DEFUSE 3 Non-DAWN Patients

A Closer Look at Late Window Thrombectomy Selection

Thabele M. Leslie-Mazwi, MD; Scott Hamilton, PhD; Michael Mlynash, MD, MS;
Aman B. Patel, MD; Lee H. Schwamm, MD; Maarten G. Lansberg, MD; Michael Marks, MD;
Joshua A. Hirsch, MD; Gregory W. Albers, MD

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

M echanical thrombectomy for emergent large vessel occlu-

sion (ELVO) stroke is well established as standard of
care for patients presenting within 6 hours of last known well
(LKW) time.1 The treatment benefit is such that stroke sys-
tems of care are being designed to support the rapid mobiliza-
tion of resources sufficient to treat these patients with ELVO.2
Recently, 2 extended time window trials, DAWN (Clinical
Mismatch in the Triage of Wake Up and Late Presenting Strokes
Undergoing Neurointervention With Trevo)3 and the DEFUSE
3 trial (Endovascular Therapy Following Imaging Evaluation
for Ischemic Stroke),4 were published. These trials proved that
patients with documented ELVO and limited infarcted brain tis-
sue identified on advanced imaging who undergo endovascular
therapy in treatment windows later than 6 hours have better
functional outcomes than patients treated with standard medical
therapy alone. The powerful treatment effect was maintained for
appropriately selected populations ≤16 hours (in DEFUSE 3)4
and 24 hours (in DAWN)3 from LKW time.
In response to this new data, the American Heart Association/
American Stroke Association Acute Stroke Guidelines for 2018
recommend thrombectomy ≤24 hours under trial inclusion cri-
teria—a position embraced by neurointerventional societies.5,6
The DAWN trial used a selection paradigm that assigned a pre-
treatment core infarct threshold (maximum of 50 mL) based on
patient age and presenting National Institutes of Health Stroke
Scale (NIHSS). DEFUSE 3 was more inclusive, taking patients

