Parameter Optimized Treatment for Acute Ischemic Stroke

Transcription

1 Heart & Stroke Barnett Memorial Lectureship and Visiting Professorship Parameter Optimized Treatment for Acute Ischemic Stroke December 2, 2016, Thunder Bay, Ontario Adnan I. Qureshi MD Professor of Neurology, Neurosurgery, and Radiology President, International Society of Interventional Neurology Zeenat Qureshi Stroke Institutes, St. Cloud, MN, USA and PingAn Hospital, Shijiazhuang, China, Zeenat Qureshi Institute of Clinical Neurosciences, Donka National Hospital, Conakry, Guinea, Qureshi Medical Education Center, Xuan Wu Hospital, Beijing, China Presenter disclosure Speaker: Dr. Adnan Qureshi Relationships with commercial interests: Grants/Research Support: National Institute of Neurological Disorders and Stroke (U01-NS062091, PI: Qureshi; and U01-NS061861, PI: Palesch), part by an Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center (H23-4-3, PI: Toyoda). Other: Chiesi USA, Inc.and Astellas Pharma, Inc., supplied intravenous nicardipine for study use. 1

2 Disclosure of commercial support This program has received financial support from the Heart and Stroke Foundation in the form of an Honorarium and logistical cost to support the Lectureship. This program has received in-kind support from the Northwestern Ontario Regional Stroke Network and Thunder Bay Regional Health Sciences Centre in the form of logistical support. Potential for conflict(s) of interest: IV nicardipine manufactured by Chiesi USA, Inc.and Astellas Pharma, Inc can be used to treat acute hypertensive response. Mitigating potential bias The speaker will refer in all cases to guideline recommended and evidence based management and interventions When there is discussion regarding items that are not directly supported by randomized clinical trials, the speaker will indicate this issue in his responses/comments 2

3 Objectives Identify the parameters that determine the results of both intravenous thrombolytic treatment and endovascular treatment for acute ischemic stroke. Identify strategies for optimizing the parameters for such treatments. Highlight the findings of the recent randomized trials and implications for patient management and future of endovascular therapy; Summarize recent advances in endovascular devices such as SOLITAIRE or TREVO stent retrievers Understand the recent changes in guidelines for treatment of acute ischemic stroke Explain the management of acute hypertensive response in patients with Intracerebral hemorrhage Trends in thrombolytic use in United Increasing use of endovascular and intravenous thrombolytics in US Years Hassan AE: Stroke Nov;43(11):

4 ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? 4

5 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: Re: N Engl J Med 2015;372: 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 5

6 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 6

7 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 mrs 0-2 at 3 months 61% 24% 86% 60% 58% 33% 40% 22% Saver JL, Lancet. 2012;380: Nogueira RG. Lancet 2012;380:

8 New generation stent retrievers Case examples New generation stent retrievers Case examples 8

9 ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? Summary of trials: post-procedure angiographic recanalization IMS III MR-CLEAN ESCAPE IV rt-pa only Standard Standard N TICI 2B-3 41% NR 59% NR 72.4% NR Near complete or complete recanalization 9

10 Summary of trials: post-procedure angiographic recanalization IMS III MR-CLEAN ESCAPE IV rt-pa only Standard Standard N TICI 2B-3 41% NR 59% NR 72.4% NR Define 2B Perfusion of 2/3 or greater of the distribution of the occluded artery Perfusion of 1/2 or greater of the distribution of the occluded artery Complete filling of all vascular territory, but the filling is slower than normal Summary of trials: post-procedure angiographic recanalization IMS III MR-CLEAN ESCAPE IV rt-pa only Standard Standard N TICI 2B-3 41% NR 59% NR 72.4% NR There is more to the story than just differences in rates of recanalization between trials Near complete or complete recanalization 10

11 IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE Control Control N mrs 29% 27% 12% 6% 35% 17% 0-1 mrs % 40% 33% 19% 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 Control Control Control Control N mrs 29% 27% 40% 26% 35% 17% 0-1 mrs % 40% 60% 40% 53% 29% Treatment more effective! 11

