1. Endovascular Stroke Intervention: Standard of Care and Future Directions
Sameer A. Ansari, MD, PhD
Associate Professor
Departments of Radiology, Neurology, and Neurological Surgery
Northwestern University, Feinberg School of Medicine

2. Disclosures
No significant conflicts of interest or financial relationships to disclose with respect to industry consulting, or speaking.
There will be no discussion of unapproved/off-label or investigational device utilization.
Research Support:
NCT (PI) DAWN – Active NU Research Support (Stryker)
NCT (Co-I) START
Other Support:
NCT (PI) STARRT 13GRNT AHA (PI)
NCT (PI) FRED RSD1207 RSNA (PI)
NCT (PI) HEAT 1R01NS A1 (Co-I)
1R25NS (Co-I)
1R21EB A1 (Co-I)

3. Acute Ischemic Stroke High Mortality
>700,000 Strokes Annually in North America,
Every 45 seconds in the United States
High Mortality
Most Common Life Threatening Neurological Disease
3rd/4th Leading Cause of Death
200,000 Strokes are Fatal, every 3 minutes
30-day Mortality for Ischemic Stroke ~ 8-12%
5 year Mortality for Carotid Territory Stroke ~ 40%
Rehabilitation, Stroke Prevention, Chronic Management

4. Acute Ischemic Stroke High Morbidity
Most Common Cause of Long Term Disability
Long Term Survivors
15% Institutional Care
30% Dependent in Activities of Daily Living
60% Decreased Socialization Outside Home
Human and Economic Cost to US
~ $43 billion annually / 3 million Americans

5. Acute Ischemic Stroke Intervention
NEJM / International Stroke Conference
Five RCTs Demonstrated the Clinical Benefit of Endovascular Therapy (ET) for Patients with Emergent Large Vessel Occlusions (ELVO)
Significance ?  Time Constraints to Intervention
Only < 3-10 % Patients Present < 3 hours in Time for IV tPA

6. Acute Ischemic Stroke Intervention
Benefits of IV tPA
Time Dependent < 4.5 h
1.9 million neurons/min
Patient Eligibility for
ET Benefit ?
Poor Efficacy of IV tPA in ELVO
66% distal MCA, 35% proximal MCA, 9% ICA
Eligible ELVO-ET Population ~ 1-3% Ischemic Stroke
Severe Strokes (~ 60-80% Mortality / Morbidity)
Long Term Disabilities – Higher Proportion of
Healthcare Cost
Saver JL. Lancet 2010

7. History Acute Ischemic Stroke Intervention – Early 20th Century,
Traditional Nihilism, Limited to Post-Stroke Care / Rehab
1995 – Landmark NINDS RCT - IV tPA (Level 1A)
Improved Functional Outcomes / Independence with IV tPA (alteplase) < 3 hours  39% vs 26% (mRS 0-1)
1999 – PROACT-2 RCT – IA pro-urokinase vs IV heparin
Large Vessel Occlusions (M1-M2 MCA) (Level 2A)
Recanalization (TIMI 2-3)  66% vs 18%
Ineligible for IV tPA < 6 hours  40% vs 25% (mRS 0-2)

8. History 2004-2012 – IMS Investigators - IV tPA + IA Therapy (ET)
Thrombectomy Device Development
2006 – 1st Generation Devices
MERCI, Multi-MERCI Trials
Coil Retrievers
2008 – ECASS3 RCT - Extended IV tPA Time Window
IV tPA < 4.5 hours  52% vs 45% (mRS 0-1) (Level 1A)
2009 – 2nd Generation Devices
Penumba Pivotal/POST Trials
Aspiration Catheters

9. History 2012 – 3rd Generation Thrombectomy Devices SWIFT/TREVO2 Trials
Stent Retrievers
Balloon Flow Arrest
Large Bore Aspiration
2013 – 3 RCTs on IV tPA + IA ERT – No Clinical Benefit
IMS-3 / SYNTHESIS / MR RESCUE Trials
Valuable Lessons on Selection / Failure in Trial Design
Patients – Severe Neurological Symptoms ↑NIHSS
Target – Large Vessel Occlusions (ELVO)
Reperfusion – Modern Devices to ↑ TICI 2b/3
Time – Optimization of Imaging/Intervention Workflow
Tissue – Imaging Selection to Differentiate / DEFUSE-2
Salvageable Ischemic versus Futile Infarcted Tissue

