Current Neurology and Neuroscience Reports (2020) 20:35

https://doi.org/10.1007/s11910-020-01055-1

STROKE (H.-C. DIENER, SECTION EDITOR)

Thrombolysis beyond 4.5 h in Acute Ischemic Stroke

Mark R. Etherton 1 & Rajan R. Gadhia 2 & Lee H. Schwamm 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review The purpose of this article is to review the current approaches using neuroimaging techniques to expand
eligibility for intravenous thrombolytic therapy in acute ischemic stroke patients with stroke of unknown symptom onset.
Recent Findings In recent years, several randomized, placebo-controlled trials have shown neuroimaging-guided approaches to
be feasible in determining eligibility for alteplase beyond 4.5 h from last known well, and efficacious for reducing disability.
DWI-FLAIR mismatch on MRI is an effective tool to identify stroke lesions less than 4.5 h in onset in patients with stroke of
unknown symptom onset. Additionally, an automated perfusion-based approach, assessing for a disproportionate amount of
salvageable tissue, is effective in identifying patients likely to benefit from late window alteplase treatment.
Summary In patients with stroke of unknown symptom onset, an individualized approach using neuroimaging to determine time
of stroke onset or presence of salvageable brain tissue is feasible in the acute setting and associated with improved long-term
outcomes.

Keywords Ischemic stroke . Thrombolysis . Neuroimaging . Systems of care

Introduction onset; for example, in those patients awakening with deficits

The administration of intravenous thrombolytic therapy for
acute ischemic stroke is traditionally predicated on time from
last known well (LKW) as a surrogate for stroke onset. Using
LKW as one of the main eligibility criteria for intravenous
thrombolysis treatment, alteplase is efficacious for reducing
long-term disability in patients treated within 0–3 h and 3–
4.5 h of LKW [1, 2]. Despite the proven efficacy of alteplase
for acute ischemic stroke, however, the majority of patients do
not receive this therapy due to delay in patient arrival, inability
to determine LKW, and/or patients awakening with stroke
symptoms [3, 4]. Compounding this issue, LKW is a conser-
vative estimate of stroke onset. In more than a third of ische-
mic stroke patients, LKW does not coincide with actual stroke
(termed wake-up strokes) [5–9], which further limits throm-
bolytic therapy eligibility.
Given that the majority of ischemic stroke patients do not
receive treatment with thrombolytic therapy and stroke onset
is conservatively time-based with LKW, there is much interest
in novel approaches to safely expand thrombolytic therapy for
ischemic stroke patients. One area of focus has been the ap-
plication of neuroimaging-guided approaches to increase
thrombolysis eligibility in patients with stroke of unknown
symptom onset (SUSO) [10]. In this review, we will discuss
the current evidence investigating intravenous thrombolysis
beyond 4.5 h from LKW and the neuroimaging-based ap-
proaches to individualize thrombolytic therapy in SUSO.

