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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
Therapy strategies, studies and guidelines
• Current guidelines
2018 2019
Stroke, 2018 European Stroke Journal, 2019
Introduction
Therapy strategies, studies and guidelines
• Levels of evidence
Introduction
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
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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
Therapy strategies, studies and guidelines
• IV thrombolysis (rTPA)
• 1st line treatment for AIS
• 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
2018: New trials … New challenges
IV Thrombolysis
Need for more efficient recanalization treatment
Therapy strategies, studies and guidelines
• IV thrombolysis (rTPA)
• 1st line treatment for AIS
• 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
2018: New trials … New challenges
IV Thrombolysis
Therapy strategies, studies and guidelines
• IV thrombolysis (rTPA)
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
2018: New trials … New challenges
IV Thrombolysis
Therapy strategies, studies and guidelines
• IV thrombolysis (rTPA)
• Wake‐up study (2018)
2018: New trials … New challenges
IV Thrombolysis
2018
Therapy strategies, studies and guidelines
Imaging: DWI_FLAIR mismatch
From: Vilela P, Rowley HA, Eur J Radiol 2017
• IV thrombolysis (rTPA)
• 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
2018: New trials … New challenges
IV Thrombolysis
• mRS 0‐2
• Altepase: 74%
• Placebo: 65%
2018
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
• Evolution of EVT (IA thrombolysis / thrombectomy):
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)
Therapy strategies, studies and guidelines
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
• Evolution of EVT (IA thrombolysis / thrombectomy):
Therapy strategies, studies and guidelines
Endovascular trea
tmen
t (EVT)
Dark ages
Therapy strategies, studies and guidelines
• Evolution of EVT (IA thrombolysis / thrombectomy):
– 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)
Therapy strategies, studies and guidelines
• 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)
Therapy strategies, studies and guidelines
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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)
Therapy strategies, studies and guidelines
• 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)
Therapy strategies, studies and guidelines
• 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)
Therapy strategies, studies and guidelines
• 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%
mRS 0‐2 difference= 6.8%
2018: New trials … New challenges
Endovascular trea
tmen
t (EVT)
Therapy strategies, studies and guidelines
Arterial occlusion present in the initial CTA
mRS 0‐2 difference= 8.7%
mRS 0‐2 difference= 6.4%
mRS 0‐2 difference= 13.4%
• IMS III (2006 – 2012): subgroup analysis and secondary end points
Broderick JP, et al. Endovascular therapy after intravenous t‐PA versus t‐PA alone for stroke. NEJM 2013 Mar 7;368(10):893‐903
– 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)
Therapy strategies, studies and guidelines
• IMS III (2006 – 2012): subgroup analysis and secondary end points
Broderick JP, et al. Endovascular therapy after intravenous t‐PA versus t‐PA alone for stroke. NEJM 2013 Mar 7;368(10):893‐903
– 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)
Therapy strategies, studies and guidelines
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• Evolution of EVT (IA thrombolysis / thrombectomy):
– 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)
Therapy strategies, studies and guidelines
Endovascular trea
tmen
t (EVT)
New hope for AIS treatment
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
Endovascular trea
tmen
t (EVT)
Positive Endovascular Treatment (EVT) Trials
Therapy strategies, studies and guidelines
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)
Positive Endovascular Treatment (EVT) Trials
Therapy strategies, studies and guidelines
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)
Therapy strategies, studies and guidelines
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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)
Therapy strategies, studies and guidelines
• 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)
Therapy strategies, studies and guidelines
• 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)
Therapy strategies, studies and guidelines
• 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 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
• CTP 30% of normal voxel relative cerebral blood flow of the normal tissues • MRI ‐ DWI
• 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)
Therapy strategies, studies and guidelines
DEFUSE 3: 6 ‐ 16h
NEJM February 22, 2018NEJM January 4, 2018
DAWN: 6 ‐ 24h
Endovascular trea
tmen
t (EVT)
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
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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
Therapy strategies, studies and guidelines
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2018 2019
Stroke, 2018 European Stroke Journal, 2019
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2018
All AIS Imaging Recommendations:
• Non contrast CT
• Fast Imaging (50% of cases in <20min)
• CT Angio
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2018
6‐24h AIS Imaging Recommendations:
• CTP or MRI (DWI or PWI) for eligibility criteria
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2018
AIS ImagingRecommendations:
• Collateral circulation assessment
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
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
Therapy strategies, studies and guidelines
• Current guidelines
2018
AIS MT treatment (<6h after onset)Recommendations:
• M2 and M3 segments• Basilar / Vertebral arteries• Anterior, Posterior Cerebral Arteries
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2018
6‐24h AIS MT treatment Recommendations:
• Dawn and Diffuse 3 inclusion criteria
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2019
European Stroke Journal, 2019
Guidelin
es
Therapy strategies, studies and guidelines
• Current guidelines
2019
AIS MT treatment (<6h after onset)Recommendations:
• M2 MCA segment• Basilar Artery
• Current guidelines
Guidelin
es
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
16.10.2019
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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
Therapy strategies, studies and guidelines
Mechanical Thrombectomy – Randomized Controlled Trials
RCT
Therapy strategies, studies and guidelines
Starting after 01/01/2018
from: clinicaltrials.gov
Open
Questions
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
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
Therapy strategies, studies and guidelines
Therapy strategies, studies and guidelines
Pedro Vilela MD, MSc
Lisbon ‐ Portugal