Recent Developments in The Acute Treatment of Intracerebral Hemorrhage

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
Recent Developments
The new
generation
is coming…
Recent Developments
…
Recent Developments
No dedicated ICH classification…

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

prone lesions…
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
Classification
Ischemic stroke
Hemorrhagic stroke
By location:
• Lobar / deep
By etiology:
Deep versus lobar
Deep versus lobar
78-year old man
Arterial hypertension
Dyslipidemia
Alcohol abuse
Sudden onset left
hemiparesis
Deep versus lobar
Hemorrhagic infarction
Deep versus lobar
72-year old man
Former smoker
Cognitive decline
Sudden onset aphasia
Dural arteriovenous fistula
Dural arteriovenous fistula
Classification
Ischemic stroke
Hemorrhagic stroke
By location:
• Lobar / deep
By etiology:
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
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
Classification
Cigarette smoking
Carotid Brain
Stenosis Infarction
embolism
Tabacco infarct…
Primary infarct…
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…
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…
Classification
Risk Factors
Underlying Brain
Cause Hemorrhage
Do not use:
Primary ICH
Hypertensive Hemorrhage
Classification
Cordonnier C, Al Shahi Salman R, Henon H, von Kummer R, Leys D, Stapf C (in preparation)
Recent Developments

prone lesions…
Diagnosis
3 countries
F, NL, UK
3 disciplines
NR°, NS, NRO
3 methods
CT, MRI, A°
Stroke 2010;41;685-690
Diagnosis
3 countries
F, NL, UK
3 disciplines
NR°, NS, NRO
3 methods
CT, MRI, A°
Stroke 2010;41;685-690
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
Active smoker
Sudden onset headache
followed by coma
Aneurysm Rupture
58-year old man
Aterial hypertension
Feeling sick >1 week
Admitted: acute confusion
Temp 38,2°C
CRP 125 mg/dl
Cardiac murmur
Endocarditis & mycotic aneurysms
Endocarditis & mycotic aneurysms
Therapeutic Emergency
1) Antibiotics
2) Embolization
3) Valve replacement
42-year old woman
Thunderclap headache
related to sexual activity
Improving after 2 hours
CT: normal
Day 1
LP: normal
MRI: normal
MRA: normal
Reversible Cerebral Vasoconstriction Syndrome
Day 1 Day 8
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

Risik:
• Women
• Migraine history
Ducros A (2010) Stroke

Ducros A (2007) Brain 130:3091
48-year old woman
Cigarette smoking
Hormonal contraception
Unusual headaches >2 days
Sec. generalized seizure
Persistent aphasia
Right homonymous hemianopia
MRV T2*
Cerebral venous thrombosis
HEPARIN!!
MRV T2*
Hemorrhagic Infarction
Miller-Fisher C, 2000
Miller-Fisher C, 2000
disease
Inflammation
• Vasculitis

disease
Inflammation
• Vasculitis
!

Diagnostic Work-up
Diagnostic Work-up
CT scan
CT angio
MRI/MRA
Angiogram
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
Diagnostic Work-up
CT scan N=152 prospective patients
N=67 (44%) women
Mean age: 63 years (SD +/-12)
CT angio
MRI/MRA
Angiogram
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%
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 (?!)

2-step diagnosis
Initial MRI: cortical hematoma

Angiography: normal
Arteriovenous Malformation
3-month follow-up MRI: negative

3-month follow-up angiography showing L MCA AVM
Arteriovenous Malformation
Embolization: AVM occlusion

2-step diagnosis
♀ 37 years, left internuclear

ophtalmoplegia, ataxia,
dissociated sensory deficit
Cerebral Cavernous Malformation
T1 & gadolinium T2*

Recent Developments: Diagnostic Workup
Every ICH has an underlying etiology

- Rule: there is only secondary ICH
- Avoid: “primary ICH”, “hypertensive ICH”, …

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

cause
Some causes require acute treatment decisions
- Arterial disease: aneurysm, hem infarction, …
- Venous disease: thrombosis, DAVF, …
- Systemic disease: endocarditis, vasculitis, …

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, …)
Recent Developments

prone lesions…
Etiological subgroups = Therapeutic Subgroups
disease
Inflammation
• Vasculitis

Etiological subgroups = Therapeutic Subgroups
disease
Inflammation
• Vasculitis

Acquired small vessel disease
Progression Volume increase (mass effect)

Ventricular extension
(24h) Hydrocephalus
Intracranial pressure
Brain stem compression
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
Prospective, multicenter
N=268, age >18
ICH < 6hrs, <100ml
Spot-sign positive:
N=61 (23%)
Lenticulostriate artery
• Degenerative changes
• Vessel wall rupture
• Extravasation
• Hematoma growth
• Tamponating effect
• Degenerative changes  Risk Factor Control

• Extravasation
• Hematoma growth
• Tamponating effect

• 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!

