Endovascular Treatment of Acute Ischemic Stroke Dr. S Kumar Reddy MD Neurovascular and Interventional Radiology Director Interventional Radiology Via Christi Health – Wichita, KS
Endovascular Treatment of
Acute Ischemic Stroke
Dr. S Kumar Reddy MD
Neurovascular and Interventional Radiology
Director Interventional Radiology
Via Christi Health – Wichita, KS
No Disclosures
Via Christi Therapy trial site for Penumbra 3D separater Stent
retriever
IA Stroke Therapy Outline:
Goal of stroke intervention –save the penumbra
Time is brain
Review of IA stroke therapy trials – How did we get here?
Review of IA stroke trials – Pharmacotherapy
Review of IA stroke trials – 1st generation Mechanical embolectomy devices and aspiration-based embolectomy techniques
Review of IA stroke trials – 2nd generation Mechanical embolectomy devices (Stentrievers)
Review of IMS III – NINDS supported randomized trial
Review of randomized trials with positive results for mechanical thrombectomy using second generation devices – a new paradigm shift in IA stroke therapy
Comments on stroke imaging
How do we treat stroke at the Christi health
Summary
Time is Brain !
Emergent Large Vessel
Occlusion (ELVO)
- M1 Occlusion
- Carotid T Lesion
IA Stroke Therapy
Time is Brain.
On average 32000 cells die/second.
Every treatment delay of 30 min decreases chance of favorable outcome by 10%.
Angiographic outcomes vs Clinical outcomes.
Great recanalization rates don’t guarantee great clinical outcome.
Ultimately we want to achieve not only improvement in NIHSS, but also want low 30 and 90 day modified Rankin scores (i.e good functional outcome).
IA Stroke Therapy
TIMI – Thrombolysis in Myocardial Infarction
0 – Absence of forward flow
1 – Faint flow beyond occlusion, with incomplete filling distally
2 – Partial sluggish flow with complete filling of distal territory
3 – Normal flow restoration
TICI – Thrombolysis in Cerebral Infarction
0 – No flow beyond occlusion
1 – Penetration beyond occlusion with minimal perfusion
2 – Penetration beyond obstruction with partial perfusion
A – Less than 2/3 of vascular territory
B – Complete filling beyond obstruction, but perfusion is sluggish
C – Near complete perfusion with only few distal cortical vessel occlusion
3 – Complete perfusion
mRS – Modified Rankin Score
0 – No neurological symptoms
1 – No significant disability despite symptoms; able to carry out ADL
2 – Slight disability –able to live independently
3 – Moderate disability requiring some help, able to walk w/o help
4 – Moderately severe disability, unable to walk without assistance,
unable to attend to own bodily needs without assistance
5 – Severe disability, bedridden, incontinent requiring constant
nursing care.
6 - Dead
IV Stroke Therapy Trials
IV Pharmacotherapy Trials
NINDS (624)– Statistically improved outcomes when IV tPa given 0-3hr
ECASS I (620) , ECAS II (800) – Europe, supports NINDS
ATLANTIS I (142) (0-6 hrs)
ATLANTIS II (547) (3-5hrs)
In 1996 FDA approved IV tPA between 0-3hr if selection criteria met.
AHA/ASA extended therapeutic window to 4.5hrs for subset of pts with following exclusion criteria.
Age > 80
Use of anticoagulants
Diabetic with prior stroke
NIHSS > 24
IA Stroke Therapy
Evidence Based Medicine (EBM)
Treatments need to be supported by randomized control trials
Ethics – Do no harm
Implications for reimbursement
Until recently only IV tpa has been shown to be efficacious by RTC - level 1A evidence (1996)
IA therapy was deemed “experimental” and supported only by small trials, often not randomized with best medical therapy and often industry driven with poor Level 1A evidence for stroke therapy.
Positive earlier device trials – devices were FDA approved for “successful clot/foreign body retrieval” but not “successful stroke treatment”
2013 IMS III trial stopped early due to no overall benefit of IA therapy
2014 Positive trials with 2nd generation devices showed efficacy of EVT
IV Stroke therapy
Limited efficacy of IV tPA for ELVO especially for large vessel clot burden greater than 8mm
Transcranial US
29% recanalization for M1 ELVO
20.3% recanalization for combined M1 and distal ICA ELVO
6% recanalization for proximal ICA ELVO
IA Stroke Therapy
IA Pharmacotherapy
Goal is to deliver lower dose but higher concentration of drug directly
into clot to reduce systemic effects.
