Joshua W. Osbun, MD Assistant Professor Departments of Neurosurgery, Neurology and Radiology Disclosures

• Microvention, Inc. • Unrestricted Educational Grant • Consulting Agreement • PI: RAGE Trial • Cerenovus Neurovascular • PI: NAPA Trial

Department of Neurosurgery Objectives • Overview: The Foundation and Terminology

• The Past: How did we get here?

• The Present: What are we doing and what drives our Clinical Decisions?

• The Future: What’s Next on the Horizon?

Department of Neurosurgery (For the Neurosurgeons) FOUNDATIONS AND TERMINOLOGY

Department of Neurosurgery Last Known Normal (LKN)

Department of Neurosurgery Stroke in the United States

• 795,000 per year • 87% Ischemic • 13% Hemorrhagic • 130,000 Deaths/year • ~20% (140,000) from Large Vessel Occlusions • Only 38% of patients knew to call 911 at onset of symptoms

Data from cdc.gov

Department of Neurosurgery Department of Neurosurgery Stroke Terminology • NIHSS • NIH Stroke Scale • Graded 0-42

Neurosurgery Residents: iPhone-->App Store- -> NIH Stroke Scale

Department of Neurosurgery Stroke Terminology Thrombolysis in Cerebral Infarction “TICI” • Graded 0-3 Based on Distal Flow Past Lesion

Department of Neurosurgery Stroke Terminology • Proximal Arterial/Large Vessel Occlusion • ICA Terminus • MCA-M1 • Basilar • ??? M2

• High NIHSS Lesions (>10) • ~20% of all Ischemic Stroke

Department of Neurosurgery LVO

Department of Neurosurgery Department of Neurosurgery Department of Neurosurgery Department of Neurosurgery Proximal Arterial Occlusions: Low Rates of tPA Recanalization and Poor Natural History

Site of 6-Month 6-Month 6-Month 6-Month Occlusion mRS 0-2 Mortality mRS 0-2 Mortality Overall Overall NIHSS ≥10 NIHSS ≥10

MCA-M2 54% 21% 23% 41% (26/48) (10/48) (5/22) (9/22) MCA-M1 38% 23% 23% 32% (20/52) (12/52) (8/34) (11/34) ICA-T 38% 23% 7% 36% (10/26) (6/26) (1/14) (5/14) JAMA Neurol. 2014 Feb;71(2):151-7

Department of Neurosurgery Stroke Terminology • ASPECTS Score • “Alberta Stroke Program Early CT Score” • www.aspectsinstroke.com • Intraclass Correlation Coeff (ICC) • ICC=0.69 • .6-.75 Good • .75-1.00 Excellent • ASPECTS= 10 • No Early Ischemic Changes • ASPECTS=0 • Holohemispheric Infarct • ASPECTS <7 • Poor Outcome with Thrombolysis or Intra- arterial Therapy • ASEPCTS >7 • Good Outcome with Thrombolysis or Intra- arterial Therapy

Department of Neurosurgery Stroke Terminology • RAPID • Computer-automated software for objective analysis of CT Perfusion output • Analysis is performed in real time as CT perfusion images are acquired • Instantaneous data output to Email/Smartphone

• CT Perfusion in Stroke • Useful for determining size of core infarct with Cerebral Blood Volume (CBV) and Cerebral Blood Flow (CBF) • Useful for Determining Hypo-perfused at-risk Penumbra with Tmax and Mean Transit Times (MTT) • Allows for determination of a large, completed stroke even if the patient is within the intervention window • Allows for determination of salvageable penumbra for patients outside standard intervention window

• www.ischemaview.com

Department of Neurosurgery RAPID Output

Department of Neurosurgery RAPID Output

Department of Neurosurgery RAPID Output

Department of Neurosurgery How Did We Get Here? THE PAST

Department of Neurosurgery Why Do We Need More than rTPA for Acute Stroke?

Department of Neurosurgery Very few patients receive IV t-PA therapy!

686,000

Percent of Total Stroke Patients Receiving IV tPA = ~3%

18% 123,000

45% 55,000 45% 25,000

Ischemic Patients Patients Patients Stroke Presenting <3 Eligible for IV Receiving IV Population Hours tPA tPA

DespiteSource: Guidelines> decade for the Early of Management clinical of experiencePatients with Ischemic Stroke,- currently AHA 2003 only ~5% of all AIS receive IV rt-PA Reeves, Arora et al. 2005; Kleindorfer, Lindsell et al. 2008

Department of Neurosurgery IV rt-PA Has a Strong Time Dependency!

Marler JR et al. Neurology 2000;55:1649-1655

. 1st 90 min: NNT = 3 Hacke W et al. Lancet. 2004 Mar 6;363(9411):768-74 . 1st 3 hours: NNT = 8.4 . 3-4.5 hours: NNT = 14

Department of Neurosurgery Proximal Arterial Occlusions: tPA > No Treatment Reperfusion after IV tPA in the ESCAPE Trial

Intervention Control

IV tPA No IV tPA IV tPA No IV tPA

TICI 2b/3 70.5% 77.3% ….. ….. mAOL 2-3 ….. ….. 37.3% 7.1%

mAOL assessed on CTA done at 2-8h post randomization

Department of Neurosurgery IV rt-PA Has a Limited Effect Over Proximal Arterial Occlusions!

