ular Treatment for Acute Ischemic Stroke Vishal B. Jani MD Assistant Professor Interventional Neurology, Division of Department of Neurology. Creighton University/ CHI health Omaha NE Disclosure None 1
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Tpa VIDEO 3
First Clot Retriveal Device 2001 2012 4
ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? 5
Increasing use of endovascular and intravenous thrombolytics in US Trends in thrombolytic use 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0.1 1.2 0.3 1.4 2.0 0.5 0.4 2.3 2.6 0.6 0.6 3.4 2004 2005 2006 2007 2008 2009 Years Hassan AE: Stroke. 2012 Nov;43(11):3012-7 Summary of trials IMS III MR-RESCUE SYNTHESIS EXPANSION Eligible patients who Patients with largevessel, Patients within 4.5 anterior- had received IV rt-pa hours after symptom within 3 hours after symptom onset circulation occlusion within 8 hours after symptom onset onset NIHSS score of 10 (8-9 with documented arterial occlusion) IV rt-pa only Stratified by presence of favorable penumbral pattern (substantial salvageable tissue) or not Standard IV rt-pa only A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75. 6
Summary of trials IMS III MR-RESCUE SYNTHESIS EXPANSION Eligible patients who Patients with largevessel, Patients within 4.5 anterior- had received IV rt-pa hours after symptom within 3 hours after symptom onset circulation occlusion within 8 hours after symptom onset onset NIHSS score of 10 (8-9 with documented arterial occlusion) IV rt-pa only Stratified by presence of favorable penumbral pattern (substantial salvageable tissue) or not Standard IV rt-pa only A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75. Summary of trials: clinical outcome at 3 months IMS III MR-RESCUE SYNTHESIS EXPANSION IV rt- Standard IV rt- PA only PA only N 434 222 64 54 181 181 mrs 0-1 29% 27% 23% 33% 30% 35% mrs 0-2 43% 40% 38% 61% 42% 46% A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75. 7
Summary of trials: clinical outcome at 3 months IMS III MR-RESCUE SYNTHESIS EXPANSION IV rt- Standard IV rt- PA only PA only N 434 222 64 54 181 181 mrs 0-1 ular 29% 27% treatment 23% remains 33% 30% unproven 35% mrs 0-2 43% 40% 38% 61% 42% 46% A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75. Re: Statewide utilization--minnesota Hospital Association data. Proportion of ischemic stroke pts (%) Hassan AE. International Stroke Conference 2015: Nashville, TN, Feb 11 th -13 th, 2015. 8
Re: Statewide utilization--minnesota Hospital Association data. Proportion of ischemic stroke pts (%) Never went away!! Hassan AE. International Stroke Conference 2015: Nashville, TN, Feb 11 th -13 th, 2015. ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? 9
Multicenter Randomized Clinical Trial of ular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) ular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) Re: N Engl J Med 2015;372: 11-20. Re: Published on February 11, 2015, at NEJM.org.. IMS III, MR CLEAN, and ESCAPE trials IMS III MR-CLEAN ESCAPE Eligible patients who had received IV rt- PA within 3 hours after symptom onset NIHSS score of 10 (8-9 with documented arterial occlusion) IV rt-pa (0.6 mg/kg) [All] Patients with largevessel, anteriorcirculation occlusion within 6 hours after symptom onset Patients with small infarct core +anterior circulation occlusion+ moderate-to-good collaterals within 12 hours after symptom onset NIHSS score of 2 NIHSS score of >5 IV rt-pa (0.9 mg/kg) [445/500, 89%] IV rt-pa (0.9 mg/kg) [238/315, 76%] (IA 22 mg rt-pa) IV rt-pa only (+IV 0.3 mg/kg) (IA 30 mg rt-pa/ 400K UK Standard (IA 10 mg rt-pa) Standard 10