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

618
 Leslie-Mazwi et al   A Closer Look at Late Window Thrombectomy   619
broadly with pretreatment core infarct volumes ≤70 mL who
had substantial penumbral volumes. Benefit of thrombectomy
was sustained for the DEFUSE 3 patients who were not candi-
dates for inclusion in DAWN.4
A deeper understanding of treatment effect in DEFUSE
3 patients who would have been excluded from the DAWN
trial is important because this group of patients is heteroge-
nous and includes patients with larger core volumes, as well
as lower presenting NIHSS scores. We hypothesized that the
favorable treatment effect is maintained across all subgroups
of DEFUSE 3 patients who would have been excluded from
DAWN, but the magnitude of treatment signal might differ be-
tween subgroups. Differences in treatment effect, if identified,
may help guide treatment decisions or inform the study design
for future clinical trials in patients with ELVO.
Methods
DEFUSE 3 was a randomized, open-treatment, blinded end point trial
to compare endovascular therapy plus medical management versus
medical management alone in patients with acute ischemic stroke.
Details of the study have been published previously.4 The authors de-
clare that all supporting data are available within the article. The study
was funded by the National Institutes of Health through StrokeNet—a
network of >300 American hospitals with a central institutional re-
view board that provided ethics approval for the study. Patients were
enrolled at 38 US centers if they met both clinical and imaging el-
igibility requirements and could undergo initiation of endovascular
treatment between 6 and 16 hours from LKW (including symptoms
on waking). All patients or their legal representatives provided writ-
ten informed consent before randomization.
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Patient Eligibility
Eligible patients had an NIHSS of ≥6, prestroke modified Rankin
Scale (mRS) score of 0 to 2, initial infarct volume (ischemic core)
<70 mL, a ratio of volume of ischemic tissue (penumbra) to infarction
of ≥1.8, and an absolute volume of potentially reversible ischemia of
≥15 mL. Estimates of the volume of the ischemic core and penumbral
regions were calculated with automated image processing software,
called RAPID (iSchemaView, Menlo Park, CA), using computed to-
mography or magnetic resonance perfusion imaging. On meeting el-
igibility criteria, patients were randomly assigned in a 1:1 ratio to
endovascular therapy plus medical management versus medical man-
agement alone using a web-based dynamic randomization system.
Standard medical therapy based on current American Heart
Association/American Stroke Association guidelines was admin-
istered to patients in both arms of the study, including tPA (tissue-
type plasminogen activator) for eligible patients presenting with 4.5
hours of onset who were subsequently randomized in the DEFUSE 3
time window. For endovascular patients, groin puncture had to occur
within 90 minutes of the qualifying imaging, and any FDA-approved
thrombectomy device could be used for thrombectomy, at the discre-
tion of the neurointerventionalist.
By comparison, eligibility for patients with ELVO after 6 hours
from LKW in the DAWN trial required an NIHSS of ≥10, prestroke
mRS 0 or 1, and evidence of a clinical deficit in excess of the volume
of infarcted tissue (core-clinical mismatch). Established core infarct
was defined on magnetic resonance diffusion weighted imaging or au-
tomated computed tomographic perfusion maps using the same auto-
mated software as DEFUSE 3 and patients categorized into 3 groups
using the following parameters: 0 to 20 mL core infarct and NIHSS
≥10 and age ≥80 years, 0 to 30 mL core infarct and NIHSS ≥10 and
age <80 years, 31 to 50 mL core infarct and NIHSS ≥20 and age
<80 years. The trial utilized the Trevo device (Stryker Neurovascular)
exclusively. Trial details are also published previously.3 Both trials
were Institutional Review Board approved and Health Insurance
Portability and Accountability Act compliant.
Outcomes
The primary outcome measure in DEFUSE 3 was mRS score7 at 90
days. A score of 0 to 2 points (functional independence) served as the
secondary efficacy measure. For the current study, the secondary out-
come measure (mRS, 0–2 at 90 days) was used as the primary end point
because the small sample size resulted in violation of the proportional
odds assumption for the ordinal analysis. A variety of additional out-
come measures (angiographic, radiological, and safety) were assessed.
Subgroup Determination
The eligibility criteria of the DAWN trial were applied to the
DEFUSE 3 patient data, and DEFUSE 3 patients not meeting DAWN
criteria (DEFUSE 3 non-DAWN) were identified. Three reasons led
to DAWN exclusion criteria that would still have allowed inclusion to
be met for DEFUSE 3 patients: infarct core too large (CTL; based on
DAWN NIHSS and age criteria), NIHSS too low (presentation scores
of 6–9), or baseline mRS of 2 at presentation. Only 13 DEFUSE 3
patients had a prestroke mRS of 2, which was inadequate to address
whether these patients had a favorable response to thrombectomy;
therefore, these patients were categorized by their NIHSS scores,
based on the fact they would have not proceeded to imaging eval-
uation under the DAWN trial exclusion process. Three had NIHSS
6 to 9 on presentation, and, therefore, these three were included in
the analysis of patients with NIHSS too low for DAWN. Analysis
was, therefore, performed for CTL versus core-not-too-large (CNTL)
patients and for NIHSS 6 to 9 versus NIHSS ≥10 patients. These in-
dividual subgroups were compared with the remainder of the DAWN-
ineligible DEFUSE 3 population, as well as the entire DEFUSE 3
population. The primary outcome analyzed was dichotomized func-
tional neurological outcome (mRS, 0–2), with relationships between
clinical, imaging, and procedural outcomes assessed.
Statistical Analysis
For the description of the general characteristics of the study pop-
ulation, and comparison to the DEFUSE 3 population as a whole,
percentages are reported for categorical variables, means and SDs for
parametric variables, and medians and interquartile ranges (IQRs)
for nonparametric variables. The Pearson χ2 test, Student t test, and
Wilcoxon rank-sum tests, as appropriate, were used to compare cate-
gorical and continuous variables between patient groups, respectively.
Adjusted logistic models of the mRS 0 to 2 outcome were developed
for the patients from DEFUSE 3 that would have been ineligible for
DAWN based on low baseline NIHSS (6–9) or core volumes that
were too large (patients aged ≥80 years with core volume >20 mL,
patients aged <80 years with baseline NIHSS <20 and core volume
>30 mL, and all patients with core volumes >50 mL). In 3 cases,
patients had both baseline NIHSS scores <10 and a CTL for DAWN
eligibility. These patients were classified as ineligible based on their
NIHSS scores because that criterion alone would have excluded them
from DAWN imaging evaluation.
Data already support the benefit of thrombectomy for the
DEFUSE 3 non-DAWN population as whole.4 Our goal of evaluating
the effect of thrombectomy within that population, and whether one
subgroup within that population benefits more than another, was re-
stricted to comparing subgroups within the DEFUSE 3 non-DAWN
population alone. Results of the logistic models were reported as raw
and adjusted risk ratios. The adjusted risk ratios were evaluated with
95% CIs. Distribution of the mRS among the DEFUSE 3 non-DAWN
patient subgroups was presented in horizontal bar graphs.
Results
DEFUSE 3 patients were recruited from May 2016 to May
2017, when the trial was terminated early for efficacy by the
Data and Safety Monitoring Board; 182 patients were ran-
domized. Applying the eligibility criteria of the DAWN trial
to the DEFUSE 3 data, direct population overlap was 62%.
For the 71 enrolled DEFUSE 3 non-DAWN–eligible patients,
 620  Stroke  March 2019

