therapy strategies, studies and guidelines - pedro vilela strategies... · 1strandomized trial...

16.10.2019

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Therapy strategies, studies and guidelinesPedro Vilela MD

Lisbon ‐ Portugal

Summary

Therapy strategies, studies and guidelines

• Lecture summary

• Introduction

• IntraVenous (IV) thrombolysis data

• Mechanical Thrombectomy (MT) data

• RCT and Open questions

• Conclusions

Introduction


• Current guidelines

2018 2019

Stroke, 2018 European Stroke Journal, 2019

Introduction


• Levels of evidence

Introduction


Acute ischemic stroke treatment: paradigm shift

• Until 2015 IV thrombolysis (rTPA) • Only “evidence‐based” treatment• Imaging main role: exclusion hemorrhage / …stroke mimics

• 2015 Paradigm shift IA thrombectomy (endovascular treatment EVT)

• New “evidence‐based” treatment• Rigorous patient selection: non‐invasive brain and vessel imaging• Better outcomes for worse cases

• Imaging roles: cornerstone for patient selection• Exclusion: hemorrhage / …stroke mimics

• Inclusion:• Infarct core: ASPECTS score; CT perfusion; MR‐ DWI• Salvageable tissue: CT perfusion; MR‐ DWI• Large vessel Occlusion

IV thrombolysis

IV thrombolysis trials


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• IV thrombolysis (rTPA)

• 1st line treatment for AIS

– 1995 ‐ National Institute of Neurological Disorders and Stroke (NINDS) trial ‐intravenous (IV) tPA was given within 3 hours of stroke symptoms

– 2008 ‐ European Cooperative Acute Stroke Study (ECASS III) trial ‐ intravenous (IV) tPAwas given within 4.5 hours of stroke symptoms

– IV rTPA

• NINDS ≤ 3h & ECASS III ≤ 4.5h after stroke onset

• No hemorrhage

Wahlgren et al. Lancet 2008;372:1303‐1309. Lees et al. Lancet 2010;375:1695‐1703.NINDS NIH website. Stroke proceedings. Latest update 2008 del Zoppo, Ann of Neurol 1992

2018: New trials … New challenges

IV Thrombolysis




• Drawbacks:

– Low rate of recanalization for proximal arterial (Large Vessel) occlusions

0%

50%

100%

ICA M1 M2 M3

9%

35%54%

66%

Wahlgren et al. Lancet 2008;372:1303‐1309. Lees et al. Lancet 2010;375:1695‐1703.NINDS NIH website. Stroke proceedings. Latest update 2008 del Zoppo, Ann of Neurol 1992


IV Thrombolysis

Need for more efficient recanalization treatment




• Drawbacks:– Only 2‐12% of AIS patients receive

IV thrombolysis with rt‐PA

• Only 11% of all thrombolysed AIS patients receive rt‐PA within 90 min of symptom onset

– Better clinical outcome reduces over time…

0.2 0.3 0.81.6

2.9

4.73.2

7.88.5

9.210.610.710.2

13.915.3

0

5

10

15

20

Arrival Time (min after symptoms onset)

90 180

Wahlgren et al. Lancet 2008;372:1303‐1309. Lees et al. Lancet 2010;375:1695‐1703.NINDS NIH website. Stroke proceedings. Latest update 2008 del Zoppo, Ann of Neurol 1992 Henke Lancet 2004


IV Thrombolysis



Wahlgren et al. Lancet 2008;372:1303‐1309. Lees et al. Lancet 2010;375:1695‐1703.NINDS NIH website. Stroke proceedings. Latest update 2008 del Zoppo, Ann of Neurol 1992 Henke Lancet 2004


IV Thrombolysis



• Wake‐up study (2018)


IV Thrombolysis

2018


Imaging: DWI_FLAIR mismatch

From: Vilela P, Rowley HA, Eur J Radiol 2017


• Wake‐up study (2018)

• Inclusion: • Patients with ischemic lesion on MRI‐DWI but no parenchymal hyperintensity on MRI‐

FLAIR indicates that the stroke occurred approximately within the previous 4.5 hours


IV Thrombolysis

• mRS 0‐2

• Altepase: 74%

• Placebo: 65%

2018


Imaging: DWI_FLAIR mismatch

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• Evolution of EVT (IA thrombolysis / thrombectomy):

Endovascular Approach

of the Stroke

IV and/or IA Thombolytic

Alteplase (rtPA),reteplase,

prourokinase, urokinase

PROACT II1998

Endovascular trea

tmen

t (EVT)