12 IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE Control Control Control N mrs 29% 27% 12% 6% 35% 17% 0-1 mrs % 40% 33% 19% 53% 29% Untreated (control) group did worse- PATIENT SELECTION IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE Control Control Control N mrs 29% 27% 12% 6% 35% 17% 0-1 mrs % 40% 33% 19% 53% 29% Was treatment more effective or untreated group did worse? 12

13 IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months IMS III MR-CLEAN ESCAPE Control Control Control N mrs 29% 27% 12% 6% 35% 17% 0-1 mrs % 40% 33% 19% 53% 29% Was treatment more effective or untreated group did worse?--both ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? 13

14 IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE Control Control Control N Median age Median NIHSS score NIHSS score 20 ASPECTS /654 (31%) 183/500 (37%) 83/307 (40%) 378/654 (58%) 376/500 (75%) 250/304 (82%) IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE AlbertaEndo- StrokeControl ProgramEndo- Control Control Early Computed vasc Tomography vasc Score (ASPECTS) N Median what-is-aspects/ age Median NIHSS 0 10 score NIHSS Diffuse 204/654 (31%) 183/500 (37%) 83/307 No (40%) score 20 involvement Extent of ischemic changes ischemic throughout changes ASPECTS the MCA378/654 (58%) 376/500 (75%) 250/304 (82%)

15 IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE Control Control N Median age Median NIHSS score NIHSS score 20 ASPECTS CLEAN CT SCAN /654 (31%) 183/500 (37%) 83/307 (40%) 378/654 (58%) 376/500 (75%) 250/304 (82%) IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE Control Control Control Control N Intracrani al occlusion confirmed prior to Anterior circulation 192 (44%) 92 (41%) 100% 100% 100% 100% 97.7% 98.2% 100% 100% 100% 100% 15

16 IMS III versus MR CLEAN versus ESCAPE Baseline characteristics IMS III MR-CLEAN ESCAPE Control Control N Intracrani al occlusion confirmed prior to Anterior circulation 192 (44%) 92 (41%) 100% 100% 100% 100% 97.7% 98.2% 100% 100% 100% 100% IMS III versus MR CLEAN versus ESCAPE Clinical outcome at 3 months Confirmed arterial occlusion by CT/MR angiography prior to randomization IMS III MR-CLEAN ESCAPE Control Control Control Control N mrs 45% 38% 33% 19% 53% 29% 0-2 Better results if acute ischemic patients with CT/MR angiographic occlusion selected Re: Radiology. 2014;273(1):

17 So what was it about MR CLEAN and ESCAPE trials? Patients who have CT scans with minimal ischemic changes Patients with CT/MR angiographic confirmed occlusion Patients not eligible for IV rt PA received revascularization Controls received IV rt-pa at later time interval (3-4.5 hrs) Higher recanalization rate Shorter procedure time Better endovascular in Netherlands/Canada or better IV rt-pa in US Possible Possible 10%-25% of control group Not reported-possible Possible Not reported-mr CLEAN-yes for ESCAPE?? So what was it about MR CLEAN and ESCAPE trials? Patients who have CT scans with minimal ischemic changes Possible Patients with CT/MR angiographic Possible confirmed occlusion Patients not eligible for IV rt PA 10%-25% of control received revascularization All of the mentioned with groupvariable Controls received IV rt-pa contribution at Not reported-possible later time Highlights interval (3-4.5 the multifaceted hrs) determinants Higher recanalization of endovascular rate treatment Possible success Shorter procedure time Better endovascular in Netherlands/Canada or better IV rt-pa in US Not reported-mr CLEAN-yes for ESCAPE?? 17

18 ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? ular treatment versus medical treatment [including IV rt-pa] Time window for recruitment in 15 trials Re: Qureshi AI. Am J Neuroradiol 2016: 2016: 37: <3 hours <4.5 hours <6 hours IMS III <8 hours SWIFT-PRIME hours MR-CLEAN, EXTEND IA, SYNTHESIS-EXPANSION, SYNTHESIS-PILOT, MELT, PROACT I/II, Ducrocq et al. REVASCAT, MR-RESCUE, Roubec et al. ESCAPE, Macleod et al. 18

