Mechanical thrombectomy beyond the 6 hours. Mahmoud Rayes, MD Medical Director, Stroke program Greenville Memorial Hospital

Mechanical thrombectomy beyond the 6 hours Mahmoud Rayes, MD Medical Director, Stroke program Greenville Memorial Hospital

Disclosures None

Worldwide statistics 1 IN 6 people will have a stroke at some time in their life EVERY 6 SECONDS someone dies of a stroke This year, nearly 6 MILLION people worldwide will die from a stroke By the year 2015, that # will climb to 6.5 MILLION 15 MILLION strokes occur annually worldwide deaths annually stroke is responsible for more deaths annually than those attributed to AIDS, tuberculosis and malaria combined Statistics from the World Stroke Organization/World Stroke Campaign 2013; World Health Organization

US statistics

Each minute

Why revascularization works Penumbr a (at risk) Core (irreversibly damaged)

Large vessel occlusions Scope of the problem Common: 40-50% of all ischemic stroke Severe: 5x higher mortality, 3-fold reduction in good outcome Respond poorly to intravenous thrombolytic (tpa) Successful Opening of Occlusion by Intravenous tpa: Middle Cerebral Artery: 42% Carotid Terminus: 27% Recanalization and clinical outcome of occlusion sites at baseline CT angiography in the Interventional Management of Stroke III trial. Radiology. 2014 Oct;273(1):202-10. doi: 10.1148/radiol.14132649. Epub 2014 Jun 5.

http://neuropathology-web.org/

Meta-analysis Shows a Strong Correlation Between Revascularization and Good Patient Outcomes 70% 60% 58.1% % of Patients 50% 40% 30% 20% 10% 24.8% 41.6% 14.4% 13.7% 12.5% 0% Good Outcome (mrs 0-2) 90-Day Mortality SICH * Revascularized Non-revascularized *Differences in sich were not statistically significant between the revascularized and non-revascularized groups Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke. 2007 Mar;38(3):967-73.

Endovascular intervention MERCI Device Penumbra Aspiration System Stent Retrievers Solitaire 2 Device Trevo Device

Critical success factors Faster times Careful selection Better study design Improved Outcomes Newer devices

Time vs tissue window Interaction between time to treatment and reperfusion therapy in patients with acute ischemic stroke. Lansberg MG1, Dabus G. J Neurointerv Surg. 2013 May;5

MER trials SWIFT PRIME (Global) EXTEND IA (AUS, NZ) REVASCAT (Spain) ESCAPE (Global) MR CLEAN (Netherlands) Randomization of patients to best medical care vs best medical care + Endovascular Time Window Studied Onset to 6 hours Onset to 6 hours Onset to 8 hours Onset to 12 hours Onset to 6 hours Number of Patients 196 70 206 316 500 Age 18-80 >18 18-80 >18 >18 Analysis of Primary Endpoint Rankin Shift Reperfusion at 24 hrs and dramatic NIHSS improvement at 3d Rankin Shift Rankin Shift Rankin Shift Imaging Modality NCCT, CTA, CTP or MRI/MRA/PWI NCCT, CTA, CTP Mismatch CTA or MRA, ASPECTS NCCT, CTA, Collateral assessment on multiplhase CTA ASPECTS ASPECTS Median NIHSS 17/17 13/17 17/17 17/16 18/17 Primary Device Studied Solitaire Device Solitaire Device Solitaire Device Solitaire Device Stent retrievers Statistically Significant Benefit

ESCAPE Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

Inclusion Criteria Acute ischemic stroke Age > 18 years Last-seen-well time to randomization < 12 hours ASPECTS >5 Baseline NIHSS >5 at time of randomization Good functional status: pre-stroke modified Barthel Index >95, not living in a nursing home; fully independent Confirmed symptomatic intracranial occlusion based on CTA in anterior anatomy (Carotid T, M1, 2 or more M2 s not including the anterior temporal artery) Moderate to good collaterals on CTA Endovascular treatment can be initiated within 60 minutes of baseline NCCT with target CT to first recanalization of 90 minutes M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

Baseline Patient Characteristics Characteristic Intervention (N=165) Control (N=150) Age Year Median (IQR) 71 (60-81) 70 (60-81) Female Sex 52.1% 52.7% Caucasian 87.3% 87.3% Baseline NIHSS Median (IQR) 16 (13-20) 17 (12-20) Hypertension 63.6% 72.0% Diabetes Mellitus 20.0% 26.0% Atrial Fibrillation 37.0% 40.0% M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

Time Parameters Time from onset to start of IV alteplase 125 110 Time from onset to randomization 172.5 169 Time from onset to first reperfusion 241 Time from CT to first reperfusion 84 Time from CT to groin pucture 51 0 50 100 150 200 250 300 Minutes (Median) Control Intervention M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

