Greater Cincinna+ Acute Stroke: At the Cu(ng Edge. Relevant Industry Disclosure. The Last 50 Years 9/18/16

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1 Greater Cincinna+ Acute Stroke: At the Cu(ng Edge Pooja Khatri, MD, MSc Professor of Neurology Director of Acute Stroke Research University of CincinnaD Relevant Industry Disclosure The UC Dept of Neurology receives funds from Genentech for my effort as Lead PI of the PRISMS Trial The Last 50 Years 1958: First IV thrombolysis 1974: Clinical CT scans 1983: First endovascular thrombolysis 1995: IV rtpa 1999: IA pro-urokinase 2015: Endovascular Therapy 1

2 9/18/16 Pilot NINDS Trials NINDS Study Double-blinded Placebo controlled NIH-sponsored 0.9mg/kg IV t-pa 624 padents Treatment within 3 hrs 1/2 within 90 minutes 1/2 within minutes Subsequent IST3 trial showed efficacy out to 4.5 hours UC Stroke Team Coverage 16 local hospitals in-person EMS brings pts to nearest hospital Stroke MD drives to all local hospitals Encourage pre-nodficadon (prior to CT) Coordinator goes if possible trial candidate StarDng telemedicine at some of these 8 regional hospitals telemedicine only Assessment by telemedicine Drip/ship to UCMC for post-tpa care Addi+onal ~8 regional hospitals Assessment by phone Drip/ship to UCMC for post-tpa care ~3000 consultadon calls in 2015 ~350 treatments in 2015 ~100 treatments in

3 IV Thrombolysis Kleindorfer, Stroke 2004, Adeoye, Stroke 2011 IV Thrombolysis JCAHO Stroke Ctrs IV rtpa DRG by CMS Kleindorfer, Stroke 2004, Adeoye, Stroke 2011 Improved Outcomes by IV rtpa NINDS, NEJM, : No symptoms at all 1: No significant disability despite symptoms; able to carry out all usual dudes and acdvides 2: Slight disability; unable to carry out all previous acdvides, but able to look acer own affairs without assistance 3: Moderate disability; requiring some help, but able to walk without assistance 4: Moderately severe disability; unable to walk without assistance and unable to adend to own bodily needs without assistance 5: Severe disability; bedridden, incondnent and requiring constant nursing care and adendon 6: Dead 3

4 Improved Outcomes by IV rtpa NINDS, NEJM, : No symptoms at all 1: No significant disability despite symptoms; able to carry out all usual dudes and acdvides 2: Slight disability; unable to carry out all previous acdvides, but able to look acer own affairs without assistance 3: Moderate disability; requiring some help, but able to walk without assistance 4: Moderately severe disability; unable to walk without assistance and unable to adend to own bodily needs without assistance 5: Severe disability; bedridden, incondnent and requiring constant nursing care and adendon 6: Dead 61% Intra-Arterial Drug Delivery IllustraDon by Christafordis, AJNR, 2012 PROACT II ( ) Sponsored by Abbod Laboratories, Inc. R-pro-urokinase + heparin vs heparin alone PosiDve trial (n=180) mrs 0-1 of 40% (ly+c) vs 25% (p=0.04) FDA wanted 2 nd trial; r-pro-uk no longer available Furlan, JAMA,

5 MERCI Retriever: FDA-Cleared on August 11, 2004 Single-arm trial (n=151) Treatment started within 8 hours RecanalizaDon in 46% (ITT) Devices can also open up arteries (FDA Clearance) Smith, Stroke, 2005 More Effec+ve Devices Revasculariza+on Rates Improve 2004à2012 Fargen, JNIS,

6 Revasculariza+on Rates Improve 2004à2012 But Were We Making Pa/ents Be1er? Fargen, JNIS, 2012 Endovascular Tx for IV-rtPA Treated Strokes: NIH-funded IMS III Trial ( ) IV tpa ini+ated within 3 hours NIHSS >/=10 (or 8-9 with ICA, M1, BA on CTA) Randomized within 40 min of IV rtpa start Adjunc+ve Endovascular Therapy Start by 5 hours, max procedure duradon of 2 hours, and complete by 7 hours IV rtpa Alone Broderick, NEJM, 2013 NIH-Funded IMS III Trial ( ) First Pa+ent In Sept 26, 2006 Last Pa+ent In April 17, Year 6