19 Meta-analysis: 15 trials 2949 subjects analyzed 90 d outcomes Modified Rankin scale [0-2] 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) Modified Rankin scale [0-1] 0 (no symptoms), 1 (no significant disability) Odds ratio 1.8, 95% CI , 95% CI Survival 1.1, 95% CI Re: Qureshi AI. Am J Neuroradiol 2016: 37: Favor medical Favor endovascular Meta-analysis: 15 trials 2949 subjects analyzed 90 d outcomes Modified Rankin scale [0-2] 0 (no symptoms), 1 (no significant disability), or 2 (slight disability) Odds ratio Odds of achieving a favorable outcome or Modified excellent Rankin outcome scale [0-1] at 3 months post- significant disability) 0 (no symptoms), 1 (norandomization is approximately 80% higher with endovascular treatment among patients with Survival acute ischemic stroke Re: Qureshi AI. Am J Neuroradiol 2016: 37: Favor medical Favor endovascular 19

20 Meta-analysis: 15 trials 90 d outcomes-modified Rankin Scale 0-2 Permitted IV rt-pa prior to endovascular Odds ratio 2.1, 95% CI Did not permit IV rt-pa prior to endovascular 1.5, 95% CI Re: Qureshi AI. Am J Neuroradiol 2016: 37: Favor medical Favor endovascular Meta-analysis: 15 trials 90 d outcomes-modified Rankin Scale 0-2 Permitted IV rt-pa prior to endovascular Odds ratio 2.1, 95% CI Did not permit IV rt-pa prior to endovascular Odds of achieving a favorable1.5, outcome 95% CI at months post-randomization higher with endovascular even in pts who already received IV rt-pa Re: Qureshi AI. Am J Neuroradiol 2016: 37: Favor medical Favor endovascular 20

21 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% Meta-analysis: 15 trials 2906 subjects analyzed Safety endpoints Post-procedure symptomatic intracerebral hemorrhage Odds ratio 1.2, 95% CI No significant difference in comparable patients Re: Qureshi AI. Am J Neuroradiol 2016: 37: Favor medical Favor endovascular 21

22 ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? Time to Treatment + Recanalization Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol 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 22

23 Parameter Optimized ular Treatment Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol 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 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 23

24 Parameter Optimized ular Treatment Re: Qureshi AI. A report from the Working Group of International Congress of Interventional Neurology. J Vasc Interv Neurol 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!! Do it WELL!! 80% 75% 70% Angiographic recanalization ular Treatment of Acute Ischemic Stroke Design of MR CLEAN and ESCAPE? Interpreting the results? Most likely to benefit? Meta-analysis? Time efficient treatment? Protocol? 24

25 2013 American Heart Association/American Stroke Association Guidelines for the Early Management of Patients With Acute Ischemic Stroke: (Stroke. 2013;44: ) 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 2015 American Heart Association/American Stroke Association Focused Update (Stroke. 2015; 46: ) Patients eligible for intravenous rt PA should receive intravenous rt PA even if IA treatments are being considered. 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 Class I; Level of Evidence A 25

26 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) 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 26

27 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, ESCAPE, and other recent trials 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. Zeenat Qureshi Institutes 2016 Thank you St. Cloud, Minnesota, USA Donka National Hosp, Conakry, Guinea PingAn Hosp, Shijiazhuang, China Xuan Wu Hosp, Beijing, China 27

28 Illustrative case: 94 years old F Hemispatial neglect, left hemiplegia, left visual field deficits, gaze deviation. National Institutes of Health Stroke scale score -20 Symptom onset at 12:30 hrs. Previous history of: Atrial fibrillation and chronic warfarin treatment Multiple transient ischemic attacks Previous ischemic stroke in 2014 In assisted living due to neurological deficits, cognitive deficits, and severe arthritis. Deteriorated clinically since arrival in outside ED Patient's International Normalized Ratio was 2.3 was therefore was not a candidate for intravenous rt-pa. Illustrative case: what we do not know 94 years old F- EXCLUDED IN TRIALS Hemispatial neglect, left hemiplegia, left visual field deficits, gaze deviation. National Institutes of Health Stroke scale score -20 Symptom onset at 12:30 hrs. Previous history of: Atrial fibrillation and chronic warfarin treatment Multiple transient ischemic attacks Previous ischemic stroke in 2014 In assisted living due to neurological deficits, cognitive deficits, and severe arthritis. EXCLUDED Deteriorated clinically since arrival in outside ED Patient's International Normalized Ratio was 2.3 was therefore was not a candidate for intravenous rt-pa. EXCLUDED 28