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

Baseline CTL (n=33) DEFUSE 3 CNTL (n=149) P Value

Age, y; median (IQR) 72 (58–83) 70 (60–78) 0.512
Age ≥80 y, n (%) 14 (42) 32 (21) 0.016
Men, n (%) 19 (58) 71 (48) 0.302
NIHSS, median (IQR) 18 (14–21) 15 (11–20) 0.174
Wake-up stroke, n (%) 17 (52) 74 (50) 0.278
Witnessed onset, n (%) 9 (27) 57 (38)
Unwitnessed onset, n (%) 7 (21) 18 (12)
tPA treatment, n (%) 6 (18) 12 (8) 0.103
Randomized to intervention, n (%) 18 (55) 74 (50) 0.612
Imaging
 Imaging with MRI/MRP, n (%) 10 (30) 39 (26) 0.6285
 ASPECTS on baseline CT, median (IQR) 7 (7–9) 8 (7–9) 0.020
 ICA occlusion, n (%) 14 (42) 54 (36) 0.507
 Good collaterals on CTA, n (%) 10 (45) 87 (81) <0.001
 Ischemic core volume, mL; median (IQR) 45.2 (37.6–60.4) 7.3 (0–13.9) <0.001
 Perfusion lesion volume, mL; median (IQR) 145.8 (127.3–184.7) 98.7 (67.5–144.4) <0.001
Time and process (in HH:MM)
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 Onset:imaging, median (IQR) 9:08 (7:02–11:09) 10:24 (8:23–12:17) 0.030