Summary of trials: what was endovascular treatment? IMS III MR-CLEAN ESCAPE IV rt- PA only Standard Standard N=423 No treatment (n=89) Stent retriever (n=5) N=233 No treatment (n=37) Stent retriever (n=190) N=165 No treatment (n=14) Stent retriever (Recommended) Symptom onset-femoral puncture Mean time 206 min Median time 260 min Median time 185 min Summary of trials: what was endovascular treatment? IMS III MR-CLEAN ESCAPE IV rt- PA only Standard Standar d N=423 N=233 No Procedure treatment No treatment (n=89) initiation from (n=37) Stent onset<300 retriever min Stent retriever (n=5) Procedure (n=190) completion from Symptom initiation<120min onset-femoral puncture Mean time 206 min Median time 260 min N=165 No Procedure treatment (n=14) initiation from Stent CT scan<60 retriever min (Recommended) Procedure completion from initiation <90 min Median time 185 min 11
Devices to treat acute ischemic stroke patients with arterial occlusion Thrombectomy Thrombectomy + Retriever Angioplasty balloon Coil based Merci Penumbra aspiration Stent based Solitaire Trevo New generation stent retrievers: FDA approval in 2012 SOLITAIRE stent Retriever Merci Retriever TREVO stent Retriever Merci Retriever Partial/ complete recanalization 61% 24% 86% 60% mrs 0-2 at 3 months 58% 33% 40% 22% Saver JL, Lancet. 2012;380:1241-1249 Nogueira RG. Lancet 2012;380:1231-1240 12
New generation stent retrievers Case examples New generation stent retrievers Case examples 13
ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? Summary of trials: post-procedure angiographic recanalization IMS III MR-CLEAN ESCAPE IV rt-pa only Standard Standard N 434 222 233 267 165 150 TICI 2B-3 41% NR 59% NR 72.4 % NR 14
IMS III versus MR CLEAN Complete /partial recanalization by CT angiography 24 hrs post-randomization IMS III MR-CLEAN N 190 92 233 267 Recanalization 86% 66% 84% 57% Re: N Engl J Med 2015;372:11-20. Re: Radiology. 2014;273(1):202-10. IMS III versus MR CLEAN Complete /partial recanalization by CT angiography 24 hrs post-randomization IMS III MR-CLEAN There is more to the story than just N differences 190 in 92 rates of recanalization 233 267 Recanalization between 86% trials 66% 84% 57% Re: N Engl J Med 2015;372:11-20. Re: Radiology. 2014;273(1):202-10. 15
IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE N 434 222 233 267 mrs 29% 27% 12% 6% 0-1 mrs 0-2 43% 40% 33% 19% Was treatment more effective or untreated group did worse? IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE N 434 222 233 267 mrs 0-1 mrs 0-2 29% 27% 40% 26% 43% 40% 60% 40% Treatment more effective! 16
IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE N 434 222 233 267 165 150 mrs 29% 27% 40% 26% 35% 17% 0-1 mrs 0-2 43% 40% 60% 40% 53% 29% Was treatment more effective or untreated group did worse? IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE N 434 222 233 267 165 150 mrs 0-1 mrs 0-2 29% 27% 40% 26% 35% 17% 43% 40% 60% 40% 53% 29% Was treatment more effective or untreated group did worse?--both 17
IMS III versus MR CLEAN versus ESCAPE IMS Baseline III characteristics MR-CLEAN ESCAPE N 434 222 233 267 165 150 Median 69 68 66 66 71 70 age Median 17 16 17 18 16 17 NIHSS score NIHSS score 20 ASPECTS 8-10 204/654 (31%) 183/500 (37%) 83/307 (40%) 378/654 (58%) 376/500 (75%) 250/304 (82%) IMS III versus MR CLEAN versus ESCAPE IMS Baseline III characteristics MR-CLEAN ESCAPE N 434 222 233 267 165 150 Median age 69 68 66 66 71 70 Median 17 16 CLEAN 17 CT 18 SCAN 16 17 NIHSS score NIHSS score 20 ASPECTS 8-10 204/654 (31%) 183/500 (37%) 83/307 (40%) 378/654 (58%) 376/500 (75%) 250/304 (82%) 18
