Intracranial revascularization in Acute Stroke: Data and · PDF fileIntracranial...

Intracranial

revascularization in Acute

Stroke: Data and Trials

Session 4: Target Stroke

S. Mangiafico

Interventistica Neurovascolare

AOUCareggi

Firenze

disclosure

• Codaman Neurovascular

Recanalization is an independent predictor of favorable clinical outcome

NEJM, March 2013

5

SYNTHESIS exp (1 feb. 2008-16 apr.2012)

362 pts with ischemic stroke onset within 4.5 h. Randomization 1:1

181 Endovasc.

Median onset-to-groin 3.45 h

Interquartile (3:14-4.20)

181 i.v.

Median onset-to-needle 2.75 h

Interquartile (2:20-3:20) P<0.01

mRS 0-1 (3 m)

30.4%

mRS 0-1 (3 m)

34.8% OR (adjusted for age, sex, stroke severity, AF) 0.71 (CI 95% 0.44-1.14) P=0.16

Fatal or non Fatal symptomatic hemorrhage in 6% in both groups

Synthesis Analisi per sottogruppi

SYNTHESIS: CRITICAL POINTS

Low recanazatin rate due to Old devices ( only in 15% )

• Uselected vascular occlusion, unselcted perfusion patterns

• No bridging no rescue

Delayed Groin puncture after 1 h vs iv tpa administaration

•

IMS III Phase III, randomized, open-label trial

iv t-PA vs iv t-PA associated with Endovascular treatment

IMS III ( 25 ago 2006-17 april 2012)

656/900 Pts eligible for i.v. tPA within 3 h ; 58 centers.

Trattamento endovascolare aggiuntivo rapporto 2 :1 (434 endovasc vs 222 iv t-PA)

Primary outcome mRS 0-2 ( 3 m): 40.8% endovasc. Vs 38.7% IV t-PA

1.5 percent. (95%CI -6.1 - 9.1)

Futility of combined

treatment with regard

to primary Outcome

(mRs 0-2) lower than

20%

NIHSS

(median)

17/ 16

Techniques used for EVT

i.a. Thrombolysis

Solitaire (only 4% !)

EKOS

Merci

IMS 3: very low recanalization rates

correlation TICI-outcome (mRS 0-2)

TICI 0 : 12.7%

TICI 1: 27.6%

TICI 2a : 34.3%

TICI 2b : 47.9%

TICI 3: 71.4%

(P<0.001)

Broderick JP et al. N Engl J Med 2013;368:893-903

Reperfusion rates, TICI 2b -3 (end of the procedure DSA)

38% ICA

44% complete M1,

44% single M2 occlusion,

23% for multiple M2 occlusions

But…

Better outcome

Stroke onset –IV

tPA < 120 min

Better outcome

In severe stroke

NIHSS> 20

Better outcome

If stroke onset-

IV treatment

Within 2 h

NIHSS > 20

182 pts of IMS3

Recanalizatione within 7h

Average Time-to-reperfusion 325’

7

With CTA-confirmed occlusion at baseline, representative of current practice, IMS III has a positive outcome for endovascular therapy.

IMS III: Considering patients with documented occlusion through CT-Angiography, the

endovascular treatment seems to be effective

Endovascular

confers a real

benefit across the

spectrum of mRS

A. Demchuk, IMS III: Comparison of

Outcomes between IV and IV/IA

Treatment in Baseline CTA Confirmed

ICA, M1, M2 and Basilar Occlusions,

slide 20, Presented at ISC 2013,

Honolulu, Hawaii

MR RESCUE

phase 2b, randomized, controlled,open-label (blinded outcome), multicenter trial

conducted at 22 sites in North America

study within 8 hours after the onset of large vessel,anterior-circulation strokes

Mechanical Embolectomy (MerciRetriever or Penumbra System) vs Standard Care.

Randomization was stratified according to whether the patient had a favorable

penumbral pattern (substantial salvageable tissue and small infarct core) or a non

penumbral pattern (large core or small or absent penumbra).

Outcomes 90-day modified Rankin scale,

MR RESCUE

In summary, patients between the

ages of 18 and 85 years, NIHSS

scores of 6 to 29 who had a large-

vessel, anterior-circulation ischemic

stroke were randomly assigned within

8 hours after the onset of symptoms

to undergo either mechanical

embolectomy (Merci Retriever or

Penumbra System)

or standard medical care.

Patients who were treated with

intravenous t-PA without successful

recanalization were eligible if

magnetic resonance angiography or

CT angiography after the treatment

showed a persistent target occlusion

A favorable penumbral pattern was

defined as a predicted infarct core of

90 ml or less and a proportion of

predicted infarct tissue within the at-

risk region of 70% or less.

