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DEFUSE 3 Non-DAWN Patients: A Closer Look at Late Window Thrombectomy Selection
DEFUSE 3 Non-DAWN Patients: A Closer Look at Late Window Thrombectomy Selection
Background and Purpose—DAWN (Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing
Neurointervention With Trevo) and DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic
Stroke) established thrombectomy for patients with emergent large vessel occlusions presenting 6 to 24 hours after
symptom onset. Given the greater inclusivity of DEFUSE 3, we evaluated the effect of thrombectomy in DEFUSE 3
patients who would have been excluded from DAWN.
Methods—Eligibility criteria of the DAWN trial were applied to DEFUSE 3 patient data to identify DEFUSE 3 patients not
meeting DAWN criteria (DEFUSE 3 non-DAWN). Reasons for DAWN exclusion in DEFUSE 3 were infarct core too
large, National Institutes of Health Stroke Scale (NIHSS) score 6 to 9, and modified Rankin Scale score of 2. Subgroups
were compared with the DEFUSE 3 non-DAWN and entire DEFUSE 3 cohorts.
Results—There were 71 DEFUSE 3 non-DAWN patients; 31 patients with NIHSS 6 to 9, 33 with core too large, and 13 with
premorbid modified Rankin Scale score of 2 (some patients met multiple criteria). For core-too-large patients, median
24-hour infarct volume was 119 mL (interquartile range, 74.6–180) versus 31.5 mL (interquartile range, 17.6–64.3)
for core-not-too-large patients (P<0.001). Complications and functional outcomes were similar between the groups.
Thrombectomy in core-too-large patients compared with the remaining DEFUSE 3 non-DAWN patients conveyed benefit
for functional outcome (odds ratio, 20.9; CI, 1.3–337.8). Comparing the NIHSS 6 to 9 group with the NIHSS ≥10
patients, modified Rankin Scale score 0 to 2 outcomes were achieved in 74% versus 22% (P<0.001), with mortality in
6% versus 23% (P=0.024), respectively. For patients with NIHSS 6 to 9 compared with the remaining DEFUSE 3 non-
DAWN patients, thrombectomy trended toward a better chance of functional outcome (odds ratio, 1.86; CI, 0.36–9.529).
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Conclusions—Patients with pretreatment core infarct volumes <70 mL but too large for inclusion by DAWN criteria
demonstrate benefit from endovascular therapy. More permissive pretreatment core thresholds in core-clinical mismatch
selection paradigms may be appropriate. In contrast to data supporting a beneficial treatment effect across the full range of
NIHSS scores in the entire DEFUSE 3 population, only a trend toward benefit of thrombectomy in patients with NIHSS
6 to 9 was found in this small subgroup. (Stroke. 2019;50:618-625. DOI: 10.1161/STROKEAHA.118.023310.)
Key Words: brain ◼ brain ischemia ◼ humans ◼ standard of care ◼ thrombectomy
Received August 27, 2018; final revision received October 10, 2018; accepted November 5, 2018.
From the Neuroscience Institute, Massachusetts General Hospital, Boston (T.M.L.-M., A.B.P., L.H.S., J.A.H.); and Stanford Stroke Center, Stanford
University Medical Center, Palo Alto, CA (S.H., M. Mlynash, M.G.L., M. Marks, G.W.A.).
Presented in part at the International Stroke Conference, Honolulu, HI, February 6, 2019.
Correspondence to Thabele M. Leslie-Mazwi, MD, Department of Neurology, Massachusetts General Hospital, Wang 7-739R, 55 Fruit St, Boston, MA
02114. Email tleslie-mazwi@mgh.harvard.edu
© 2018 American Heart Association, Inc.
Stroke is available at https://www.ahajournals.org/journal/str DOI: 10.1161/STROKEAHA.118.023310
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Leslie-Mazwi et al A Closer Look at Late Window Thrombectomy 619
the reasons for ineligibility were as follows: 31 patients criteria, with 8 patients overlapping more than a single DAWN
with NIHSS too low (presentation scores of 6–9), 33 unique core volume category), and 13 patients with baseline mRS of
patients with infarct CTL (based on DAWN NIHSS and age 2 at presentation (some patients met >1 criteria).
Table 1. Characteristics of DEFUSE 3 Non-DAWN Core-Too-Large Versus All DEFUSE 3 Core-Not-Too-Large Patients
Table 2. Characteristics of DEFUSE 3 Non-DAWN NIHSS 6 to 9 Versus All DEFUSE 3 NIHSS ≥10 Patients
DAWN patients treated with endovascular versus best medical understandably led to a therapeutic nihilism toward patients
management for the NIHSS 6 to 9 and the NIHSS ≥10 groups. with larger established core infarct and proved foundational
For patients with NIHSS 6 to 9, thrombectomy conveyed a for selection criteria in certain early window trials,12–14 as well
better chance of functional outcome, with an odds ratio of as DAWN3 and DEFUSE 3.4 Post-treatment infarct volumes
1.86 (CI, 0.36–9.529); however, results were not statistically have been predictors of 90-day mRS in post hoc exploratory
significant in this small subgroup. analyses of the SWIFT PRIME (Solitaire With the Intention
for Thrombectomy as Primary Endovascular Treatment)15
Discussion and ESCAPE (Endovascular Treatment for Small Core and
Our findings demonstrate that for patients treated with me- Proximal Occlusion Ischemic Stroke)16 trials. The present
chanical thrombectomy between 6 and 16 hours from LKW, analysis of CTL patients demonstrated benefit from throm-
the benefit of thrombectomy seems sustained for DEFUSE 3 bectomy for a dichotomized outcome of functional inde-
patients meeting DAWN exclusion criteria. Despite the small pendence. The CTL treatment result is noteworthy also for
number of patients in the CTL subgroup, significant treat- the fact that >40% of the group was at least 80 years old.