 Imaging:puncture, median (IQR) 0:54 (0:36–1:34) 0:59 (0:41–1:20) 0.957
 Puncture:reperfusion, median (IQR) 0:36 (0:27–0:55) 0:40 (0:27–1:00) 0.635
 Onset:reperfusion, median (IQR) 11:44 (10:14–13:05) 12:19 (9:44–13:42) 0.601
Outcomes
 Functional independence at 90 d, n (%) 8 (24) 48 (32) 0.369
 mTICI 2b/3, n (percentage of endovascular patients) 16 (89) 54 (73) 0.222
 Infarct volume at 24 h, median (IQR) 119.0 (74.6–180.0) 31.5 (17.6–64.3) <0.001
 Infarct growth, median (IQR) 83.9 (39.4–135.8) 23.8 (11.7–51.1) <0.001
 Reperfusion >90% at 24 h, n (%) 13 (50) 58 (50) 1.0
 Complete recanalization on MRA/CTA, n (%) 13 (50) 66 (49) 0.945
 Reperfusion >90% at 24 h or complete recanalization 13 (48) 67 (49) 0.970
on MRA/CTA, n (%)
Safety
 Death at 90 d, n (%) 6 (18) 30 (20) 0.799
 Symptomatic intracranial hemorrhage, n (%) 3 (9) 7 (5) 0.391
 Parenchymal hematoma type 2, n (%) 2 (6) 9 (6) 1.0
 Early neurological deterioration, n (%) 3 (9) 17 (11) 0.774
ASPECTS: n=27 and 115; perfusion lesion volume: n=33 and 147; good collaterals (modified Tan method, CTA only): n=22 and 108; imaging
to puncture, median: n=18 and 74; puncture to reperfusion: n=16 and 64; onset to reperfusion: n=16 and 64; infarct volume at 24 h: n=32 and
147; infarct growth: n=32 and 147; mTICI 2b/3: n=18 and 74; reperfusion >90% at 24 h: n=26 and 116; complete recanalization on MRA/CTA:
n=26 and 134; reperfusion >90% at 24 h and complete recanalization on MRA/CTA: n=27 and 138. ASPECTS indicates Alberta Stroke Program
Early CT Score; CNTL, core not too large; CT, computed tomography; CTA, computed tomography angiography; CTL, core too large; DEFUSE 3,
Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke; HH, hours; ICA, internal carotid artery; IQR, interquartile range; MM,
minutes; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; MRP, magnetic resonance perfusion; mTICI, modified
Thrombolysis in Cerebral Infarction score; NIHSS, Institutes of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
 Leslie-Mazwi et al   A Closer Look at Late Window Thrombectomy   621
CTL Patients
Baseline Characteristics
Table 1 details characteristics and outcomes for the patients
with CTL compared with the entire DEFUSE 3 CNTL
patients. The CTL population contained 42% of patients
>79 years of age, compared with 21% in the CNTL group
(P=0.016). No significant difference in method of stroke de-
tection was present; ≈50% of both groups were diagnosed
with wake-up strokes. Core size was determined by computed
tomography perfusion in 70% of patients in the CTL group,
compared with 74% of patients in the CNTL group. Median
ASPECTS (Alberta Stroke Program Early CT Score) for the
CTL patients was 7, compared with 8 for the CNTL patients
(P=0.02), with no differences noted for level of vascular occlu-
sion. Consistent with the difference in ASPECTS, ischemic
core volume was 45 mL (IQR, 37.6–60.4) compared with 7.3
mL (IQR, 0–13.9) for the CNTL patients. Significant differ-
ence was also present for the measured volume of the perfu-
sion lesion. For the CTL patients, median volume was 145.8
mL (IQR, 127.3–184.7), and for the CNTL, median perfusion
volume was 98.7 mL (IQR, 67.5–144.4). Similar proportions
of patients in each group were randomized for intervention
(55% of the CTL and 50% of the CNTL cohort).
Process and Procedural Variables
Time from onset to reperfusion (11 hours 44 minutes for the
CTL and 12 hours 19 minutes for CNTL group) and other
process metrics were similar between the 2 groups. Target re-
perfusion was also similar, achieved in 89% of the CTL group
compared with 73% of the CNTL group.
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Outcomes
No differences in functional outcome were seen between
the 2 groups (mRS of 0–2 in 24% of the CTL versus 32%
of the CNTL group), despite significant differences in in-
farct growth between enrollment and 24-hour scans. The
CTL group experienced infarct growth of 83.9 mL (IQR,
39.4–135.8) compared with 23.8 mL (IQR space, 11.7–
51.1) in the CNTL group. For CTL patients, median infarct
volume at 24 hours was 119 mL (IQR, 74.6–180), compared
with only 31.5 mL (IQR, 17.6–64.3) for the CNTL patients.
Despite these differences in infarct volumes, rates of death
and symptomatic intracranial hemorrhage were equivalent
between the 2 groups.
Figure 1 shows the mRS distributions for the patients
treated with endovascular versus best medical management
for the DEFUSE 3 non-DAWN patients divided as CTL versus
CNTL. For patients with CTL, after adjustment for prognostic
factors of age and NIHSS, the odds ratio for functional out-
come was 20.9 (CI, 1.3–337.8).
NIHSS 6 to 9 Patients
Baseline Characteristics
Table 2 details characteristics and outcomes for the patients
with NIHSS 6 to 9 compared with the entire DEFUSE 3
NIHSS ≥10 patients. Median NIHSS was 8 (IQR, 7–9) for this
population, compared with 18 (IQR, 14–21) for the NIHSS
≥10 cohort. No differences in age, sex, randomization to
endovascular therapy, or tPA exposure were present. Thirty-
five percent of the NIHSS 6 to 9 group was imaged with mag-
netic resonance imaging, compared with 25% of the patients
with NIHSS ≥10. Wake-up strokes accounted for almost 40%
of the NIHSS 6 to 9 population. Nineteen patients (61%) of
the NIHSS 6 to 9 group and 73 patients (48%) of the NIHSS
≥10 groups were randomized to intervention (P=0.189)
Process and Procedural Variables
No differences were present between the 2 groups for process
timing, with 12 hours and 21 minutes median time to reperfu-
sion for the NIHSS 6 to 9 group, compared with 12 hours and
8 minutes for the NIHSS ≥10 patients. Reperfusion rates were
similar between the groups, 68% versus 78%, respectively
(P=0.547), with similar maintained reperfusion at 24 hours.
Figure 1.  Functional outcomes for core-too-
large vs core-not-too-large patients in the
DEFUSE 3 (Endovascular Therapy Following
Imaging Evaluation for Ischemic Stroke) non-
DAWN (Clinical Mismatch in the Triage of Wake
Up and Late Presenting Strokes Undergoing
Neurointervention With Trevo) population. mRS
indicates modified Rankin Scale.
 622  Stroke  March 2019