PROACT trial • intra‐arterial urokinase• within 6 hours of stroke symptom onset



Endovascular Approach

of the Stroke

IV and/or IA Thombolytic

Mechanical Methods

Alteplase (rtPA),reteplase,

prourokinase, urokinase

EndovascularBy-Pass

Intracranial stentEnterpriseWinspan

…

Proximal devices

ThromboaspirationPenumbra, Vasco ASPIAngioJET

Distal devices

MerciPhenoxCatch

In-TimeSnares

SolitaireTrevoReviveAperio

…

Stentrievers

PROACT II1998

Endovascular trea

tmen

t (EVT)


SYNTHESIS 2013IMS III 2013MR RESCUE 2013

TREVO 2 2012SWIFT 2012SYNTHESIS 2010

IAT MERCITREVOSOLITAIRE

ITATHROMBECTOMY

BREKENFELD 2010 TASCHNER 2011 BROUSSALIS 2012FESL 2012LEKER 2012MOHLENBRUCH 2012

SALLUSTIO 2013

GOBIN 2004

SMITH 2005

KIM 2006

DEVLIN 2007

BOSE 2008SMITH 2008

HALLEVI 2009GRUNWALD 2009LEE 2009STRUFFERT 2009MATTEWS 2009

ABOU‐CHEBL 2010CASTANO 2010KULCSAR 2010LOH 2010NAYAK 2010ROTH 2010TARR 2010

BRINJIKJI 2011COSTALAT 2011KANG 2011MENON 2011MITEFF 2011PARK 2011ROTH 2011STAMPFL 2011

CASTRO‐ALFONSO 2012COHEN 2012DAVALOS 2012DORN 2012GANDINI 2012KIM 2012MACHI 2012MPOTSARIS 2012PSYCHOGIOS 2012SAN ROMAN 2012

FREI 2013MORDASINI 2013

MERCI MERCIPENUMBRA

MERCIPENUMBRASOLITAIRE

PENUMBRASOLITAIRE

PENUMBRASOLITAIRETREVO



Endovascular trea

tmen

t (EVT)

Dark ages



– IMS III subgroup analysis: benefit in patient’s with Carotid T/L occlusions and tandem ICA and M1 occlusions on baseline CTA

– Other trials ongoing….

NEJM March 2013

Endovascular trea

tmen

t (EVT)


• MR RESCUE (2004 – 2011):– Treatment within 8 hours after stroke (standard care vs endovascular‐ IA

thrombolytics/Merci/Penumbra)

1st randomized trial testing the penumbra hypothesis

– Patients with penumbra had better outcome that patients without penumbra

– Endovascular treatment was not associated with better clinical outcome

Kidwell CS,et al. A trial of imaging selection and endovascular treatment for ischemic stroke. NE JM. 2013 Mar 7;368(10):914‐23.

Endovascular trea

tmen

t (EVT)


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• MR RESCUE (2004 – 2011):– Treatment within 8 hours after stroke (standard care vs endovascular‐ IA

thrombolytics/Merci/Penumbra)

1st randomized trial testing the penumbra hypothesis

– Patients with penumbra had better outcome that patients without penumbra

– Endovascular treatment was not associated with better clinical outcome

Kidwell CS,et al. A trial of imaging selection and endovascular treatment for ischemic stroke. NE JM. 2013 Mar 7;368(10):914‐23.

Endovascular trea

tment (EVT)


• Synthesis (2008 – 2012):

– Conclusion: endovascular (IA) therapy is not superior to standard IV thrombolysis in acute ischemic stroke within 5.5 hours from onset

Ciccone A, et al. Endovascular treatment for acute ischemic stroke. NEJM. 2013 Mar 7;368(10):904‐13 .

P< 0.001

Endovascular trea

tmen

t (EVT)


• Synthesis (2008 – 2012):

– Conclusion: endovascular (IA) therapy is not superior to standard IV thrombolysis in acute ischemic stroke within 5.5 hours from onset

Ciccone A, et al. Endovascular treatment for acute ischemic stroke. NEJM. 2013 Mar 7;368(10):904‐13 .

P< 0.001

Endovascular trea

tmen

t (EVT)


• IMS III (2006 – 2012):

– Adjunctive endovascular therapy did not show significant clinical benefit (functional independence mRS 0‐2) compared to IV rTPA alone

Broderick JP, et al. Endovascular therapy after intravenous t‐PA versus t‐PA alone for stroke. NEJM 2013 Mar 7;368(10):893‐903

mRS 0‐2 difference= 1.5%

mRS 0‐2 difference= ‐1%



Endovascular trea

tmen

t (EVT)


Arterial occlusion present in the initial CTA




• IMS III (2006 – 2012): subgroup analysis and secondary end points


– IA treatment showed higher recanalization rate on proximal arterial occlusions

– Trend to better 90 day mRS in patients with proximal arterial occlusion present in initial CTA treated with IA thrombectomy

Endovascular trea

tmen

t (EVT)


• IMS III (2006 – 2012): subgroup analysis and secondary end points


– Good clinical outcome following angiographic reperfusion with IA therapy is strongly time‐dependent.

