Time-based approach to stroke evidence

Summary

ASPECT SCORE http://www.aspectsinstroke.com/

0-6 hours LVO without large CT hypodensity

< 1/3 MCA territory (or core < 70 ml) or ASPECTS >/=6

Consider proceeding directly to Thrombectomy

4.5-6 hours with CT hypodensity

Use advanced imaging to exclude large completed infarct

CTP most available yet technically remains quite variable

Core= CBF<30% (<70 ml) , at risk= Tmax>6 seconds

Mismatch at least 1.8

MRI more logistic challenge but more consistent results

6-24 hours

Use advanced imaging for potential thrombectomy candidates

Unknown time (but last seen well <24 hours)

DWI/FLAIR mismatch for thrombolysis

2018 AHA/ASA guidelines

· All acute stroke patients: Noninvasive cervical and cerebral vascular imaging (Level 1A evidence)

· 6-24 hours from last known well: CT Perfusion or MRI diffusion/perfusion (Level 1A evidence). Penumbral imaging is recommended after 6 hours, before is largely based on non-contrast CT. the goal of all this imaging is to determine the core.

· Acute IV treatment altered by CT hypodensity, CT dense MCA, MR microbleeds or delay for further imaging (Level 3, no benefit).

· Interesting: prognostic importance of CT aspects is similar to CTP core volume prognosticating 3 month outcomes https://jnis.bmj.com/content/neurintsurg/11/7/670.full.pdf

· “If you can measure the core, there is no need to measure penumbra” Gil Gonzales, UMass.

· CTP compared to DWI: 95% confidence limits for ctp is 54 to minus 59 ml!! https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.114.007117

· Odds ratio of favorable outcome if patients were chosen with ctp vs mri. Likelihood of a patient having a good outome is better by a factor of 2 if selected by mri vs ct even though these patients received treatment 30 mins later. Also, HERMES: Treatment benefit to EVT, regardless of admission CTP derived “core” volume. Don’t refuse thrombectomy based on CTP under 6 hours.

https://pubmed.ncbi.nlm.nih.gov/30413385/

· Core measurement error CTP>DWI

· DWI good outcomes > CTP

· DWI futile thrombectomy < CTP

· Core from CTP unreliable especially <6h from last known well. Ghost core concept. https://www.karger.com/Article/Fulltext/490117

· CTP and DWI: Under 6 hours, these imaging studies help with prognostication not treatment decision https://www.ahajournals.org/doi/10.1161/strokeaha.115.010250

· Benefit to thrombectomy at every aspects except the lowest aspects. There is not a precise need to differentiate ASPECTS 5 to 8 because they are all going to get treated

https://pubmed.ncbi.nlm.nih.gov/30264728/

· Remember, the patient’s deficit comes from core and penumbra. So if you image non contrast and the patient has a large deficit, you have a large penumbra.

· NIHSS vs CT perfusion maps: no difference in treatment decision http://www.ajnr.org/content/33/10/1893

Alteplase therapy evidence:

Jury is still out if iv alteplase benefits or hurts thrombectomy within 4.5 hours.

Non-inferiority study of thrombectomy alone vs combined with alteplase at 4.5 hours https://www.nejm.org/doi/full/10.1056/NEJMoa2001123

Pooled analysis of 6756 patients from 9 trials suggest no benefit of alteplase over placebo after 5 hours https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60584-5/fulltext

However, extending up to 9 hours in another metaanalysis showed benefit https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31053-0/fulltext

RAPID: what is the HIR (hypoperfusion intensity ratio)? Ratio of the Tmax>10s to >6s volume. Basically core volume (Tmax >10s) / ischemic volume (Tmax >6s). Low HIR indicates good collaterals (less core, large penumbra). It correlates with angiographic collaterals https://onlinelibrary.wiley.com/doi/abs/10.1111/ene.14181?af=R

https://jnis.bmj.com/content/neurintsurg/early/2020/05/07/neurintsurg-2020-015953.full.pdf

Under 6 hours

MR CLEAN https://www.nejm.org/doi/full/10.1056/nejmoa1411587

Any age

NIHSS ³ 2

Imaging based on CT angiography (no penumbral imaging)

LVO required

“No benefit to thrombectomy with poor collaterals”

https://pubmed.ncbi.nlm.nih.gov/26903582/

Benefit to EVT regardless of presence of imaging mismatch

https://pubmed.ncbi.nlm.nih.gov/26542698/

EXTEND-IA https://www.nejm.org/doi/full/10.1056/nejmoa1414792

Any age

Any NIHSS

Imaging using CT angiography and/or CT Perfusion (rapid)