Table 2.  Characteristics of DEFUSE 3 Non-DAWN NIHSS 6 to 9 Versus All DEFUSE 3 NIHSS ≥10 Patients

DEFUSE 3 NIHSS ≥10

Baseline NIHSS 6 to 9 (n=31) (n=151) P Value
Age, y; median (IQR) 63 (57–73) 72 (60–80) 0.048
Age ≥80 y, n (%) 5 (15) 41 (27) 0.198
Men, n (%) 13 (42) 79 (52) 0.292
NIHSS, median (IQR) 8 (7–9) 18 (14–21) <0.001
Wake-up stroke, n (%) 12 (39) 79 (52) 0.382
Witnessed onset, n (%) 14 (45) 52 (34) 0.382
Unwitnessed onset, n (%) 5 (16) 20 (13) 0.382
tPA treatment, n (%) 5 (16) 13 (9) 0.318
Randomized to intervention, n (%) 19 (61) 73 (48) 0.189
Imaging
 Imaging with MRI/MRP, n (%) 11 (35) 38 (25) 0.238
 ASPECTS on baseline CT, median (IQR) 9 (8–10) 8 (7–9) 0.003
 ICA occlusion, n (%) 9 (29) 59 (39) 0.293
 Good collaterals on CTA, n (%) 14 (67) 83 (76) 0.361
 Ischemic core volume, mL; median (IQR) 5.0 (0–17.4) 10.1 (2.7–26.3) 0.043
 Perfusion lesion volume, mL; median (IQR) 100.1 (66.5–136.4) 116.9 (77.6–158.8) 0.057
Time and process (in HH:MM)
 Onset:imaging, median (IQR) 10:28 (8:29–12:41) 10:15 (7:59–11:44) 0.536
 Imaging:puncture, median (IQR) 1:01 (0:51–1:30) 0:56 (0:39–1:26) 0.481
 Puncture:reperfusion, median (IQR) 0:31 (0:25–1:00) 0:40 (0:28–0:59) 0.279
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 Onset:reperfusion, median (IQR) 12:21 (11:22–15:29) 12:08 (9:32–13:22) 0.285