•Outcome : mRS 0-2

•Outcome : On 7-day CT or MRI perfusion

imaging,

•Successful reperfusion was defined as a

reduction of 90% or more in the volume of the

perfusion lesion from baseline with the time

until the peak of the residue function of more

than 6 seconds.

118 patients who met the full eligibility criteria.

Overall, 68 of 118 patients (58%) had a

favorable penumbral pattern on final core

laboratory review.

Misure di Outcome

MR RESCUE

Conclusions

study did not confirm hypothesis that penumbral imaging would identify

patients who would differentially benefit from endovascular therapy for

acute ischemic stroke within 8 hours after symptom onset

regardless of penumbral-imaging pattern on study entry, no significant

differences were noted in clinical and imaging outcomes for patients undergoing

embolectomy,as compared with those receiving standard medical care.

MR Rescue, Comments • Low recanalization rates (obsolete devices)

• Therapeutic window too wide (late treatments, futile recanalizations)

• Wide latency between imaging and endovascular treatment

• i.v. t-PA used in 37% of patients • • Heterogeneity of perfusional imaging (CT, MR)

• It might be possible that patients with a favorable panumbral pattern

could have a good clinical outcome independently from type of treatment (collaterals)

The trials lesson

• SYNTHESIS expansion and IMSIII ( t-PA vs i.a. thrombolysis IA/ i.v. r-tPA vs i.v. r-tPA + endovascular treatment) : the missed favorable result for i.a. treatment dependend on the inappropriate selection of patients (no documented occlusions) and on the missed used of stent-retrievers (low recanalization rates) although the time to groin was respectively of 225 and 196 mins

• MR rescue - ( within6 h) ( tPA vs TPA+ thrombectomy): too long time-to-treatment, low recanalization rates

New devices

The TREVO 2 study

Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel

occlusions in acute ischaemic stroke (TREVO 2): a randomised trial (trevo vs

merci) Raul G Nogueira et al. for the TREVO 2 Trialists Lancet 2012; 380: 1231–40

SWIFT (Solitaire FR with the Intention for Thrombectomy) Study Solitaire flow restoration device versus the Merci Retriever in

patients with acute ischaemic stroke (SWIFT): a randomised,

parallel-group, non-inferiority trial

Jeffrey L Saver, et al. for the SWIFT Trialists Lancet 2012; 380: 1241–49

3 months mRS

Patients included in the trial

may be ineligible for or have

failed IV tPA within an 8-hour

window

New trials

• New device

• Documented major intracranial vascular

occlusion

• Perfusional Imaging of volume of infarction

26

Courtesy of Dr. Castaño

Stents: immediate flow restoration

Retrievers: removed after thrombectomy

Distal and within the occlusion

SolitaireTM, TREVO® , REVIVE, PRESET, EMBO-TRAP

Castaño C et al. Stroke 2010

Rohde S et al.Stroke 2011

San Román L et al. Stroke 2012

New neuroendovascular thrombectomy devices

27

Schellinger et al. Stroke 2008

Lansberg MG et al. Stroke 2008

TCDx - Angio-CT/ASPECTS Angio-MR/DWI

Mismatch

Neuroimaging tools to identify salvageable brain

Ottobre 2014

Febbraio 2015

Aprile 2015

29

OTR: median time from onset to randomisation; OTG: median time

from onset to groin puncture; mRS, modified Rankin scale; BMT:

Best medical therapy (includes IV alteplase if eligible); RCT,

randomised controlled trial; EVT, endovascular therapy; ICA, internal

carotid artery; CTP, computer tomography perfusion

* MRI or CTP mismatch >1.8 in the first 71 patients

Clinical trial

Control

Time

window

OTR time

(randomisatio)

Trial end Proven

occlusion

Ischaemic

penumbra

IV alteplase

(%)

OTG time Stent-

riever

Outcome

variable

MR CLEAN

(n=500)

IV alteplase

6.0h

204 min

Ended ICA, M1, M2,

A1, A2

NA rt-PA

failure

89%

260 min 81% mRS at 90d

(shift)

ESCAPE

(n=316)

BMT

12.0h

169 min

Halted ICA, M1 ASPECT 6-10

Good collaterals

Bridging

75%


(shift)

EXTEND IA

(n= 70)

IV alteplase

4.5h

157 min

Halted ICA, M1, M2 CTP or MRI

Tmax 6sec

Core <70mL

Bridging

100%

210 min 100% 24h

reperfusion

3 days NIHSS

SWIFT

PRIME

(n=196)

Iv alteplase

6h

188 min

Halted ICA, M1 ASPECT 6-10*

Bridging

100%

224 min 100% mRS at 90d

(shift)

REVASCAT

(n=206)

BMT

8.0h

223 min

Halted

after 1st

interim

ICA, M1 ASPECT 6-10 rt-PA failure

(30’) 73%

269 min 100% mRS at 90d

(shift)

Design of recently published RCT on EVT

1 - Berkhemer OA et al. N Engl J Med 2015;372:11-20.

