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New trend in acute ischemic

stroke management

Jesada Keandoungchun, MD

Acute Stroke treatment base on level I evidence

Stroke units

ASA in 48 h

1993 1995 1997 2007 2008-18

IV rtPA in 3 h

IV rtPA in 4.5 h

Hemicraniectomy

1998

IA proUK in 6 h

2004 2005

CLOTBUST

MERCI in 8 h

PWI/DWI mismatch 2003 IVT +

Antiplatelets

Neuroprotection

Anticoagulant

IV/IA ++IV/IA

All stroke patients are potentially eligible

↓ 3% in mortality

↓ 5% in long term dependency

Benefits persists up to 10 y

Lancet 2004; 363: 834–5

Routine Care as Specialist

Stroke UnitIVT: Number needed to treat to excellent recovery (mRS 0, 1)

Hacke W et al. Lancet 2004;363:768-774.

Lees KR et al. Lancet 2010;375:1695-1703.

2.5 vs 3.2%; OR 23

1 vs 0.8%; OR 22

8.2 vs 9.1%; OR 11

ASA 160-300 mg in 48 h (IST, CAST, MAST-I)

Stroke 2000;31:1240-1249

3 days after onset

Early Hemicraniectomy in Malignant MCA infarct

Lancet Neurol 2007; 6: 215–22

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Acute Ischemic Stroke treatment: level I evidence

Stroke units

ASA in 48 h

1993 1995 1997 2007 2008-10

IV rtPA in 3 h

IV rtPA in 4.5 h

Hemicraniectomy

1998

IA proUK in 6 h

2004 2005

CLOTBUST

MERCI in 8 h

PWI/DWI mismatch 2003 IVT +

IV/IA ++IV/IA

Lancet 2008; 371: 1612–23

Acute Stroke treatment base on level I evidence

Stroke units

ASA in 48 h

1993 1995 1997 2007 2008-18

IV rtPA in 3 h

IV rtPA in 4.5 h

Hemicraniectomy

1998

IA proUK in 6 h

2004 2005

CLOTBUST

MERCI in 8 h

PWI/DWI mismatch 2003 IVT +

Antiplatelets

Neuroprotection

Anticoagulant

IV/IA ++IV/IA

Thailand: IV rtPA, Stroke unit

NEW TREND

Female 81 y present with quadriparesis, drowsy, ophthalmoparesis (NIHSS 24) 1 h and S/P CABG for 2 days.

Thrombolysis: postoperative stroke

Neurol Clin 2006; 24: 783-793

Major surgery within 14 days

INCLUSION criteria

• Age ≥ 18 years

• Onset < 4.5 hours

• Clinical diagnosis of ischemic stroke

EXCLUSION criteria

• SBP ≥ 185 or DBP ≥ 110 mmHg

• Symptoms rapidly improving or minor symptoms (NIHSS ≤ 4)

• Seizure with postictal deficit

• Plasma glucose < 50

• Arterial puncture at a noncompressible site or LP within 7 days

• Major surgery within 14 days

• GI hemorrhage or urinary tract hemorrhage within 21 days

• Stroke or head trauma or MI within 3 months

• Symptoms of SAH (diffuse headache, stiffness of neck)

• Previous intracranial hemorrhage

• If oral anticoagulant, INR >1.7, heparin in previous 48 h, aPTT > 40

• Platelet count < 100,000

• Intraaxial intracranial neoplasm

• IE, Aortic dissection

• CT show ICH, multilobar infarct (hypodensity > 1/3 cerebral hemisphere)

IV Thrombolysis eligible criteria3-4.5 h

Age ≤80 y

without DM + prior stroke

NIHSS ≤25

not taking any OACs

Conclusions: application of SMART criteria is safe and effective

Journal of Stroke and Cerebrovascular Diseases, 2016; 25 (5): 1110–1118

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Journal of Stroke 2015;17(2):123-126

