broadening the stroke window in light of the dawn trial cme... · 2018-06-11 · figure 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

• 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

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

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

Presenter

Presentation Notes

Table 1 Characteristics of the Patients at Baseline.

Efficacy Outcomes.

Presenter

Presentation Notes

Table 2 Efficacy Outcomes.

Distribution of Scores on the Modified Rankin Scale at 90 Days.

Presenter

Presentation Notes

Figure 1 Distribution of Scores on the Modified Rankin Scale at 90 Days. Shown is the distribution of scores for disability on the modified Rankin scale (which ranges from 0 to 6, with higher scores indicating more severe disability) among patients in the thrombectomy group and the control group, both in the overall intention-to-treat population (Panel A) and in subgroups defined according to time of stroke onset (Panel B). The numbers in the bars are percentages of patients who had each score; the percentages may not sum to 100 because of rounding. For the first primary end point, scores on the modified Rankin scale were weighted according to average values calculated from patient-centered and clinician-centered studies. For the second primary end point, functional independence was defined as a score of 0, 1, or 2 on the modified Rankin scale.

Subgroup Analyses of the First Primary End Point.

Presenter

Presentation Notes

Figure 2 Subgroup Analyses of the First Primary End Point. The first primary end point was the mean score for disability on the utility-weighted modified Rankin scale at 90 days. To determine the utility-weighted score, the score on the modified Rankin scale is weighted according to average values calculated from patient-centered and clinician-centered studies. The following weights are assigned to scores 0 through 6 on the modified Rankin scale: 10.0, 9.1, 7.6, 6.5, 3.3, 0, and 0, respectively. The utility-weighted modified Rankin scale ranges from 0 (death) to 10 (no symptoms or disability). Adjusted differences were estimated with the use of a Bayesian general linear model with adjustment for infarct volume. In the forest plots, the size of the box is proportional to the sample size. The Bayesian posterior probability of heterogeneity is the probability of an interaction between the subgroup and the treatment benefit; a probability of greater than 0.975 or less than 0.025 was considered to be a significant interaction. Subgroups for mismatch between the severity of the clinical deficit and the infarct volume were defined according to the following criteria: patients in Group A were 80 years of age or older, had a score of 10 or higher on the National Institutes of Health Stroke Scale (NIHSS; scores range from 0 to 42, with higher scores indicating a more severe deficit), and had an infarct volume of less than 21 ml; those in Group B were younger than 80 years of age, had a score of 10 or higher on the NIHSS, and had an infarct volume of less than 31 ml; and those in Group C were younger than 80 years of age, had a score of 20 or higher on the NIHSS, and had an infarct volume of 31 to less than 51 ml. The analysis for occlusion site did not include a subgroup with occlusion of the second segment of the middle cerebral artery because of the small number of patients in that subgroup.

Safety Outcomes.

Presenter

Presentation Notes

Table 3 Safety Outcomes.

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

Presenter

Presentation Notes

Figure 1 Example of Perfusion Imaging Showing a Disproportionately Large Region of Hypoperfusion as Compared with the Size of Early Infarction. A 59-year-old man presented with a “wake-up stroke” (having awakened with symptoms of stroke) 13 hours after he was last known to be well. The score on the National Institutes of Health Stroke Scale (NIHSS; range, 0 to 42, with higher scores indicating a greater deficit) was 23. A baseline CT perfusion scan that was obtained with the use of RAPID software shows a region of severely reduced cerebral blood flow (<30% of that in normal tissue), which represents the early infarct (ischemic core), of 23 ml (pink) and a region of perfusion delay of more than 6 seconds, which represents hypoperfused tissue, of 128 ml (green).

Baseline Characteristics of the Patients and Features of Thrombectomy.

Presenter

Presentation Notes

Table 1 Baseline Characteristics of the Patients and Features of Thrombectomy.

Scores on the Modified Rankin Scale at 90 Days.

Presenter

Presentation Notes

Figure 2 Scores on the Modified Rankin Scale at 90 Days. Patients in the endovascular-therapy group received endovascular therapy plus standard medical therapy. Patients in the medical-therapy group received standard medical therapy alone. Scores on the modified Rankin scale range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability, 3 moderate disability, 4 moderately severe disability, 5 severe disability, and 6 death. There was a significant difference favoring the endovascular-therapy group over the medical-therapy group in the overall distribution of scores (unadjusted common odds ratio, 2.77; 95% CI, 1.63 to 4.70; P<0.001).