29 Inter-hospital transfer, intubated, endovascular treatment Occlusion of M2 segment MCA Stent retriever 4X20 mm deployed No thrombolytics Retracted under suction No proximal balloon occlusion-- Complete recanalization 1840 hrs 1850 hrs 1856 hrs Inter-hospital transfer, intubated, endovascular treatment-what we do not know Occlusion of M2 segment MCA?? Stent retriever 4X20 mm deployed No thrombolytics?? Retracted under suction No proximal balloon occlusion??-- Complete recanalization 1840 hrs 1850 hrs 1856 hrs 29

30 Post procedure Immediate post treatment tissue perfusion map- Tissue perfusion less on right MCA distribution MICROVASCULAR FAILURE ischemia/ microemboli/ platelet activation Day 2- Extubated, National Institutes of Health Stroke scale score=8 Treatment of acute hypertensive response in patients receiving thrombolysis (Qureshi AI: Circulation 2008 Jul 8;118(2):176-87) 30

31 Acute hypertensive response may increase the risk of post-thrombolysis intracerebral hemorrhage Impaired autoregulation +SBP Reperfusion +coagulopathy (Qureshi AI: Circulation 2008 Jul 8;118(2):176-87) SBP and post-thrombolytic ICH Studies ECASS II (Stroke. 2001; 32(2):438-41) Multicenter rt-pa stroke survey (Circulation 2002;105: ) EPITHET (Stroke. 2010; 41(1):72-7) Patients with acute ischemic stroke Intracranial hemorrhage rate Predictor (8%) Baseline SBP (13%) Pretreatment SBP (15%) Weighted SBP 1-24 h 31

32 American Heart Association Guidelines- Thrombolysis Systolic blood pressure is <=185 mm Hg and their diastolic blood pressure is <=110 mm Hg (Class I, Level of Evidence B) before lytic therapy is started. Maintained below 180/105 mm Hg for at least the first 24 hours after intravenous rtpa treatment. Blood pressure recommendations should be followed in patients undergoing intra-arterial thrombolysis (Class I, Level of Evidence C). American Stroke Association Stroke Council. Stroke. 38(5): , 2007 May. Post-hoc analysis of NINDS rt-pa trial Stroke. 29(8):1504-9, 1998 Aug. Acute ischemic stroke and received rt-pa SBP >180 mm Hg (3-24 hours after symptom onset) Antihypertensive treatment (N=65) No antihypertensive treatment (N=112) Clinical improvement at 24 hours 32% 52% 32

33 Post-hoc analysis of NINDS rt-pa trial Stroke. 29(8):1504-9, 1998 Aug. Clinical improvement at 24 hours Acute ischemic stroke and received rt-pa SBP >180 mm Hg (3-24 hours after symptom onset) More severe hypertension Antihypertensive treatment (N=65) 32% 52% No More antihypertensive abrupt decline of BP in treatment response to(n=112) antihypertensive medication Post-hoc analysis of NINDS rt-pa trial Stroke. 29(8):1504-9, 1998 Aug. More severe hypertension Acute ischemic stroke and received rt-pa SBP >180 mm Hg (3-24 hours More after abrupt symptom decline onset) of BP in response to antihypertensive medication Antihypertensive No(recanalization antihypertensive is associated treatment (N=65) treatment with spontaneous (N=112) BP decline) Clinical improvement at 24 hours Occlusion 32% Recanalization 52% Reocclusion BP high BP normal BP high 33

34 Special considerationspost thrombolytic patients Greater level of susceptibility to blood pressure decline/fluctuations (presumably related to recanalization). -Mattle HP, et al. Stroke. Feb 2005;36(2): First 6 hours is the period of maximum fluctuations in blood pressure following thrombolytic treatment. -Aiyagari V, et al. Stroke. Oct 2004;35(10):