Urokinase
Pro-Urokinase
Tpa
Retivase
Tenecteplace
ReoPro
IA Stroke Therapy Trials
Early IA Pharmacotherapy Trials
PROACT – I (Prolyse for Acute Cerebral Thromboembolism I
Trial)
PROACT –II
MELT (Middle Cerebral Artery Embolism Local Fibrinolytic
Intervention Trial)
Is it safer and more efficacious if smaller dose and higher
concentration of thrombolytic delivered directly to site of clot?
IA Stroke therapy
PROACT –I
Recombinant Pro-urokinase
40 pts enrolled rpro-UK + heparin vs.. heparin alone, MCA occlusions
6hr symptom onset
Results Recanalization rates
Rpro-UK 58%
Heparin 15%
Symptomatic ICH Rpro-UK 15.4%
Heparin 7.1%
Good Outcomes Rpro-UK 30.8%
Heparin 21.4%
90-day mortality Rpro-UK 26.9%
Heparin 42.9%
Results did not reach statistical significance
IA Stroke Therapy
PROACT – II
Prospective, randomized, placebo-controlled phase III trial
180 pts
Markedly higher recanalization rates in pro-UK compared to
placebo (66% vs. 18%)
Higher incidence of symptomatic ICH (10% vs. 2% for placebo)
No difference in mortality (27% vs. 25%)
90 day mRS 2 or less (rpro-UK 40% vs. placebo 25%)
Reached statistical significance
Rpro-UK not readily available for clinical use
IA Stroke therapy
MELT
Japanese study studying Urokinase
114 pts with MCA occlusion
Treatment within 6hr of symptom onset
73.7% recanalization rate
mRS 0-2 (49.1% vs. 38.6% with placebo)
mRS 0-1 (42.1% vs. 22.8% with placebo)
Symptomatic ICH (9% vs. 2% with placebo)
Study stopped when IV rt-PA was approved for acute stroke
therapy
Similarly to Rpro-UK, UK is not approved in USA for acute stroke
therapy.
IA Stroke Therapy - Mechanical
Guide wires, Balloons, Stents – usually adjunctive to tPA
Mechanical Clot Retrieval (with / without pharmacotherapy)
Goal is to remove clot burden from the occluded vessel.
Merci -2005
Penumbra - 2008
Solitaire - 2012
Trevo -2012
3D separator (We are currently enrolled in Therapy trial)
IA Stroke Therapy Trials
Early Mechanical Thrombectomy Trials
Merci Device
Merci Trial
Multi-Merci Trial
Merci device approved by FDA in 2005, indicated for clot retrieval, not stroke treatment.
Suction aspiration
Penumbra – Pivotal Trial
Stent retrievers
Solitaire – SWIFT
Trevo – Trevo I and Trevo II trials
These studies showed increasing rates of recanalization especially with stent retrievers (stentrievers), but no direct comparison with maximum medical therapy
IA stroke Therapy – Merci Trial
MERCI trial
Prospective, single-arm, multicenter trial
Use of device within 8 hr of symptom onset
141 pts
Pts ineligible for IV t-PA
INR <1.7
TIMI grade 2-3 achieved in 68/141 (48%)
51/141 (36%) pts received adjuvant IA t-PA, snare
38/141 were within 3hr of symptom onset (not eligible for IV t-PA
18/141 procedural complications, 10 (7.1%) were clinically significant
11/141 (7.8%) symptomatic ICH
Mortality rate
31.8 % in recanalized group
54.2% in non-recanalized group
mRS 0-2
46.% in recanalized group
10.4 % in non-recanalized group
Reached statistical significance
Revascularization was independently associated with good neurological outcome
IA Stroke Therapy – Multi Merci Trial
Multi-Merci trial
164 pts
Used both first and second generation Merci devices
Revascularization rates
55% using device alone
68% with device plus adjunctive therapy
48 pts (29.3%) received IV t-PA prior to angiography
9.8% procedural complications, 5.5% were clinically significant
Symptomatic ICH 9.8%, Asymptomatic 30.5%
No difference in ICH in pts who also received IV t-PA
Mortality rate 25% in recanalized group, 52% in non-recanalized group (p < 0.001)
mRS 0-2
49% in recanalized group
9.6% in non-recanalized group
Demonstrated increased survival and improved outcome associated with recanalization
No control arm to conclusively show thrombectomy improves stroke outcome
Penumbra Device
IA Stroke Therapy – Pivotal Trial
Penumbra (The Penumbra Pivotal Stroke Trial)
125 pts, single arm, no placebo, 8hr symptom onset
81.6% revascularized to TIMI 2 to 3
12.8 % complication rate with 2.4% serious
28% ICH at 24hrs, 11.2 were symptomatic
All causes of mortality 32.8% at 90 days
25% achieving mRS 0-2
Proved safety and effectiveness of device
Improved recanalization rate over Merci
Supports previous conclusion that revascularization was
independently associated with good neurological outcome
Improved recanalization over Merci data
IA stroke Therapy
IA Stroke Therapy – SWIFT Trial
SWIFT
Solitaire flow restoration device versus Merci device trial.
