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

Copyright © 2015 StrykerNV00015840.AB | Page 1 of 2

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!