Triaging stroke patients for IA Therapy: When to be aggressive and ...

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Triaging stroke patients for IA Therapy: When to be aggressive and ...

DWI Lesion as a Pivotal

Biomarker for

Intra-arterial Stroke Therapy

Albert J. Yoo, MD

Director of Acute Endovascular Stroke Therapy

Division of Diagnostic and Interventional

Neuroradiology,

Massachusetts General Hospital


Presenter Disclosure

• Penumbra, Inc.

– Research support: Core imaging lab for stroke

imaging trials

• Remedy Pharmaceuticals, Inc.

– Research support: Core imaging lab for GAMES Pilot

trial


Take-home messages

• Final infarct volume is a critical determinant of

outcome following intra-arterial stroke therapy

• Pre-treatment core infarct volume predicts the

clinical response to endovascular therapy

• DWI is the best available imaging tool to quantify

hyperacute core infarct volume


Take-home messages

• Final infarct volume is a critical determinant of

outcome following intra-arterial stroke therapy

– Quantifying absolute lesion volume is important

• Pre-treatment core infarct volume predicts the

clinical response to endovascular therapy

• DWI is the best available imaging tool to quantify

hyperacute core infarct volume


Final infarct volume: A pivotal

biomarker following IAT

• Methods

– Consecutive AIS pts treated with IAT:

• Anterior circulation PAO

• Final infarct imaging between 24 hrs and 2 weeks

• Available 90-day mRS

• Results

– 107 pts with mean age 67 yrs and median NIHSSS 17

– TICI 2-3 reperfusion: 73%

– Median time to final infarct imaging: 41.8 hrs (NCCT in 58.9%)

– Median final infarct volume: 71.4 mL

– Only final infarct volume and age were independent predictors of

90-day mRS 0-2

– Final infarct volume was the single best discriminator of 90day

good outcome (mRS 0-2; AUC=0.86)

Stroke. 2012; In press.


Final infarct volume: A pivotal

biomarker following IAT

Stroke. 2012; In press.


PATIENTS WITH M1 OCCLUSION (N=178): MULTIVARIATE ANALYSIS

PREDICTORS OF GOOD OUTCOME

Odds Ratio p value 95% CI

Age 0.84 0.001 0.773-0.925

Follow-up DWI

Volume 0.98 0.004 0.971-0.994

Courtesy of Dr. Tudor Jovin

Zaidi et al, Stroke 2011 (abstract)


ROC INFARCT VOLUME VS. OUTCOME

Courtesy of Dr. Tudor Jovin


Volume thresholds for poor outcomes

Volume threshold

(cm 3 )

Specificity (95% CI)

for poor outcome

Odds ratio (95% CI)

for poor outcome

P-value

>80 85.2% (66.3-95.8%) 8.63 (2.73-27.3) 90 88.9% (70.8-97.5%) 10.3 (2.86-37.0) 100 92.6% (75.7-98.9%) 14.5 (3.22-65.5) 110 96.3% (81.0-99.4%) 27.3 (3.54-211.2) 120 100% (87.1-100%) --- ---

Poor outcome = mRS 3-6

Stroke. 2012; In press.


Risk of sICH vs. Infarct size

• In multicenter study of 645 pts treated with

IV or IA thrombolysis, (Ann Neurol 2008; 63:52-60)

– Larger baseline DWI lesion volume was an

independent predictor of sICH

– DWI volume >100 mL 16.1% sICH rate

• DEFUSE post hoc analysis (Stroke 2007; 38:2275-8)

– Risk of sICH in large infarcts is further

increased by reperfusion


Imaging selection for IAT

• The important question: How much brain

is dead on arrival?


Take-home messages

• Final infarct volume is a critical determinant of

outcome following intra-arterial stroke therapy

• Pre-treatment core infarct volume predicts the

clinical response to endovascular therapy

– Is perfusion imaging necessary?

• DWI is the best available imaging tool to quantify

hyperacute core infarct volume


Stroke 2003; 34:2426-35.


