SỰ CẦN THIẾT PHÂN LOẠI CHẨN

ĐOÁN ĐỘT QUỴ NHỒI MÁU NÃO

CẬP NHẬT CÁC NGHIÊN CỨU MỚI

TỪ HỘI NGHỊ ĐỘT QUỴ HOA KỲ

& ĐỘT QUỴ CHÂU ÂU 2016

GS.TS Lê Văn Thính

BVBM-ĐHYHN

TS.BS Nguyễn Huy Thắng

BV115-TP HCM

STROKE CLASSIFICATION1

ENCHANTED2

ARUBA3

Outline

STROKE CLASSIFICATION

1.0 OCSP CLASIFICATION (BAMFORD)

TOAST CLASIFICATION

Phân Loại Đột Quỵ

4

Small vessel disease

Large artery disease

CÁC NGUYÊN NHÂN ĐỘT QUỴ

Cardioembolism

Stroke of undetermined etiology

30-40%

10-20%

30-40%

Uncommon cause of Stroke

Oxfordshire classification (OCSP)

Trial of Org 10172 in Acute Stroke

Treatment (TOAST)

6

Phân Loại Đột Quỵ Thiếu Máu

7

Toàn Bộ Tuần Hoàn Trước

Một phần Tuần Hoàn Trước

Tuần Hoàn Sau

Hội chứng NMN lổ khuyết

PHÂN LOẠI BAMFORD

8

9

Phân loại TOAST

10

Bệnh lý xơ vữa mạch máu lớn

Significant (>50%)

stenosis

Occlusion of a major

brain artery or

branch cortical

artery

Presumably due to

atherosclerosis

11

MFV 240cm/s

Thuyên tắc não do huyết khối từ tim

BN nữ, 37T, rung nhĩ, hẹp 2 lá

18

Atrial myxoma Thrombus of

the left ventricle

Small-artery occlusion (Lacune)

LS: H/c nhồi máu não lổ

khuyết, không có t/c vỏ não

T/C: Tiểu đường, THA

CT/MRI: bình thường, tổn

thương thân não hoặc

vùng dưới vỏ <1.5cm

Duplex/arteriography:

Không ghi nhận tắc hẹp

ĐM lớn ≥ 50%

Stroke of undetermined etiology

Các khảo sát cân lâm sàng không xác định

được nguyên nhân đột quỵ.

Chưa hoàn tất các khảo sát CLS

≥ 2 nguy cơ có thể là nguyên nhân của đột

quỵ

21

So Sánh 2 Phân Loại Đột Quỵ

25

MCA37%

ExCr ICA23%

BA9%

VA11%

InCr ICA7%

PCA7%

ACA6%

PROSAC

9 university hospitals

Using DWI and MRA

Throughout Korea

, 2008-2010

Distribution of symptomatic atherosclerotic

vascular lesions in 1,000 acute stroke patients

ICAS:ECAS = 7:3 Kim JS et al.

Stroke 2012

Risk factors – dyslipidemia, Mets

syndrome

Genes

Vascular tortuosity

Contamination

ICAS vs. ECAS

Limitations in resolution (often flow

dependent)

Artifact

Can not evaluate vessel wall

pathology

45-yr old man without risk factors -- Diagnosis ?

High resolution vessel wall MRI

Patients who visited AMC with

(1) unilateral MCA disease (≥50% stenosis or

occlusion), (2) were ≤55 years old and had no or

minimal (≤1) atherosclerotic risk factors (3)

suspected as having ICAS on MRA

We excluded patients with a confirmed diagnosis

HR-MRI performed

Ahn SH, Kim JS et al, Stroke 2015

Stroke mechanisms of ECAS

Mostly, artery to artery embolism

Vulnerable plaque, platelet aggregation

Inflammation

& Hemodynamic- not major stroke

Platelet aggregation ++

Perforator (branch)

occlusion

Artery to artery

embolism

Mechanisms of stroke in ICAS

In situ

Thrombotic

occlusion

Platelet aggregation ++

Kết Luận

•Trong chẩn đoán ĐQ, việc phân loại ĐQ là

rất quan trọng và cần thiết.

