Page 54 - Read Online

Inoue et al. Vessel Plus 2021;5:11 I http://dx.doi.org/10.20517/2574-1209.2020.99 Page 7 of 10

Figure 4. Sample of a DWI-FLAIR mismatch case. The upper figure shows DWI positive but FLAIR negative, which can suppose that this
case is within 3 to 4.5 h of onset. The lower case has both positive signals in DWI and FLAIR which can be assume that onset is beyond 4.5 h.

the placebo group, and the adjusted odds ratio was 1.61 (1.09-2.36; P = 0.02), indicating the effectiveness
of alteplase in the wake-up strokes. The reasons for the unknown onset time were 89.4% in the alteplase
group, and 89.2% in the placebo group, most of which were onset at wake-up, and the median NIHSS were
both 6 (mild to moderate). Vascular occlusion was observed in 33.7% in the alteplase group and 34.1%
in the placebo group. The ischemic core of DWI was 2.0 mL in the alteplase group and 2.5 mL in the
placebo group, both of which were minor infarctions. The median mRS after 90 days was 1 for the alteplase
group and 2 for the placebo group (adjusted odds ratio 1.62, 1.17-2.23, P = 0.003), and death after 90
days was 4.1% and 1.2%, respectively (adjusted odds ratio 3.38, 0.92-12.52, P =0.07). As a safety endpoint,
intraparenchymal hematomas type 2 (PH2) was higher (4.0%) in the alteplase group than in the placebo
group (0.4%) (adjusted odds ratio 10.46, 1.32-82.77, P = 0.03), and symptomatic intracranial hemorrhage
(sICH) was 2.0% and 0.4% respectively (adjusted odds ratio 4.95, 95%CI: 0.57-42.87, P = 0.15) based on
[43]
the SITS-MOST criteria , but with no significant difference. In summary, IVT was safe and effective in
waking up patients who had a DWI-FLAIR mismatch on MRI imaging even with or without occluded
blood vessels.

In Japan, a similar wake-up trial, the THAWS study, completed registration in July 2018 following the
[44]
WAKE-UP study results and was also published . The THAWS study is slightly different from the WAKE-
UP study, such as the PROBE method (Prospective, Randomized, Open, Blinded-Endpoint) that does not
[45]
use a placebo drug, and the use of a Japanese-specific alteplase dose (alteplase 0.6 mL/kg) . Forty facilities
participated, and 131 patients were registered. Although the rate of mRS 0-1 at 90 days was not significantly
different between the alteplase group and the standard medical treatment group (47% vs. 48%, relative risk
0.97, 95%CI: 0.68-1.41, P = 0.892), in terms of safety, both sICH (PH type 2 bleeding and deterioration in
NIHSS 4 points or higher, 1.4% vs. 0%, P > 0.99) and death (2.8% vs. 3.3%, P > 0.99) at 90 days onset had
no significant difference between the groups. Several reasons can explain why the efficacy could not be
shown, as in the WAKE-UP study. One was that the number of registrants was about 50% of the initial plan
due to the early termination of the study, and the registration term was strongly overlapped when the EVT
showed substantial evidence. Thus, many wake-up patients were taken to the cath lab instead. Another