Disclosures • Nothing to disclose Current Management of • Research Funding: – American Heart Association Acute Ischemic Stroke – NIH/NINDS Nerissa U. Ko, MD, MAS Professor of Neurology May 8, 2015 Selected slides courtesy of Wade Smith, MD, PhD Overview Focal brain ischemia • Pathophysiology of focal ischemia • Time dependent • Focal ischemia is different from • Role of acute revascularization global ischemia • Energy failure-> • Update on endovascular therapies Ca ++ entry and cell death • Glutamate toxicity • Stroke centers: New challenges • Apoptosis TIME IS BRAIN 1
Role of Time – IV rtPA Most Recent Pooled Analysis of IV rtPA Trials • NINDS Part 1 • NINDS Part 2 • ATLANTIS A • ATLANTIS B • ECASS II • ECASS III • EPITHET Lees et al., Lancet, 2010 Stroke Revascularization 2014 Khatri et al • IV tPA • Embolectomy – Proven efficacy – Stent retrievers better – Better outcome earlier in – Solitaire, Trevo, Merci all subgroups Penumbra all able to recanalize vessels • IA lytics – No clinical efficacy data – Proven efficacy – Trials showing no benefit – Unapproved for IA tPA • SYNTHESIS- Expansion – Earlier is better, <6 hours • IMS-III Study • MR RESCUE NEJM 2013 2
Endovascular stroke trials Stroke Revascularization 2015 • IV tPA • Embolectomy • MR CLEAN January 1, 2015 – Proven efficacy – Multiple devices • EXTEND-IA February 15, 2015 – Better outcome earlier in (Solitaire, Trevo, Merci • ESCAPE February 15, 2015 Penumbra, etc.) all able all subgroups • SWIFT PRIME April 17, 2015 to recanalize vessels • IA lytics • REVASCAT April 17, 2015 – Stent retrievers better – Proven efficacy – Several new trials – Unapproved for IA tPA showing clinical efficacy – Earlier is better, <6 hours Modified Rankin Scale (mRS) 0- Normal 1- Deficit by no disability 2- Minor disability, can walk independently 3- Needs a gait aid 4- Wheel chair bound 5- Bed bound 6- Expired 3
Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population. MR-CLEAN • Netherlands, randomized pragmatic trial of IA embolectomy versus best medical therapy, IV t-PA allowed CT/CTA: ICA/M1/M2/A2 N=267 Medical Therapy Outcome: N=233 90-Day R Device 1:1 mRS Stroke IV t-PA if eligible < 4.5 hr Berkhemer OA et al. N Engl J Med 2014; 372:11 Berkhemer et al , NEJM, (2015) 372:11 EXTEND-IA • Australia, randomized trial of IA embolectomy versus best medical therapy, IV t-PA required CT/CTA/CTP: ICA or M1 Salvageable tissue Core < 70 cc N=35 No further Rx Outcome: N=35 Reperfusion at 3d R Solitaire 1:1 NIHSS drop of ≥ 8 Stroke IV t-PA Trial Stopped 0.9 mg/kg by DSMB < 4.5 hr Campbell et al , NEJM 2015; 372:1009-18 4
EXTEND-IA P <0.001 P <0.001 ns P =0.009 Campbell et al , NEJM 2015; 372:1009-18 Campbell et al , NEJM ePub Feb 15, 2015 EXTEND-IA 5
ESCAPE • International, randomized trial of best medical therapy (BMT) vs. BMT + embolectomy, (IV t-PA optional) CT/CTA/CTP: ICA or M1/M2 ASPECT 6-10 (non-con) N=150 Good collaterals (CTA) No further Rx N=165 Outcome: R Embolectomy mRS at 90 day 1:1 Stroke IV t-PA Trial Stopped 0.9 mg/kg by DSMB < 4.5 hr if eligible Goyal et al , NEJM 2015; 372:1019-30 Goyal et al , NEJM 2015; 372:1019-30 ESCAPE RR 2.1 (1.7-2.2) RR 0.5 (0.3-0.8) ns Goyal et al , NEJM ePub Feb 15, 2015 6
SWIFT-Prime • International, randomized trial of IV t-PA vs. IV t-PA + IA embolectomy, (IV t-PA required) CT/CTA/CTP: ICA or M1 N=97 ASPECT 7-10 (non-con) No further Rx Outcome: mRS at 90 day N=98 R Solitaire (Shift analysis and 1:1 mRS ≤ 2) Stroke IV t-PA Trial Stopped 0.9 mg/kg by DSMB < 4.5 hr Saver et al , NEJM 2015 Apr 17 e pub Saver et al , NEJM 2015 Apr 17 e pub SWIFT-Prime OR 2.8 (1.5-4.9) ns ns Saver et al , NEJM 2015 Apr 17 e pub 7
REVASCAT • Spain (Catalonia), randomized trial of best medical therapy vs. IA embolectomy (+IV tPA if eligible) CTA/MRA: ICA or M1 N=103 Onset within 8 hrs Best medical therapy Outcome: mRS at 90 day N=103 R Solitaire (Shift analysis and 1:1 mRS ≤ 2) Stroke IV t-PA Trial Stopped 0.9 mg/kg by DSMB < 4.5 hr Jovin TG et al , NEJM 2015 Apr 17 e pub Jovin TG et al , NEJM 2015 Apr 17 e pub Summary of RCTs UCSF Acute Stroke Protocol Met Primary Improved Trial Year NNT Endpoint? Mortality? Yes 7 PROACT 1999 No Yes MELT No Synthesis 2013 No n/a No MR RESCUE 2013 No n/a No IMS-III 2013 No n/a No Yes 7 MR CLEAN 2015 No ESCAPE 2015 Yes 3 Yes Yes 3 EXTEND-IA 2015 No Yes 2.6 SWIFT-Prime 2015 No REVASCAT 2015 Yes 6 No 8
Stroke Centers Stroke Centers • System approach for stroke shown to improve outcomes Primary Comprehensive • Pre-printed orders, leadership, QA, connection Stroke Stroke to community/EMS Center Center • Joint Commission accreditation and auditing • Comprehensive stroke centers with IV and IA techniques endovacular capability certification started IV t-PA Image Guidance Medical Support • Increasing need in light of new trial data ± Imaging Guidance Neurosurgical support (hemicraniectomy) Challenges Conclusions • Pathophysiology of acute focal ischemia requires • Providing this care to everyone emergency treatment • Prehospital delays • Revascularization can lead to better outcomes, but • Interfacility transfers needs to be achieved quickly before irreversible injury and increased risk for harm • IA therapy for large vessel ischemic stroke now has Level 1 evidence for efficacy (7 positive RCTs) • Current Stroke Centers are just the beginning • Systems need to be built to provide these therapies • We now need to get faster at treatment 9
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