2 - Goyal M et al. N Engl J Med 2015; ePub February 11

3 - Campbell BCV et al. N Engl J Med 2015; ePub February 11

4 - Saver J et al. N Engl J Med 2015, ePub April 17

5 – Jovin T et al. N Engl J Med 2015, ePub April 17

30







Clinical trial

Control

Time

window

OTR time

(randomisatio)

Trial end Proven

occlusion

Ischaemic

penumbra

IV alteplase

(%)

OTG time Stent-

riever

Outcome

variable

MR CLEAN

(n=500)

IV alteplase

6.0h

204 min

Ended ICA, M1, M2,

A1, A2

NA rt-PA

failure

89%


(shift)

ESCAPE

(n=316)

BMT

12.0h

169 min


Good collaterals

Bridging

75%


(shift)

EXTEND IA

(n= 70)

IV alteplase

4.5h

157 min


Tmax 6sec

Core <70mL

Bridging

100%

210 min 100% 24h

reperfusion

3 days NIHSS

SWIFT

PRIME

(n=196)

Iv alteplase

6h

188 min


Bridging

100%

224 min 100% mRS at 90d

(shift)

REVASCAT

(n=206)

BMT

8.0h

223 min

Halted

after 1st

interim


(30’) 73%

269 min 100% mRS at 90d

(shift)







31







Clinical trial

Control

Time

window

OTR time

(randomisatio)

Trial end Proven

occlusion

Ischaemic

penumbra

IV alteplase

(%)

OTG time Stent-

riever

Outcome

variable

MR CLEAN

(n=500)

IV alteplase

6.0h

204 min

Ended ICA, M1, M2,

A1, A2

NA rt-PA

failure

89%


(shift)

ESCAPE

(n=316)

BMT

12.0h

169 min


Good collaterals

Bridging

75%


(shift)

EXTEND IA

(n= 70)

IV alteplase

4.5h

157 min


Tmax 6sec

Core <70mL

Bridging

100%

210 min 100% 24h

reperfusion

3 days NIHSS

SWIFT

PRIME

(n=196)

Iv alteplase

6h

188 min


Bridging

100%

224 min 100% mRS at 90d

(shift)

REVASCAT

(n=206)

BMT

8.0h

223 min

Halted

after 1st

interim


(30’) 73%

269 min 100% mRS at 90d

(shift)







32







Clinical trial

Control

Time

window

OTR time

(randomisatio)

Trial end Proven

occlusion

Ischaemic

penumbra

IV alteplase

(%)

OTG time Stent-

riever

Outcome

variable

MR CLEAN

(n=500)

IV alteplase

6.0h

204 min

Ended ICA, M1, M2,

A1, A2

NA rt-PA

failure

89%


(shift)

ESCAPE

(n=316)

BMT

12.0h

169 min


Good collaterals

Bridging

75%


(shift)

EXTEND IA

(n= 70)

IV alteplase

4.5h

157 min


Tmax 6sec

Core <70mL

Bridging

100%

210 min 100% 24h

reperfusion

3 days NIHSS

SWIFT

PRIME

(n=196)

Iv alteplase

6h

188 min


Bridging

100%

224 min 100% mRS at 90d

(shift)

REVASCAT

(n=206)

BMT

8.0h

223 min

Halted

after 1st

interim


(30’) 73%

269 min 100% mRS at 90d

(shift)







<

33







Clinical trial

Control

Time

window

OTR time

(randomisatio)

Trial end Proven

occlusion

Ischaemic

penumbra

IV alteplase

(%)

OTG time Stent-

riever

Outcome

variable

MR CLEAN

(n=500)

IV alteplase

6.0h

204 min

Ended ICA, M1, M2,

A1, A2

NA rt-PA

failure

89%


(shift)

ESCAPE

(n=316)

BMT

12.0h

169 min


Good collaterals

Bridging

75%


(shift)

EXTEND IA

(n= 70)