Endovascular Therapy (EVT) in 6 hHighly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES)

collaboration RECANALIZATION REPERFUSION Recovery

Endovascular Therapy in 6 h

EVT with stent retriever (I, A) in

AIS receiving IV r-tPA in 4.5 h + ICA or M1-MCA (BA)

prestroke mRS 0 -1, age ≥18 y, NIHSS ≥6

ASPECTS ≥6

EVT (groin puncture) in 6 h TSS EVT guideline 2016

ASA Guidelines 2015Mean NIHSS: MR CLEAN 17: RAMA 18 (sICH 6%)

28.5

33

19

35.8

18

16

35.7

28

43

0

21

22

0% 20% 40% 60% 80% 100%

Ramathibodi

MR CLEAN

control

mRS 0-2 mRS 3 mRS 4-5 mRS 6

↑ 14%

Endovascular Therapy: ASA Guidelines 2015

EVT with stent retriever (I, A) in

AIS receiving IV r-tPA in 4.5 h

ICA or M1-MCA

prestroke mRS 0-1, age ≥18 y

NIHSS ≥6

ASPECTS ≥6

EVT (groin puncture) in 6 h

JAMA. 2016;316(12):1279-1288

Concept of acute stroke: Time is Brain

Minutes Hours

Every 1 minute delay in Supratentorial Stroke

“Death of 1.9 million neurons, 14 billion synapses, 12

km of myelinated fibers, accelerated aging 3.1 wk”

Stroke 2006; 37: 263-266

Infarct growth rates in patients with ICA or MCA occlusions: DEFUSE 2

Stroke. 2018; 49: 768-771

50%: slow growth: < 3 ml/h

30%: medium growth: 3-10 ml/h

20%: rapid growth: 15-100 ml/h

JNNP 2018; 0: 1–7

New trend in acute ischemic stroke management

Time base Tissue base

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CTP mismatch: CBF/TmaxThrombectomy 6 to 24 Hours after Stroke with a Mismatch

between Deficit and Infarct (DAWN trial)

• AIS 6-24 h (median 12 h), ICA or MCA-M1 occlusion + mismatch between clinical deficit & infarct volume

NEJM 2018;378:11-21

mRS 0-2: 49 vs 13%, posterior probability of superiority, >0.999

sICH: 6 vs 3%, P=0.50, Mortality 19 vs 18%, P=1.0

Thrombectomy for Stroke at 6 to 16 Hourswith Selection by Perfusion Imaging (DEFUSE 3 trial)

• AIS 6-16 h (median 12 h), ICA or MCA-M1 occlusion + perfusion mismatch

NEJM 2018;378:11-21

mRS 0-2: 45 vs 17%, OR 2.67 P<0.001

sICH: 7 vs 4%, P=0.75, Mortality 14 vs 26%, P=0.05

Intervent Neurol 2018;7:513–521

rCBF <0.3 143 Tmax>6s 422ml

M 70 y + Rt. anterior circulation infarct, NIHSS 19

NIHSS after EVT: 14, D5: 5; mRS 3M: 2

DAWN, DEFUSE 3-

IVT 4.5-9 h

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IVT 4.5-9 h or wake up stroke

• AIS 4.5-9 h or wake up (median 7 h) + perfusion mismatch

Lancet 2019 doi.org/10.1016/S0140-6736(19)31053-0

mRS 0-1: 36 vs 29%, P=0.01

sICH: 5 vs 0.5%, P=0.03, Mortality 14 vs 9%, P=0.19

Antiplatelets: single or combine; Anticoagulants: UFH, LMWH

Neuroprotection: Mg, Albumin, Membrane stabilizers, Statins,

Hypothermia, Hyperbaric Oxygen

↑ CBF: Volume expansion, Induced HT, EECP

Complications

• Progressive stroke: volume, BP, …

• Brain edema, HTF: ICP control, surgery

• Seizure: AED

• Infection: ↓ Temp, aspiration, DVT/PE: elastic stockings, …

BP if > 220/120 mmHg : ↓ 15% of BP except HT encephalopathy,

aortic dissection, acute renal failure, pulmonary edema, MI

• start antiHT medication at 24 h

BS: 80-140 mg/dL

Rehabilitation: 48 h after stable

New trend: other AIS management

Stroke 2007; 38; 1655-1711

CHANCE: Clopidogrel in High-Risk Patients with Acute

Nondisabling Cerebrovascular Events

• RCT: Clopidogrel 75 mg (300mg d1) + ASA 75-300mg for 21 days then Clopidogrel

vs ASA

• 5,170 AIS patients (age ≥40y): NIHSS≤3, TIA (ABCD2 ≥ 4) within 24 h; F/U 90 d

• BP < 160/100

1° outcome: stroke: 8.2 vs 11.7% (HR 0.68; 0.57-0.81)