•Từ phân loại ĐQ, thầy thuốc có thể xác

định nguyên nhân và cơ chế của ĐQ, trên

cơ sở đó sẽ có lựa chọn điều trị thích hợp.

ENCHANTED

2.0Answer reliably efficacy and safety questions in acute IS

Compared to standard-dose (0.9 mg/kg) rtPA,

low-dose (0.6 mg/kg) i.v. rtPA

Proven medical reperfusion treatment for acute

ischaemic stroke within 4.5 hours of symptom onset,

butrisk of symptomatic intracerebral haemorrhage (ICH)

risk of early death

• Most regulatory authorities - approved dose 0.9mg/kg

• Japan approval - lower dose (0.6mg/kg)

• Variable dose in Asia – related to patient affordability

and clinician concern over ICH risk

37

Background – intravenous alteplaserecombinant tissue plasminogen activator - rtPA

38

Hypotheses - compared to standard-dose (0.9

mg/kg) rtPA, low-dose (0.6 mg/kg) i.v. rtPA is：

1. ‘non-inferior’ - clinical outcome (mRS 2-6) at 90-

days

2. safer - lower risk of major sICH?

Compared to guideline recommended BP control

(<185 mmHg systolic target before initiation of

rtPA),

is rapid intensive BP lowering (130-140 mmHg

SBP target):

3. superior - clinical outcomes (mRS 2-6) at 90-days

Dual aims: to answer reliably efficacy and

safety questions in acute ischaemic stroke

ENCHANTED clinical network

Australia (4 sites)

Chile (4 sites)

China (27 sites) + Hong Kong (1 site)

Brazil (6 sites)

United Kingdom (26 sites)

39

Colombia (2 sites)

Norway (1 site)

Italy (3 sites)

Vietnam (6 sites)

Taiwan (8 sites)

Thailand (1 site)

S Korea (12 sites)

Singapore (1 site)

In thrombolysis-eligible patients with acute ischaemic

stroke, lower dose (0.6mg/kg) dose rtPA :

• Not shown to be noninferior to standard-dose (0.9

mg/kg) for primary outcome (conventional binary 0-1 vs 2-6

mRS)

• Shown to be noninferior to standard-dose (0.9mg/kg) with

respect to global functional outcome (shift on mRS)

• Comparable EQ-5D and all other clinical measures

• Caused fewer deaths, less ICH, and less fatal ICH

• Consistency of findings in all pre-specified subgroups

40

Major findings of ENCHANTED

In thrombolysis-eligible acute ischaemic stroke

patients, low-dose rtPA:

• Is safer - fewer symptomatic or fatal ICH, and fewer

deaths

• Is non-inferior (ie equally effective) for global functional

recovery (shift), both ITT and PP

Low-dose alteplase to be seriously considered for all

patients with acute ischaemic stroke considered at high

risk of ICH, regardless of age, ethnicity and severity

41

Implications for Clinicians

3.0Compare best possible AVM eradication

vs Medical management alone

A Randomized trial of Unruptured Brain AVMsFive-year Results

43

•BN nữ, 35 tuổi, nhập viện vì co giật.

•Được chẩn đoán AVM 3cm vùng đính P, “có

nguy cơ vỡ rất cao”.

•Được can thiệp “thành công” bằng kỹ thuật

can thiệp nội mạch

Author | 00 Month Year44

A Randomized trial of Unruptured Brain AVMsFive-year Results

Stapf C1,2,3 Overbey JR4 Mohr JP1 Moskowitz AJ4 Vicaut E2 Parides MK4

for the international ARUBA Investigators

1 Stroke Center, Columbia University, New York, NY

2 Univ Paris Diderot – Sorbonne Paris Cité, Paris, France

3 CRCHUM, Université de Montréal, Montreal, QC, Canada

4 InCHOIR, lcahn Sch of Med at Mount Sinai, New York, NY

Christian Stapf, M.D.