This article is part of the Topical Collection on Stroke

History of Time as Eligibility Determinant
* Mark R. Etherton for Alteplase
metherton@partners.org
The original alteplase trials in ischemic stroke sought to de-
1
JPK Stroke Research Center, Department of Neurology,
termine the window of eligibility where alteplase would be
Massachusetts General Hospital (MGH) and Harvard Medical safe and potentially of clinical benefit (Table 1). Time from
School, Boston, MA, USA LKW was utilized as a conservative estimate of stroke onset.
2
Department of Neurology, Eddy Scurlock Stroke Center, Houston The European Cooperative Acute Stroke Study (ECASS I),
Methodist, Houston, TX, USA was the first randomized, double blind, placebo-controlled
 35 Page 2 of 8
Table 1 Summary of notable randomized trials of alteplase > 3 h from stroke onset
Study Imaging modality # Treated Time window (h)
CT-based
ATLANTIS CT 547 3–5
ECASS III CT 418 3–4.5
Perfusion lesion-ischemic core
EPITHET MRI 52 3–6
DIAS II MRI or CTP 125 3–9
EXTEND* MRI or CTP 200 4.5–9
DWI-FLAIR mismatch
WAKE-UP MRI 503 > 4.5
THAWS* MRI 131 4.5–12
*terminated early due to publication of WAKE-UP
Abbreviations: CTP computed tomography perfusion, DWI diffusion-weighted imaging, FLAIR fluid attenuated inversion recovery, MRI magnetic
resonance imaging, mRS modified Rankin scale score
trial testing intravenous alteplase (1.1 mg/kg) for ischemic
stroke within 6 h of LKW [11]. ECASS I observed no differ-
ence between alteplase and placebo in 90-day modified
Rankin Scale (mRS) scores; however, the results were influ-
enced by the high prevalence of major protocol violations
(17.4%) largely pertaining to imaging inclusion criteria.
Shortly after the publication of ECASS I, the National
Institute of Neurological Disorders and Stroke (NINDS) rt-
PA study group showed that patients with acute ischemic
stroke who received alteplase (0.9 mg/kg) within 3 h of
LKW, as compared to placebo, were at least 30% more likely
to have minimal or no disability at 3 months [1].
Building on the results of the NINDS rt-PA study, several
subsequent trials set out to evaluate the efficacy of alteplase in
time-based windows extending beyond 3 h from LKW.
ECASS II evaluated the efficacy of alteplase (0.9 mg/kg)
within 0–6 h of LKW in 800 participants [12]. Overall, no
difference was observed in rates of favorable outcomes at
90 days (mRS < 2, alteplase 40.3%; placebo 36.6%; P =
0.28) with 80% of participants being enrolled in the 3–6 h
window [12]. The Alteplase ThromboLysis for Acute
Noninterventional Therapy in Ischemic Stroke (ATLANTIS)
trial was a phase 3, randomized, double blind, placebo-
controlled trial looking specifically at alteplase (0.9 mg/kg)
in ischemic stroke 3–5 h from LKW [13]. Of note, the
ATLANTIS trial was originally designed to look at the 3–
6 h window but the study was suspended and time window
modified due to safety concerns regarding the 5–6 h window.
In 547 stroke patients randomized to alteplase within 3–5 h of
LKW, ATLANTIS showed no difference in rates of favorable
outcomes at 90 days (mRS < 2, alteplase 42.3%; placebo
38.9%; P = 0.42).
To further define the relationship between time-to-
treatment and therapeutic benefit of alteplase, a meta-
analysis of ATLANTIS, ECASS I and II, and the NINDS rt-
Curr Neurol Neurosci Rep (2020) 20:35
Outcome
90-day mRS < 2. alteplase 42.3%; placebo 38.9%; P = 0.42
90-day mRS < 2. alteplase 52.4%; placebo 45.2%; P = 0.04
Infarct growth. alteplase 1.18; placebo 1.79; P = 0.054
Favorable clinical outcome* 47% (90 μg/kg), 36% (125 μg/kg), 46% (placebo)
90-day mRS < 2. alteplase 35.4%; placebo 29.5%; P = 0.04
90-day mRS < 2. alteplase 53.3%; placebo 41.8%; P = 0.02
90-day mRS < 2. alteplase 47%; placebo 48%; P = 0.89
PA trial was performed [14]. For 2775 participants treated
within 6 h of LKW, the odds of a favorable 90-day outcome
increased with shorter time from stroke onset to start of treat-
ment. Importantly, in the 3–4.5 h window the odds ratio for
favorable 90-day outcome with alteplase was 1.4 (95% confi-
dence interval 1.1–1.9) with no difference in the hazard ratio
for death (1.24, 95% confidence interval 0·84–1·84) [14]. This
meta-analysis suggested that the time window of eligibility for
alteplase could be safely extended to 4.5 h and potentially
improve long-term outcomes. The randomized, double blind,
placebo-controlled ECASS III trial confirmed this hypothesis
showing that alteplase (0.9 mg/kg) for ischemic stroke within
3–4.5 h of LKW was associated with reduced disability (90-
day mRS < 2, alteplase 52.4%; placebo 45.2% P = 0.04).
The results of the early trials of alteplase for acute ischemic
stroke resulted in its approval by the United States Food and
Drug Administration for patients with ischemic stroke in the
3-h window and recommendation by the American Heart
Association (AHA)/American Stroke Association (ASA) for
use in the 3–4.5 h window (class
I; level of evidence B-R) [15].
Neuroimaging as a Time Stamp of Stroke
Onset
Intravenous alteplase is safe and efficacious within 4.5 h of
LKW. In an effort to expand thrombolytic therapy to patients
with SUSO, however, neuroimaging-based approaches have
been employed to function as a radiographic time stamp of
stroke lesions < 4.5 h in age and thereby define a subset of
SUSO patients that may benefit from thrombolysis. DWI-
FLAIR mismatch, the presence of a visible ischemic lesion
on diffusion-weighted imaging (DWI) and absence of any
corresponding parenchymal hyperintense lesion on the fluid-
Curr Neurol Neurosci Rep (2020) 20:35 Page 3 of 8 35

