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

from the time the patient was last known to be well, in contrast to the EXTEND definition of wake-up
stroke measured from the midpoint of sleep.

Other studies
At the same time as EXTEND trial, ECASS-4 also evaluated perfusion imaging of the penumbra for
[32]
[33]
thrombolysis . The THAWS trial used the same DWI-FLAIR mismatch concept as WAKE-UP trial.
These trials were terminated early following the WAKE-UP results. Individually, they did not demonstrate a
difference in favorable outcome between alteplase and control groups [32,33] . This is likely a reflection of these
studies lacking sufficient statistical power due to the relatively low number of recruited patients to
demonstrate the desired effect (ECASS-4119 patients recruited with planned 264 patients and THAWS 131
patients recruited with planned 300 patients). MR WITNESS was a phase 2a, open-label safety trial of
intravenous thrombolysis in stroke patients with unwitnessed symptom onset within 4.5 to 24 h time
window. The trial is different from WAKE-UP which used visual analysis of DWI-FLAIR mismatch. MR
WITNESS tested quantified DWI-FLAIR mismatch (qDFM) as imaging selection criteria. The results were
encouraging with regards to the use of qDFM to guide therapy. Eighty patients were recruited with 39%
[34]
achieving mRS 0-1 at 90 days while only one patient sustained symptomatic intracranial hemorrhage .

Pooled results
A meta-analysis of EXTEND, ECASS4, and EPITHET provided strong evidence of efficacy for patients with
an unknown time of onset or in the extended time window . Note that this was pooled individual data,
[35]
much more powerful than a standard meta-analysis. Another research group independently confirmed
these findings with their meta-analysis of EXTEND, WAKE-UP and ECASS4 . A further meta-analysis of
[36]
combined EXTEND, WAKE-UP, ECASS4, and THAWS data demonstrated a strong benefit of
thrombolysis vs. placebo for independent functional outcome for the unclear time of onset subset .
[37]

Guideline adaptation
The Australian Clinical Guidelines for Stroke Management has strongly recommended that for patients
[38]
with potentially disabling ischemic stroke who meet perfusion mismatch criteria in addition to standard
clinical criteria, intravenous alteplase (dose of 0.9 mg/kg, maximum of 90 mg) should be administered up to
9 h after the time the patient was last known to be well, or from the midpoint of sleep for patients who wake
[38]
with stroke symptoms, unless immediate endovascular thrombectomy is planned . The American Heart
Association/American Stroke Association guidelines were last updated in 2019 and prior to publication of
[39]
the EXTEND trial. The European Stroke Organisation (ESO) had already released a consensus statement
that IV alteplase may be considered for patients with acute ischemic stroke 4.5 to 9 h from onset with a
[40]
penumbral mismatch back in 2018 . This has recently been formalized, with the group stating that “for
patients with ischemic stroke of 4.5 to 9 h duration (known onset time) and with CT or MRI core/perfusion
mismatch, and for whom mechanical thrombectomy is either not indicated or not planned, we recommend
[41]
intravenous thrombolysis with alteplase” .
UNANSWERED QUESTIONS
Implementation
Implementing the DWI-FLAIR protocol requires access to MR scanner. This may not be possible outside of
tertiary teaching hospitals. By contrast, multimodal CT scanners are available even in rural parts of
Australia and can be combined with automated perfusion analysis . An advantage of DWI-FLAIR
[27]
mismatch over multimodality CT is that it can be used in patients with significant renal impairment.
Further it can be read visually and without investment in expensive software. It can be argued that to
achieve the trial results of EXTEND and DEFUSE3, investment in software such as RAPID is required. The
hospitals involved in these trials have experience with using RAPID software and can recognize false