2° outcome: severe bleeding: 0.2 vs 0.2% (HR 0.94; 0.24-3.79)

hemorrhagic stroke: 0.3 vs 0.3% (HR 1.01; 0.38-2.70)

• Chinese: CYP2C19 *2 50% *3 7% in Asian

• Traditional Chinese Medicine 24%N Engl J Med 2013;369:11-19

Circulation. 2015;132:40-46

1 year

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial

Clopidogrel 600mg day1 + ASA vs ASA (162 mg OD x 5 days then 50-325 mg 90 days)

AIS NIHSS≤3, TIA (ABCD2 ≥4) within 12 h; F/U 90 d

N Engl J Med 2018; 379:215-225

TARDIS: The Triple Antiplatelets For Reducing Dependency In Ischemic Stroke

PROBE: A+D+C vs ASA+Dypyridamole or Clopidogrel 1M

3096 AIS/TIA (NIHSS 2.8, ABCD2 >4) patients in 48 h; F/U 90 d

Early stop trial

Lancet. 2018;391: 850-859

6 vs 7%

20 vs 9%

Antiplatelet Treatment

1. Administration of aspirin is recommended in patients with AIS within 24 to 48

hours after onset. For those treated with IV alteplase, aspirin administration

is generally delayed until 24 hours later but might be considered in the

presence of concomitant conditions for which such treatment given in the

absence of IV alteplase is known to provide substantial benefit or

withholding such treatment is known to cause substantial risk.

2. Aspirin is not recommended as a substitute for acute stroke treatment in

patients who are otherwise eligible for IV alteplase or mechanical

thrombectomy.

3. In patients presenting with minor stroke, treatment for 21 days with dual

antiplatelet therapy (aspirin and clopidogrel) begun within 24 hours can be

beneficial for early secondary stroke prevention for a period of up to 90 days

from symptom onset.

4. Ticagrelor is not recommended (over aspirin) in the acute treatment of

patients with minor stroke.

I, A

III, B-R

IIa, B-R

III, B-R

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Antiplatelets: single or combine; Anticoagulants: UFH, LMWH

Neuroprotection: Mg, Albumin, Membrane stabilizers, Statins,

Hypothermia, Hyperbaric Oxygen

↑ CBF: Volume expansion, Induced HT, EECP

Complications

• Progressive stroke: volume, BP, …

• Brain edema, HTF: ICP control, surgery

• Seizure: AED

• Infection: ↓ Temp, aspiration, DVT/PE: elastic stockings, …

BP if > 220/120 mmHg : ↓ 15% of BP except HT encephalopathy,

aortic dissection, acute renal failure, pulmonary edema, MI

• start antiHT medication at 24 h

BS: 80-140 mg/dL

Rehabilitation: 48 h after stable

New trend: other AIS management

Stroke 2007; 38; 1655-1711

Therapeutic Induced Hypertension in Acute Stroke Patients with Non-CE Stroke: Multicenter, RCT (SETIN-HYPERTENSION)

ESOC 2018

Phenylephrine (0.12mg/ml) Start: 10cc/h

↑ 10cc/h q 30-60min, for SBP ↑ 10-25mmHg/h

Up to 160cc/h or SBP 200mmHg

Therapeutic Induced Hypertension in Acute Stroke Patients with Non-CE Stroke: Multicenter, RCT (SETIN-HYPERTENSION)

