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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
• 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
• I have no financial disclosures related to this presentation
Ischemic Penumbra
From: Acute Stroke Intervention: A Systematic
Review JAMA. 2015;313(14):1451-1462.
doi:10.1001/jama.2015.3058
Benefit of IV tPA Outcome NNT Nl/Near Normal 8.3 Improved 3.1 For every 100 patients treated with
tPA, 32 benefit, 3 harmed Improved outcome is strongly
correlated with successful recanalization
--Saver, Arch Neurol 2004 --AAN/ACEP/AHA Patient Educational Tool 2008
Take Home
• IV tPA Good! • Problem: Doesn’t work well on big vessels
IV tPA often fails to recanalize LVO Recanalization with IV tPA
None
Partial
Complete
IV tPA fails more often than it succeeds for large artery occlusions
Reported complete recanalization rates vary: 18% - 50% ICA terminus ~ 6%
--Rubiera et al, Stroke 2011 --Alexandrov et al, Stroke 2011
Failure
Partial
Success
Next Step? • Intra-arterial Thrombolysis in AIS
– More efficient way? – Fewer complications?
• MERCI® Retrieval System
– Flexible nitinol wire with helical shape once deployed
• Penumbra Reperfusion system
– Reperfusion catheter directed to clot face and mechanical separators are used to macerate clot while aspiration pump applied (-20inches/Hg)
The newest class of devices • Stent + Retriever = Stentriever
• Solitaire™ FR Revascularization device (Covidien) – Overlapping stent design that is fully retrievable
once deployed – Sizes range between 4-6mm diameter, 15-40mm
length
• 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
• Aspiration Catheter
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
• Does Endovascular therapy work?
Endovascular Treatment for LVO stroke: 9 RCTs
• PROACT II • MELT • MR RESCUE • IMS III • MR CLEAN • ESCAPE • SWIFT PRIME • EXTEND IA • REVASCAT
Endovascular Treatment for LVO stroke: 9 RCTs
• PROACT II • MELT • MR RESCUE • IMS III • MR CLEAN • ESCAPE • SWIFT PRIME • EXTEND IA • REVASCAT
– 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
• Number needed to treat for outcome of mRS 0-2 = 3
• MR CLEAN provided first positive multi-center randomized trial demonstrating benefit of IA therapy, leading to early halting/analysis of other ongoing trials
EXTEND IA • Extending the time for Thrombolysis in
Emergency Neurological Deficits – Intra-Arterial
• Published in NEJM Feb. 2015
• Presented at ISC (Nashville) 2015
EXTEND-IA
• 70 subjects randomized to IV tPA alone vs tPA plus endovascular treatment
• Stopped early due to efficacy
Campbell et al, NEJM, 2015
• 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
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
ESCAPE
OR = 2.6 95% CI: 1.7-3.8
Goyal et al, NEJM 2015
SWIFT PRIME
• 196 subjects
• Used perfusion imaging
• Stopped early due to efficacy
Saver et al, NEJM 2015
SWIFT PRIME
RR = 1.70 95% CI 1.23-2.33
Saver et al, NEJM 2015
REVASCAT
• 206 subjects
• within 8 hours
• Terminated early due to results of other trials
Jovin et al, NEJM 2015
REVASCAT
OR = 1.7 95% CI: 1.05-2.8
Jovin et al, NEJM 2015
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, 846–854
http://dx.doi.org/10.1016/S1474-4422(15)00140-4
HERMES 2016 A patient level meta-analysis
Endovascular treatment more than doubles the chance of a good outcome
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
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)
Take Home
• IA therapy works! • Problem: For whom does it work best?
• 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
• 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
DAWN
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
• “Clinical-infarct Mismatch” – Patients with disproportionately high NIHSS given
size of infarcted area on imaging
AND
– Have gotten to hospital late in the game
• 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%
– Other important findings • Procedural Complications – 7% • Symptomatic ICH—6% vs 3% • Death 19% vs 18%
Characteristics of the Patients at Baseline.
Nogueira RG et al. N Engl J Med 2018;378:11-21
Efficacy Outcomes.
Nogueira RG et al. N Engl J Med 2018;378:11-21
Distribution of Scores on the Modified Rankin Scale at 90 Days.
Nogueira RG et al. N Engl J Med 2018;378:11-21
Subgroup Analyses of the First Primary End Point.
Nogueira RG et al. N Engl J Med 2018;378:11-21
Safety Outcomes.
Nogueira RG et al. N Engl J Med 2018;378:11-21
DEFUSE 3
Who was included?
• Small infarct with large penumbra – <70 cc – Ischemia/Infarct >1.8 – Volume of penumbra >15 cc
• 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
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;378:708-718
Baseline Characteristics of the Patients and Features of Thrombectomy.
Albers GW et al. N Engl J Med 2018;378:708-718
Scores on the Modified Rankin Scale at 90 Days.
Albers GW et al. N Engl J Med 2018;378:708-718
Clinical and Imaging Outcomes.
Albers GW et al. N Engl J Med 2018;378:708-718
Subgroup Analyses.
Albers GW et al. N Engl J Med 2018;378:708-718
LIMITED POWER DUE TO EARLY TERMINATION OF STUDY
Positive treatment effect in DEFUSE 3, even including larger ischemic core and milder stroke symptoms
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)
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 10.2-16.3 – Both studies are “Tissue” based, not “time” based
anyways
• Nonetheless, results are striking.
• Why is there larger benefit in the late window trials?
Favorable outcome rates in early vs late window thrombectomy trials.
Gregory W. Albers Stroke. 2018;49:768-771
Copyright © American Heart Association, Inc. All rights reserved.
Estimated infarct growth rates in patients with internal carotid artery or middle cerebral artery occlusions.
Gregory W. Albers Stroke. 2018;49:768-771
Copyright © American Heart Association, Inc. All rights reserved.
Favorable outcome rates in MR CLEAN vs SWIFT PRIME and EXTEND-IA.
Gregory W. Albers Stroke. 2018;49:768-771
Copyright © American Heart Association, Inc. All rights reserved.
• 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
HOW DO WE MODIFY OUR PRACTICE?
BRAIN IMAGING
-<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
-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
Mechanical Thrombectomy
-- Extended time window for treatment is appropriate for those with large clinical-infarct mismatch -- Specific use of RAPID software probably not necessary
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)
– What size of ischemic core is too big in the delayed window?
– How far can the late window be stretched?
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
THANK YOU