attenuated inversion recovery (FLAIR) sequence (Fig. 1), is
one approach that has been used to identify patients within
4.5 h of stroke onset [16, 17]. Several studies have shown that
DWI-FLAIR mismatch can function as a radiographic time
stamp of stroke onset as it has a relatively high specificity
(71–93%) and moderate sensitivity (48–62%) for identifying
stroke lesions within 4.5 h of onset [16–20]. The DWI-FLAIR
mismatch approach therefore holds potential to expand access
to thrombolytic therapy by identifying SUSO patients within
4.5 h of stroke onset that historically would not have been
treated with alteplase due to unknown LKW.
At present, three large phase 2a or 3 studies have now been
completed in SUSO patients using the presence of DWI-
FLAIR mismatch to determine eligibility for alteplase [21••,
22, 23]. The MR WITNESS trial (A Study of Intravenous
Thrombolysis with Alteplase in MRI-Selected Patients), was
a phase 2a, open-label multicenter trial of alteplase (0.9 mg/kg)
in SUSO patients with DWI-FLAIR mismatch 4.5–24 h from
LKW [24]. MR WITNESS utilized quantitative DWI-FLAIR
mismatch whereby the lesion was deemed FLAIR negative if
the signal intensity ratio between the lesion and contralateral
homologous region was < 1.15. Of 80 participants, only 1
experienced symptomatic intracranial hemorrhage (sICH)
and rates of favorable outcome were comparable to ECASS
III (mRS < 2 44%) [22].
Subsequently, two phase 3 trials evaluated alteplase in
SUSO patients using qualitative DWI-FLAIR mismatch, de-
fined as an acute ischemic lesion on DWI without any corre-
sponding parenchymal hyperintense lesion on FLAIR. The
European multicenter, randomized double-blind, placebo-
controlled, phase 3 efficacy and safety of MRI-based throm-
bolysis in Wake-Up Stroke (WAKE-UP) trial evaluated the
efficacy of alteplase in SUSO patients > 4.5 h from LKW with
qualitative DWI-FLAIR mismatch [21••]. WAKE-UP was
halted after enrolling 503 out of a planned 800 patients due
to cessation of funding. Notably, 859 participants were screen
failures with 455 of those participants having visible FLAIR
lesions. Of those randomized, treatment with alteplase was
associated with favorable outcomes at 90 days (mRS < 2,
alteplase 53.3%; placebo 41.8%; P = 0.02). Rates of sICH
and death were increased with alteplase treatment but did
not achieve statistical significance (sICH ECASS III criteria,
alteplase 2.4%; placebo 0.4%; P = 0.1. death, alteplase 4.1%;
placebo 1.2%; P = 0.07). Importantly, the median time from
LKW to treatment was 10.3 h with 89% of the SUSO popu-
lation due to nighttime sleep. In addition, and in consideration
of the overall generalizability, WAKE-UP was comprised of
relatively mild strokes with median NIHSS score 6 and DWI
lesion volume 2–2.5 mL. Another phase 3 trial of DWI-
FLAIR mismatch in SUSO, the THrombolysis for Acute
Wake-up and unclear-onset Strokes (THAWS) is a multicen-
ter, prospective, open-label phase 3 trial of reduced dose
alteplase (0.6 mg/kg, approved for stroke patients in Japan)
in patients 4.5–12 h from LKW was prematurely stopped re-
cruitment due to the results of WAKE-UP [23]. Preliminary
results for 131 patients showed no difference in favorable
outcomes at 90 days (mRS < 2, alteplase 47%; placebo 48%;
P = 0.89) and only one alteplase-treated patient with sICH.