Merci already approved by FDA for clot retrieval (not stroke
therapy)
Study designed to show non-inferiority of Solitaire device
58 pts in Solitaire group, 55 pts in Merci group
Primary efficacy outcome was achieved more often in solitaire
group (61% Solitaire vs.. 24% Merci group)
More people had good 3 month neurological outcome with
Solitaire group (58% solitaire vs. 33% Merci group)
90 day mortality is lower in the Solitaire Group (17% vs. 38%)
IA Stroke Therapy – Trevo
Trevo – Single arm
Almost 50% of patients (46.7%) treated within 3 hours
Significant baseline severity (NIHSS median 18, range 8,28)
82% occlusions of ICA or M1
92% recanalized to TICI 2a or higher
78% recanalized to TICI 2b or higher
55% functional independence (mRS 0-2) at 90 days
5% SICH (SITS-MOST; 1 device-related)
5% rate of Device-related Serious Adverse Events
Not a randomized study, but very encouraging for further development
Trevo 2 – Double blinded with Merci
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Device Specific Trials
~sICH and Revascularization have varying definitions
Other Randomized Clinical Trials
Trial Inclusion Criteria Imaging Specific Inclusion
Criteria
Device(s)
Used in
Intervention
Arm
Time From
Symptom
Onset
TICI 2b/3
Revascularization
Rate in the
Intervention Arm~
mRS 0-2
at 90 days
sICH~ Mortality
at 90 days
TREVO AIS including occlusion of proximal
artery, Age 18-85, NIHSS 8-30
Angiographically confirmed LVO Trevo®
Retriever
<8 hours 78.3% (n=60) 55.0%
(n=60)
5% 20.0%
TREVO2 AIS, Age 18-85, Treatable
within 8hrs from time assessed
at baseline
Angiographically confirmed LVO Trevo
Retriever
<8 hours 67.8% (n=88) 40.0%
(n=88)
6.8% 33.0%
TRACK Trevo Retriever must be the FIRST
retrieval device used in the case,
Any age, Any time of onset, All
treatable anatomy
N/A Trevo
Retriever
N/A 75.0% (n=579) 48.5%
(n=409)
7.5% 20.1%
NASA All patients received the Solitaire
FR device as the first choice
device to restore blood flow
Included patients treated outside
8hrs if imaging indicated a
significant mismatch, worsening
mild deficit on presentation, or
posterior circulation strokes
Solitaire See “Imaging
required …”
72.5% (n=354) 42.0%
(n=354)
9.9% 30.2%
SWIFT AIS, Age 22-85, NIHSS (≥8 and
≤30), Failure to respond to IV-tPA
Exclusion: CT or MRI evidence of
intracranial hemorrhage or major
ischemic infarction
Solitaire <8 hours 75.9% (n=58) 36.4%
(n=58)
1.7% 17.2%
STAR Age ≥18 and <85, NIHSS 8-30,
mRS ≤2
Angiographically confirmed LVO Solitaire <8 hours 79.2% (n=202) 57.9%
(n=202)
1.5% 6.9%
Trial Inclusion
Criteria
Imaging Specific
Inclusion
Criteria
Device(s)
Used in
Intervention
Arm
Time
From
Symptom
Onset
Avg.