10. IMS-3 IMS-3 Trial – Phase 3, Multicenter, RCT 2:1
656 Patients (434 IV tPA + IA ET vs 222 IV tPA alone)
NIHSS > 8-10, Symptom Onset < 3 hours
Trial Terminated, Futility for Clinical Benefit:
mRS days: 38.7% IV tPA vs 40.8% ERT, (p=0.25)
Despite Trial Limitations, Subgroups with ET Benefit
NIHSS 8-19: 51.8% vs 51.2% (p=0.83)
NIHSS ≥ 20: 16.8% vs 23.8% (p=0.06)
CTA LVO: % vs 47.2% (p=0.0114)
IV tPA < 120 min and Recanalization < 4.5h (OR 1.77)
TICI 2b-3 vs TICI 0-2a Revascularization
~ mRS days: 48.2% vs 13.9% (p=0.001)

11. MR CLEAN
Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands
Phase 3 RCT 1:1, 500 Patients (267 IV tPA / 233 IV tPA + ET )
↑↓ Patient: Inclusion NIHSS > 2 (Median NIHSS 17-18)
↑ Target: CT/CTA - LVO (ICA, M1/M2)
↑ Reperfusion: Stent Retrievers 81.5%
TICI 2b/ %
↓↓ Time: Symptom Onset to IV tPA < 4.5 h
IA Treatment < 6 hour ~ 3h Delay IV tPA  GP
↓ Tissue: No Imaging (MR DWI-PWI /CTP) Selection
NCCT- median ASPECTS 9

12. MR CLEAN mRS 0-2 at 90 days: 19.1% vs 32.6%
IMS-3: 38.7% vs 40.8% (No ELVO 25%)

13. Onset to Groin Puncture
MR CLEAN
IV tPA
IV tPA + ET
Onset to IV tPA (89%)
85 min
87 min
Onset to Groin Puncture
260 min (3 hour delay)
Onset to TICI 2b/3 (58.7%)
332 min
*mRS 0-2 at 90 days
19.1%
32.6%
*DWI volume at 7 days
80 mL
49 mL
*NIHSS ≥ 20
OR 1.85 (95% CI, )
*Age ≤ 80 years
OR (95% CI, )
*Age ≥ 80 years
OR 3.24 (95% CI, )
SICH
6.4%
7.7%
NTE/DTE
0.4%
5.6%
Mortality
22%
21%

14. ESCAPE
Endovascular treatment for Small Core and Proximal Occlusion Ischemic Stroke – Trial Halted for ET Benefit
University of Calgary – Phase 3 RCT, 315 Patients MM ± ET
Invitation for Centers of Stroke Excellence
↑Patient: Inclusion NIHSS > 5 (Median NIHSS 16-17)
↑ Target: CTA LVO (ICA/M1)
↑↑Reperfusion: Stent Retrievers %
TICI 2b/3 72.4%
↑Time: Symptom Onset < 12 hours ± IV tPA
CTA to Groin Puncture < 60 minutes
CTA to Recanalization < 90 minutes
↑↓Tissue: CT ASPECTS MP CTA (Collaterals)

15. Onset to Groin Puncture
ESCAPE
IV tPA / MM
IV tPA / MM + ET
Onset to IV tPA (75%)
125 min
110 min
Onset to Groin Puncture
185 min (75 min)
CTA to Groin Puncture
51 min
Onset to TICI 2b/3 (72.4%)
241 min
*NIHSS at 24 hours 13 6
*mRS 0-2 at 90 days
29.3%
53%
SICH
2.7%
3.6%
*Mortality
19%
10.4%

