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

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: NCT02142283 (PI) DAWN – Active NU Research Support (Stryker) NCT00963989 (Co-I) START Other Support: NCT02225223 (PI) STARRT 13GRNT17340018 AHA (PI) NCT01801007 (PI) FRED RSD1207 RSNA (PI) NCT01407952 (PI) HEAT 1R01NS089926-01A1 (Co-I) 1R25NS080949 (Co-I) 1R21EB017928-01A1 (Co-I)

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

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

Acute Ischemic Stroke Intervention 2014-2015 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

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

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)

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

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

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 0-2 90 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: 38.5% 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 0-2 90 days: 48.2% vs 13.9% (p=0.001)

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/3 58.7% ↓↓ 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

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

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, 1.06 - 2.31) *Age ≤ 80 years OR 1.6 (95% CI, 1.13 - 2.27) *Age ≥ 80 years OR 3.24 (95% CI, 1.21- 8.62) SICH 6.4% 7.7% NTE/DTE 0.4% 5.6% Mortality 22% 21%

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 86.1% 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 6-10 + MP CTA (Collaterals)

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%

ESCAPE

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

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%

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

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%

SWIFT PRIME

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

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 %

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

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%

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

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

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

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

Thank you ! Questions?