Outcomes
 Functional independence at 90 d, n (%) 23 (74) 33 (22) <0.001
 mTICI 2b/3, n (percentage of endovascular patients) 13 (68) 57 (78) 0.547
 Infarct volume at 24 h, median (IQR) 33.3 (9.5–64.8) 39.8 (24.2–110.4) 0.026
 Infarct growth, median (IQR) 23.2 (6.7–43.1) 29.1 (13.2–88.1) 0.117
 Reperfusion >90% at 24 h, n (%) 14 (52) 57 (50) 0.831
 Complete recanalization on MRA/CTA, n (%) 13 (48) 66 (50) 0.889
 Reperfusion >90% at 24 h or complete 14 (50) 66 (48) 0.860
recanalization on MRA/CTA, n (%)
Safety
 Death at 90 d, n (%) 2 (6) 34 (23) 0.024
 Symptomatic intracranial hemorrhage, n (%) 0 (0) 10 (7) 0.216
 Parenchymal hematoma type 2, n (%) 0 (0) 11 (7) 0.216
 Early neurological deterioration, n (%) 4 (13) 16 (11) 0.753
ASPECTS: n=21 and 121; perfusion lesion volume: n=31 and 149; good collaterals (modified Tan method, CTA only): n=21 and
109; imaging to puncture: n=19 and 73; puncture to reperfusion: n=14 and 66; onset to reperfusion: n=14 and 66; infarct volume at
24 h: n=31 and 148; infarct growth: n=31 and 148; mTICI 2b/3: n=19 and 73; reperfusion >90% at 24 h: n=27 and 115; complete
recanalization on MRA/CTA: n=27 and 133; reperfusion >90% at 24 h and complete recanalization on MRA/CTA: n=28 and 137.
ASPECTS indicates Alberta Stroke Program Early CT Score; CNTL, core not too large; CT, computed tomography; CTA, computed
tomography angiography; CTL, core too large; DEFUSE 3, Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke;
HH, hours; ICA, internal carotid artery; IQR, interquartile range; MM, minutes; MRA, magnetic resonance angiography; MRI, magnetic
resonance imaging; MRP, magnetic resonance perfusion; mTICI, modified Thrombolysis in Cerebral Infarction score; NIHSS, Institutes
of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
 Leslie-Mazwi et al   A Closer Look at Late Window Thrombectomy   623
Outcomes
Ninety-day functional independence was more likely in the
low NIHSS group, with 23 patients (74%) in the NIHSS 6
to 9 group achieving mRS 0 to 2 compared with 33 patients
(22%) of the NIHSS ≥10 group (P<0.001). The overlapping
odds ratios for NIHSS 6 to 9 versus ≥10 showed no interaction
with treatment effect. Six percent of the NIHSS 6 to 9 group
died, compared with 23% of the NIHSS ≥10 group (P=0.024).
Figure 2 shows the mRS distributions for the DEFUSE 3 non-
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DAWN patients treated with endovascular versus best medical
management for the NIHSS 6 to 9 and the NIHSS ≥10 groups.
For patients with NIHSS 6 to 9, thrombectomy conveyed a
better chance of functional outcome, with an odds ratio of
1.86 (CI, 0.36–9.529); however, results were not statistically
significant in this small subgroup.
Discussion
Our findings demonstrate that for patients treated with me-
chanical thrombectomy between 6 and 16 hours from LKW,
the benefit of thrombectomy seems sustained for DEFUSE 3
patients meeting DAWN exclusion criteria. Despite the small
number of patients in the CTL subgroup, significant treat-
ment benefit was detected. For those with low NIHSS, there
was a favorable trend in this small subgroup. The comparison
group in this study was restricted to patients with NIHSS ≥10
who did not meet DAWN criteria, rather than all DEFUSE 3
patients, as detailed in Methods. When the entire DEFUSE 3
population was evaluated, patients with NIHSS as low as 6
were shown to have a significant benefit utilizing the ordinal
analysis of the mRS—the primary end point of the study.8
It is important to view these results in the context of cur-
rent stroke care. With irrefutable proof of benefit now estab-
lished for mechanical thrombectomy, further improvements
in treatment delivery and patient outcomes involve 3 major
areas of focus. First, refinement of our identification and tri-
age of ELVO. Second, improved thrombectomy techniques to
achieve greater rates of rapid recanalization and the evalua-
tion of the role of neuroprotection. Third, expansion of our
Figure 2.  Functional outcomes for National
Institutes of Health Stroke Scale (NIHSS) 6 to 9
vs NIHSS ≥10 patients in the DEFUSE 3 (Endo-
vascular Therapy Following Imaging Evaluation