16. ESCAPE

17. EXTEND-IA
EXtending the Time for Thrombolysis in Emergency Neurological Deficits - Intra-Arterial - Trial Halted for Benefit
Australia, National Stroke Research Institute -
Phase 2 RCT, 70 Patients IV tPA ± ET
↑ Patient: No NIHSS Inclusion (Median 13-17)
↑ Target: CTA LVO (ICA/M1-M2)
↑↑Reperfusion: Stent Retriever 86% / TICI 2b/3 86%
↑↑ Time: Symptom Onset to IV tPA < 4.5 hours
Symptom Onset to Groin Puncture < 6h
↑↑Tissue: CTP or MR DWI-PWI Mismatch (RAPID) Tmax >6 sec and DWI/CT-rCBF< 30% Mismatch > 1.2, Penumbra > 10 ml
Core Infarct Volume < 70mL

18. Onset to Groin Puncture MR/CTP Core /Perfusion > 6-9
EXTEND-IA
IV tPA
IV tPA + ET
Onset to IV tPA (100%)
145 min
127 min
Onset to Groin Puncture
210 min (83 min)
CT to Groin Puncture
93 min
Onset to TICI 2b/3 (86%)
248 min
MR/CTP Core /Perfusion > 6-9
18 mL / 115 mL
12 mL /106 mL
*Infarct Core at 24 hours
35 mL
11 mL
*NIHSS< 8 at 72 hours
37%
80%
*mRS 0-2 at 90 days
40%
71%
SICH 6% 0%
NTE/DTE
5.7%
Mortality
20% 9%

19. SWIFT PRIME
Solitaire FR With the Intention For Thrombectomy as PRIMary Endovascular Treatment for Acute Ischemic Stroke - Trial Halted Covidien Industry Sponsored ET Benefit
Phase 3 RCT 195 Patients 1:1 IV tPA ± ERT (Solitaire)
↑ Patient: NIHSS >8-29 (Median 17)
↑ Target: CTA/MRA LVO (ICA/M1)
↑↑Reperfusion: Stent Retriever 100%, TICI 2b/3 88%
↑↑Time: Symptom Onset to IV tPA < 4.5 hours
Symptom Onset to Groin Puncture < 6 h
Groin Puncture < 90 min from CTP/MRP
↑↑Tissue: CT ASPECTS 7-10 or
CTP /MR DWI-PWI Mismatch (RAPID) 78-87%
CT-rCBF or DWI Core Infarct< 50 mL Mismatch > 1.8, Penumbra > 15 ml

20. SWIFT PRIME IV tPA IV tPA + ET *mRS 0-2 at 90 days 35.5% 60.2%
Onset to IV tPA (100%)
117 min
110 min
Presentation to Groin Puncture
90 min
MR/CTP to Groin Puncture
57 min
Onset to TICI 2b/3 (88%)
252 min
MR/CTP Core /Perfusion Imaging
77 %
85%
*Reperfusion at 27h
40.4%
82.8%
*Improvement NIHSS at 27 hours
3.9 points
8.5 points
*mRS 0-2 at 90 days
35.5%
60.2%
SICH
3.1% 1%
Mortality
12.4%
9.2%

21. SWIFT PRIME

22. REVASCAT Phase 3 RCT 206 Patients 1:1 MM ± ERT (Solitaire)
Randomized Trial of Revascularization with Solitaire FR Device versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting within Eight Hours of Symptom Onset – 4 Spanish Centers, Trial Halted ET Benefit
Phase 3 RCT 206 Patients 1:1 MM ± ERT (Solitaire)
↑ Patient: NIHSS > 6, Median 17
↑ Target: CTA/MRA LVO (ICA/M1-M2)
↑ Reperfusion: Stent Retriever 100%, TICI 2b/3 67%
↓ Time: Symptom Onset < 8 hours
> 2 hour Delay IV tPA to Groin Puncture
↑↑Tissue: CT ASPECTS 7-10
MR DWI ASPECTS 6-10
CTP / MR DWI-PWI Small Core