IV alteplase

4.5h

157 min


Tmax 6sec

Core <70mL

Bridging

100%

210 min 100% 24h

reperfusion

3 days NIHSS

SWIFT

PRIME

(n=196)

Iv alteplase

6h

188 min


Bridging

100%

224 min 100% mRS at 90d

(shift)

REVASCAT

(n=206)

BMT

8.0h

223 min

Halted

after 1st

interim


(30’) 73%

269 min 100% mRS at 90d

(shift)







MR CLEAN october 2014

ESCAPE february 2015

EXTEND-IA february 2015

april 2015

REVASCAT april 2015

Clinical trial Median NIHSS

improvement at

24h

mRS 0-2

T vs C

Adj. OR, 95%CI

24h Complete

recanalisation

T vs C

Infarct volume

median (IQR)

T vs C

MR CLEAN

(n=500)

IV alteplase

-2.6 33% vs 19%

2.2 (1.4, 3.4)

75% vs 34% 49 (22,96)

vs

79 (34-125)

ESCAPE

(n=316)

BMT

-4.0 53% vs 29% NA NA

EXTEND IA

(n= 70)

IV alteplase

80% vs 37% 71% vs 40%

4.2 (1.4, 12)

94% vs 43% 11 (0, 24)

vs 35 (6, 73)

SWIFT PRIME

(n=196)

Iv alteplase

-4.6 60% vs 35%

2.7 (1.5, 4.9)

83% vs 40%* NA

REVASCAT

(n=206)

BMT

58% vs 20% 44% vs 28%

2.1 (1.1, 4.0)

NA 16 (8, 58)

vs

39 (12, 87)

T, thrombectomy; C, control; IQR, interquartile range; mRS, modified

Rankin score; BMT, best medical therapy; OR, odds ratio

* Successful reperfusion (>90%) on CTP or MRI

I farct growth

Decrease of 8 or ore poi ts i NIHSS score or score = 0-2

Clinical outcomes NIHSS improvement at 24 h

mRS 0-2 ( 3 m)






Clinical trial

Control

Death at 90 days

Thrombectomy

vs Control

SICH (PH2)

Thrombectomy

vs Control

Malignant

oedema

Thrombectomy

vs Control

SAH

Thrombectomy

vs Control

Progressing

stroke

Thrombectomy

vs Control

MR CLEAN

(n=500)

IV alteplase

21% vs 22% 6% vs 5.2% NA 0.9% vs 0% 20% vs18%

ESCAPE

(n=316)

BMT

10% vs 19% 3.6% vs 2.7% 5% vs 11% 0.6% vs 0% NA

EXTEND IA

(n= 70)

IV alteplase

9% vs 20% 0% vs 6% NA 1% vs 0% NA

SWIFT PRIME

(n=196)

IV alteplase

9% vs 12% 0% vs 3.1% NA 4% vs 1% NA

REVASCAT

(n=206)

BMT

18%/ vs 15% 1.9% vs 1.9% 11% vs 10% 4.9% vs 1.9% 15% vs 13%

BMT: Best medical therapy (includes IV alteplase if eligible); SICH,

symptomatic intracerebral haemorrhage; SAH, subarachnoid

haemorrhage

Alteplase (rt-PA) does not have marketing approval in Europe

for treatment >4.5 hours after stroke onset.

Safety variables






Clinical trial Median NIHSS

improvement at

24h

mRS 0-2

T vs C

Adj. OR, 95%CI

24h Complete

recanalisation

T vs C

Infarct volume

median (IQR)

T vs C

MR CLEAN

(n=500)

IV alteplase

-2.6 33% vs 19%

2.2 (1.4, 3.4)

75% vs 34% 49 (22,96)

vs

79 (34-125)

ESCAPE

(n=316)

BMT

-4.0 53% vs 29% NA NA

EXTEND IA

(n= 70)

IV alteplase

80% vs 37% 71% vs 40%

4.2 (1.4, 12)

94% vs 43% 11 (0, 24)

vs 35 (6, 73)

SWIFT PRIME

(n=196)

Iv alteplase

-4.6 60% vs 35%

2.7 (1.5, 4.9)

83% vs 40%* NA

REVASCAT

(n=206)

BMT

58% vs 20% 44% vs 28%

2.1 (1.1, 4.0)

NA 16 (8, 58)

vs

39 (12, 87)

T, thrombectomy; C, control; IQR, interquartile range; mRS, modified

Rankin score; BMT, best medical therapy; OR, odds ratio

* Successful reperfusion (>90%) on CTP or MRI

I farct growth

Decrease of 8 or ore poi ts i NIHSS score or score = 0-2

GROWTH INFARCTION






Recanalization rate

Functional outcome by recanalization rate

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

30% 40% 50% 60% 70% 80% 90% 100%

MR CLEAN

EXTEND IA

ESCAPE SWIFT PRIME

REVASCAT

mR

S ≤

2 (%

)

