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Page 6 of 9 Lim et al. Vessel Plus 2021;5:34 https://dx.doi.org/10.20517/2574-1209.2021.44

positive cases. As such it is not certain if the results of the trials can easily be replicated without the aid of an
[42]
experienced stroke physician or radiologist .
Minor ischaemic stroke
The use of perfusion imaging to aid alteplase therapy in patients with minor ischemic stroke is unclear.
Minor ischemic stroke is often defined as an NIHSS less than or equal to 5. Clinical trials of alteplase in
patients with minor stroke have not used advanced imaging. This was the case with the negative PRISM
trial . It is possible that advanced imaging may help to find an enriched cohort who may benefit from
[43]
reperfusion therapy. An observational study demonstrated that mismatch between hypoperfused tissue and
ischemic core in high risk TIA and minor ischemic stroke is predictive of neurological deterioration, infarct
[44]
progression, and disability . This concept has not yet been tested in clinical trial.
Is alteplase the best choice of thrombolysis agent?
Unanswered questions remain about the optimal choice of thrombolysis agent in the early window.
Although some evidence exists for tenecteplase in perfusion-selected patients within 6 h of onset or with
[45]
[47]
large vessel occlusion within 4.5 h , the best choice remains unanswered. The NOR-TEST trial
[46]
demonstrated that tenecteplase was not superior to alteplase in the early window, but its non-inferiority is
yet to be answered. The ongoing TASTE trial (NCT04071613) is addressing the comparison between early
intravenous tenecteplase and intravenous alteplase within 4.5 h of stroke onset using perfusion imaging
selection.

Does systemic reperfusion work up to 24 h after stroke onset?
The penumbra can remain viable for up to 48 h after stroke onset in selected patients . Studies such as this
[48]
one suggest that thrombolysis beyond 9 h is possible. Two trials are currently recruiting to address this. The
ETERNAL trial (NCT04454788) seeks to answer whether reperfusion of penumbral tissue with tenecteplase
in patients with large vessel occlusion is beneficial. This phase III, prospective, randomized, open-label,
blinded endpoint design is evaluating patients presenting to the emergency department with a hyperacute
stroke due to large vessel occlusion who are eligible for thrombectomy, and who have a perfusion mismatch.
Patients will be randomized to receive tenecteplase or standard care before clot retrieval. TIMELESS
(NCT03785678) is a phase III, prospective, double blind, randomized, placebo-controlled trial that seeks to
test the efficacy and safety of tenecteplase in patients with a large vessel occlusion (internal carotid artery or
middle cerebral artery) and penumbral tissue within 4.5 to 24 h. The primary outcome will be the ordinal
modified Rankin Scale score at day 90.

What is the best way to reperfuse in the late time window in patients with or without large vessel
occlusion?
In patients with large vessel occlusion, the utility of direct thrombectomy or bridging therapy with
intravenous thrombolysis followed by thrombectomy within the late time window, is being studied. The
DIRECT MT trial demonstrated non-inferiority of direct thrombectomy compared to bridging therapy
within 4.5 h of stroke onset. However, this study utilized non-contrast CT for patient selection . There are
[49]
a number of ongoing trials attempting to answer the same question, including DIRECT-SAFE
(NCT03494920) and MR CLEAN-NO IV (ISRCTN80619088) trials. For the same question but in the
beyond 4.5 h time window, the ETERNAL and TIMELESS trials will, hopefully, provide the answers. In
patients with large vessel occlusion who are ineligible for thrombectomy, whether intravenous thrombolysis
will prove to be superior to placebo for functional improvement is another area of considerable interest. The
final difficult patient group are those without large vessel occlusion in the late time window.