for Ischemic Stroke) non-DAWN (Clinical Mis-
match in the Triage of Wake Up and Late Pre-
senting Strokes Undergoing Neurointervention
With Trevo) population. mRS indicates modified
Rankin Scale.
pool of potential patients by identifying a favorable treatment
effect in populations currently excluded from thrombectomy
care.9 The recent publication of DAWN and DEFUSE 3 adds
powerfully to this last goal, demonstrating treatment benefit
extending into later treatment windows. As we aim to expand
candidacy further still, understanding treatment effect within
this late window population is paramount.
Larger pretreatment core infarct increases the likelihood
of a poor functional outcome.10,11 These observations have
understandably led to a therapeutic nihilism toward patients
with larger established core infarct and proved foundational
for selection criteria in certain early window trials,12–14 as well
as DAWN3 and DEFUSE 3.4 Post-treatment infarct volumes
have been predictors of 90-day mRS in post hoc exploratory
analyses of the SWIFT PRIME (Solitaire With the Intention
for Thrombectomy as Primary Endovascular Treatment)15
and ESCAPE (Endovascular Treatment for Small Core and
Proximal Occlusion Ischemic Stroke)16 trials. The present
analysis of CTL patients demonstrated benefit from throm-
bectomy for a dichotomized outcome of functional inde-
pendence. The CTL treatment result is noteworthy also for
the fact that >40% of the group was at least 80 years old.
These findings suggest a more permissive pretreatment core
threshold for core-clinical mismatch selection paradigms may
be appropriate.
Not all large core patients are likely to have similar benefit.
The threshold pretreatment volume for preserved benefit in
patients with larger established core infarct is uncertain. There
is promising, emerging data for treatment effect in patients
with large established core infarcts. A recent subgroup anal-
ysis of MR CLEAN (Multicenter Randomized Clinical Trial
of Endovascular Treatment for Acute Ischemic Stroke in the
Netherlands) suggested that patients with ASPECTS 5 to 7 ben-
efitted from thrombectomy,17 with limited benefit observed for
patients with ASPECTS 0 to 4. Of 53 patients in the THRACE
trial (Mechanical Thrombectomy After Intravenous Alteplase
Versus Alteplase Alone After Stroke) with pretreatment core
infarct >70 mL, a total of 12 achieved functional outcome,
 624  Stroke  March 2019
with outcome determined, in part, by level of vascular occlu-
sion.18 Therefore, although the frequency of good outcomes is
lower in patients that present with large infarcts, there remains
a population that likely benefits. Our CTL patients had less ro-
bust collaterals and a median infarct volume of 115 mL when
imaged 24 hours after randomization and benefit of thrombec-
tomy was demonstrated, despite infarct growth being signifi-
cantly greater than in the CNTL group. Given similar levels of
vascular occlusion between the 2 groups, this likely signifies a
relative collateral inadequacy in the CTL patients and, there-
fore, faster infarct progression. As the limits of pretreatment
core infarct are tested further, it also is likely that our expecta-
tions for outcome will need to evolve for patients with core in-
farct >70 mL. In DEFUSE 3, as well as the present analysis, a
dichotomized outcome based on functional independence was
utilized, but for large core patients, this could miss improve-
ment in severe disability or death, and other, more discrimina-
tory metrics are likely to be required to understand the impact
of treatment in this population.
Core infarct volume alone is unlikely the sole determi-
nant of treatment response for patients with larger established
infarcts at presentation. Patients with large amounts of vi-
able penumbra despite the size of their core infarct may ben-
efit from thrombectomy.19,20 In this study, patients with core
infarcts too large for inclusion in DAWN also demonstrated
significant penumbral tissue. DEFUSE 3 inclusions specifi-
cally required a mismatch ratio of ≥1.8, indicating penumbral
tissue almost double the volume of core, and for these patients,
benefit of thrombectomy is strongly maintained. For patients