Imaging selection for IAT

• An acute infarct volume threshold of 70 cm 3

has a high specificity for predicting a poor

outcome 1,2

1 Sanak et al. Neuroradiology. 2006; 48: 632-9.

2 Yoo et al. Stroke. 2010; 41:1728-35.


• Methods:

– N = 34 patients

– DWI/PWI prior to IAT

– Recanalization Success

– Time to Recanalization

– Final Infarct Volume

– Good Outcomes = 3 month mRS ≤ 2

Stroke 2009; 40: 2046-54.


Number of Good vs Poor

Clinical Outcome by Imaging Selection and Time to Recanalization

14

12

10

8

6

4

2

0

64%

Clinical Outcome

p


Volume (cm 3 )

350

300

250

200

150

100

50

0

Admission DWI and MTT

p


Definitions (DEFUSE 2)

Variable Criteria

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

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 NIHSSS at

day 30 or NIHSSS of ≤1 at day 30

*in patients with a baseline PWI(Tmax>6s) lesion that is ≥10 ml

**in patients with a major vessel occlusion (TICI 0 or 1) on baseline imaging

DEFUSE 2 Investigator Meeting, Palo Alto, December 2011

Courtesy of Dr. Greg Albers


• For proximal artery occlusions treated with IAT,

smaller core infarct volumes better outcomes

• Xe-enhanced CT: Jovin et al, Stroke. 2003; 34: 2426-2433

• MRI DWI: Yoo et al., Stroke. 2009; 40: 2046-2054

• CT Perfusion CBV: Gasparotti et al., AJNR. 2009; 30: 722-

727

• CTA Source Images: Lev et al., Stroke. 2001; 32: 2021-

2028

• NCCT ASPECTS: Hill et al., Stroke. 2003; 34: 1925-1931

(PROACT-II); Hill et al., AJNR. 2006; 27: 1612-1616 (IMS-

1); Goyal et al., Stroke. 2011; 42:93-97 (Penumbra Pivotal)


Imaging selection for IAT

• Does perfusion imaging add any further

information?


CBF (mL/

100g/min):

>20

8 to 20

0 to 8

Stroke 2003; 34:2426-35.


Imaging selection for IAT

• PWI/DWI mismatch is not discriminatory in

the setting of large vessel occlusion –

volume of MCA territory is ~300cm 3


• 116 pts with ICA or proximal MCA occlusions

• MRI DWI/PWI (MTT or TTP with 4 sec delay

threshold)

• 90/93 pts with DWI volume ≤100mL had at least

100% mismatch

Courtesy of Dr. R. Gilberto González


• Single-center, 10 year experience (~40 treatments/yr)

• Identified 8 patients with matched DWI/PWI lesions

(


• Median DWI volume: 119.5 mL

– 83% with >100 mL lesion

• Median PWI volume: 118.0 mL

TTP DWI


• Can the NIHSS score be used to identify a

clinically significant territory at risk?


Approximately 30% of patients with MCA M1

segment occlusions have an NIHSS score


NIHSS


IA efficacy vs. NIHSS

Target NIHSS: ≥10

PROACT II (JAMA. 1999;282:2003-2011)


• Clinically significant penumbra for IAT:

– Proximal artery occlusion

– Significant neurological deficit (e.g.,

NIHSSS ≥10)

– Small pre-treatment core infarct (e.g., ≤70

mL)


Take-home messages

• Final infarct volume is a critical determinant of

outcome following intra-arterial stroke therapy

• Pre-treatment core infarct volume predicts the

clinical response to endovascular therapy

• DWI is the best available imaging tool to quantify

hyperacute core infarct volume


How should we measure core?

• With the best available method:

diffusion MRI

• Highly sensitive (91-100%) and

specific (86-100%) within the first 6

hrs of stroke onset

– Similar accuracy to 11 C flumazenil PET

• Allows volumetric quantification

• Excellent inter-reader agreement

• Class I, level of evidence A

recommendation*

* Stroke 2009; 40: 3646-3678

Neurology 2010; 75: 177-185


Is diffusion lesion reversal

a significant problem?

• Several reports of DWI lesion reversibility (8-44%)

– Tissue reperfusion is a prerequisite

– Other predictors: earlier time to imaging, smaller reduction in

ADC

• However unlikely to be clinically significant

– Has not been demonstrated to improve clinical outcomes*

– Mean volumes of tissue reversal are small (5-16 cm 3 )

– Delayed regrowth into the initial lesion is seen, even when blood

flow is restored

– EPITHET post-hoc analysis**: when taking into account chronic

infarct involution, true reversal in 6.4% with median volume of

2.7 cm 3 (IQR: 1.6-6.2 cm 3 )

* Stroke 2004; 35:514-519.