ment benefit was detected. For those with low NIHSS, there These findings suggest a more permissive pretreatment core
was a favorable trend in this small subgroup. The comparison threshold for core-clinical mismatch selection paradigms may
group in this study was restricted to patients with NIHSS ≥10 be appropriate.
who did not meet DAWN criteria, rather than all DEFUSE 3 Not all large core patients are likely to have similar benefit.
patients, as detailed in Methods. When the entire DEFUSE 3 The threshold pretreatment volume for preserved benefit in
population was evaluated, patients with NIHSS as low as 6 patients with larger established core infarct is uncertain. There
were shown to have a significant benefit utilizing the ordinal is promising, emerging data for treatment effect in patients
analysis of the mRS—the primary end point of the study.8 with large established core infarcts. A recent subgroup anal-
It is important to view these results in the context of cur- ysis of MR CLEAN (Multicenter Randomized Clinical Trial
rent stroke care. With irrefutable proof of benefit now estab- of Endovascular Treatment for Acute Ischemic Stroke in the
lished for mechanical thrombectomy, further improvements Netherlands) suggested that patients with ASPECTS 5 to 7 ben-
in treatment delivery and patient outcomes involve 3 major efitted from thrombectomy,17 with limited benefit observed for
areas of focus. First, refinement of our identification and tri- patients with ASPECTS 0 to 4. Of 53 patients in the THRACE
age of ELVO. Second, improved thrombectomy techniques to trial (Mechanical Thrombectomy After Intravenous Alteplase
achieve greater rates of rapid recanalization and the evalua- Versus Alteplase Alone After Stroke) with pretreatment core
tion of the role of neuroprotection. Third, expansion of our infarct >70 mL, a total of 12 achieved functional outcome,
624 Stroke March 2019
with outcome determined, in part, by level of vascular occlu- more adequate collaterals, maintaining not only viability
sion.18 Therefore, although the frequency of good outcomes is but even function of mildly ischemic tissue. Penumbral sus-
lower in patients that present with large infarcts, there remains tenance into late windows further selects for those patients
a population that likely benefits. Our CTL patients had less ro- with adequate collaterals.
bust collaterals and a median infarct volume of 115 mL when The present study is subject to several limitations, in-
imaged 24 hours after randomization and benefit of thrombec- cluding those typical of subgroup analyses. DEFUSE 3 was
tomy was demonstrated, despite infarct growth being signifi- terminated early when results of DAWN were presented, and,
cantly greater than in the CNTL group. Given similar levels of therefore, equipoise for further randomization was lost. This
vascular occlusion between the 2 groups, this likely signifies a limits the sample size for the present analyses. The small
relative collateral inadequacy in the CTL patients and, there- sample size limits statistical power, and these data should thus
fore, faster infarct progression. As the limits of pretreatment be considered as hypothesis generating, needing confirmation
core infarct are tested further, it also is likely that our expecta- from larger randomized trials. Further, we cannot comment
tions for outcome will need to evolve for patients with core in- on treatment in patients after 16 hours. However, these find-
farct >70 mL. In DEFUSE 3, as well as the present analysis, a ings provide new insights into the treatment effect in DEFUSE
dichotomized outcome based on functional independence was 3 non-DAWN patients and inform future efforts to expand
utilized, but for large core patients, this could miss improve- thrombectomy candidacy.
ment in severe disability or death, and other, more discrimina-
tory metrics are likely to be required to understand the impact Conclusions
of treatment in this population. Patients with pretreatment core infarct volumes <70 mL but
Core infarct volume alone is unlikely the sole determi- too large for inclusion by DAWN criteria demonstrate benefit
nant of treatment response for patients with larger established from endovascular therapy. This suggests a more permissive
infarcts at presentation. Patients with large amounts of vi- pretreatment core threshold for core-clinical mismatch selec-
able penumbra despite the size of their core infarct may ben- tion paradigms may be appropriate. Enrollment of larger pre-
efit from thrombectomy.19,20 In this study, patients with core treatment core volumes represents an important area of future
infarcts too large for inclusion in DAWN also demonstrated study. Although treatment effect was maintained across all
significant penumbral tissue. DEFUSE 3 inclusions specifi- NIHSS thresholds in the DEFUSE 3 study for the primary end
cally required a mismatch ratio of ≥1.8, indicating penumbral point, in this subgroup, only a trend toward benefit of throm-
tissue almost double the volume of core, and for these patients, bectomy was seen in late window patients with less severe
benefit of thrombectomy is strongly maintained. For patients clinical deficit on presentation.
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