Full Professor

Department of Neurosciences

Université de Montréal

Principal Scientist, CRCHUM

Attending Vascular Neurologist, CHUM

Brain Arteriovenous Malformations

Clinical issues:

• Hemorrhage

• Epilepsy

• Focal deficits

• Headaches

• Asymptomatic

Al-Shahi R & Stapf C, Practical Neurology, 2005

USA / Canada:

5000 new cases detected per year (mean age: 40 years)

3000 (60%) diagnosed unruptured

• Prospective

• Internet-based

– Real time

– Online Monitoring

• Randomized

– 1:1

– 400 patients planned

• NIH/NINDS

– Funding

– DSMB

• International

– Americas

– Europe

– Australasia

• Multidisciplinary

– Neurosurgery

– Neuroradiology

– Radiotherapy*

– Neurology

* Local or associated site

ARUBA

• International

– Americas

– Europe

– Australasia

• Prospective

• Internet-based

– Real time

– Online Monitoring

Standard of care

Best possible AVM eradication

versus

Medical management alone

Experimental study arm

ARUBA

Inclusion:

• Unruptured Brain AVM confirmed by MRI

• Age > 18 years

• Informed consent

Exclusion:

• Previous AVM hemorrhage

• Prior AVM treatment

• AVM considered untreatable for eradication

• …

ARUBA

Primary Endpoint:

Time to Death or Symptomatic Stroke

• Symptomatic Hemorrhage or Infarction

• CT / MRT

Secondary Endpoint:

Neurological Deficit

• Rankin Scale ≥ 2

• Status 5 years post randomization

ARUBA

Year 1 - 5 Year 6 - 10

20122007

n=226 55% mean follow-up 33·3 months

ARUBAA Randomized trial of Unruptured Brain AVMs

DSMB: April 15, 2013

Enrollment stopped!

Year 1 - 5 Year 6 - 10

20122007

n=226

n=110 Medical management

mean follow-up 50.4 months

n=116 Interventional treatment

ARUBAA Randomized trial of Unruptured Brain AVMs

2017

July 15, 2015

Data locked

ARUBAPatient baseline profiles (n=226 AVM patients)

ARUBA cohort

n=226

Demographics

Age (yrs), mean

Female gender

Clinical Presentation

Seizure

Asymptomatic

Mod. Rankin Score

mRS 0

mRS 1

44 (±12)

94 (42%)

97 (43%)

94 (42%)

108 (48%)

118 (52%)

Patient baseline profiles (n=226 AVM patients)

ARUBA

ARUBA cohort

n=226

Scotland1

n=204

Finland2

n=187

Demographics

Age (yrs), mean

Female gender

Clinical Presentation

Seizure

Asymptomatic

Mod. Rankin Score

mRS 0

mRS 1

44 (±12)

94 (42%)

47 (±16)

83 (41%)

36 (±15)*

80 (43%)

97 (43%)

94 (42%)

85 (42%)

101 (50%)

n.a.

n.a.

108 (48%)*

118 (52%)

26 (13%)

104 (51%)

n.a.

n.a.

1 Al-Shahi Salman R, et al. JAMA. 2014;311:1661-1669. 2 LaaksoA, et al. Neurosurgery. 2008;63:244-53.

* p<0.001

Patient baseline profiles (n=226 AVM patients)

ARUBA

ARUBA cohort

n=226

Scotland 1

n=204

Finland 2

n=187

AVM anatomy

bAVM size <3cm

Lobar location

Infratentorial location

Eloquent location

140 (62%) *

205 (91%)

13 (6%)

107 (47%)

95 (47%)

187 (92%)

7 (3%)

104 (51%)

41 (22%)

137 (73%) *

10 (5%)

n.a.