Recanalisation rate (%)

Reperfusion rate

Time to recanalization

time from last seen normal to groin puncture

STUDI

O

MR-

CLEAN

ESCAP

E

EXTEN

D-IA

SWIFT-

PRIME

REVAS

CAT

Mazighi et al Circulation. 2013;127:1980-1985

Metanalysis of 7 studies on endovascular treatment

It confirms that the time

from the onset to

reperfusion influence the

mortality and the chance to

obtain a favorable outcome:

it should be considered the

main target during the

management of acute

ischemic stroke

The favorable clinical outcome (mRS score, 0–2) was significantly reduced when the

time to reperfusion increased, OR adjusted for increasing intervals of 30 minutes 0.79

(95% CI, 0.72–0.87; P<0.001)

Abilleira S et al. Stroke. 2014;45:1046-1052 Parameter: onset to groin puncture

Bridging or rescue

52

?

Probability of achieving a mRS 0-2 at 90 days with IV tPA

or mechanical thrombectomy by treatment delay

Emberson et al. Lancet 2014

Onset to IV tPA infusion or to reperfusion time in thrombectomy trials

* 2.0 hours corresponds to the theoretical shortest delay in local hospitals

IV tPA*

REVASCAT

MR CLEAN

SWIFT RIME

EXTEND – IA &

ESCAPE

4·2

Bridging or rescue

RCT OTG IV tPA Ischemic

penumbra

Outcome

Mrs 0-2 TvsC

MR CLEAN 260 min failure NA 33% vs 19%

ESCAPE 185 min bridging Aspect 6-10

good collaterals

53%vs 29%

EXTEND IA 250 min bridging Core < 70ml

(Tmax 6 sec

71% vs 40%

SWIFT PRIME 224mim bridging Aspect 6-10

(MRI-CTP)

60 vs 35%

REVASCAT 269 min failure Aspect 6-10 44 %vs 28 %

Patients selection

Imaging selection: outcome

MR Clean

ESCAPE

Goyal M et al. N Engl J Med 2015; ePub February 11

Berkhemer OA et al. N Engl J Med 2015;372:11-20

Saver J et al. N Engl J Med 2015, ePub April 17

Jovin T et al. N Engl J Med 2015, ePub April 17

SWIFT PRIME

REVASCAT

Collateral circulation

Collaterals at Angiography and Outcomes in the Interventional Management of Stroke (IMS) III Trial

Stroke Volume 45(3):759-764 February 24, 2014

RE-evaluation of IMS3 patients where the collateral circulation was assessed (83%)

The presence of good collaterals was significantly correlated to the recanalization

Significant predictor of favorable clinical outcome after 3 months

ESCAPE

Careggi Collateral Score

(CCS)

Semi-quantitative

Analysis (EXTENSION of

Collateral circulation)

Variability of the mismatch and extension of ischemic core in relation to

different grades of efficacy of collateral circulation

A B C c

E

p Ip

c c

I

p I

p

E

p E

p

CCS

0-1

CC

S2

CCS

3-5

C: core ;

Ip : Internal penumbra (savageable by recanalization);

Ep : External penumbra (savageable by collaterals)

Mangiafico S, Consoli A. CAPRI Study

Liebeskind, Stroke 2014

metanalysis

Balami et al., International Journal of Stroke 2015

Clinical Outcome for each recanalization grade and occlusion site

(Outcome Curves: mRS0-2 and mRS6 for each recanalization grade)

Anterior circulation Analysis of 22.02-16

Combined Treatment - only TM: Recanalization rates (TICI)

No significant differences in recanalization rate

Analisi del 22.02-16

Anterior circulation

TM

vs

tPA ev+TM

outcome / timing

time of end of the procedure

300 min

Analysis of 22.02-16

conclusions

• Trials and data collected from da studies and registries confirm that the favorable clinical outcome after thrombectomy depends on the recanalization grade, the time to reperfusion (better if within 240 min from the onset) and an appropriate patient selection (core extension and collateral circulation)

• In occlusions of the anterior circulation the endovascular treatment should be started withour waiting for a clinical improvement after IV tPA (bridging, no rescue)

Intracranial

revascularization in Acute

Stroke: Data and Trials

Session 4: Target Stroke

Intracranial revascularization in Acute Stroke: Data and · PDF fileIntracranial...

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