Clinical and Imaging Outcomes.

Presenter

Presentation Notes

Table 2 Clinical and Imaging Outcomes.

Subgroup Analyses.

LIMITED POWER DUE TO EARLY TERMINATION OF STUDY

Positive treatment effect in DEFUSE 3, even including larger ischemic core and milder stroke symptoms

Presenter

Presentation Notes

Figure 3 Subgroup Analyses. The forest plot shows that the difference in the risk ratio for functional independence (defined as a score on the modified Rankin scale of 0 to 2) at 90 days favored the endovascular-therapy group across all prespecified subgroups. The size of the squares is proportional to the number of patients in the subgroup. Arrows indicate that the limits of the confidence interval are not shown. The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is a tool that is used to estimate the volume of infarcted tissue. Scores range from 0 to 10, with lower scores indicating a larger area. Race and ethnic group were reported by the patient or a family member. Patients who were considered to be ineligible for the DAWN (DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention with Trevo) trial3 had one or more of the following characteristics: a prestroke score on the modified Rankin scale of 2 (13 patients); a baseline NIHSS score of less than 10 (31 patients); a baseline volume of the ischemic core of 51 ml or more (13 patients); an age of 80 years or older with a baseline volume of the ischemic core of 21 ml or more (14 patients); and an age of less than 80 years, an NIHSS score of less than 20, and a baseline volume of the ischemic core of 31 ml or more (14 patients) (some patients met multiple criteria). All other patients were considered to be eligible for the DAWN trial. A risk ratio was not calculated for a baseline NIHSS score of more than 18 because of zero outcomes in the medical-therapy group.

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

Presenter

Presentation Notes

Favorable outcome rates in early vs late window thrombectomy trials. Note that good outcome rates in the late window vs early window trials are similar in the endovascular groups, but the outcomes are less favorable in the control groups of the late window trials. Therefore, the treatment effect is larger in the late window studies (absolute increase in modified Rankin Scale score of 0–2, 19% early window vs 32% late window, P=0.006, Breslow–Day test). The HERMES study3 pooled the results of 5 early window endovascular trials. DAWN indicates DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo; DEFUSE 3, Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3; and HERMES, Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials.

Estimated infarct growth rates in patients with internal carotid artery or middle cerebral artery occlusions.

Presenter

Presentation Notes

Estimated infarct growth rates in patients with internal carotid artery or middle cerebral artery occlusions. Data regarding ischemic core growth rates over time from DEFUSE 2.4 As discussed in the text, only ≈20% of patients had rapid early growth rates (red zone), ≈30% intermediate growth (yellow), and ≈50% had slow growth (green zone). Note that the selection criteria for THRACE required thrombectomy be initiated within 5 hours, MR CLEAN within 6 hours. For SWIFT PRIME, the maximum core volume was 50 mL; 70 mL for EXTEND-IA. For DAWN, the maximum core volume was 20 mL, 30 mL, or 50 mL (based on age and National Institutes of Health Stroke Scale score); 70 mL for DEFUSE 3. DAWN treated eligible patients up to 24 hours. DAWN indicates DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo; DEFUSE 3, Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3; EXTEND-IA, Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; and SWIFT PRIME, Solitaire™ With the Intention for Thrombectomy as Primary Endovascular Treatment Trial.

Favorable outcome rates in MR CLEAN vs SWIFT PRIME and EXTEND-IA.

Presenter

Presentation Notes

Favorable outcome rates in MR CLEAN vs SWIFT PRIME and EXTEND-IA. Note that favorable outcome rates in both the endovascular and control groups are about twice as large in the 2 trials that excluded patients with larger ischemic core volumes (volumes >50 mL were excluded in SWIFT PRIME and >70 mL excluded in EXTEND-IA). *Data for SWIFT PRIME12 includes only patients with the target mismatch profile. EXTEND-IA indicates Extending the Time for Thrombolysis in Emergency Neurological Deficits—Intra-Arterial; MR CLEAN, Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands; and SWIFT PRIME, Solitaire™ With the Intention for Thrombectomy as Primary Endovascular Treatment Trial.

• 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

broadening the stroke window in light of the dawn trial cme... · 2018-06-11 · figure 1....

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