Thrombus Burden (Site) vs. Resolution after IV tPA MCA-M2: 31-44% MCA-M1: 24-32%

ICA-T: 4-8%

Del Zoppo et al., Ann Neurol 1992 Saqqur et al. Stroke. 2007 Mar;38(3): 948-954. Bhatia et al. Stroke. 2010;41: 2254-2258.

Bhatia et al. Stroke. 2010;41: 2254-2258.Department of Neurosurgery IV rt-PA Has a Limited Effect Over Proximal Arterial Occlusions!

Thrombus Burden (Length) vs. Resolution after IV tPA

Thrombus <8mm = Recanalization = Discharge mRS ≤2: ~2/3 Thrombus >8mm = No Recanalization = Discharge mRS ≤2: <1/10

Riedel et al. Stroke. 2011;42: 1775-1777

Bhatia et al. Stroke. 2010;41: 2254-2258. The Inception: 1958

Department of Neurosurgery First Generation Technology Trials: Hope for Some, Skepticism for Others

Trial Trial Design PROACT-II JAMA 282 (1999) 2003-2011 Randomized, IA pro-UK vs. IV heparin

MELT Japan Stroke 38 (2007) 2633-2639 Randomized, IA UK vs. medical treatment

IMS-I Stroke 35 (2004) 904-911 Open Label, IV t-PA + IA t-PA

IMS-II Open Label, IV t-PA + IA t-PA Stroke 37 (2006) 708

MERCI Open Label, IA thrombectomy, IA lytics allowed, IV Stroke 36 (2005) 1432-1438 disallowed Multi MERCI AJNR 27 (2006) 1177-1182 Open Label, IA thrombectomy, IA & IV lytics allowed PENUMBRA ISC 2008 Open Label, IA thrombectomy, IA lytics allowed

Department of Neurosurgery Department of Neurosurgery 2013: The Defeat 2014-15: The Victory

CRITICAL SUCCESS FACTORS

High Stroke ICA-T Severity T MCA-M1 A Faster Careful e.g. R bNIHSS≥10 G times selection E Effective T Limited Core Devices e.g. Core< 50cc; & Better Newer study ASPECTS >7 Systems of devices design Improved Care Outcomes Slide Courtesy of Nogueira RG et al. Stroke. 2013;44:3272-3274 Raul Nogueira, MD RCT Driven Evidence Based Care THE PRESENT

Department of Neurosurgery CASE • 52yo woman presents to BJH ED with sudden onset left hemiplegia, neglect, left facial droop, dysarthria • Last known normal 1 hours prior to arrival • History of hypertension, hyperlipidemia • 1ppd smoker

• Physical Exam: • 0/5 Strength Left Arm • 0/5 Strength Left Leg • Complete Left Facial Palsy • Left Hemineglect • Dysarthria • Follows Commands • Visual Field Cut- Superior Quadrantanopsia • NIHSS 14 • BP 180/101, HR 96, RR 16, O2 Sat 92% on room air

Department of Neurosurgery CT Head

ASPECTS= 10

Department of Neurosurgery CASE • Medications • Metoprolol, lisinopril, lovastatin, celexa, Asa 81mg • Labs • Plts 234 • INR 1.1 • PTT 24 • Cr 0.9 • Management • IV tPA administrated: 0.9mg/kg • 10% as Bolus • Remainder infused over 1 hour • CTA/RAPID CTP: Read as Right M1 Occlusion, small core with large penumbra • Transported to angiosuite • Needle to Groin at 90 minutes after last known normal

Department of Neurosurgery Department of Neurosurgery Angiogram

Department of Neurosurgery Angiogram/Thrombectomy

Department of Neurosurgery Angiogram/Thrombectomy

Department of Neurosurgery Thrombectomy

Department of Neurosurgery Angiogram/Thrombectomy

Department of Neurosurgery CASE

• Patient immediately begins moving left side s/p reperfusion

• Transported to ICU for overnight care

• Blood pressure management: Normotension

• NIHSS=0 at discharge to home post-procedure day 1

Department of Neurosurgery Who Gets Thombectomy in 2018? Time AGE Sx Severity IMAGING Window ASPECTS CTA/MRA CTP/MRP (RAPID)

0-6 hours ?∞? NIHSS ≥ 6 ≥6 ICA, M1, No Large Core M2**, BA (?>70mL)

6-16 Hours ?∞? NIHSS ≥ 6 ≥6 ICA, M1, Core ≤70mL M2**, BA

16-24 Hours ?∞? NIHSS ≥ 10 ≥6 ICA, M1, Age ≤80: Core≤30mL M2**, BA Age >80: Core>30mL

Department of Neurosurgery The Evidence for LKN< 6 Hours: The 5 Trials=HERMES Study ELIGIBILITY IMAGING ARMS

