Broadening the Stroke Window in Light of the DAWN Trial

Transcription

1 Broadening the Stroke Window in Light of the DAWN Trial South Jersey Neurovascular and Stroke Symposium April 26, 2018 Rohan Chitale, MD Assistant Professor of Neurological Surgery Vanderbilt University

2 Goals: Discuss the DAWN Trial and how it relates to changes in stroke algorithms Identify changes to stroke algorithm that would help hospitals implement trial results

3 I have no financial disclosures related to this presentation

4 Ischemic Penumbra From: Acute Stroke Intervention: A Systematic Review JAMA. 2015;313(14): doi: /jama

5 Benefit of IV tpa Outcome Nl/Near Normal 8.3 Improved 3.1 NNT For every 100 patients treated with tpa, 32 benefit, 3 harmed Improved outcome is strongly correlated with successful recanalization --Saver, Arch Neurol AAN/ACEP/AHA Patient Educational Tool 2008

6 Take Home IV tpa Good! Problem: Doesn t work well on big vessels

7 IV tpa often fails to recanalize LVO IV tpa fails more often than it succeeds for large artery occlusions Reported complete recanalization rates vary: 18% - 50% ICA terminus ~ 6% Recanalization with IV tpa Success Failure Partial None Partial Complete --Rubiera et al, Stroke Alexandrov et al, Stroke 2011

8 Next Step? Intra-arterial Thrombolysis in AIS More efficient way? Fewer complications?

9 MERCI Retrieval System Flexible nitinol wire with helical shape once deployed

10 Penumbra Reperfusion system Reperfusion catheter directed to clot face and mechanical separators are used to macerate clot while aspiration pump applied (-20inches/Hg)

11 The newest class of devices Stent + Retriever = Stentriever

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13 Solitaire FR Revascularization device (Covidien) Overlapping stent design that is fully retrievable once deployed Sizes range between 4-6mm diameter, 15-40mm length

14 Trevo Retreiver System (Stryker, Inc) Similar stent design as retrievable stent 4.0mm diameter, 20mm length (Now available in increased size ranges) Entire stent radio-opaque so visible during delivery

15 Aspiration Catheter

16 Endovascular treatment evolution Higher recanalization rates compared to IV tpa for LVO IA thrombolytics tpa, UK ~57% recanalization (PROACT2) Merci corkscrew device ~ 60% recanalization rate Penumbra suction device ~ 82% recanalization rate Solitaire stent-like retriever ~ 83% recanalization rate Trevo stent-like retriever ~ 86% recanalization rate

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19 Does Endovascular therapy work?

20 Endovascular Treatment for LVO stroke: 9 RCTs PROACT II MELT MR RESCUE IMS III MR CLEAN ESCAPE SWIFT PRIME EXTEND IA REVASCAT

21 Endovascular Treatment for LVO stroke: 9 RCTs PROACT II MELT MR RESCUE IMS III MR CLEAN ESCAPE SWIFT PRIME EXTEND IA REVASCAT

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26 NEJM 2015 Randomization of confirmed LVO (distal ICA, M1, M2, A1, or A2) AIS patients within 6 hours of onset to usual medical care vs. medical care and IA therapy 16 medical center enrollment of 500 patients in Netherlands NIHSS > 2 Primary outcome: mrs at 90 days

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28 Number needed to treat for outcome of mrs 0-2 = 3 MR CLEAN provided first positive multicenter randomized trial demonstrating benefit of IA therapy, leading to early halting/analysis of other ongoing trials

29 EXTEND IA Extending the time for Thrombolysis in Emergency Neurological Deficits Intra- Arterial Published in NEJM Feb Presented at ISC (Nashville) 2015

30 EXTEND-IA 70 subjects randomized to IV tpa alone vs tpa plus endovascular treatment Stopped early due to efficacy Campbell et al, NEJM, 2015

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34 Inclusion criteria: NIHSS > 5 Symptom onset < 12 hours prior mrs 0-1 at baseline ASPECTS > 5 (i.e. large core completed infarct) ICA +/- M1 occlusion CTA demonstrating moderate to good collaterals

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36 ESCAPE 326 subjects randomized to standard care vs. endovascular treatment, up to 12 hours after onset Stopped early due to efficacy Goyal et al, NEJM 2015

37 ESCAPE OR = % CI: Goyal et al, NEJM 2015

38 SWIFT PRIME 196 subjects Used perfusion imaging Stopped early due to efficacy Saver et al, NEJM 2015

39 SWIFT PRIME RR = % CI Saver et al, NEJM 2015

40 Jovin et al, NEJM 2015 REVASCAT 206 subjects within 8 hours Terminated early due to results of other trials

41 REVASCAT OR = % CI: Jovin et al, NEJM 2015

42 Figure 1. Functional outcome of patients with ischaemic stroke in trials of endovascular thrombectomyrates of independent functional outcome at 90 days after treatment (modified Rankin scale [mrs] score of 0 2) are shown for recent trials of endovascular throm... Bruce C V Campbell, Geoffrey A Donnan, Kennedy R Lees, Werner Hacke, Pooja Khatri, Michael D Hill, Mayank Goyal, Peter J Mitchell, Jeffrey L Saver, Hans-Christoph Diener, Stephen M Davis Endovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke null, Volume 14, Issue 8, 2015,

43 Endovascular treatment more than doubles the chance of a good outcome HERMES 2016 A patient level meta-analysis

44 The Importance of Time In SWIFT PRIME, 91% of patients treated within 2.5 hours of symptom onset went home normal or nearly normal This success rate drops by 10% between 2.5 and 3.5 hours Drops by 20% each subsequent hour Goyal 2016; Khatri 2009