Forty nine participants (15.5%) underwent randomization 6 hours after symptom onset

mrs 0-2 at 90-days (N=311) Common adjusted odds ratio: 1.7 (95% CI: 1.3 to 2.2) 75.0% 60.0% 45.0% 30.0% 53.0% 29.3% NNT = 4 for independence 15.0% 0.0% Intervention Control M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

90-day mrs Common adjusted odds ratio: 3.1 (95% CI: 2.0 to 4.7) M Goyal et. al. Randomized Assessment of Rapid Endovascular Treatment of Ischemic Stroke. NEJM published on February 11, 2015

REVASCAT 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 8 hours of symptom onset T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Inclusion Criteria Acute ischemic stroke Age 18-80 years Last-seen-well time to treatment (groin puncture) < 8 hours No significant pre-stroke disability (mrs<1) Baseline NIHSS >6 ASPECTS <7 on CT, CTP-CBV, CTA-SI or ASPECTS <6 on DWI MRI Confirmed symptomatic intracranial occlusion in anterior anatomy (ICA or M1) T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Baseline Patient Characteristics Characteristic Intervention (N=103) Control (N=103) Age Year Mean + SD 65.7 + 11.3 67.2 + 9.5 Male Sex 55 (53.4%) 54 (52.4%) Baseline NIHSS Median (IQR) 17.0 (14.0-20.0) 17.0 (12.0-19.0) Hypertension 62 (60.2%) 72 (69.9%) Diabetes Mellitus 22 (21.4%) 19 (18.4%) Atrial Fibrillation 35 (34.0%) 37 (35.9%) Treatment with IV tpa 70 (68.0%) 80 (77.7%) T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Time Parameters Time from onset to groin puncture 269 Time from onset to revascularization 355 Time from onset to start of IV alteplase 105 117 Time onset to imaging 183 192 0 100 200 300 400 Minutes (Median) Control Intervention T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Revascularization in Intervention Group (N=102) 100.0% 90.0% 80.0% 70.0% 65.7% 60.0% 50.0% 40.0% 30.0% 18.6% 20.0% 10.0% 0.0% mtici 2b/3 TICI 3 T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

mrs 0-2 at 90-days 75.0% 60.0% Common adjusted odds ratio: 2.1 (95% CI: 1.1 to 4.0) 45.0% 43.7% 30.0% 28.2% 15.0% 0.0% Intervention Control T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

90-day mrs Common adjusted odds ratio for 1 point improvement: 1.7 (95% CI: 1.05 to 2.8) T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Time from onset to randomization Solitaire Best medical treatment Total non-missing n 88 86 4.5h n (%) 57 ( 64.8%) 56 ( 65.1%) >4.5h n (%) 31 ( 35.2%) 30 (34.9%) T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Analysis of Functional Independence at 90- Days in Pre-Specified Subgroups T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

T.G. Jovin, et. al. Thrombectomy within 8 Hours after Symptom Onset in Ischemic Stroke. Published in the NEJM on April 17, 2015.

Pooled data from 4 trials in which the Solitaire was the only or the predominant device (SEER Collaboration) Safety and Efficacy of Solitaire Stent Thrombectomy: Individual Patient Data Meta-Analysis of Randomized Trials. Bruce C.V. Campbell,et al. Stroke. 2016;47:798-806

Safety and Efficacy of Solitaire Stent Thrombectomy: Individual Patient Data Meta-Analysis of Randomized Trials. Bruce C.V. Campbell,et al. Stroke. 2016;47:798-806

Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Goyal M1, Menon et al. Lancet. 2016 Apr

Trevo Retriever Registry Study Design DESIGN POPULATIO N TARGET VESSEL SITES SAMPLE SIZE Global, multi-center, prospective, open label study Acute ischemic stroke with large vessel occlusion Trevo Retriever must be the initial mechanical device used Any treatable large vessel in the neurovasculature Up to 100 centers total Maximum 2000; Currently enrolled 1200+ with follow up on initial 1000 complete

Baseline Characteristics Demographics and Medical History Age (mean + SD) % Female Intent to Treat (N=1000) 67.9 + 14.0 50.9% US (n=741) International (n=253) 67.5 + 14.3 69.2 + 13.4 51.1% 50.2% BMI* 28.4+ 6.5 28.7+ 6.8 26.8 + 4.7 Hypertension** 73.6% 76.9% 64.0% Dyslipidemia 43.6% 44.2% 41.9% Atrial Fibrillation 38.6% 40.9% 31.7% Diabetes Mellitus 24.5% 26.9% 17.8% Baseline NIHSS (mean + SD)*** 15.5 + 7.0 15.9 + 7.3 14.5 + 5.9 % IV tpa 48.7% 45.2% 59.5%

Time Metrics Symptom Onset to Groin Puncture 90% 80% % of Patients 70% 60% 50% 40% 30% 20% 10% 0% >1/3 of patients received treatment beyond 6 hours 0-6 hrs > 6-8 hrs > 8-12 hrs > 12 hrs US (N=382) OUS (N=90)