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with large pretreatment core infarcts and limited penumbral
tissue volume, the impact of recanalization is uncertain.
The potential for increased complications is a concern
in late window reperfusion for patients with larger core
infarcts.19 We found no evidence of harm in this population,
with comparable mortality and symptomatic hemorrhage rates
to patients with smaller, DAWN-eligible core infarct sizes. No
clear signal for harm has emerged from studies in earlier time
windows enrolling patients with lower ASPECTS.21,22 It is
possible that the risk of hemorrhage and reperfusion injury
is less than historically feared. Further, late window patients
are rarely tPA eligible and are, therefore, not at risk for tPA-
related hemorrhage.23
Similar to patients with large pretreatment core infarct,
patients with low NIHSS also represent an area of potential
expansion for thrombectomy inclusion.9 Patients in early
time windows with NIHSS 6 to 9 benefit from thrombec-
tomy. This study demonstrates a trend toward this at later
timepoints too, although that does not reach statistical sig-
nificance for the mRS 0 to 2 outcome. When evaluating the
full mRS scale in an adjusted model using the complete
DEFUSE 3 database, there was benefit on the ordinal shift
analysis for patients with a baseline NIHSS as low as 6,
with evidence that more severe levels of disability at 90
days were reduced by thrombectomy among patients with
mild NIHSS scores at baseline.8 Disability can result from
neurological worsening as collaterals fail. Benefit from
thrombectomy in patients with lower NIHSS is not as intu-
itive as for patients with high NIHSS; patients with main-
tained neurological examinations may have comparatively
more adequate collaterals, maintaining not only viability
but even function of mildly ischemic tissue. Penumbral sus-
tenance into late windows further selects for those patients
with adequate collaterals.
The present study is subject to several limitations, in-
cluding those typical of subgroup analyses. DEFUSE 3 was
terminated early when results of DAWN were presented, and,
therefore, equipoise for further randomization was lost. This
limits the sample size for the present analyses. The small
sample size limits statistical power, and these data should thus
be considered as hypothesis generating, needing confirmation
from larger randomized trials. Further, we cannot comment
on treatment in patients after 16 hours. However, these find-
ings provide new insights into the treatment effect in DEFUSE
3 non-DAWN patients and inform future efforts to expand
thrombectomy candidacy.
Conclusions
Patients with pretreatment core infarct volumes <70 mL but
too large for inclusion by DAWN criteria demonstrate benefit
from endovascular therapy. This suggests a more permissive
pretreatment core threshold for core-clinical mismatch selec-
tion paradigms may be appropriate. Enrollment of larger pre-
treatment core volumes represents an important area of future
study. Although treatment effect was maintained across all
NIHSS thresholds in the DEFUSE 3 study for the primary end
point, in this subgroup, only a trend toward benefit of throm-
bectomy was seen in late window patients with less severe
clinical deficit on presentation.
Sources of Funding
DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation
for Ischemic Stroke) was supported by grants from the National
Institutes of Health.
Disclosures
Dr Hirsch is a consultant/advisory board member at Medtronic
and Cerenova. Dr Hamilton is a consultant/advisory board
member at Penumbra and Medtronic and receives research sup-
port from Stanford. Dr Patel receives honoraria from Penumbra and
Microvention. Dr Schwamm is a consultant/advisory board member
at DSMB-lifeIMAGE, Penumbra, Medtronic, and Vizai and reports
research support from Genentech. Dr Marks receives honoraria from
Medtronic and ThrombX Medical. Dr Albers reports ownership in
iSchemaView and is a consultant/advisory board member at iSch-
emaView and Medtronic. The other authors report no conflicts.
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