Time to
Groin
(mins)
TICI 2b/3
Revascularization
Rate in
Intervention Arm~
mRS 0-2 at 90 days NNT sICH~
(intervention;
control)
Mortality at
90 days (intervention;
control)
Intervention
Arm
Control
Arm
Odds
Ratio
(95% CI)
THERAPY Age 18-85
years, NIHSS
>8
CT
- Clot length >8mm
- Infarct <1/3 MCA
100%
Penumbra
System
<8 hours 226 70.0% (n=50) 38.0% 30.4% 1.76
(0.86,
3.59)
N/A 10.9%; 11.3% 12%; 23.9%
Device Specific Trials
SWIFT and TREVO 2 have the highest rates of revascularization
with good clinical outcomes (mRS 0-2) when compared to first-
generation Merci device (Level IA evidence)
Safety of the stent retrievers is established
Symptomatic ICH and mortality are in line with other
landmark stroke trials
Cannot directly compare TREVO 2 vs SWIFT vs Penumbra
START trials since there are too many differences in trial
design and definitions as well as patient population
Stent retriever +/- thrombo-aspiration need to be randomized
against best medical therapy
IA Stroke Therapy Trials
Interventional Management of Stroke (IMS)
IMS I
IMS II
IMS III - 2013
IMS III - No current data to support advantage of IA therapy
over IV therapy from 0-4.5 hours from symptom onset.
IA Stroke Therapy Trials – IMS III
IMS III – funded by NINDS (National Institute of Neurological
Disorders and Stroke)
PHASE III TRIAL – Results presented 2013 ASA meeting
900 PTS (2:1) COMBINED IV + IA vs. IV
Trial stopped early when preplanned interim analysis showed no
statistical benefit or difference in mRS score at three months.
Study stopped due to futility, not safety concerns
656 total pts enrolled
Both modalities point to time to treatment is most important factor.
Extensive subgroup analysis may give indication who may benefit
from IA therapy
IA Stroke Trials With Negative Results SYNTHESIS
Randomized trial comparing IV tPA versus endovascular therapy
Showed similar rates of favorable clinical on: Between endovascular therapy and intravenous TPA with no clear advantage for intra-arterial therapy
MR RESCUE
Best medical treatment versus best medical treatment plus EVT
MRI/MR perfusion
CT perfusion
Merci, Penumbra, Stentrievers
Embolectomy showed no benefit over best medical therapy
IA Stroke Therapy Trials – IMS III
Documentation of ELVO was not required
Subgroups and trial design
16 percent of endovascular arm had no thrombus or treatable
thrombus in the ICA, M1, or proximal M2
The trial was spread over several generations of stroke devices
Stent retrievers only used in 1.5 percent of patients
Those patients with CTA demonstrating ELVO trended toward
benefit of IA therapy
Those patients with ELVO and NIHSS > 20 tend toward benefit of
IA therapy
Strong trend towards benefit if IV tPA is given within 2 hours and
intra-arterial intervention less than 90 minutes after IV tPA.
IA Stroke Therapy
So how do you optimize for efficacy of EVT
Pick the right patient
ELVO
High ASPECT score
Minimize time between symptom onset and treatment
Use 2nd generation stroke devices
Stentrievers
Solitaire
Trevo
Thromboaspiration
Penumbra
5MAX ACE, ACE 64, ADAPT technique
Stroke systems of care to optimize door to groin stick
IA Stroke Therapy Trials With Positive Results
MR CLEAN – OCT 29th 2014, presented in Istanbul, Turkey
Study done in Netherlands
500 pts, 18yrs, no upper age limit
233 – IA, 267- control
NIHSS > 2
Open label, blinded assessment of functional outcome at 90 days
mRS, Barthel Index for level of disability
Blinded neuroimaging at baseline and 90 days
Two blinded assessors, with a third if there was disagreement
IA – Mechanical + - thrombolytics
IA Stroke Therapy Trials With Positive Results
MR CLEAN
Stentrievers were used in 97% of IA pts
IA arm pts had more percent of patients who shifted to a lower
mRS at 90 days than control arm. Similar trend in NIHSS
IA arm 80% recanalization rates compared to 32% in control arm
As seen in other studies, IA arm had slightly higher serious adverse
events.