Ann Neurol 2004; 55:105-112.

** Neurology 2010; 75:1040-1047.


• Identifying infarct core using CT:

Limitations of perfusion imaging for

defining core


• CBV

What CTP parameter best

defines core?

– Wintermark M, et al. Stroke; 37: 979-985

– Schaefer PW, et al. Stroke; 39: 2986-2992

• CBF

– Bivard A, et al. Cerebrovasc Dis 2011; 31:

238-245

– Kamalian S, et al. Stroke 2011; 42:1923-1928


• Findings:

• CBF is the most accurate parameter for DWI core

• Between three different post-processing algorithms,

significant variation exists in optimal parameter

thresholds (optimal CBF: 4.7 vs 5.4 vs 10 ml/100g/min)

• Conclusion: Quantitative thresholds have limited

generalizability between platforms

Stroke 2011; 42:1923-1928.


Sources of variability in

perfusion imaging

• Patient

– Delay and dispersion (variable collaterals and stenoses between

AIF and tissue)

• Acquisition

– Duration of cine imaging (truncation of tissue contrast-time

curve)

– Shuttle mode (increased image noise)

• Post-processing

– ROI selection of AIF and VOF

– Delay-sensitive vs. delay correction

– Blackbox algorithms (vendor-specific and not well validated)

• Analysis

– Choice of perfusion parameter


“Clinical treatment decisions that involve diagnostic test

results cannot be based on such inconsistent values or on

such variable definitions of tissue state any more than use of

a therapy should be based on inconsistent treatment trials.”


• “Until reproducibility

is improved…, MR

is not suitable for

reliable quantitative

perfusion

measurements….”

JCBFM 2002; 22: 1149-56.


Intraobserver variability Interobserver variability

• “…on the basis of postprocessing variability alone, if the

true CBF value is 20 mL/100g/min, measurements of

CBF…can vary by approximately ±7-10 mL/100g/min….”

AJNR 2004; 25:97-107.


MGH approach to IAT selection

Rule out hemorrhage,

IV tPA eligibility

Proximal artery

occlusion, cervical

disease

Infarct size estimation

Expert Rev Cardiovasc Ther 2011; 9:857-876.


Conclusion

• Absolute infarct volume is a pivotal biomarker following

IAT

• For IAT selection, core infarct size is a surrogate for

collateral physiology and predicts clinical response to

IAT

– Diffusion MRI is the best available method for quantifying the

infarct core in the treatment setting

• Identifying infarct core using perfusion imaging (CTP) is

questionable and requires further standardization and

validation NCCT remains the best validated CTbased

approach


The problem with NCCT

• NCCT is much less sensitive than MRI for

detection of acute infarction (75%

sensitivity 1 ), especially when it is large

(>33% of MCA territory; 14-43%

sensitivity 2 )

1 Barber PA, et al. Stroke. 1999; 30: 2059-65.

2 Lansberg MG, et al. Neurology. 2000; 54: 1557-61.


NCCT vs DWI

Δ15 min.


• Alberta Stroke

Program Early

CT Score

• Reliable, semiquantitative

• ASPECTS:

scored from 0 to

10 – lower score

indicates more

ischemic burden

ASPECTS

C

IC

M1

L

I

M2

M3

M4

M5

M6


• PROACT-II: IAT x dichotomized ASPECTS interaction


• Two experienced

neuroradiologists

• Moderate

agreement for

dichotomized

ASPECTS (0-7 vs.

8-10: κ=0.53)

• 76.8% observed

rate of agreement

AJNR 2012; In press.


Is ASPECTS >7

the right threshold?

AJNR 2012; In press.

• For terminal ICA or

proximal M1 occlusions:

– Usually have

ASPECTS ≤7

– Caudate, lentiform and

insula (perforator

supply)

– These patients can do

well after IAT

• ~50% of patients with

ASPECTS 7-8 prone

to disagreement using

threshold of > vs. ≤7

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