Fig. 1 Clinical and advanced

imaging criteria for patient
selection in the WAKE-UP and Clinical Advanced Imaging
Criteria Criteria Candidate by Imaging Not a Candidate by Imaging
EXTEND trials of alteplase in
stroke of unknown symptom
onset. Abbreviations: CBF—
cerebral blood flow; CT— Age 18-80
DWI/FLAIR mismatch
computed tomography; DWI— WAKE-
NIHSS < 25
diffusion-weighted imaging; UP DWI lesion < 1/3 MCA
territory.
FLAIR—fluid-attenuated inver- LKW > 4.5 h
sion recovery; MRI—magnetic
DWI FLAIR DWI FLAIR
resonance imaging; Tmax—
Time-to-maximum

Penumbra
core CT
mismatch
Age > 18 ratio > 1.2
CBF Tmax CBF Tmax
EXTEND NIHSS 4-26 Penumbra
core absolute
LKW 4.5-9 h difference >
10 ml

Core < 70 ml MRI

DWI Tmax DWI Tmax

 35 Page 4 of 8
The results of the MR WITNESS, WAKE-UP, and
THAWS trials demonstrate that the DWI-FLAIR mismatch
approach, as a neuroimaging time stamp of stroke onset in
SUSO, is clinically feasible and expands thrombolytic treat-
ment for patients that previously would have been ineligible
using conventional time-based criteria. In addition, WAKE-
UP showed that in patients with SUSO, treatment with
alteplase, guided by DWI-FLAIR mismatch, was efficacious
with reduced long-term disability. As a result, the revised
2019 AHA/ASA guidelines state that the qualitative DWI-
FLAIR mismatch approach could be beneficial for the evalu-
ation of SUSO patients (class IIa, level of evidence B-R) [15].
An important question moving forward is, given the high rates
of screen failure for DWI-FLAIR mismatch, what is a cost-
effective strategy for resource utilization with this approach?
One approach would be to triage the SUSO population direct-
ly to CT and, if no CT evidence of overt early/established
ischemic changes, then proceed with MRI to assess for
DWI-FLAIR mismatch. Regardless, the results of these trials
employing DWI-FLAIR mismatch in SUSO populations un-
derscore the idea that there are subgroups of ischemic stroke
patients that benefit from thrombolytic therapy beyond the
traditional time of LKW-based window.
Neuroimaging to Identify Target Mismatch
for Extended Window Thrombolysis
In contrast to the application of neuroimaging to function as a
time stamp of stroke onset in SUSO, an alternative approach
to extend the window for thrombolysis has been to utilize
neuroimaging to assess the individual level of irreversible ver-
sus reversible injury. While time from stroke onset strongly
correlates with progression of ischemic injury, there is signif-
icant inter-individual variability [25]. This has led to the hy-
pothesis that while time from stroke onset is paramount, indi-
viduals with a significant extent of reversible injury may still
benefit from thrombolytic therapy independent of the tradi-
tional time windows of eligibility.
MRI and CT perfusion-based imaging techniques have
been applied to quantify the infarct core (irreversible injury)
and ischemic penumbra (potentially salvageable tissue at risk
for progressing to infarct). On MRI, the DWI hyperintense
lesion, which is secondary to cytotoxic edema-induced re-
stricted diffusion, is interpreted as the infarct core based on
its high probability for infarction [26, 27]. In contrast to MRI,
CT-perfusion approximates the infarct core by using relative
cerebral blood flow maps to identify areas with significant
hypoperfusion as being high risk for progression to infarct
[28]. Both MRI and CT-perfusion use tracer arrival time met-
rics to identify the ischemic penumbra as potentially salvage-
able tissue [29–36].
Curr Neurol Neurosci Rep (2020) 20:35
Several randomized trials have applied perfusion-based
neuroimaging to identify stroke patients with target mismatch,
defined as a disproportionate amount of salvageable tissue to
ischemic core, that may benefit from late window thromboly-
sis (Fig. 1). The Echoplanar Imaging Thrombolytic
Evaluation Trial (EPITHET) was a phase 2, randomized,
placebo-controlled trial of alteplase in 101 ischemic patients
3–6 h from LKW [37]. MR perfusion was obtained in 101
patients before and after randomization to alteplase or place-