ESOC 2018

mRS 0-2: 75 vs 63.2%, P <0.05

sICH: 1.3 vs 0%, P=0.313, Mortality 1.3 vs 0%, P=0.313

An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischemic stroke up to 24 h from onset (ImpACT-24B)

• AIS without thrombolysis 8-24 h (median 16 h)

Lancet 2019 doi.org/10.1016/S0140-6736(19)31192-4

mRS 0-2: 44 vs 42%, P=0.31: cortical stroke: 35 vs 27%, P=0.06

sICH: 0.6 vs 1.3%, P=0.19, Mortality 14.2 vs 12.3%, P=0.38

An injectable implant to stimulate the sphenopalatine ganglion for treatment of acute ischemic stroke up to 24 h from onset (ImpACT-24B)

• AIS without thrombolysis 8-24 h (median 16 h)

Lancet 2019 doi.org/10.1016/S0140-6736(19)31192-4

mRS 0-2: 44 vs 42%, P=0.31: cortical stroke: 35 vs 27%, P=0.06

sICH: 0.6 vs 1.3%, P=0.19, Mortality 14.2 vs 12.3%, P=0.38

TOAST classification

Large artery atherosclerosis

Small vessel occlusion

Cardioembolism

Other determined etiology

Undetermined etiology

Lancet 1991; 22; 1521-6

Causes

New trend in 2° stroke prevention

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Caplan: Neurology 1989;39;1246

Small artery occlusion 46%

Large artery stenosis

Intracranial 36%

Extracranial 10%

Cardioembolic 8%

Arch Neurol. 2002; 59:259-263

Stroke mechanism: Lacunar Infarct Cerebral Angiography

Intracranial stenosis: vascular wall imaging

Stroke. 2014;45:2457-2460

7T MRI

NeuroImage 168 (2018) 452–458

Adapt from Frontiers in Neurology 2016; 37: 1-16

AF detection AAA

PFO, …

DVT leg/ pelvis

D-dimer, APS, …

Genetic testing- GLA gene analysis

(www.geneticrama.com)

- Prothrombin mutation

(FII20210G>A)

- FV Leiden

(FV1691G>A)

- MELAS 3243 A>G

- NOTCH3 gene

- RNA gene, …

CT chest, Abdomen

PET

Leptomeningeal Biopsy

Causes of Ischemic Stroke

The more you look, the more you find

Stroke. 2014;45:1186-1194

2nd stroke prevention based on level I evidence

†Calculations based on mean follow-up of 3.9 years in PROGRESS

(NNT=25) and median 4.9 years in SPARCL (NNT=45)

Lancet 2008; 371: 1612–23

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Carotid Endarterectomy (CEA) or Carotid artery stent (CAS)

↓ Stroke risk 26% 13% / 5 y (NASCET)

11.5 6% / 5 y (ACST, ACAS)

CEA vs CAS long term outcome

Intracranial stenting

If Fail medicationSAMMPRIS trial NEJM 2011;365:993-

1003

Anticoagulation in stroke patients + AF

Circulation. 2017;135:00–00. DOI: 10.1161/CIR.0000000000000477

Meta-analysis of RCT on NOACs vs warfarin for 2nd stroke prevention New trend in 1ᵒ, 2ᵒ Stroke Prevention

Modified Risk RR

HT (Target < 130mmHg

especially in lacunar

stroke)

8

DLP (/38.7mg/dL) 1.25

Smoking 1.9

DM 1.8-6.0

Atrial Fibrillation 4.0

Physical inactivity 2.7

Stroke. 2011;42:517-584http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.04.006

Only 50% of Thai stroke patients achieve BP target: inadequate anti-HT drugs; poor compliance

i-stroke J Stroke Cerebrovasc Dis. 2014;23(3):476-83

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Conclusion: new trend in acute ischemic stroke management

Acute Stroke treatment

• IVT < 4.5 4.5-9 h

• EVT up to 24 h or more

• Antiplatelets: ASA ASA + loading Clopidogrel

• Increase CBF: induce HT, …

2◦ stroke prevention

• Antiplatelets: single or combined

• Anticoagulants: warfarin NOACs

• …

Primary prevention: BP target <130