LVO required

Core < 70 mL (from rCBF <30% and penumbra with Tmax > 6 sec)

Mismatch ³ 1.2

Intervention: thrombolysis

SWIFT PRIME https://www.nejm.org/doi/full/10.1056/nejmoa1415061

Age 18-80

NIHSS ³ 8

Imaging based on CT angiography or MRI and perfusion

ASPECTS 6-10 or 1/3 MCA territory on CT/MR

LVO required

No cervical ICA occlusion

Core < 50 mL (on MRI or CT) (pre-revision)

Mismatch > 1.8

Ischemic penumbra <15 cc

ESCAPE (under 12 hours) https://www.nejm.org/doi/full/10.1056/nejmoa1414905

Any age

Any NIHSS

Imaging based on CT angiography (preferably multiphase CTA)

LVO required

ASPECTS 6-10

Good collaterals (>50%) of MCA

HERMES of the above 4 plus REVASCAT https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00163-X/fulltext

6 to 16 hours

DEFUSE 3 https://www.nejm.org/doi/full/10.1056/NEJMoa1713973

NIHSS ³6

Imaging based on CT and MR perfusion (rapid)

LVO required (ICA or M1)

Core <70 ml, Penumbra Tmax > 6s

Mismatch ratio ³1.8

Mismatch volume ³15 ml

Intervention: Thrombectomy NNT 3.2

6 to 24 hours

DAWN https://www.nejm.org/doi/full/10.1056/nejmoa1706442

Imaging based on CT angiography and perfusion (rapid)

LVO required (ICA or M1)

Age and NIHSS, and core size based on following criteria:

A) Age ³80, NIHSS ³10, Core <21

B) Age <80, NIHSS ³10, Core <31

C) Age <80, NIHSS ³20, Core 31 to 51

Intervention: Thrombectomy NNT 3

Argument against perfusion: Sub analysis: “High percentage of patients with good/fair aspects (6+) have imaging mismatch according to these criteria. Do you need CTP to tell you there is a mismatch?” https://jnis.bmj.com/content/neurintsurg/early/2020/04/03/neurintsurg-2020-015921.full.pdf

The additional benefit of imaging based mismatch above and beyond a clinical-core mismatch in a real world situation is unknown.

Argument against perfusion (M. Goyal): the combination of NCCT and CTA can identify ELVO patients who are candidates up to 24 hours from symptom onset. Do not confuse the ability to prognosticate outcome with the ability to identify treatment candidates.

Unknown onset (wake up stroke/unwitnessed stroke, must be under 24 hours)

WAKE-UP https://www.nejm.org/doi/full/10.1056/nejmoa1804355

MRI DWI positive/FLAIR negative mismatch guides i.V. alteplase

Proves this can effectively select patients for i.V. thrombolysis

DWI/FLAIR mismatch can safely select patients https://pubmed.ncbi.nlm.nih.gov/29689135/

What is core?

Rapid: rCBF <30%. Also, Tmax>10 seconds.

DWI? ADC<620

Flumazenil-PET is the gold standard

DWI is the operational standard

DWI core > 70ml “1/3 MCA Rule” is a pivotal imaging marker for poor outcome and associated with higher ICH risk. (A. Yoo and P. Schaefer)

Difference in the speed of infarct progression.

Some patients have whole MCA infarcted at 2.5 hours

Others have almost nothing at 8 hours.

https://pubmed.ncbi.nlm.nih.gov/25190444/

CTP/DWI correlation?

CBF is best across platforms. https://pubmed.ncbi.nlm.nih.gov/21546490/

CTP core threshold: early is different from late! https://pubmed.ncbi.nlm.nih.gov/31480968/

CTP is highly variable for core in individual patients. Variability is 50 to 60 mls. https://www.ahajournals.org/doi/full/10.1161/STROKEAHA.114.007117

Late trials upcoming

MR CLEAN-LATE

CT Perfusion > 1/3 MCA

6-24 hours

Large core stroke trials

SELECT2

ASPECTS 3-5, (rCBF<30% or ADC<620) >50 ml

TESLA

ASPECTS 2-5

TENSION

CT or MR ASPECTS 3-5

RESCUE Japan

CT or MR ASPECTS 3-5

LASTE France

CT or MR ASPECTS 0-5 (3-5 for age > 80)

LOW NIHSS stroke

ENDLOW

NIHSS <6