bo, which allowed the investigators to look at the effect of
alteplase on lesion growth, reperfusion rates, and clinical out-
comes in patients with perfusion-diffusion mismatch. The ma-
jority of patients had perfusion-diffusion mismatch (86%),
defined as perfusion-DWI volume > 10 mL or perfusion/
DWI ratio > 1.2. In the alteplase group, decreased infarct
growth (alteplase 54%; placebo 77%, P = 0.03), increased re-
perfusion (alteplase 56%; placebo 26%, P = 0.01), but no dif-
ference in 90-day outcomes was observed [37]. In follow up,
the phase 3, randomized, placebo-controlled trial Extending
the Time for Thrombolysis in Emergency Neurological
Deficits (EXTEND) was pursued [38••, 39]. EXTEND en-
rolled stroke patients 4.5 to 9 h from LKW or the mid-point
of sleep with perfusion lesion-ischemic core mismatch on
MR- or CT-perfusion. The definition of perfusion lesion-
ischemic core mismatch was ratio > 1.2, absolute difference >
10 mL, and ischemic core volume < 70 mL. Notably, the
definition of salvageable/critically hypoperfused tissue in
EXTEND was a time to maximum of the residue function
exceeding 6 s as compared to 2 s, which was used in
EPITHET [37]. Over 8 years, 225 patients were enrolled in
EXTEND with the trial being terminated early due to loss of
equipoise after publication of WAKE-UP [21••]. Notably, pa-
tients in whom endovascular thrombectomy was planned were
not enrolled in EXTEND and there was a significant number
of patients with large-vessel occlusions (69–72%) in the study
population. Similar to WAKE-UP, EXTEND enrolled pre-
dominantly wake-up stroke patients (65%). The median time
from LKW to treatment was 7.2–7.5 h. Enrolled patients dem-
onstrated significant perfusion lesion-ischemic core mismatch
(ischemic core volume 2.4–4.6 mL and perfusion lesion vol-
ume 74.3–78.0 mL). Patients treated with alteplase were more
likely to have good outcomes at 90 days (mRS < 2, alteplase
35.4%; placebo 29.5%, P = 0.04) with no increase in death
and rates of sICH (alteplase 6.2%; placebo 0.9%; P = 0.07)
comparable to ECASS III. A meta-analysis of individual pa-
tient data from EXTEND, EPITHET, and ECASS4-EXTEN,
emphasized these findings, showing that in 410 patients in-
cluded in the three trials, patients in the alteplase group had
increased rates of excellent 90-day outcome (mRS < 2.
alteplase 36%; placebo 29%; adjusted odds ratio 1.86; 95%
CI 1.15–2.99, P–0.011) despite increased rates of sICH
(alteplase 5%; placebo < 1%; adjusted odds ratio 9.7; 95%
CI 1.23–76.55; P = 0.031) [40].
Curr Neurol Neurosci Rep (2020) 20:35
Aside from alteplase, several trials have investigated alter-
native tissue plasminogen activators in extended window
stroke patients with perfusion lesion-ischemic core mismatch.
The Desmoteplase in Acute Ischemic Stroke Trials (DIAS) 2
trial was a phase 3, randomized, placebo-controlled trial of the
alternative tissue plasminogen activator desmoteplase in is-
chemic stroke patients 3–9 h from LKW with infarct core-
perfusion mismatch (> 20%) [41]. In 186 patients, no differ-
ence was observed in rates of favorable outcome at 90 days or
sICH. The phase 2B trial of tenecteplase for acute ischemic
stroke, compared tenecteplase to alteplase in stroke patients
within 6 h of LKW, verified arterial occlusion, and perfusion
lesion-ischemic core mismatch > 20% [42]. Analysis of the 75
patients randomized showed the tenecteplase group to have
increased rates of reperfusion (79.3% vs. 55.4%; P = 0.004),
and improved 90-day outcomes (mRS < 2 36% vs. 11%; P =
0.02) compared to alteplase [42].
Together, these trials using neuroimaging to identify per-
fusion lesion-ischemic core mismatch have shown the ap-
proach is feasible in the emergent setting to efficiently triage
acute stroke patients for potential treatment with thrombolytic
therapy. Moreover, the promising results of EXTEND suggest
that a CT perfusion-based approach can identify patients with
viable brain tissue beyond 4.5 h from LKW that may benefit
from alteplase treatment [38••]. The applicability of this neu-