N IMS III versus MR CLEAN versus ESCAPE Baseline characteristics Intracrani al occlusion confirmed prior to Anterior circulation IMS III MR-CLEAN ESCAPE 434 222 233 267 165 150 44% 41% 100% 100% 100% 100% 97.7% 98.2% 100% 100% 100% 100% IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE N Intracrani al occlusion confirmed prior to 44% 41% 100% 100% 100% 100% 19
ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? IMS III versus MR CLEAN: Predefined strata: Time interval to randomization Strata No. pts Odds ratio (95% CI) MR CLEAN Onset-randomization 120 min 449 1.69(1.21-3.68) Onset-randomization <120 min 51 1.57 (0.51-4.85) ESCAPE Onset-randomization >180 min 146 2.5 (1.4-4.5) Onset-randomization 180 min 165 2.6 (1.5-4.5) IMS III Onset-IV rt-pa >120 min 310 0.88 (0.62 1.24) Onset-IV rt-pa 120 min 345 1.24 (0.88 1.74) 20
IMS III versus MR CLEAN versus ESCAPE: Predefined strata: Time interval to randomization Strata No. pts Odds ratio (95% CI) Multicenter Randomized Clinical Trial of ular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Onset-randomization 449 1.69(1.21-3.68) 120 min IMS III MR ESCAPE Onset-randomization 51 CLEAN 1.57 (0.51-4.85) <120 min Interventional Management of Stroke (IMS) III Onset-IV rt-pa >120 310 0.88 (0.62 1.24) min Onset-IV rt-pa 120 345 Time 1.24 (0.88 1.74) min IMS III versus MR CLEAN versus ESCAPE: Alberta Stroke Program Early Computed Tomography Score (ASPECTS) Strata No. pts Odds ratio (95% CI) MR CLEAN ASPECTS 0-4 28 1.09 (0.14-8.46) ASPECTS 4-7 92 1.97 (0.89-4.35) ASPECTS 8-10 376 1.61 (1.11-2.34) ESCAPE ASPECTS 6-7 54 2.7 (1.0-7.2) ASPECTS 8-10 250 2.6 (1.7-4.1) IMS III ASPECTS 0-7 271 1.12 (0.67 1.87) ASPECT 8-10 378 1.03 (0.79 1.34) 21
IMS III versus MR CLEAN versus ESCAPE: Alberta Stroke Program Early Computed Tomography Score (ASPECTS) Strata No. pts Odds ratio (95% CI) MR CLEAN ASPECTS 0-4 28 1.09 (0.14-8.46) ASPECTS 4-7 92 1.97 (0.89-4.35) ASPECTS 8-10 376 1.61 (1.11-2.34) ESCAPE Clean CT scan matters more if patient evaluated in 3-12 hrs (than 0-3 ASPECTS 6-7 54 2.7 (1.0-7.2) hrs) after symptom onset ASPECTS 8-10 250 2.6 (1.7-4.1) IMS III ASPECTS 0-7 271 1.12 (0.67 1.87) ASPECT 8-10 378 1.03 (0.79 1.34) IMS III versus MR CLEAN versus ESCAPE: Predefined strata: Alberta Stroke Program Early Computed Tomography Score (ASPECTS) Strata No. pts Odds ratio (95% CI) MR CLEAN ASPECTS 0-4 28 1.09 (0.14-8.46) ASPECTS 4-7 92 1.97 (0.89-4.35) ASPECTS 8-10 376 1.61 (1.11-2.34) ESCAPE ASPECTS 6-7 54 2.7 (1.0-7.2) ASPECTS 8-10 250 2.6 (1.7-4.1) IMS III ASPECTS 0-7 271 1.12 (0.67 1.87) ASPECT 8-10 378 1.03 (0.79 1.34) 22
No patient subgroup identified that does not benefit from endovascular treatment except those with extensive ischemic changes on pretreatment CT scan Risk of post-thrombolysis intracerebral hemorrhage Impaired autoregulatio n +SBP Reperfusion +coagulopathy (Qureshi AI: Circulation 2008 Jul 8;118(2):176-87) IV rt-pa ular 6% 10% 23
IMS III versus MR CLEAN Adverse events IMS III MR-CLEAN ESCAPE N 434 222 233 267 165 150 Symptom 6.2% 5.8% 7.7% 6.4% 3.6% 2.7% atic ICH Parenchy mal hematoma 9.6% 7.5% 6% 6% 4.8% 2.0% SAH 11.5% 5.8% 0.9% 0% 3% 1.3% Re: N Engl J Med 2015;372:11-20. Re: N Engl J Med 2013;368:893-903. ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol? 24
