemagneaneurysm treatment Grèce
Hongrie République Tchèque
Turquie
Primary Hemorrhage Prevention by
Interventional Lesion Eradication

Proportion of unruptured or asymptomatic status


at diagnosis increases for:
• Arterial aneurysms
• Cerebral cavernous malformations (CCM)
• Arteriovenous malformations (AVM)
Primary Hemorrhage Prevention by
Interventional Lesion Eradication

Proportion of unruptured or asymptomatic status


at diagnosis increases for:
• Arterial aneurysms
• Cerebral cavernous malformations (CCM)  TRIAL?
• Arteriovenous malformations (AVM)
ClinicalTrials.gov identifier:
NCT00389181

www.arubastudy.org

A Randomized Trial of Unruptured Brain AVMs


ARUBA
• International • Prospective
– Americas • Internet-based
– Europe – Real time
– Australasia – Online Monitoring
• Multidisciplinary • Randomized
– Neurosurgery – 1:1
– Neuroradiology – 400 patients planned
– Radiotherapy* • NIH/NINDS
– Neurology – Funding
* Local or associated site – DSMB
ARUBA
• International • Prospective
– Americas • Internet-based
– Europe – Real time
– Australasia – Online Monitoring

Standard of care
Best possible AVM eradication
versus
Medical management alone
Experimental study arm
ARUBA
“As Randomized” Results (time to 1st stroke or death)

Risk reduction: 73%


ARUBA
“As Treated” analysis (time to 1st stroke or death)

Risk reduction: 81%


ARUBA
Results, n=223
Secondary outcome
Death or disability (mRS ≥2), 12 month
ARUBA
Results, n=223
Secondary outcome
Death or disability (mRS ≥2), 12 month

Rankin 0-1 Rankin 2-6*

*RR 0.4 (95% CI 0.1-0.8)


ARUBA
Results, n=223
Secondary outcome
Death or disability (mRS ≥2), 24 month

Rankin 0-1 Rankin 2-6*

*RR 0.2 (95% CI 0.1-0.6)


Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…


No standardized ICH diagnostic workup…
No specific ICH treatment…
Un- certainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…
Intracerebral Hemorrhage
Recent Developments

No dedicated ICH classification…!


No standardized ICH diagnostic workup…!
No specific ICH treatment…!
Un certainty regarding preventive
intervention for unruptured, hemorrhage-
prone lesions…!
Intracerebral Hemorrhage
Recent Developments