roimaging approach is reinforced by the late window
endovascular trials, DAWN and DEFUSE 3 [43, 44]. These
endovascular thrombectomy trials utilized neuroimaging to
select patients for late-window endovascular thrombectomy,
up to 24 h from LKW, based on the presence of salvageable
tissue (target mismatch) and showed a pronounced treatment
effect [43, 44].
Wake-Up Stroke: A Unique SUSO Subgroup
In about a quarter of stroke patients, the time of symptom
onset is not known, frequently because the patient awakes
from sleeping [7, 9]. Based on their time of LKW being prior
to going to sleep, wake-up stroke (WUS) patients are typically
excluded from treatment with intravenous alteplase. However,
there is a growing body of evidence to suggest that WUS
represents a distinct entity of SUSO with the possibility that
stroke onset actually occurs on awakening [8, 45–50]. Several
studies of patients with WUS versus witnessed-onset morning
strokes have shown comparable clinical presentations, CT
findings, and outcomes [7, 47, 51–53].
The aforementioned EXTEND and WAKE-UP trial results
have demonstrated the efficacy of advanced neuroimaging
approaches to guide alteplase decision making in SUSO pop-
ulations comprised predominantly of WUS [21••, 38••].
Under the premise that the onset of WUS is contiguous with
awakening and LKW therefore is immediately prior to
Page 5 of 8 35
awakening, several other studies have applied traditional
CT-based methods to guide alteplase decision making for
WUS [54–57]. Two small prospective studies of WUS have
demonstrated comparable safety for alteplase treatment [56,
58]. The Wake-up Stroke trial was a small, prospective, open-
label investigation of alteplase in 40 WUS patients within 3 h
of symptom discovery [56]. Similarly, the Safety of
Intravenous Thrombolytics in Stroke on awakening (SAIL-
On) trial, was a small prospective, open-label study of
alteplase in 20 WUS patients within 4.5 h of symptom discov-
ery [58]. Both studies were of relatively mild strokes (median
NIHSS score 6) but patients were treated with alteplase at a
mean time of 10.3–10.6 h from LKW. No sICH was reported
in either study. The preliminary results of these small prospec-
tive studies of WUS patients using the assumption that time of
awakening equals stroke onset are promising. The ongoing
Tenecteplase in Wake-up Ischemic Stroke Trial (TWIST)
[59], which plans to randomize 500 WUS patients to
tenecteplase within 4.5 h of awakening, should provide much
more information on the neuroimaging requirements for
thrombolysis decision making in this patient population.
Based on the EXTEND and WAKE-UP study results, a
compelling argument can be made for a separate pathway
for triage of WUS and SUSO patients. A triage algorithm
which would allow for additional advanced screening of pa-
tients based on the inclusion and exclusion criteria within the
studies would allow for potentially more patients treated with
thrombolytic therapy and improved functional outcomes. The
AHA/ASA updated guidelines in 2019 reflect the findings of
the WAKE-UP study, and an indication to screen patients and
consider treatment with extended window lytic therapy [15].
The findings presented within the update of the 2018 guide-
lines does not account for the EXTEND study and use of CTP
in screening patients; however, we can expect future updates
to be more inclusive.
Future Directions
The implicit belief of these investigations into neuroimaging-
guided thrombolysis in the extended window is that LKW is
an imperfect indicator of stroke onset and/or salvageable brain
tissue. By using neuroimaging-guided approaches to either
function as a radiographic time stamp or assess for salvageable
tissue, WAKE-UP, and EXTEND respectively showed effica-
cy for identifying SUSO patients likely to have clinical benefit
with alteplase treatment. Moving forward, there are several
important clinical implications and limitations of these trials
that reflect the direction of ongoing clinical trials in ischemic
stroke.
First and foremost, these trials hold potential to increase the