No statistical difference in overall death rates at 90 days
Intervention significantly better for pts presenting with NIHSS > 20
Intervention significantly better than control group for pts who
presented beyond 120 min
IA Stroke Therapy Trials With Positive Results
ESCAPE
Canadian study
315 pts, randomized IV tPA or no tx vs. IV tPA plus EVT
Endovascular therapy of small core anterior circulation stroke
Emphasis was on reducing time post CT to EVT
Goal was recanalization within 90 minutes of CT
Achieved median time from CT to groin puncture of 51 minutes
mRS 0-2 was 53% for EVT versus 29% for control arm at 90
days
Symptomatic ICH – 2.7 % for EVT vs. 3.6% control
Mortality – EVT 10.4% vs. 19.0% control
IA Stroke Therapy Trials With Positive Results
EXTEND IA
Australian study – 70 pts
Randomized trial of ELVO in the anterior circulation with favorable
imaging profile using advanced imaging
All patient’s received IV tPA
35 pts also received endovascular therapy
Initial NIH SS of the control arm was 13, and the EVT arm 17
mRS 0-2 at 90 days 71% EVT vs. 40% control
Symptomatic hemorrhage 0% EVT vs. 6% control
Clinical Trials Summary:Acute Ischemic Stroke
Randomized Clinical Trials with Positive Results for Mechanical Thrombectomy
Odds
(within 30 days)
ASPECTS ≥6
(p=0.50)
~sICH and Revascularization have varying definitions*Imaging requirement was expanded after 71 patients and is reported in the supplemental index
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TrialInclusionCriteria
Imaging SpecificInclusion Criteria
Device(s)
Used in
Intervention
Arm
Time
From
Symptom
Onset
Avg.
Time to
Groin
(mins)
TICI 2b/3Revascularization
Rate in Intervention Arm~
mRS 0-2 at 90 days
NNTsICH~
(intervention; control)
Mortality at
90 days
(intervention;
control)InterventionArm
ControlArm
Adjusted
Ratio(95% CI)
MR CLEAN
(N = 500)
AIS, Age ≥18,
NIHSS ≥2
CTA, MRA, DSAconfirmed LVO
97% stent retriever
(~66% Trevo®
Retriever),
2% other
mechanical
<6 hours 260 58.7% (n=196) 33% (n=233)19%
(n=267)
2.16
(1.39-3.38)7 7.7%; 6.4%
18.9%; 18.4%
ESCAPE(N = 316)
AIS, Age ≥18,NIHSS >5
CT/CTA
Confirmed LVO
Small core infarct
on CTA or CTP
(ASPECT ≥6)
86% stent
retriever
(~23% Trevo)<12 hours 185 72.4% (n=156) 53% (n=164)
29.3%(n=147)
1.8(1.4-2.4)
4 3.6%; 2.7% 10.4%; 19%
*SWIFT
PRIME(N = 196)
AIS, Age 18-80,
NIHSS 8-29,IV-tPA within
4.5hrs of onset
of stroke
CT/CTA or MRI/MRA
Confirmed LVO MRI showing core
infarct ≤1/3 MCA (or≤100cc of tissue)
100%
Solitairestent retriever
<6 hours 224 88% (n=83) 60.2% (n=98)35.5%
(n=93)
2.75
(1.53,4.94)
40%, 3%
(at 27hrs)9%, 12%
EXTEND-IA(N = 70)
AIS, Age >18,
Pre-stroke
mRS ≤0-1
CTA/CTP or MRA/MRP
Confirmed LVO Mismatch on perfusion
Ischemic core lesion
volume <70ml
100%
Solitairestent retriever
<6 hours 210 86.2% (n=29)71%
(n=35)40%
(n=35)4.2
(1.4-12)3.2 0%, 6% 9%; 20%
REVASCAT(N = 206)
AIS, Age ≥18 and
≤85, NIHSS >6,
no significantpre-stroke disability
(mRS <1)
CTA/MRA or DSAconfirmed LVO
ASPECTS >6 on
DWI MRI ASPECTS ≥7 on CT
100%
Solitairestent retriever
<8 hours 269 65.7% (n=102) 43.7% 28.2%2.1
(1.1, 4.0)7
1.9%; 1.9%(p=1.00)
18.4; 15.5%
SOLUMBRA
mRS – Modified Rankin Score
0 – No neurological symptoms
1 – No significant disability despite symptoms; able to carry out ADL
2 – Slight disability –able to live independently
3 – Moderate disability requiring some help, able to walk w/o help
4 – Moderately severe disability, unable to walk without assistance,
unable to attend to own bodily needs without assistance
5 – Severe disability, bedridden, incontinent requiring constant
nursing care.
