Approach To Reperfusion Therapy For Acute Ischemic Stroke

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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Approach to reperfusion therapy for acute ischemic

stroke
Authors: Jamary Oliveira-Filho, MD, MS, PhD, Owen B Samuels, MD
Section Editors: José Biller, MD, FACP, FAAN, FAHA, Jonathan A Edlow, MD, FACEP, Alejandro A Rabinstein, MD
Deputy Editor: John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Mar 08, 2023.
INTRODUCTION
The most important factor in successful reperfusion therapy of acute ischemic stroke is early
treatment. Nonetheless, selection of appropriate candidates for reperfusion demands a
neurologic evaluation and a neuroimaging study. In addition, reperfusion therapy for acute
stroke requires a system that coordinates pre-hospital emergency services, emergency
medicine, stroke neurology, intensive care services, interventional neuroradiology, and
neurosurgery to provide optimal treatment.
This topic will review the use of reperfusion therapy for patients with acute ischemic stroke,
focusing on early thrombolytic therapy with intravenous thrombolysis (IVT). The administration
of IVT for acute ischemic stroke, including dosing, monitoring, and complications, is reviewed in
detail separately. (See "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic
use".)
Mechanical thrombectomy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for

acute ischemic stroke".)
REPERFUSION THERAPIES
The immediate goal of reperfusion therapy for acute ischemic stroke is to restore blood flow to
the regions of brain that are ischemic but not yet infarcted. The long-term goal is to improve
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outcome by reducing stroke-related disability and mortality. Options for reperfusion therapy
that are proven effective include intravenous thrombolysis (IVT) and mechanical thrombectomy
(MT).
Intravenous thrombolysis
Alteplase — IVT with alteplase is the mainstay of treatment for acute ischemic stroke,
provided that treatment is initiated within 4.5 hours of the time last known well. Eligibility
criteria are outlined in the table ( table 1). Because the benefit of alteplase is time dependent,
it is critical to treat patients as quickly as possible. Alteplase, a recombinant tissue plasminogen
activator (tPA), initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converting
entrapped plasminogen to plasmin. In turn, plasmin breaks up the thrombus.
Benefit by time to treatment — IVT with alteplase improves functional outcome at three
to six months when given within 4.5 hours of ischemic stroke onset [1-8].
The benefit of IVT for acute ischemic stroke decreases continuously over time from symptom
onset, as shown in meta-analyses of randomized trials [1,3,4,9] and a registry that analyzed
data from over 58,000 patients treated with IVT within 4.5 hours of ischemic stroke symptom
onset [2]. In the registry, each 15-minute reduction in the time to initiation of IVT treatment was
associated with an increase in the odds of walking independently at discharge (4 percent) and
being discharged to home rather than an institution (3 percent) and a decrease in the odds of
death before discharge (4 percent) and symptomatic hemorrhagic transformation of infarction
(4 percent) [2]. Similarly, another study of over 61,000 patients treated with IVT found that
shorter door-to-needle times were associated with lower all-cause mortality at one year and a
reduced risk of hospital readmission at one year [10].
A 2014 meta-analysis evaluated individual patient data from 6756 patients (including more than
1700 who were older than age 80 years) with acute ischemic stroke who were allocated to IVT
or control in the NINDS, ATLANTIS, ECASS (1, 2, and 3), EPITHET, and IST-3 trials [4]. The primary
outcome measure was the proportion of patients achieving a good stroke outcome at three or
six months as defined by a modified Rankin scale score ( table 2) of 0 or 1 (ie, no significant
disability). The following observations were reported:
● For treatment within 3 hours of stroke onset, alteplase led to a good outcome for 33
percent, versus 23 percent for control (odds ratio [OR] 1.75, 95% CI 1.35-2.27). The number
needed to treat (NNT) for one additional patient to achieve a good outcome was 10.
● For treatment from 3 to 4.5 hours, the proportion with a good outcome in the alteplase
and control groups was 35 and 30 percent (OR 1.26, 95% CI 1.05-1.51, NNT 20).
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● For treatment beyond 4.5 hours, the proportion with a good outcome in the alteplase and
control groups was no longer significant at 33 and 31 percent (OR 1.15, 95% CI 0.95-1.40,
NNT 50).
● The benefit of alteplase was similar regardless of patient age or stroke severity.
● Alteplase increased the risk of symptomatic intracranial hemorrhage (6.8 percent, versus
1.3 percent for control, OR 5.55, 95% CI 4.01-7.70); the number needed to harm (NNH) for
one additional patient to have a symptomatic intracranial hemorrhage was 18. Alteplase
also increased the risk of fatal intracranial hemorrhage within seven days (2.7 versus 0.4
percent, OR 7.14, 95% CI 3.98-12.79, NNH 44); this risk was similar regardless of age,
stroke severity, or treatment delay. Alteplase treatment had no significant effect on other
early or late causes of death.
● Death at 90 days was slightly higher in the alteplase group (17.9 percent, versus 16.5
percent in the control group, hazard ratio 1.11, 95% CI 0.99-1.25), a result that just missed
statistical significance.
In agreement with other meta-analyses [1,3,7], these observations confirm that the sooner IVT
is initiated, the more likely it is to be beneficial, and that the benefit extends to treatment
started within 4.5 hours of stroke onset [4]. The results also show that alteplase is beneficial
regardless of patient age, stroke severity, or the associated increased risk of symptomatic or
fatal intracranial hemorrhage in the first days after alteplase treatment. The odds of a favorable
three-month outcome decrease as the interval from stroke onset to start of alteplase treatment
increases ( figure 1) [1]. Beyond 4.5 hours, harm may exceed benefit.
Benefit with imaging selection of patients — IVT may be beneficial for select patients
who wake-up with stroke more than 4.5 hours after they were last known well or those who
have unknown time of symptom onset, if they have an acute ischemic brain lesion detected on
diffusion magnetic resonance imaging (MRI) but no corresponding hyperintensity on fluid-
attenuated inversion recovery (FLAIR) MRI. This imaging mismatch (diffusion positive/FLAIR
negative) correlates with a stroke onset time of 4.5 hours or less [11].
Limited clinical trial evidence suggests that IVT is beneficial for select patients who meet
imaging criteria indicative of recent cerebral infarction and/or significant salvageable brain
tissue, even if they do not qualify based upon traditional time windows, although results have
been inconsistent:
● The placebo-controlled Wake-Up Stroke trial selected 500 adults with unwitnessed stroke
onset who had an ischemic parenchymal brain lesion on MRI diffusion-weighted imaging
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but no corresponding hyperintensity on FLAIR [12]. Nearly 90 percent of enrolled patients