45 A Change in the Standard of Care There became five independent RCTs that all support modern endovascular treatment for acute ischemic stroke Eligible patients with LVO should be offered endovascular treatment Guidelines have been updated to reflect this (class I, level A)

46 Take Home IA therapy works! Problem: For whom does it work best?

47 Unanswered clinical questions: Wake up stroke Perfusion imaging vs. plain CT scan How late is too late? What rules apply in posterior circulation? Access to care to improve transfer EMS Assessment tools Mobile CT Decision on which hospital to route patient towards Improvement in transfer times

48 Unanswered clinical questions: Wake up stroke Perfusion imaging vs. plain CT scan How late is too late? What rules apply in posterior circulation? Access to care to improve transfer EMS Assessment tools Mobile CT Decision on which hospital to route patient towards Improvement in transfer times

49 DAWN

50 Thrombectomy 6-24 hrs after stroke with a mismatch between deficit and infarct Imaging Large Vessel Occlusion Small Infarct Volume Clinical: 6 to 24 hours since onset High NIHSS

51 Clinical-infarct Mismatch Patients with disproportionately high NIHSS given size of infarcted area on imaging AND Have gotten to hospital late in the game

52 206 patients randomized Thrombectomy (N=107) vs Medical Care (N=99) Primary Endpoints (90 days): Post-stroke disability on Utility Weighted Modified Rankin Scale 5.5 vs 3.4 Functional Independence (mrs 0-2) 49% vs 13%

53 Other important findings Procedural Complications 7% Symptomatic ICH 6% vs 3% Death 19% vs 18%

54 Characteristics of the Patients at Baseline. Nogueira RG et al. N Engl J Med 2018;378:11-21

55 Efficacy Outcomes. Nogueira RG et al. N Engl J Med 2018;378:11-21

56 Distribution of Scores on the Modified Rankin Scale at 90 Days. Nogueira RG et al. N Engl J Med 2018;378:11-21

57 Subgroup Analyses of the First Primary End Point. Nogueira RG et al. N Engl J Med 2018;378:11-21

58 Nogueira RG et al. N Engl J Med 2018;378:11-21 Safety Outcomes.

59 DEFUSE 3

60 Who was included? Small infarct with large penumbra <70 cc Ischemia/Infarct >1.8 Volume of penumbra >15 cc

61 182 patients were randomized Thrombectomy (N=92) vs Medical therapy(n=90) Measured outcomes mrs of 0-2 at 90 days = 45% vs 17% Death at 90 days = 14 % vs 26% Symptomatic ICH = 7% vs 4%, not significant

62 Example of Perfusion Imaging Showing a Disproportionately Large Region of Hypoperfusion as Compared with the Size of Early Infarction. Albers GW et al. N Engl J Med 2018;378:

63 Baseline Characteristics of the Patients and Features of Thrombectomy. Albers GW et al. N Engl J Med 2018;378:

64 Albers GW et al. N Engl J Med 2018;378: Scores on the Modified Rankin Scale at 90 Days.

65 Clinical and Imaging Outcomes. Albers GW et al. N Engl J Med 2018;378:

66 Subgroup Analyses. LIMITED POWER DUE TO EARLY TERMINATION OF STUDY Positive treatment Albers effect GW et al. in N Engl DEFUSE J Med 2018;378: , even including larger ischemic core and milder stroke symptoms

67 WEAKNESSES How many patients need to be screened to find 1 eligible patient? Where did inclusion criteria come from? Is it applicable in real world? (Group A-B-C all with different eligibility requirements)

68 WEAKNESSES Need for RAPID software? Last Known Well vs First Time Seen Unwell DAWN- wake-up strokes LKW 13 hours, FTSU 5 hours Is window really 24 hours? DAWN Interquartile range Both studies are Tissue based, not time based anyways

69 Nonetheless, results are striking. Why is there larger benefit in the late window trials?

70 Favorable outcome rates in early vs late window thrombectomy trials. Gregory W. Albers Stroke. 2018;49: Copyright American Heart Association, Inc. All rights reserved.

71 Estimated infarct growth rates in patients with internal carotid artery or middle cerebral artery occlusions. Gregory W. Albers Stroke. 2018;49: Copyright American Heart Association, Inc. All rights reserved.

72 Favorable outcome rates in MR CLEAN vs SWIFT PRIME and EXTEND-IA. Gregory W. Albers Stroke. 2018;49: Copyright American Heart Association, Inc. All rights reserved.

73 Understand Stroke Evolution Rate of stroke growth different for different people Some people will have very slow growth of ischemic core Favorable collateral circulation eventually fails

74 HOW DO WE MODIFY OUR BRAIN IMAGING PRACTICE? -<6 hours We still obtain CTP -- helps streamline stroke process -- avoids having to make real-time decision about who gets one and who does not

75 -6-24 hours Since OSH may not have perfusion imaging -- Apply DEFUSE 3 exclusion criteria: -- ASPECT < 6 not mandatory for transfer -- Apply DAWN exclusion criteria: -- established infarct > 1/3 MCA territory not mandatory for transfer

76 Mechanical Thrombectomy -- Extended time window for treatment is appropriate for those with large clinical-infarct mismatch -- Specific use of RAPID software probably not necessary

77 Other Clinical Implications More accurate selection criteria: Is thrombectomy beneficial in early window if you can identify early large ischemic core? Do we need repeat CTA once patient arrives to CSC? Identifies development of completed infarct, hemorrhagic conversion, recanalization Or is it a waste of time critical (especially for those with no collaterals/fast stroke growth rate)

78 What size of ischemic core is too big in the delayed window? How far can the late window be stretched?

79 CONCLUSIONS More people may benefit from thrombectomy than we know. Making treatment available will take a lot of work Triage Streamlining systems of care Efficiency

80 THANK YOU