– Every 30 minute delay in reperfusion is associated with a 10% relative reduction in probability of good clinical outcome (mRS 0‐2) ‐ Multivariable Model ‐

– Faster endovascular reperfusion in the IMS III trial may have yielded a positive result.

Endovascular trea

tmen

t (EVT)


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– IMS III subgroup analysis: benefit in patient’s with Carotid T/L occlusions and tandem ICA and M1 occlusions on baseline CTA

– Other trials ongoing….

NEJM March 2013

Endovascular trea

tmen

t (EVT)


Endovascular trea

tmen

t (EVT)

New hope for AIS treatment


Endovascular trea

tmen

t (EVT)

Positive Endovascular Treatment (EVT) Trials

from Neuronews@ https://neuronewsinternational.com/neuronews‐issue‐28‐us‐edition/

MR CLEANEXTEND IAESCAPESWIFT PRIMEREVASCAT

THRACE

DAWNDEFUSE 3


Endovascular trea

tmen

t (EVT)



Stroke treatment: Results

Meta‐analysis (HERMES STUDY)

Total: 1287 patients

90 days mRS 0‐2: good outcome

EVT: 46%

Control: 26.5 %

NNT 2.6

From: Goyal M et al, Lancet Neurology 2016

Endovascular trea

tmen

t (EVT)



NEJM January 4, 2018

DAWN: 6 ‐ 24h

• September 2014 through February 2017• 26 centers in the United States, Canada,

Europe, and Australia• 206 Patients: 107 to the EV group and 99

to the medical group

Endovascular trea

tmen

t (EVT)


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DEFUSE 3: 6 ‐ 16h

• May 2016 through May 2017• 38 centers in the United States• 182 Patients: 92 to the EV group and 90 to

the medical group

NEJM February 22, 2018NEJM January 4, 2018

DAWN: 6 ‐ 24h

• September 2014 through February 2017• 26 centers in the United States, Canada,

Europe, and Australia• 206 Patients: 107 to the EV group and 99

to the medical group

Endovascular trea

tmen

t (EVT)


• DEFUSE 3 – 6‐12 H

• TIME: 6 ‐12 H (last seen well)• NIHSS >6• Pre‐STROKE disability: mRS 0‐2• LVO: ICA (extra or intracranial or tandem)

/ MCA – M1• …• Exclusion:

• Pregnancy• Severe, terminal illness (<6month

life‐expectancy)• INR > 3; previous rTPA• Platelets < 50 000• Non controlled hypertension (SBP>

185; dBD>110 mmHg)• Glucose <50 / >400

• DAWN – 6 ‐24 H

• TIME: 6 ‐12 H (last seen well)• NIHSS ≥ 10• Pre‐STROKE disability: mRS 0‐1• LVO: ICA (extra or intracranial or

tandem) / MCA – M1• …• Exclusion:

• Pregnancy or lactating• INR > 3; APTT >3; • Platelets < 50 000• Non controlled hypertension (SBP>

185; dBD>110 mmHg)• Glucose <50 / >400

Endovascular trea

tmen

t (EVT)


• DAWN – RAPID software• Core: (ischemic core volume)

• CTP 30% of normal voxel relative cerebral blood flow of the normal tissues • MRI ‐ DWI

• Groups• ≥80 years of age/NIHSS ≥10 / mismatch + infarct volume <21 ml• <80 years of age/NIHSS ≥10 / mismatch + infarct volume <31 ml• <80 years of age/NIHSS score of ≥20 / mismatch + infarct volume 31 to <51

ml

Endovascular trea

tmen

t (EVT)


• DAWN – RAPID software• Core: (ischemic core volume)


• Groups• ≥80 years of age / NIHSS ≥10 / mismatch + infarct volume of <21 ml• <80 years of age / NIHSS ≥10 / mismatch + infarct volume of <31 ml• <80 years of age / NIHSS score of ≥20 / mismatch + infarct volume of 31 to <51 ml

• DEFUSE 3 – RAPID software• Core: (ischemic core volume) < 70 ml


• Mismatch: ratio >1.8 and volume >15 ml• mismatch = Core – Tmax > 6s• CTP / MRP – Tmax

• If no perfusion study: DWI < 25 ml (Core)

Endovascular trea

tmen

t (EVT)