Spetzler-Martin I

Spetzler-Martin II

Spetzler-Martin III

Spetzler-Martin IV

Spetzler-Martin V

65 (29%) *

72 (32%) *

64 (29%)

23 (10%)

0

30 (15%)

51 (25%)

41 (20%)

18 (9%)

2 (1%)

13 (7%)

15 (27%)

61 (33%)

46 (25%) *

14 (8%) *

1 Al-Shahi Salman R, et al. JAMA. 2014;311:1661-1669. 2 LaaksoA, et al. Neurosurgery. 2008;63:244-53.

* p<0.001

Spetzler Martin Grading Scale

• Size of AVM

Small (<3 cm) 1

Medium (3-6 cm) 2

Large (>6 cm) 3

Location

Noneloquent site 0

1

Eloquent site*

Venouse drainage

Superficial 0

Deep 1

Primary outcome, n=226“As Randomized” (time to 1st stroke or death)

ARUBA

Primary outcome, n=226“As Randomized” (time to 1st stroke or death)

ARUBA

Primary outcome, n=226“As Randomized” (time to 1st stroke or death)

NNH: 5 (95% CI 3 - 13)

ARUBA

ARUBAOutcome per Randomization

(intention to treat)

Interventional Therapy

(N=116)

n %

41 35.3

Medical Management

(N=110)

n %

15 13.6

P Value

Symptomatic stroke or death <0.0001

Any incident stroke

Hemorrhagic

Ischemic

40

30

10

34.5 13

9

4

11.8 <0.0001

Any death

AVM-related

Not AVM-related

4

2

2

3.4 2

0

2

1.8 0.49

Outcome on Treatment **

(per protocol)

Interventional Therapy

(N=106)

n %

43 40.6

Medical Management

(N=120)

n %

13 10.8

P Value

Symptomatic stroke or death <0.0001

Any incident stroke

Hemorrhagic

Ischemic

42

29

13

39.6 11

10

1

9.2 <0.0001

Any death

AVM-related

Not AVM-related

4

2

2

3.8 2

0

2

1.7 0.33

** N=8 (3.5%) patients randomized to MM crossed over to IT.

N=15 (6.6%) patients randomized to IT never received therapy. N=3 suffered a stroke prior to the initiation of IT

ARUBAPrimary outcome, n=226

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

ARUBA

• Primary outcome, n=226

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

• NNH: 3 (95% CI 2 - 6)

ARUBASecondary Outcome

Death or disability (mRS ≥2) at 5 years

ARUBASecondary Outcome

Death or disability (mRS ≥2) at 5 years

ARUBASecondary Outcome

Death or disability (mRS ≥2) at 5 years

38%

18%

ARUBASecondary Outcome

Death or disability (mRS ≥2) at 5 years

38%

18%

40%

17%

ARUBAHarm, n=226

Serious Adverse Events (as randomized)Event Type Interventional

(n=116)

Medical

(n=110)

p

N Rate per N Rate per

Events pat/year Events pat/year

Stroke

Any 52 11.0945 16 3.3338 <0.001

Hemorrhagic 39 8.3209 11 2.2920 <0.001

Ischemic 13 2.7736 5 1.0418 0.054

Focal Deficit*

Any 20 4.2671 3 0.6251 <0.001

Persistent 7 1.4935 1 0.2084 0.032

Reversible 13 2.7736 2 0.4167 0.004

Epileptic seizures 95 20.2688 68 14.1686 0.023

Headache episode 116 24.7493 111 23.1282 0.609

* unrelated to stroke, epilepsy

Primary outcome subgroup analyses (as randomized)

Medical management better Preventive intervention better

Primary outcome subgroup analyses (as randomized)

Medical management better Preventive intervention better

ARUBASecondary analyses: outcome by treatment modality

* Primary endpoint: Symptomatic stroke or death

** DocumentedAVM removal required cerebral angiography by study protocol. For n=16 (15%) patients, the

AVM status was unknown, n=43 (41%) had a documentedAVM remnant on last follow-up imaging.