Outcome metrics 90 day mrs (0-2) by presentation 60% P = 0.1880 % of Patients mrs (0-2) 50% 40% 30% 20% 10% 0% 0-6 hrs (N = 555) > 6 hrs (N = 285)

Time Metrics Symptom Onset Revascularization (minutes, median) Symptom Onset to Endovascular Hospital ED (including transfers) 190 ED to Imaging 54 Imaging to Angio Suite 54 19 Groin Puncture to Revascularization 54 50 Symptom Onset to Revascularization 190 54 19 50 Total: 313 minutes (median) from symptom onset to revascularization (including transfer patients)

Results Sub Analysis: Good Functional Outcomes (mrs 0-2 at 90 days) in AHA-Like Cohort Trevo Registry (N=323) "AHA Guideline-like" Cohort* 58.1% 32.4% 9.6% HERMES Intervention Arm (N=633) 46.0% 38.7% 15.3% HERMES Control Arm (N=645) 26.5% 54.6% 18.9% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% mrs 0-2 mrs 3-5 mrs 6

Results Safety Endpoints - sich 5.0% 4.5% 4.0% 3.5% 3.0% 2.5% 2.0% 1.5% 1.0% 0.5% 0.0% 1.2% Trevo Retriever Registry AHA Guideline-like cohort* (N=323) (ECASS III) 4.4% 4.3% HERMES Interventional Arm (N=634) (Multiple Definitions) HERMES Control Arm (N=653) (Multiple Definitions) * Includes patients with a pre-stroke mrs 0-1, receiving IV tpa within 4.5 hours or contraindicated for tpa, ICA or M1 occlusion, age > 18, baseline NIHSS > 6, treatment (groin puncture) initiated within 6 hours from symptom onset.

Why MER would work beyond 6 hours Acute Ischemic stroke represents a dynamic process Infarct expansion does vary based on time, residual blood flow, collateral blood flow etc Tissue fate is influenced not only by the duration of ischemia, but also by the severity of ischemia Time while accurate, remains imprecise marker for brain physiology There is significant variance in the rate of infarct development and progression Advanced brain imagin remains the most readily available and valuable biomarker for stroke

Ischemic Stroke Tissue-Window in the New Era of Endovascular Treatment. Michael D. Hill, Mayank Goyal, et al. Stroke. 2015;46:2332-2334

Ongoing trials Trevo and Medical Management Versus Medical Management Alone in Wake Up and Late Presenting Strokes (DAWN) Age 18 Baseline NIHSS 10 6 to 24 hours after time last known well < 1/3 MCA territory involved, as evidenced by CT or MRI Occlusion of the intracranial ICA and/or MCA-M1 as evidenced by MRA or CTA

Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE 3) Inclusion criteria Age 18-90 years Baseline NIHSSS is 6 and remains 6 immediately prior to randomization Endovascular treatment can be initiated (femoral puncture) between 6 and 16 hours of stroke onset

Numbers needed to treat MR CLEAN: 7 in favor of intervention EXTEND-IA: 3 in favor of intervention ESCAPE: 4 in favor of intervention SWIFT-PRIME: 4 in favor of intervention

Number Needed to treat

CEA for symptomatic carotid stenosis (>70%): 6 Aspirin for secondary stroke prevention: 200 Coumadin in Atrial Fibrillation: 3 Hemicraniectomy for malignant stroke: 2

Case 1 69 Y/O CF with MHx of HTN LKN 8:00 am Seen in ER at 5:50 PM NIHSS 18

NIHSS 6 at 24 hrs NIHSS 2 at discharge mrs 1 at 3 month

Case 2 35 Y/O CM with no significant medical hx 1 week history of headache, dizziness, nausea and vomiting Presented to outside hospital 1/7/15 around 11 pm Intubated around 12 am Transferred to another hospital CTA head and neck showed basilar artery thrombosis

Transferred to GMH and was taken for MER Around 530 am

NIHSS 3 at 9 months mrs 1

GHS treatment data Ischemic Stroke Treatment Rates (IV tpa + Endovascular Thrombectomy) GMH SC 35.6% 30.3% 32.1% 12.5% 13.2% 11.8% 10.5% 23.0% 16.3% 13.9% 14.3% 20.5% 15.7% 18.0% 19.1% 19.3% 2009 2010 2011 2012 2013 2014 2015 2016

GHS treatment data IV tpa Admin <30 min from arrival Median Door to Recanalization time, minutes 12.30% 12.20% 10.70% 21.90% 17.90% 15.50% 38.40% 21.90% 19% 160 140 120 100 80 60 40 133 133 139 97 121 111 107 110 114 20 2014 2015 2016 0 2014 2015 2016 GMH All SC Hosp All CSC GMH SC CSC

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