DEFUSE 3: 6 ‐ 16h

NEJM February 22, 2018NEJM January 4, 2018

DAWN: 6 ‐ 24h

Endovascular trea

tmen

t (EVT)


Stroke treatment – CLINICAL RESULTS:

Number Needed to Treat (NNT)

NINDS 2 / ECASS III NNT 8 – 15

HERMES (5 MT trials) NNT 2.6

DAWN NNT 2.8

Acute Coronary Syndrome (STEMI)* AAS ‐ NNT 42

Thrombolysis ‐ NNT 43‐200 (depending on timing)

*from: Therapy (NNT) Reviewshttp://www.thennt.com/home‐nnt/

Clin

ical results


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Swift‐Prime

Stroke treatment – Cost‐effectiveness evaluation:

Interventional Stroke treatment (compared with IV treatment)

from: Shireman T et al Stroke 2016

Economical results


Guidelin

es



2018 2019

Stroke, 2018 European Stroke Journal, 2019

Guidelin

es



2018

All AIS Imaging Recommendations:

• Non contrast CT

• Fast Imaging (50% of cases in <20min)

• CT Angio

Guidelin

es



2018

6‐24h AIS Imaging Recommendations:

• CTP or MRI (DWI or PWI) for eligibility criteria

Guidelin

es



2018

AIS ImagingRecommendations:

• Collateral circulation assessment

Guidelin

es



2018

AIS MT treatment (<6h after onset)Recommendations:

• Occlusion: ICA; MCA‐M1• < 6h• ASPECTS ≥ 6 • Prestroke mRS 0‐1• NIHSS ≥ 6

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Guidelin

es



2018


• M2 and M3 segments• Basilar / Vertebral arteries• Anterior, Posterior Cerebral Arteries

Guidelin

es



2018

6‐24h AIS MT treatment Recommendations:

• Dawn and Diffuse 3 inclusion criteria

Guidelin

es



2019

European Stroke Journal, 2019

Guidelin

es



2019


• M2 MCA segment• Basilar Artery


Guidelin

es


2019

European Stroke Journal, 2019

6 ‐ 12h AIS MT treatment Recommendations:

• ASPECTS ≥ 6• Good collateral patterns

Stroke diagnosis & treatment – GUIDELINES

Arterial occlusion

Acute Ischemic Stroke

Large Vessel Occlusion (LVO) CTA / MRA

ASPECT Score CT / MRIExtension of the infarct

R/O hemorrhage / stroke mimic

Guidelin

es


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Stroke diagnosis & treatment – GUIDELINES

Arterial occlusion

Acute Ischemic Stroke

Large Vessel Occlusion (LVO) CTA / MRA

ASPECT Score CT / MRI

Time: < 4.5 h

IV rTPA (thrombolysis)

Extension of the infarct

Endovascular treatment (EVT)

Time: < 6 h Time: > 6 h; < 24h

Salvage brain (penumbra) CTP / DWI

R/O hemorrhage / stroke mimic

Guidelin

es


Mechanical Thrombectomy – Randomized Controlled Trials

RCT


Starting after 01/01/2018

from: clinicaltrials.gov

Open

Questions


Mechanical Thrombectomy – Open Questions

• Best method for patient triage & transport: • mobile stroke unit; • drip and ship vs mothership; RECECAT study• …

• Best imaging method: NC CT; CTA; CTP; MRI‐DWI MR CLEAN LATE trial Open

Questions


Mechanical Thrombectomy – Open Questions

• Patients not included in the previous RCT

Prestroke higher deficits (mRS >2 at baseline)

Mild Neurological deficits (NIHSS <5) ENDOLOW; IN EXTREMIS trial

Large stroke (ASPECTS <6; Core >70mL) TENSION; IN EXTREMIS; TESLA trials

Distal Occlusions (MCA – M2)

Basilar artery occlusions BEST trial

Direct MT (no rTPA) SWIFT DIRECT; MR CLEAN no IV trials

Conclusions

Conclusions• There has been a major paradigm shift for AIS diagnosis and management

and

neuroradiology (diagnostic and therapeutic / intervention) has a central position

• Non‐invasive multimodality imaging is critical for patient selection:• identification of large vessel occlusion and salvageable brain tissue

• opens the opportunity for patients with unknown time of stroke onset (up to 25% of patients) to be treated with IV thrombolysis and/or EVT

• Imaging is shifting from excluding patients to include more patients

• Endovascular treatment (EVT) is the standard of care for large vessel occlusion (LVO) acute ischemic stroke



Pedro Vilela MD, MSc

Lisbon ‐ Portugal

therapy strategies, studies and guidelines - pedro vilela strategies... · 1strandomized trial...

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