The n e w e ng l a n d j o u r na l of m e dic i n e

Edi t or i a l

A New DAWN for Imaging-Based Selection

in the Treatment of Acute Stroke
Werner Hacke, M.D., Ph.D., D.Sc.

Two years ago, the publication of the MR CLEAN
trial (Multicenter Randomized Clinical Trial of
Endovascular Treatment for Acute Ischemic Stroke
in the Netherlands),1 which investigated endovas-
cular mechanical thrombectomy for the treatment
of acute ischemic stroke, was called “a first step
in the right direction.” Since then, there have
been five trials of thrombectomy for stroke that
have shown positive outcomes. A pooled analysis
of these trials2 confirmed the efficacy of throm-
bectomy that is performed within 6 hours after
the onset of stroke in patients with occlusion of
a cerebral large vessel (intracranial internal carotid
artery or proximal middle cerebral artery).
The DAWN trial (DWI or CTP Assessment with
Clinical Mismatch in the Triage of Wake-Up and
Late Presenting Strokes Undergoing Neurointer-
vention with Trevo), results of which are now
reported in the Journal,3 investigated the efficacy
and safety of endovascular thrombectomy that is
performed 6 to 24 hours after the onset of stroke.
The trial was halted on the basis of results of a
prespecified interim analysis, which suggested a
high probability of success. The trial included
patients with occlusion of a large cerebral vessel
who presented between 6 and 24 hours after the
onset of stroke. Patients underwent successful
thrombectomy, even though the usually accepted
window for stroke treatment is within 6 hours
after the first observation of symptoms. Further-
more, approximately 60% of the patients had
had their first stroke symptoms when they woke
up, which meant that the time of stroke onset
was not known; this circumstance is currently a
contraindication to endovascular or thrombolytic
treatment. However, patients in the DAWN trial
were selected specifically because they had a re-
gion of brain that was poorly perfused but not yet
infarcted. In essence, the usual 6-hour time win-
dow for stroke treatment was replaced with a
“tissue window.”
Some readers may struggle with the Bayesian
statistics and unusual primary end point that were
used in the DAWN trial. They should be assured
that the positive outcome of the trial was not due
to complex statistical maneuvering or the use of
an unconventional end point, which involved a
utility-weighted modification of the usual Rankin
scale. Even with the use of basic parametric sta-
tistics and an end point that is typically used in
stroke trials, the DAWN trial had strikingly posi-
tive results.
In the DAWN trial, dichotomized scores on
the modified Rankin scale were conveniently ob-
tained as a coprimary end point, and these scores
allow for comparison with other trials. How do
the results of the DAWN trial compare with re-
sults of other trials of thrombectomy for stroke,
such as those included in the meta-analysis?2 In
the DAWN trial, the rate of the second primary end
point of functional independence (defined as a
score of 0, 1, or 2 on the modified Rankin scale,
which ranges from 0 to 6, with higher scores
indicating more severe disability) at 90 days was
49%, and in the meta-analysis, the rate was 46%;
these similar findings suggest that the use of a
“tissue window” in choosing patients for throm-
bectomy is as good as the use of a time window.
However, it is also worth emphasizing that the
13% rate of functional independence in the con-
trol group in the DAWN trial was lower than the
26% rate in the control group in the pooled analy-
sis. This low rate of functional independence is
probably the best we can expect for patients with

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 The n e w e ng l a n d j o u r na l
severe stroke who have occlusion of a large vessel
that has not been recanalized by 24 hours after
stroke onset.
The use of imaging studies to detect evidence
of ischemic but not yet infarcted brain tissue
(known as penumbral tissue) in selecting patients
to undergo thrombectomy has been explored for
almost two decades, with varying success. These
imaging approaches are designed to detect brain
tissue that can be saved by means of reperfusion.
Several methods for the detection of ischemic
penumbral tissue have been introduced. The
DAWN trial required evidence of a small infarct
core on magnetic resonance imaging or perfu-
sion computed tomography (CT), in addition to
evidence of a clinical deficit that was dispropor-
tionately severe relative to the infarct.2 Two re-
cent trials of thrombectomy with a short time
window between the onset of stroke symptoms
and treatment4,5 also required evidence of pen-
umbral tissue on imaging studies. In these two
trials, this approach to identifying brain tissue
that is at risk for infarction resulted in the high-
est rates of functional independence ever reported
with thrombectomy (60% and 71%).
In contrast, two randomized trials of intrave-
nous thrombolysis6,7 that required evidence of
penumbral tissue on imaging studies had strik-
ingly negative outcomes, probably because the pa-
tients had only small infarct cores and small
penumbral regions, which generally would not be
expected to improve with recanalization. In the
DAWN trial, the patients had larger penumbral
regions, which reflected the requirement for oc-
clusion of a large cerebral vessel.
The DAWN trial gives us hope that trials in-
vestigating the use of late intravenous thromboly-
sis that require the presence of ischemic tissue
might have positive outcomes. The WAKE-UP trial
(Efficacy and Safety of MRI-Based Thrombolysis
in Wake-up Stroke; ClinicalTrials.gov number,
NCT01525290) required evidence of a small in-
farct core on diffusion-weighted imaging and no
evidence of an infarct on fluid-attenuation inver-
sion recovery imaging; this combination of find-
ings indicates that the onset of stroke symptoms
(which were observed at awakening) most likely
occurred less than 4 hours earlier. The trial was
terminated after an interim analysis, but the re-
sults have not yet been reported. The ECASS-4
EXTEND trial (European Cooperative Acute Stroke
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of m e dic i n e
Study 4: Extending the Time for Thrombolysis in
Emergency Neurological Deficits; EudraCT num-
ber, 2012-003609-80), which is investigating the
mismatch between diffusion-weighted MRI and
perfusion MRI, and the EXTEND trial (Extending
the Time for Thrombolysis in Emergency Neuro-
logical Deficits; EudraCT number, 2014-002864-
33), which uses an automated method that is based
on perfusion CT, are approaching their interim
analyses. The results of the DEFUSE 3 trial (Endo-
vascular Therapy Following Imaging Evaluation
for Ischemic Stroke 3; ClinicalTrials.gov number,
NCT02586415), which investigated the use of
thrombectomy 6 to 16 hours after the patients were
last known to be well, should be reported soon.
These imaging-based approaches represent a
new “DAWN” for the selection of patients who
are likely to benefit from thrombectomy that is
performed far longer after the onset of stroke
than current guidelines suggest, at least among
patients who have severe stroke, vascular occlu-
sion, and penumbral tissue. However, the results
of the DAWN trial do not support a general lib-
eralization of the time window for thrombecto-
my or thrombolysis. Reducing the time from the
onset of stroke to treatment remains essential
and results in the best outcomes. It is likely that
a limited proportion of patients with occlusion
of a large vessel who present late after the onset
of stroke will have a small infarct core and a
large volume of tissue at risk, as did the patients
in the DAWN trial. For those patients, late throm-
bectomy works — but as of now, as far as we
know, it works only for them.
Disclosure forms provided by the authors are available with
the full text of this editorial at NEJM.org.
From the Department of Neurology, University of Heidelberg,
Heidelberg, Germany.
This editorial was published on November 11, 2017, at NEJM.org.
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2015;​372:​2285-95.
 Editorial

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DOI: 10.1056/NEJMe1713367
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