Time to Treatment + Recanalization Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75 Time to treatment 0 min 228 min 285 min 357 min Modified Rankin scale 0-2 at 3 m 60% 50% 40% 30% 100% 80% 75% 70% Angiographic recanalization Parameter Optimized ular Treatment Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75 Time to treatment 0 min 228 min 285 min 357 min Modified Rankin scale 0-2 at 3 m 60% 50% 40% 30% 100% 80% 75% 70% Angiographic recanalization 25
Parameter Optimized ular Treatment Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75 Time to treatment 0 min 228 min 285 min 357 min Modified Rankin scale 0-2 at 3 m 60% 50% 40% 30% 100% 80% 75% 70% Angiographic recanalization Parameter Optimized ular Treatment Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol. 2014 May;7(1):56-75 Time to treatment 0 min 228 min 285 min 357 min Modified Rankin scale 0-2 at 3 m Just do it is 60% 50% 40% not enough 30% 100% Do it FAST!! 80% 75% Do it 70% WELL!! Angiographic recanalization 26
ular Treatment of Acute Ischemic Stroke Pre-MR CLEAN and ESCAPE era? Design of MR CLEAN and ESCAPE? Interpreting the results? Interpreting subgroup analysis? Time efficient treatment? Protocol and guidelines? 2013 American Heart Association/American Stroke Association Guidelines for the Early Management of Patients With Acute Ischemic Stroke: (Stroke. 2013;44:870-947) Patients eligible for intravenous rt PA should receive intravenous rt PA even if IA treatments are being considered. IA fibrinolysis is beneficial for treatment of carefully selected patients with major ischemic strokes of <6 hours duration caused by occlusions of the MCA Class I; Level of Evidence A Class I; Level of Evidence B 27
2015 American Heart Association/American Stroke Association Focused Update (Stroke. 2015; 46: 3020-3035) Patients eligible for intravenous rt PA should Class I; receive intravenous rt PA even if IA treatments Level of are being considered. Evidence A Patients should receive endovascular therapy with a stent retriever if: a. Prestroke mrs score 0 to 1, b. Receiving intravenous r-tpa<4.5 hrs, c. Causative occlusion of the ICA or proximal MCA (M1). d. Age 18 years, e. NIHSS score of 6, f. ASPECTS of 6, and g. Treatment can be initiated (groin puncture) within 6 hours of symptom onset Class I; Level of Evidence A Protocol for acute ischemic stroke treatment Qureshi AI, Georgiadis AL: Textbook of Interventional Neurology 2011: Cambridge, UK 0-4.5hrs IV thrombolysis NIHSS score <10 NIHSS score 10 Ischemic stroke 3-6 hrs >6 hrs CT/MRI Perfusion- Volume mismatch ular treatment (mechanical/ pharmacological approach) 28
Protocol for acute ischemic stroke treatment New protocol Ischemic stroke 0-4.5hrs 3-6 hrs >6 hrs IV thrombolysis CT angiogram occlusion + CT angiogram occlusion + Collaterals + Ischemic changes on CT- NIHSS CT angiogram score occlusion <10 - NIHSS CT angiogram score occlusion 10 + ular treatment (stent retrievers/ pharmacological approach) SHORT PROCEDURE Conclusions IMS III, SYNTHESIS EXPANSION, and MR RESCUE trials did not support a large magnitude benefit of endovascular treatment in subjects randomized in all three trials. MR CLEAN and ESCAPE trial demonstrated a significant benefit with endovascular treatment in patients with acute ischemic stroke using unique patient selection criteria and treatment paradigms. Larger magnitude benefits can be expected with implementation of parameter optimized endovascular treatment in patients with ischemic stroke who are candidates for IV thrombolytics. 29
Thank you. Vishal Jani MD +1(402) 578-3219 vbjani@yahoo.com 30