• Extravasation Local Hemostasis
• Hematoma growth
N=841 patients
<4h after onset
Primary Endpointt:
Rankin 5 or 6
Follow-up: 30 days

• Vessel wall rupture Local Hemostasis
• Extravasation  Factor VIIa: no benefit!
• Hematoma growth

• Vessel wall rupture Local Hemostasis
• Extravasation  - STOP-IT (USA)
• Hematoma growth - SPOTLIGHT (CA)
- TICH (UK) - STOP-AUST (AU)

• Extravasation  Local Hemostasis
• Hematoma growth  Surgical evacuation
Surgical Evacuation
Cerebellar Hematoma
Surgical Evacuation
Cerebellar Hematoma
Surgical Evacuation
Cerebral Hematoma
Surgical Evacuation
N=1033 patients
Supratentorial hemorrhage <72h
Surgical evacuation versus non invasive management
Surgery < 24h post randomisation
Surgical Evacuation
Primary endpoint:
Glasgow Outcome
Scale
Follow-up : 6 months
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

• Hematoma growth  Surgical intervention
MISTIE, SWITCH, …

• Hematoma growth  Acute blood pressure
• Tamponating effect lowering therapy
High arterial BP Low arterial BP
!
Management of Hypertension in Acute Stroke
Once upon a time…
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)
Once upon a time…
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

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
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

Blood pressure therapy
‘The pressure is now back to normal…’

INTERACT 2
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
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

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)
• 2839 patients between Octobre 2008 et August 2012
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)
Number of target systolic BP reached (<140mmHg)
Blood Pressure Variability and Outcome (mRS>2)
Manning et al Lancet Neurol 2014;13:364-373

Practical Implications
Acute BP lowering therapy is beneficial, if

- INTENSE (systolic target <140mmHg )

- Predefined treatment protocol

- IV line (continuous)

- IV line (continuous)
- BP monitoring (every 15min over 1h)

- FAST (<60 min)

- FAST (<60 min)
- Stroke alert: ‘thrombolysis’ type attitude

- FAST (<60 min)
- Avoid any delays (imaging  unit, iv line, …)

- FAST (<60 min)
- Avoid any delays (imaging  unit, iv line, …)
- Team approach / training (Drs, nurses)

- FAST (<60 min)
- SUSTAINED (>24h and beyond)

- FAST (<60 min)
- Benefit for hyperacute (<24h) phase

- FAST (<60 min)
- Benefit for postacute (<7 days) phase

- FAST (<60 min)
- Benefit for postacute (<7 days) phase
- Long-term benefit (lifetime prevention)

- FAST (<60 min)
Updated AHA/ASA Recommendations

- upcoming soon -
Recent Developments

prone lesions…
Recent Developments

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)
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

• Cerebral cavernous malformations (CCM)

• Cerebral cavernous malformations (CCM)  TRIAL?
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
Rankin 0-1 Rankin 2-6*
*RR 0.4 (95% CI 0.1-0.8)

ARUBA
Results, n=223
Secondary outcome
Rankin 0-1 Rankin 2-6*
*RR 0.2 (95% CI 0.1-0.6)

Recent Developments

Un- certainty regarding preventive
prone lesions…
Recent Developments
No dedicated ICH classification…!

No standardized ICH diagnostic workup…!
No specific ICH treatment…!
Un certainty regarding preventive
prone lesions…!
Recent Developments

Recent Developments in The Acute Treatment of Intracerebral Hemorrhage

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Recent Developments in The Acute Treatment of Intracerebral Hemorrhage

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Recent Developments in the

Acute Treatment of Intracerebral Hemorrhage

Adj. Assist. Professor of Neurology

New York City

No dedicated ICH classification…

No dedicated ICH classification…

No dedicated ICH classification…

Reversible cerebral Hemorrhagic Infarction

Ducros A (2007) Brain 130:3091

Ducros A (2010) Stroke

Reversible cerebral Hemorrhagic Infarction

Reversible cerebral Hemorrhagic Infarction

CT angio Arterial/venous find: Aneurysm, spot sign

imaging negative Diagnosis (?!)

Initial MRI: cortical hematoma

3-month follow-up MRI: negative

Embolization: AVM occlusion

♀ 37 years, left internuclear

T1 & gadolinium T2*

Every ICH has an underlying etiology

Every ICH has an underlying etiology

Every ICH has an underlying etiology

Every ICH has an underlying etiology

No dedicated ICH classification…

Reversible cerebral Hemorrhagic Infarction

Reversible cerebral Hemorrhagic Infarction

Progression Volume increase (mass effect)

Brain CT (with contrast):

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

• Degenerative changes  Risk Factor Control

• Degenerative changes  Risk Factor Control

BP lowering by 80% less

• Degenerative changes  Risk Factor Control

• Degenerative changes  Risk Factor Control

• Degenerative changes  Risk Factor Control

• Degenerative changes  Risk Factor Control

But: 25% crossover

• Degenerative changes  Risk Factor Control

• Degenerative changes  Risk Factor Control

High arterial BP Low arterial BP

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

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

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

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

Time from onset Relative growth P for

<2.9h -10% 10% 21% 0.02

2.9-3.6h 16% 31% 15%

≥4.9h 19% 22% 4%

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

‘The pressure is now back to normal…’

Acute spontaneous ICH

Repeat CT scans at 24 hrs in selected sites

Trial Date Duration Centres Sponsor Patients Average Average

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

Europe (64 sites)

1403 Intensive BP lowering 1436 Standard BP lowering

40 Major Among survivors

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