6 - Dead
IA Stroke Therapy Trials With Positive Results
MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME, REVASCAT
What have we learned?
IV tPA has Level IA evidence for non-ELVO when administered within 3 hrof symptom onset, and for a subset of patients up to 4.5 hrs.
Patient’s with anterior circulation stroke with documented ELVO of the ICA or M1 segment with clinical deficit, the addition of endovascular intra-arterial therapy results in superior clinical outcome based on mRS @ 90 days when compared with best medical therapy alone.
Endovascular therapy needs to be performed as soon as possible (<6hrs) for greatest benefit.
AHA class 1A evidence.
Time is Brain
To achieve outcomes supported by these landmark
studies stroke systems of care are needed
Primary Stroke Centers Optimize for IV Therapy
Comprehensive Stroke Centers Optimize for IV and/or
IA stroke therapy
Time is Brain !!
Time of onset to treatment has to be minimized
Last Well Known
EMS Called
X-Fer to stroke center
ED/Stroke team evaluation
Imaging
IV tPA and/or EVT
Time has to be optimized at each step
The second generation mechanical thrombectomy and suction thrombectomy devices have proven to be efficacious in removing clot.
Although technology will continue to improve, gains in improving good functional outcome (mRS 0-2) is still a function of time.
Note on Imaging
CT
Non contrast CT Head - 5 min
Bleed
ASPECTS
CTA Head & Neck – 15 min
CT Perfusion (CTP) – 15 min
MRI (30-45 min)
MRI
MRA
MR Perfusion
In general the more advanced the imaging the more time it takes to
acquire the study as well as the additional postprossesing time. So
there is a trade off between optimal imaging and time to treat.
Note on Imaging
How we practice
CT
Bleed
ASPECTS score
CTA
MRI / MR Perfusion
Outside 6 hr window
Wakeup stroke
Crescendo stroke / Waxing and waning symptoms
ASPECTS Scoring
ASPECTS SCORING Reliable and reproducible with little inter-observer variability
< 3 h of MCA stroke, baseline ASPECTS values correlates severity of NIHSS and with functional outcome
<= 7 or less correlated with both poor functional outcome and symptomatic intracerebral hemorrhage
We are assuming without doing a perfusion scan that there is little or no penumbra or at risk brain to rescue – we already see the completed stroke
8-10 is associated with a greater extent of benefit from IV tPA
We are assuming without doing a perfusion scan that there viable brain at risk i.e. large penumbra with small infarct core waiting to be rescued.
Most importantly all this information and predictive value is obtained from a non contrast CT.
Optimizes time with good predictive value
EVT for other types of strokes What about strokes other than ELVO in the anterior circulation
Posterior circulation / Vertebrobasilar strokes
Hypoperfusion strokes due to:
Carotid stenosis
Vertebral artery stenosis
Intracranial athrosclerosis
Wake up strokes
Vertebral artery / Carotid artery dissections
These type of strokes have their own distinct pathophysiology and can effect stroke trials negatively if included in such studies. They should be studied independently.
Yes we treat these types of strokes also.
Summary & Conclusions
Time is Brain !!
Level 1A evidence for IV tPA for small vessel occlusion and short segment (< 8mm) large vessel occlusion (NINDS 1996)
Level 1A evidence for EVT w/wo IV tPA for ELVO of the anterior circulation including M1, M1 + ICA or ICA
Door to needle time is critical for good functional outcome
Stroke systems of care and the Acute Stroke Response team is critical for optimizing outcomes
EMT
ED
Stroke Team
IMAGING
IV tPA +- EVT
THANK YOU!