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Page 6 of 10 Inoue et al. Vessel Plus 2021;5:11 I http://dx.doi.org/10.20517/2574-1209.2020.99
[34]
Response to Recanalization in Ischemic Stroke Project (CRISP) study , in which a protocol similar to
DEFUSE 2 verified only by CT perfusion, had a good prognosis in patients up to 18 h after onset with the
[1]
[2]
target mismatch. The early window EVT trials such as EXTEND-IA and SWIFT PRIME , which were
mainly performed by CT perfusion, the evidence of acute CT perfusion for early and late-onset has been
established.

As a culmination of the above, DEFUSE 3 study was designed to establish evidence from image selection
by MRI perfusion and CT perfusion in late-onset ischemic strokes. DEFUSE 3 was designed to expand the
therapeutic window up to 16 h who has a target mismatch, patients aged 18-90 years with National Institute
of Health Stroke Scale (NIHSS) score of 6 or higher, premorbid mRS 0-2, and time window of 6-16 h for
the EVT were included. As a radiological inclusion criterion, there should be a middle cerebral artery
occlusion or internal carotid artery occlusion by magnetic resonance angiography or CT angiography.
Ischemic core and penumbra would be analyzed and calculated by RAPID software. Cases with a target
profile as PWI/DWI or CBF core mismatch ratio greater than 1.8, the ischemic core of 70 mL or less, and
mismatch volume of 15 mL or more were enrolled. All devices that are approved by the United States
Food and Drug Administration (FDA) were accepted. 182 cases were registered from 38 institutions. The
frequency of mRS 0-2 after 90 days were 45% in the endovascular treatment group and 17% in the standard
treatment group. The odds ratio was 2.77 (95%CI: 1.63-4.70; P <0.001), and the number needed to treat was
2. In terms of safety, the proportion of mRS 5-6 was 14% in the endovascular treatment group and 26% in
the standard treatment group, which confirmed the safety with superiority (P = 0.05). After the publication
[35]
of DEFUSE 3 , the American Heart Association (AHA) stroke guidelines recommended the expanded
the window up to 16 h by perfusion selection . Together with the DAWN trial , which used clinical core
[37]
[36]
mismatch as a surrogate of penumbra, the expanded therapeutic window by advanced imaging for EVT has
been established.

Expanding the therapeutic Window in intravenous thrombolysis
[38]
The WAKE-UP study randomized patients with acute cerebral infarction who had a DWI-FLAIR
mismatch finding on MRI images into the alteplase treatment group (0.9 mg/kg) and the placebo treatment
group. This was a study to investigate the efficacy and safety of intravenous alteplase thrombolytic therapy
in wake-up or unknown onset stroke patients.

In the treatment of hyperacute ischemic stroke, the time from the onset is highly essential, and the golden
time window for IVT is within 4.5 h. There is a high correlation between the degree of cerebral ischemia
and the treatment time; the earlier the recanalization/reperfusion rate is, the better the clinical outcomes,
[39]
and there is less secondary symptomatologic intracranial hemorrhage . However, patients whose exact
onset times are unknown do not fit into the hyperacute treatment time frame. About one-fourth of all
cerebral infarction patients are reported to be in this wake-up/unknown onset population [40,41] . If some
approach can determine the onset time, the number of patients who can receive reperfusion therapy should
increase. Therefore, the method using the difference between the DWI and FLAIR images of MRI was
[42]
considered . Whereas DWI can visualize early ischemic changes within 1 h after the onset, FLAIR images
are unlikely to show early ischemic changes within 3 to 4.5 h of onset. When a patient with a positive DWI
and negative FLAIR images arrives, we can assume that the onset time is 3 to 4.5 h [Figure 4]. The WAKE-
UP trial was designed with this DWI-FLAIR mismatch and was conducted at 61 facilities in eight European
countries, mainly Germany. It was scheduled to enroll 800 patients from 2012 and ended early in June 2017.

The design was a randomized, double-blind, placebo-controlled trial with an intention-to-treat analysis.
The primary endpoint was the rate of complete independence as mRS 0-1 at 90 days. As a result, a total of
503 patients were randomized, and 254 patients were assigned to the alteplase group, and 249 patients were
assigned to the placebo group. The rate of mRS 0-1 at 90 days was 53.3% in the alteplase group, 41.8% in