23. Onset to Groin Puncture *CT/DWI Infarct Core at 24 h
REVASCAT
IV tPA / MM
IV tPA / MM+ ET
Onset to IV tPA (68-78%)
105 min
117 min
Onset to CTA /MRI
183 min
192 min
Onset to Groin Puncture
269 min (152 min)
Onset to TICI 2b/3 (67%)
355 min
*CT/DWI Infarct Core at 24 h
38.6 mL
16.3 mL
*NIHSS< 8 at 72 hours
20%
59%
*mRS 0-2 at 90 days
28 %
44 %
SICH
1.9 %
Mortality
15.5 %
18.4 %

24. THERAPY Phase 3 RCT 108 Patients 1:1 IV tPA ± ERT (Peumbra)
Assess the Penumbra System in the Treatment of Acute Stroke -
Study Limited due to Sample Size - Trial Halted after MR CLEAN
Per Protocol versus Intention to Treat Statistical Analysis
Penumbra Sponsored
Phase 3 RCT 108 Patients 1:1 IV tPA ± ERT (Peumbra)
↑ Patient: NIHSS > 8, Median 17-18
↑↑ Target: CTA LVO (ICA/M1-M2), Clot Length > 8 mm
↑ Reperfusion: TICI 2b/3 70%, Only 27% ACE
↑↓ Time: Symptom Onset < 4.5 hours
~ 2h Delay IV tPA  Groin Puncture
↓ Tissue: CT ASPECTS 7-10

25. Onset to Groin Puncture
THERAPY
IV tPA / MM
IV tPA / MM+ ET
Onset to IV tPA (100%)
102 min
108 min
Onset to Groin Puncture
226 min (118 min)
Onset to TICI 2b/3 (70%)
ICA Occlusion
22.6%
32.7 %
Clot Length
14.1 mm
12.9 mm
ACE Technology
27.3%
*mRS 0-2 at 90 days (PP)
29.3 %
41.5 %
SICH (PP)
11.3 %
10.9 %
Mortality (PP)
24.4%
7.3%

26. Patient, Target-Large Vessel, Time and Reperfusion
Tissue – Focused Selection, Extended Time Window ?
MR DWI, MR PWI / CTP with RAPID Post-Processing, Multiphase CTA Collaterals, qMRP-CBF, OEF

27. Conclusions
In anterior circulation ischemic stroke, presenting < 6 hours, with documented ELVO (ICA, M1-M2 MCA), and regardless of eligibility for IV tPA, addition of endovascular thrombectomy (ET) results in superior clinical outcomes compared to best medical therapy alone
AHA Class I, level of evidence A
Multiple attributable factors to the success of these ET Trials
Patient, Target Vessel, Reperfusion, Time and Tissue Selection
Time to intervention is critical to achieve successful clinical outcome – Improvement of Stroke Intervention Processes
Optimization of IV tPA, imaging and interventional workflow at CSC
Development of IV tPA bridging protocols for IA ET
Ideal goals: < 60 min from CTA/MRA to groin puncture
< 90 min presentation to groin puncture

28. Conclusions
Efficient and effective revascularization (TICI 2b/3 reperfusion) required for optimal clinical outcomes
Modern 3rd generation thrombectomy devices / techniques preferred
Stent retrievers with balloon guide for flow arrest
Large bore aspiration catheters
Careful to avoid dogma regarding thrombectomy devices
Only a single “device agnostic” trial – MR CLEAN
ESCAPE, EXTEND-IA, SWIFT PRIME – Industry support
NOT randomized trials on type of thrombectomy devices
Provides impetus for new technology and comparative device studies

29. Conclusions
Imaging based-tissue selection may allow inclusion of patients most likely to benefit from ET and exclusion of patients at risk for futile/harmful reperfusion
Collateral scoring with multiphase CTA (ESCAPE)
Penumbra-core infarct assessment using CTP or MR DWI-PWI (EXTEND-IA or SWIFT-PRIME)
Standardized post-processing techniques (RAPID)
Thresholds for exclusion (core infarct volume, penumbral mismatch ratios, penumbra definition) unclear and require further investigation
May be equipoise for clinical trial on imaging based selection
Ongoing ET studies with CTP/MR DWI-PWI tissue selection for extended time window or wake-up strokes at 6-24 hours
– DAWN, WAKE-UP and WASSABI Trials

30. Thank you ! Questions?