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Page 2 of 5 Hsu. Vessel Plus 2022;6:18 https://dx.doi.org/10.20517/2574-1209.2021.117

In 1995 in a multicenter clinical trial sponsored by the National Institute of Neurological Disorders and
Stroke (NINDS) in the National Institutes of Health of the United States, an effective therapy was eventually
established by dissolving the blood clots that occlude blood vessels supplying the brain using a fibrinolytic
agent, alteplase, which is a recombinant tissue plasminogen activator (t-PA) (NINDS and Stroke rt-PA
Study Group, 1995). Fibrinolytic therapy applying t-PA was found to be effective in improving functional
outcome in patients with ischemic stroke in a double blind, placebo-controlled randomized trial. In this
NINDS t-PA trial, published in the New England Journal of Medicine, functional recovery to normal or with
[3]
minor neurological deficit was 30% more in the t-PA group than the control group . However, the risk of
developing symptomatic intracerebral hemorrhage was 10-fold higher in the t-PA group than the control
group (6.4% vs. 0.6%). Another shortcoming of t-PA in the treatment of patients with ischemic stroke noted
in this multicenter trial in the United States was the narrow therapeutic window, restricted to 3 h within
stroke onset (extended to 4.5 h later). Until 2019, 24 years after the landmark NINDS trial of t-PA, advances
in thrombolytic therapy were finally made in a multinational trial (EXTEND) under the global leadership of
Prof. Steve Davis and Prof. Jeffrey Donnan (both were former Presidents of the World Stroke
Organization). In this multinational clinical trial, the therapeutic window of t-PA for patients with ischemic
stroke was extended from 4.5 to 9 h after stroke . The EXTEND trial took the advantage of an innovative
[3]
imaging software (RAPID) developed by the same investigator team led by Prof. Steve Davis and Prof.
Jeffrey Donnan to define the penumbra region in the ischemic brain for identifying eligible stroke patients
with ischemic but surviving brain region (penumbra) which is still eligible for salvaging with the restoration
of blood flow by t-PA. The Australian stroke investigator group has developed another multinational stroke
clinical trial aiming to broaden the therapeutic option by testing a new thrombolytic agent, teleplase.
Compared to t-PAs such as alteplase, teleplase has the advantages of lower risk in causing intracerebral
hemorrhage while carrying greater efficacy in thrombolytic action than t-PA. The TASTE trial comparing t-
PA with teleplase has been a multinational clinical trial ongoing since 2017 under the leadership of another
Australian stroke leader, Professor Mark Parsons.

Overall, therapeutic interventions for patients with stroke caused by cerebral ischemia have been limited to
thrombolysis with intravenous t-PA for dissolving the blood clots that obstruct major cerebral blood vessels
from delivering blood to the brain. The advance in the past 25 years is that the therapeutic window of t-PA
has been extended from 4.5 to 9 h after stroke onset to allow a greater proportion of patients with acute
ischemic stroke to have the benefit of receiving t-PA therapy because of the broadened therapeutic window
from 4.5 to 9 h. Symptomatic intracranial hemorrhage has remained to be the major drawback. The
multinational clinical stroke trial comparing the t-PA alteplase with teleplase (TASTE) is still ongoing under
the global leadership of Prof. Mark Parsons, another commanding principal investigator from Australia.
Prof. Henry Ma, the international coordinator of EXTEND, again has been serving the same for the TASTE
trial .
[4]

It is a great honor that both Prof. Jeffrey Donnan and Prof. Steve Davis as well as Prof. Henry Ma, the
outstanding global coordinator of the EXTEND and TASTE trials, have graciously agreed that each
contributes an article for this special issue of Vessel Plus on stroke. The distinguished international
leadership of the Australian stroke research group on the EXTEND trial has also broken new ground to
broaden the therapeutic option for stroke patients beyond t-PA therapy. As referred to above, the TASTE
trial which is ongoing aims to confirm that the thrombolytic agent tenecteplase is superior to alteplase in
thrombolytic action but carries a lower risk of developing intracranial hemorrhage under the leadership of
Prof. Mark Parson, the 4th global stroke research leader from Australia. The 5th Australian stroke trial
leader, Prof. Bernard Yan, is the principal investigator on interventional trials applying thrombectomy. His
research also covers a broad scope of stroke care and has included: (1) pre-hospital mobile unit