reperfusion

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reperfusion

Results of DEFUSE 2:

Imaging Endpoints

Presented on behalf of the

DEFUSE 2 Investigators

DEFUSE 2


Gregory W. Albers:

DISCLOSURES

DEFUSE 2

Lundbeck: Steering Committee Co-Chair, DIAS 3/4

Concentric: DSMB Chairman, Trevo 2

iSchemaView: Co-founder


Background

DEFUSE 2

Can DWI/PWI identify subgroups that have

a differential response to reperfusion?

DEFUSE-EPITHET Pooled Analysis*:

Median Growth with

Reperfusion (ml)

Median Growth

without

Reperfusion (ml)

p value

Target Mismatch (N=58) 1 27


Background

Controversy and contradictory data

regarding the scope and clinical

relevance of DWI reversibility

Uncertainty regarding the accuracy of

PWI for detecting critical hypoperfusion

DEFUSE 2


DEFUSE 2 Study Aim

To demonstrate that an automated

software (RAPID) can allow

clinicians to prospectively identify

MRI profiles that predict clinical and

radiographic outcomes following

endovascular reperfusion.

DEFUSE 2


NIH

Study design

Austria

Multi-center prospective cohort study

NINDS sponsored

9 study sites

Seattle

Utah

Stanford

Northwestern

Hawaii

Pittsburgh

Portland

DEFUSE 2


Inclusion Criteria

NIHSSS ≥5

Age ≥18

Planned endovascular acute stroke

therapy (groin puncture


DEFUSE 2 protocol

MRI

baseline

Intra-arterial

Therapy

MRI

Post-procedure

(reperfusion)

Favorable clinical response:

DEFUSE 2

MRI

Day 5

(FLAIR volume)

•NIHSS score of 0-1 at day 30 or

improvement of NIHSS score by ≥8 points

between baseline and day 30


Definitions

Variable Criteria

Target Mismatch PWI(Tmax>6s) / DWI >1.8

DWI 10s) 50% reduction in PWI (Tmax>6s)

volume at early follow-up

Reperfusion (DSA criteria) TICI 2b or 3 at completion of

procedure

Favorable Clinical

Response

≥8 point improvement in NIHSS

at day 30 or NIHSS of ≤1 at day 30


Target Mismatch

(n=78)

Reperfusion

assessed (n=78)

Day 5 MRI

(n=65)

Signed Consent

MRI performed (n=138)

Endovascular Cohort

(n=110)

Investigator determined

MRI Profile (n=104)

No Target Mismatch

(n=26)

Reperfusion

assessed (n=21)

Day 5 MRI

(n=21)

No endovascular

therapy (N=28)

Baseline PWI

technically

inadequate (n=6)

DEFUSE 2

Reperfusion can not be

assessed (n=5)

• No stroke (n=3)

• PWI


Baseline characteristics N= 104

Mean (SD) age (years) 66 (15)

Median (IQR) NIHSS 16 (11-19)

Number (%) pretreated with IV tPA treatment 53%

Median (SD) DWI volume (ml) 15 (5-32)

DEFUSE 2

Median (SD) PWI(Tmax>6s) volume (ml) 79 (43-115)

Median time (IQR) from onset to IA treatment, hrs 5.9 (4.0-7.7)


DEFUSE 2 Study

Imaging Hypothesis 1

Reperfusion is associated with

reduced infarct growth in Target

Mismatch patients compared to

patients with other MRI profiles

DEFUSE 2


DEFUSE 2: Lesion growth* in

Target Mismatch Patients (N=65)

Reperfusion

N=42

No reperfusion

N=23

Median growth (%) 39% 412% 0.003

Odds ratio for favorable clinical response

with reperfusion: 4.4 (95%CI 1.5-13.0)

* 5 day FLAIR volume – baseline DWI volume

P


DEFUSE 2: Lesion growth* in

Non-Target Mismatch Patients (N=19)

Reperfusion

N=11

No reperfusion

N=8

Median growth (%) 56% 11% 0.5

Odds ratio for favorable clinical response

with reperfusion: 0.1 (95%CI 0.007-0.93)

* 5 day FLAIR volume – baseline DWI volume

P


DEFUSE 2 Study

Imaging Hypothesis 2

Baseline lesions with ADC < 600 will

be reliably incorporated into 5 day

FLAIR (the volume of “DWI reversal”

will be small).

DEFUSE 2


Are DWI lesions reversible

with endovascular therapy?