LVO TIME NIHSS Vascular Advanced Control Tx

MR CLEAN ICA 6 hrs >2 CTA, MRA N/A +/- tPA IA M1/M2 Thombolysis A1/2 or device ESCAPE ICA 12 hrs >5 CTA CTP, +/- tPA Stent M1/2 Multiphase Retriever CTA SWIFT PRIME ICA 6 hrs 8-29 CTA, MRA CTP/MRI tPA Stent M1 (RAPID) Retriever

EXTEND-IA ICA 6 hrs >6 CTA, MRA CTP tPA Stent M1/M2 (RAPID) Retriever A1/2

REVASCAT ICA 8 hrs >6 CTA, MRA CTP, CTA tPA Stent M1 source Retriever images, MRI

Department of Neurosurgery The Evidence for LKN< 6 Hours: The 5 Trials=HERMES

Imaging mRS 0-2 TICI 2b/3 to Device(s) Used in in Trial Confirm Intervention Arm Interventi Intervention Control OR Occlusion on Arm Arm Arm (95% CI) ? IA Lytic (138), Merci Retriever® (95), EKOS IMS III No 41% 40.8% 38.7% NR (22), Penumbra (54), Solitaire FR (5)

Merci Retriever®, EKOS, MR RESCUE Yes 27% 19% 20% NR IA Lytic, Penumbra

97% Stent Retrievers, 2% 2.05 (1.56 to MR CLEAN Yes 58.7% 32.6% 19.1% other Mechanical 3.09)

1.8 (1.4 to ESCAPE Yes 86% Stent Retriever 72.4% 53% 29.3% 2.4) 3.8 (1.4 to EXTEND-IA Yes 100% Stent Retriever 86.2% 71% 40% 10.0) SWIFT 1.70 (1.23 to Yes 100% Stent Retriever 88.0% 60% 35% PRIME 2.33) 2.0 (1.1 to REVASCAT Yes 100% Stent Retriever 65.7% 43.7% 28.2% 3.5)

Department of Neurosurgery The Evidence for LKN< 6 Hours: The 5 Trials=HERMES

N= 1,288

1.8-4.2 1.7-2.6

Department of Neurosurgery MORE RCTs: Aspiration vs Stent Retreiver- Equivalent Techniques

• THERAPY

• THRACE

• ASTER

• COMPASS

Department of Neurosurgery Beyond 6 Hours: DAWN and DEFUSE-3 DAWN DEFUSE-3

Time Window 6-24 Hours 6-16 Hours Pre-Morbid Status mRS 0-1 mRS 0-2 NIHSS ≥10 ≥6 CTA/MRA ICA, M1 ICA, M1 CTP/MRP NIHSS ≥10 Core≤70mL Age <80: Core≤30mL Age ≥80: Core≤20mL NIHSS ≥20 Age <80, Core≤50mL Outcomes Tx Control p Tx Control p (n=107) (n=90) (n=92) (n=90) mRS 0-2 48.7% 13.1% <.0001 45% 17% <.001 Mortality 13.0% 18.0% .01 14% 26% .05 sICH 4.8% 3.2% .3 7% 4% .75

Department of Neurosurgery What’s Next on the Horizon? A Few Thoughts…. THE FUTURE

Department of Neurosurgery Follow the Cardiologists: Got a Question? There’s an RCT for that

In 2016, there were more than 65 RCTs Published in Interventional Cardiology

Department of Neurosurgery But the Neuro Space Doesn’t have the Numbers?

250,000-300,000 STEMI Per Year in the US

800,000 Strokes Per Year in the US

160,000 LVOs Per Year in the the US

What’s an LVO? ICA-T, M1? M2? M3?

Department of Neurosurgery Less than 6 Hours: Should we Image?

Conflicting Ideologies:

Time is Brain vs Utilization of Resources

What is an Acceptable Number of Negative Angiograms and Team Activations to improve our Outcomes by eliminating steps of care? HERMES Investigators, JAMA 2016

Department of Neurosurgery Personalized Medicine Through Clinical Trials and Technology

Clot: Red, White, Calcium, Atheroma? Is There a Specific Device for Individual Lesions?

Department of Neurosurgery Delivering Stroke Care to the Masses: A Distribution Issue • Comprehensive Stroke Center

• Primary Stroke Center

• Thrombectomy Capable Center

Conflicting Ideologies Time is Brain/ Extended Resource Availability Smith&Schwamm Stroke 2015 vs. Diluted Experience/Expertise

Department of Neurosurgery Is the Distribution Problem Solvable by AI?

Department of Neurosurgery Can the Development of Neuroprotective Agents Extend the Time Window Until Patients Can Be Transported Thrombectomy Capable Centers?

Department of Neurosurgery Conclusions

Exciting Time in Stroke Care and the Future is Bright Mechanical Thrombectomy is the Biggest Advance in Medicine since Penicillin

Time is Brain Efforts Need to Focus on Delivering More Care to More People Faster

Department of Neurosurgery Vascular Neurosurgery THANK YOU!!!

Vascular Neurology

Interventional Neuroradiology

Department of Neurosurgery