numbers of patients eligible to receive treatment with
alteplase. An outstanding question, however, is how dramatic
 35 Page 6 of 8
the increase in thrombolytic treatment rates will be? In the
case of WAKE-UP, approximately 63% of the total popula-
tion screened with MRI were deemed failures and not eligible
for randomization. Furthermore, the majority of practice set-
tings where acute stroke patients are evaluated emergently are
not equipped for 24-h hyperacute MRI capabilities. Similarly,
EXTEND required an extraordinarily long time to enroll 225
patients (8 years) of which the majority were patients with a
large-vessel occlusion determined to be ineligible for
endovascular thrombectomy. How to incorporate the ap-
proach from EXTEND into existing late window protocols
for large-vessel occlusion based on DAWN/DEFUSE 3 is an
unanswered question. A major strength, however, of
EXTEND was the reliance on CT perfusion as its neuroimag-
ing paradigm with automated perfusion imaging software. It is
intriguing to speculate on how the EXTEND approach could
be applied to facilities without endovascular capabilities and
patients presenting with intracranial arterial occlusions.
As a next step, EXTEND must be validated along with
additional trials looking at late window thrombolysis in pa-
tients with perfusion lesion-ischemic core mismatch. Several
trials are currently underway that should advance knowledge
on the optimal approach to the late window stroke patient.
TIMELESS (NCT03785678) is an ongoing randomized trial
of tenecteplase (0.25 mg/kg) in large-vessel occlusion stroke
patients (N = 456) with perfusion lesion-ischemic core mis-
match. Similarly, TEMPO-2 (NCT02398656) is a randomized
trial of tenecteplase (0.25 mg/kg) versus antiplatelet agent in
patients (N = 1274) within 12 h LKW of a transient ischemic
attack or minor stroke (NIHSS < 6) with intracranial arterial
occlusion. Lastly, the aforementioned TWIST trial of
tenecteplase (0.25 mg/kg) in WUS should greatly inform on
our approach to this stroke subpopulation.
Conclusions
The recent clinical trials using neuroimaging approaches to
guide alteplase decision making in acute ischemic stroke have
shown that select populations of SUSO patients benefit from
thrombolytic treatment beyond the traditional time-based eli-
gibility criteria. While the importance of time of stroke onset
to treatment should not be understated, an increasing role for
neuroimaging in the individualized evaluation of ischemic
stroke patients is promising for expanding eligibility to
thrombolysis.
Disclosures Drs. Etherton and Gadhia report no disclosures. Dr.
Schwamm reports the following relationships relevant to research grants
or companies that manufacture products for telemedicine, thrombolysis or
thrombectomy: scientific consultant regarding trial design and conduct to
Genentech (late window thrombolysis); user interface design and usabil-
ity to LifeImage (and holds < 1% stock options in this privately held
company); stroke systems of care to the Massachusetts Department of
Curr Neurol Neurosci Rep (2020) 20:35
Public Health; member of a Data Safety Monitoring Board (DSMB) for
Penumbra (Separator 3D NCT01584609, last payment 2016; MIND
NCT03342664, CURRENT); Diffusion Pharma PHAST-TSC
NCT03763929, CURRENT); National PI or member of National
Steering Committee for Medtronic (Victory AF NCT01693120, last pay-
ment 2015; Stroke AF NCT02700945, CURRENT); PI, late window
thrombolysis trial, NINDS (P50NS051343, MR WITNESS
NCT01282242; last payment 2017 and alteplase provided free of charge
to Massachusetts General Hospital as well as supplemental per-patient
payments to participating sites last payment 2017); PI, StrokeNet
Network NINDS (New England Regional Coordinating Center
U24NS107243, CURENT); Co-I, The Impact of Telestroke on Patterns
of Care and Long-Term Outcomes, NINDS (R01NS111952;
CURRENT); Co-I, REACH-PC, PCORI (NCT03375489; CURRENT);
Member of steering committee, Genentech (TIMELESS NCT03785678,
CURRENT).
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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