7 IMS III Trial Primary Result Halted for fudlity at n=656 of 900 (4/18/12) No safety issues sich 6.2% vs 5.9% Mortality 19% vs 22% IV/Endovascular (n=434) IV rtpa Only (n=222) mrs 0-2 (%) 177 (40.8%) 86 (38.7%) CMH p-value 0.70 (adjusted for NIHSS 8-19 vs 20+) Phase III Italian SYNTHESIS and Phase II NINDS MR RESCUE Trials were also nega?ve Broderick, NEJM, 2013 Post-IMS III Era: Trial Design Concepts Beder devices? Majority MERCI device or IA tpa only in IMS III Faster +mes to reperfusion? Faster = beder outcomes in endovascular group CTA+ only? CTA now more widespread, won t lose much Dme, concentrate treatment effect Worst clots? By locadon or length Imaging selec+on? Beder prognosis if less ischemic change on CT Randomized Endovascular Trials Worldwide Khatri, Stroke,

8 Dutch MR CLEAN POSITIVE RESULTS October 22 nd, 2014 World Stroke Congress Istanbul, Turkey CANADIAN ESCAPE & AUSTRALIAN EXTEND- IA TRIALS ANNOUNCED INTERIM ANALYSES OF OVERWHELMING EFFICACY November 7 th, 2014 PI Communica+ons Here We Are: June, 2015 TRIAL Enrolled Planned Results MR CLEAN NEJM 12/17/14 ESCAPE NEJM 2/11/15 EXTEND IA NEJM 2/11/15 SWIFT PRIME NEJM 4/17/15 REVASCAT NEJM 4/17/15 THERAPY ESOC 4/2015 THRACE ESOC 4/2015 8

9 MR CLEAN Time to Reperfusion MR CLEAN ESCAPE EXTEND-IA SWIFT-PRIME REVASCAT IMS III 332 min 241 min 248 min 252 min 355 min ICAT, M1, and M2 Cases with Reperfusion with 95% confidence bands (p=0.0045) Fransen, ISC 2015, abstract. Khatri, Lancet Neurology, 2014 ICAT, M1, and M2 Cases without Reperfusion (10%; 95% CI ) UC Endovascular Protocol Typical Endovascular Candidate Large vessel occlusion NIHSS 6 Start IA within 6 hours of onset And move as fast as possible No upper age limit If >80 yrs, then padent should be independent at baseline Access to Endo Care in the US Adeoye, Stroke,

10 Access to Endo Care in the US By ground, 56% may have access to endovascular-capable hospitals (i.e., performed single endo case). By air, 85% may have access to endovascular hospitals. Likely an overesdmate. Adeoye, Stroke, 2014 Regionaliza+on of Acute Stroke Care EMS triage of severe strokes to Comprehensive Stroke Centers (CSCs) How? Need validated user friendly scoring system Several scoring systems at various stages of development RACE, LAMS, CSTAT, 3ISS, PASS Tradeoffs? IV rtpa Dme to treatment vs endovascular Dme to treatment Faster DTN Times (<20 minutes) Meretoja, Neurology,

11 CURRENT AND UPCOMING CLINICAL TRIALS IN CINCINNATI The Current Cutng Edge Selec+ng Pa+ents for Later Treatment Using Penumbral Imaging? Kidwell, Stroke, 2013 DEFUSE 3 Trial NIH-funded, Phase 3 trial // This is a new trial! NIHSS 6+, large vessel occlusion on CTA 6-16 hours from last known well TesDng endovascular tx vs standard med mgmt in padents with penumbra on study-specific CTP Local PIs Achala Vagal and Andy Ringer; Coordinator: Cindy Werner 11