Interventional treatment received

n=106 patients

Primary endpoint*

n (row %)

Documented AVM obliteration**

n (row %)

Cumulative treatment modalities

Any endovascular (n=66) 33 (50.0) 34 (51.5)

Any surgery (n=22) 9 (41.0) 21 (95.5)

Any radiotherapy (n=57) 21 (36.8) 12 (21.1)

ARUBASecondary analyses: outcome by treatment modality

** DocumentedAVM removal required cerebral angiography by study protocol. For n=16 (15%) patients, the

AVM status was unknown, n=43 (41%) had a documentedAVM remnant on last follow-up imaging.

Interventional treatment received

n=106 patients

Primary endpoint

n (row %)

Documented AVM obliteration**

n (row %)

Cumulative treatment modalities

Any endovascular (n=66) 33 (50.0) 34 (51.5)

Any surgery (n=22) 9 (41.0) 21 (95.5)

Any radiotherapy (n=57) 21 (36.8) 12 (21.1)

Monomodal treatment (n=68)

Endovascular (n=28) 14 (50.0) 14 (50.0)

Surgery (n=7) 2 (28.6) 7 (100.0)

Radiotherapy (n=33) 8 (24.2) 6 (18.2)

Multimodal treatment (n=38)

Endovascular and Surgery (n=14) 6 (42.9) 14 (100.0)

Endovascular and Radiotherapy (n=23) 12 (52.2) 6 (26.1)

Endovascular and Surgery and Radiothx (n=1) 1 (100.0) 0 (0.0)

ARUBA• First pragmatic management trial in patients diagnosed with

an unruptured brain AVM

• Data based on a representative study cohort.

• Bias (if any) favoring intervention.

ARUBALessons learnt:

1.Patients with unruptured brain AVMs are at risk for

stroke. Spontaneous annual hemorrhage rate: 2.1%

(95% CI: 1.0-3.9)

2.The risk increases with the initiation of interventional

therapy:

• Risk of death and stroke: by factor 4.5

• Risk of functional deficits : by factor 2.5

• No benefit for: Epilepsy, headaches

3.High risk across all treatment modalities and AVM

subgroups

ARUBA

• Largest effect ever seen in a primary stroke

prevention trial: Risk reduction of 78% (for stroke

and death)

• Treatment of choice available world-wide at low-cost

• Trial results should be systematically disclosed to

patients

ARUBA• Largest effect ever seen in a primary stroke prevention trial:

Risk reduction of 78% (for stroke and death)

• Treatment of choice available world-wide at low-cost

• Trial results should be systematically disclosed to patients

Conclusion:

• Based on current knowledge, preventive interventions for

unruptured AVMs

• may be dangerous: NNH = 5 (over 5 years)

• cannot be safely recommended

• should only be offered as part of a controlled clinical study

ARUBA• Largest effect ever seen in a primary stroke prevention trial:

Risk reduction of 78% (for stroke and death)

• Treatment of choice available world-wide at low-cost

• Trial results should be systematically disclosed to patients

Conclusion:

• Based on current knowledge, preventive interventions for

unruptured AVMs

• may be dangerous: NNH = 5 (over 5 years)

• cannot be safely recommended

• should only be offered as part of a controlled clinical study

.

Standard dose IV thrombolysis is still recommended for Asian stroke patients. Low-dose alteplase to be considered for all patients with acute ischaemic stroke considered at high risk of ICH

1

For unruptured AVMs, just do LESS for …

MUCH MORE2

Conclusion

“WITHOUT HEALTH,

THERE IS NO

HAPPINESS”

THOMAS JEFFERSON

THANK YOU FOR YOUR

ATTENTION !