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Page 4 of 9 Lim et al. Vessel Plus 2021;5:34 https://dx.doi.org/10.20517/2574-1209.2021.44

[2]
patients . The DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) trial
[1]
chose to use CT or MR penumbral imaging . All these lines of inquiry have culminated into four seminal
trials that demonstrate the benefit of image-guided patient selection for reperfusion, and this will be
explored in the next section.

POSITIVE TRIALS
[1,2]
[3,4]
Four recent positive trials provide evidence for acute mechanical and systemic reperfusion therapy in
an extended time window up to 24 h, using advanced imaging criteria for patient selection.
EXTEND
The EXTEND trial selected patients based on penumbral imaging 4.5 to 9 h after stroke onset or with wake-
up stroke within 9 h from the midpoint of sleep. A total of 225 patients were enrolled, with 113 receiving
alteplase and 112 receiving placebo. The primary outcome (modified Rankin Scale) of 0-1 occurred in 35.4%
[3]
in the alteplase group and 29.5% in the placebo group . This meant there was a 44% higher likelihood of a
good outcome in the alteplase group compared to placebo - ARR 1.44 (1.01-2.06), P = 0.04 . In other words,
[3]
alteplase was shown to improve functional outcomes at 3 months when administered 4.5 to 9 h or after
wake-up stroke less than 9 h from midpoint of sleep amongst patients with perfusion mismatch. This was a
consistent effect across age, time, and large vessel strata. It is notable that in EXTEND 69% of patients in the
alteplase group had large vessel occlusion with a recanalization rate at 24 h of 67.3% without mechanical
[3]
thrombectomy . This made EXTEND the first positive trial of intravenous thrombolysis in patients in the
[31]
extended time window selected with penumbral imaging . It is also important to recognise that a
significant number of patients in EXTEND had wake up stroke.

WAKE-UP
The WAKE-UP trial selected stroke patients with unknown time of onset using selection based on DWI-
FLAIR mismatch, with DWI estimating ischemia and FLAIR estimating infarct. The investigators assumed
that the absence of FLAIR signal indicated that the ischemic injury occurred within 4.5 h of onset. After
enrolment of 503 patients, 254 received alteplase and 249 received placebo; a favorable outcome (modified
Rankin Scale of 0-1) was achieved in 53% of the alteplase group and 42% of the placebo group [adjusted
odds ratio (OR) = 1.61; 95% confidence interval (CI): 1.09-2.36; P = 0.02] . The rate of symptomatic
[4]
intracranial hemorrhage did not differ significantly, with 2.0% in the alteplase group and 0.4% in the placebo
[4]
group (OR = 4.95; 95%CI: 0.57-42.87; P = 0.15) . Such a finding then led to the termination of several other
trials that were investigating a similar concept due to a loss of equipoise [3,32,33] . This then became the first
randomized evidence of intravenous thrombolysis in patients with unknown time of symptoms guided by
[31]
advanced imaging .
DAWN and DEFUSE-3
The DAWN trial tested the concept of clinical-imaging mismatch to select patients for mechanical
reperfusion in the 6-24 h . The algorithm for clinical-imaging mismatch was complicated and based on age,
[2]
stroke severity and infarct volume. Infarct volume was defined on CT or DWI using automated software
(RAPID, iSchemiaView). For patients ≥ 80-year-old and NIHSS ≥ 10, the infarct volume had to be less than
21 mL. For patients < 80-year-old and NIHSS ≥ 10, the infarct volume had to be less than 31 mL. For
patients < 80-year-old and NIHSS ≥ 20, the infarct volume had to be between 31-51 mL. Patients selected
using this method demonstrated significantly better functional outcome at 90 days . Alternatively, the
[2]
DEFUSE-3 trial employed penumbral imaging up to 6-16 h from onset to become the first randomized
evidence of reperfusion benefit when acute stroke patients with an extended or unknown time window were
[31]
selected with penumbral imaging . Note that the time of onset of stroke for these two trials was calculated