12 NIH StrokeNET University of CincinnaD houses the nadonal clinical coordinator center (NCC) for all muldcenter trials funded by NIH PI: Broderick, Co-PIs: Khatri, Chimowitz, Cramer; Program Managers: Spilker, Frasure Also leads the regional coordinadon center (RCC) for bringing NIH-funded trials to the metropolitan region PIs: Khatri, Kleindorfer; Program Mgr: Emily Goodall NINDS Study Baseline NIHSS vs Favorable Outcome Percent favorable outcome t-pa Placebo >20 Baseline NIHSS Ingall, Stroke, 2004 NINDS Study Baseline NIHSS vs Favorable Outcome Percent favorable outcome n=58 16 placebo, 81.3% good outcome (95% C.I %) 42 IV rtpa 78.6% good outcome (95% C.I %) No interac/on by stroke severity but mild strokes were largely excluded t-pa Placebo >20 Baseline NIHSS Ingall, Stroke,

13 Current Guidelines Reflect Current State of Evidence IV rtpa for Mild Stroke? PRISMS Trial: Phase IIIb Study PopulaDon Schedule and Dose Sponsor Lead PI Local PI Coordinator 18 years with mild stroke (NIHSS 5 and not clearly disabling) able to receive tpa within 3 hours tpa 0.9 mg/kg over 60 min (ASA 325 mg placebo arm) Genentech, Inc. (academic-industry partnership) Khatri Kleindorfer Werner Clinicaltrials.gov--NCT Optimal Glucose Management? Hyperglycemia (>140 mg/dl) during the first 24 hours acer stroke is associated with poor outcomes Current AHA Guideline Reasonable to treat hyperglycemia to goal of 140 to 180 mg/dl) Class IIa, Level of Evidence C Tighter control of benefit? SHINE Trial 13

14 Optimal Antiplatelet Therapy? All padents should be started on aspirin (325 mg) within 48 hours You will prevent 1 recurrent stroke over the two weeks acer acute ischemic stroke for every 100 padents you treat (CAST, IST) AHA Class I, Level of Evidence A Early ASA and clopidogrel in TIA/mild stroke? More Efficacious IV Thrombolysis? Prior studies combining eptafibadde and rtpa: CLEAR CLEAR-ER CLEAR FDR Trial in development MOST Trial (Lead PI: Adeoye) Even Safer, More Effec+ve Devices On the Way? FDA-CLEARED MERCI RETRIEVER 2004 PENUMBRA ASPIRATION 2007 EXAMPLES OF PIPELINE. PENUMBRA 3D SEPARATOR TREVO STENT RETRIEVER 2009 NEURAVI EMBO TRAP SOLITAIRE STENT RETRIEVER 2009 MEDTRONIC LAZARUS COVER 14

15 Neuroprotec+on? Can we protect brain from ischemic injury? Even Safer, More Effec+ve Devices On the Way? FDA-CLEARED MERCI RETRIEVER 2004 PENUMBRA ASPIRATION 2007 EXAMPLES OF PIPELINE. PENUMBRA 3D SEPARATOR TREVO STENT RETRIEVER 2009 NEURAVI EMBO TRAP SOLITAIRE STENT RETRIEVER 2009 MEDTRONIC LAZARUS COVER Even Safer, More Effec+ve Devices On the Way? FDA-CLEARED MERCI RETRIEVER 2004 PENUMBRA ASPIRATION 2007 EXAMPLES OF PIPELINE. PENUMBRA 3D SEPARATOR TREVO STENT RETRIEVER 2009 NEURAVI EMBO TRAP SOLITAIRE STENT RETRIEVER 2009 MEDTRONIC LAZARUS COVER 15

16 Prevent Malignant Edema? Conclusions The CincinnaD region has played a cridcal role in the development of current acute stroke therapies IV rtpa within 4.5 hours of last known well Endovascular therapy within 6 hours of last known well The region condnues to develop new therapies through clinical trials DEFUSE-3, StrokeNET, PRISMS, SHINE, POINT, RHAPSODY ongoing Reminder: When to Call Stroke Team Call stroke team for all strokes <12 hours from Dme that padent was last known well Call us for all TIAs and strokes, no mader how mild the deficits may seem Preno+fy us before getng the CT/CTA scan results

17 Thank You! 17