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Page 8 of 10 Inoue et al. Vessel Plus 2021;5:11 I http://dx.doi.org/10.20517/2574-1209.2020.99

is that the study plan was open-labeled, and aggressive antithrombotic therapy such as antiplatelet dual-
drug therapy could be started early in the medical treatment group, which double-blinded group (such as
WAKE-UP trial) had to wait for 24 h after the infusion of alteplase/placebo. To supplement this result, we
have performed a sub-study and reported that patients with specific core volume (> 6.4 mL) would benefit
[46]
from wake-up IVT even with the low dose alteplase .

[47]
Recently, the meta-analysis for wake-up trials was published , including WAKE-UP (DWI-FLAIR
mismatch), THAWS (DWI-FLAIR mismatch), ECASS4 (PWI-core mismatch), and EXTEND (PWI-core
[48]
mismatch) . The two different radiological approaches to expand the time window are interesting, while
the PWI-core mismatch selection group also published a meta-analysis including EXTEND, ECASS4-
[49]
EXTEND, and EPITHET . From their conclusion, patients within 4.5 to 9 h from stroke onset or wake-
up stroke with salvageable brain tissue had better functional outcomes treated with alteplase than placebo,
which “literally” expanded the IVT time window. Although DWI-FLAIR mismatch may not be called an
advanced imaging compared to the PWI-core mismatch, the use of conventional sequences was unique and
could be considered in many facilities to identify patients with an acute ischemic stroke of unknown time
of onset evolving for less than 4.5 h.

CONCLUSION AND FUTURE DIRECTIONS
The therapeutic window has shown expansion in these years by evaluating various mismatches using
advanced imaging in acute ischemic strokes. Radiological information has demonstrated efficacy to
visualize things that neurological examination cannot be seen, such as penumbra. As the trials written
above have expanded the therapeutic window by advanced imaging, we may have more advanced imaging
to achieve a wider therapeutic window and better clinical outcomes in the near future.

DECLARATIONS
Authors’ contribution
Wrote the first draft and designed the study and interpretation: Inoue M
Supervised and critically reviewed the report, and approved the final version: Toyoda K

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.