Median volume of DWI reversal*:

DEFUSE 2

patients with reperfusion (N=53) 2.5 cc (IQR 0.2-5.0)

pts without reperfusion (N=27) 0.6 cc (IQR 0.1-2.2)

p = 0.03

* Volume of DWI lesion not incorporated into co-registered 5 day FLAIR


60 yo male; R M1 occlusion, NIH 7

Automated RAPID output:


Follow-up MRI (3 hrs after

endovascular therapy)


5-day FLAIR: 7 cc; 30 day NIH 1

Baseline DWI lesion 12 cc, 5 cc “DWI reversal”


DEFUSE 2 Study

Imaging Hypothesis 3

PWI lesions with >6 sec Tmax delay

following endovascular therapy will be

incorporated into 5 day FLAIR lesion

DEFUSE 2


Did post-treatment PWI lesions predict

the volume of infarction at Day 5?

Among patients who did not reperfuse (N=28),

the percentage of PWI Tmax >6 sec voxels

incorporated into the coregistered 5 day FLAIR:

69%


66 yo with L MCA / ACA lesions; NIH 18

Post-procedure MRI


Post-procedure PWI

Tmax >6 sec = 78 cc

5 day FLAIR = 73 cc


Conclusions

• Target mismatch patients who achieve early

reperfusion have less infarct growth and more

favorable clinical outcomes; these benefits did not

occur in the non-Target mismatch group.

• Baseline DWI lesions (ADC 6 sec)

following endovascular therapy is very likely to

progress to infarction.


DEFUSE 2 - Study Organization

Sponsor: the National Institute of Neurological Disorders and Stroke

DEFUSE 2

Clinical Coordinating Center: G. Albers, S. Kemp, M. Lansberg, D. Thai

Clinical Site Investigators and Coordinators: T. Jovin, L. Wechsler,

S. DeCesare, M. Wilder, A. Sherr, H. Lutsep, D. Larsen, B. Keogh,

T. Czartoski, A. Brown, R. Bernstein, K. Muskovich, C. Chang, T. Stern,

S. Warach, L. Davis, F. Fazekas

Data Management and Statistical Analysis: S. Hamilton and M. Mlynash

Image Analysis Core: M. Straka, R. Bammer, A. Tipirneni, M. Inoue

Core Radiology Lab: M. Marks and G. Zaharchuk

DSMB: J. Saver, P. Fayad, G. Howard, T. Tomsick


M. Marks

M. Mlynash

M. Moseley

M. Lansberg

J.M. Olivot

M. Inoue

S. Kemp

A . Tipirneni

M. Straka

D. Thai

R. Bammer

G. Zaharchuk

S. Hamilton


Median difference between 5 Day FLAIR

volume and the union of the (post-procedure

PWI lesion + baseline DWI): +16 cc

FLAIR was >10 cc smaller than predicted: 11%

FLAIR was >30 cc larger than predicted: 33%

DEFUSE 2

Do post-treatment PWI lesions identify

critically hypoperfused tissue?


FLAIR Volume [ml]

Predicted infarct size vs. 5 Day FLAIR volume

600

500

400

300

200

100

0

(uncorrected for edema and hemorrhage)

0 100 200 300 400 500 600

DWI1+PWI2 Prediction [ml]

unity line

R=0.85, p < 0.0001


Baseline

DWI

Baseline PWI Day after 5

PWI treatment


Target Mismatch

(n=78)

Reperfusion

(n=46)

Day 5 MRI

(n=42)

Signed Consent

MRI performed (n=138)

Endovascular Cohort

(n=110)

Investigator determined

MRI Profile(n=104)

No reperfusion

(n=32)

Day 5 MRI

(n=23)

No Target Mismatch

(n=26)

Reperfusion

(n=12)

Day 5 MRI

(n=11)

No reperfusion

(n=9)

Day 5 MRI

(n=8)

No endovascular

therapy (N=28)

Baseline PWI

technically

inadequate (n=6)

DEFUSE 2

Reperfusion can not be

assessed (n=5)

• No stroke (n=3)

• PWI


Baseline characteristics

Target

Mismatch

(n=78)

DEFUSE 2

No Target

Mismatch

(n=26)

Mean (SD) age (years) 66 (16) 63 (13)

Median (IQR) NIHSSS 14 (11-20) 18 (12-19)

Number (%) pretreated with IV tPA treatment 36 (46%) 19 (73%)

Mean (SD) DWI volume (ml) 17 (15) 56 (61)

Mean (SD) PWI(Tmax>6s) volume (ml) 83 (38) 82 (77)

Mean (SD) time from onset to IA treatment (hrs) 6.6 (2.7) 5.3 (2.1)

Number (%) with early reperfusion 46 (59%) 15 (57%)

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