awoke from sleep with stroke symptoms. The trial excluded patients last known to be well
within 4.5 hours, since they would fulfill standard eligibility criteria for alteplase; the trial
also excluded patients who were to receive MT. At 90 days, a favorable outcome (defined
by a score of 0 or 1 on the modified Rankin Scale [mRS]) was more likely for patients
assigned to intravenous alteplase compared with those assigned to placebo (53 versus 42
percent, adjusted OR 1.61, 95% CI 1.09-2.36). However, the mortality rate was
nonsignificantly higher in the alteplase group (4 versus 1 percent, OR 3.38, 95% CI 0.92-
12.52), as was the rate of symptomatic intracranial hemorrhage (2.0 versus 0.4 percent,
OR 4.95, 95% CI 0.57-42.87). Limitations to the trial include stopping early (for lack of
funding) and exclusion of patients planned for MT.
● The EXTEND trial was stopped early after publication of the Wake-Up Stroke trial. EXTEND
enrolled 225 adults (of a planned 310) who had hypoperfused but salvageable brain tissue
on automated perfusion imaging (with computed tomography [CT] or MRI) and could be
treated between 4.5 and 9 hours after the onset of ischemic stroke or awoke with stroke
symptoms, if within 9 hours from the midpoint of sleep [13]. Patients were randomly
assigned to intravenous alteplase or to placebo. At 90 days, a favorable outcome (defined
by a score of 0 or 1 on the mRS) was more likely for the intravenous alteplase group
compared with the placebo group, after adjustment for age and clinical severity at
baseline (35 versus 30 percent, risk ratio [RR] 1.44, 95% CI 1.01-2.06). However, there was
no difference between treatment groups in unadjusted analysis (RR 1.2, 95% CI 0.82-1.76).
Symptomatic intracranial hemorrhage within 36 hours of treatment was increased with
alteplase (6 versus 1 percent) and mortality was nonsignificantly higher with alteplase (12
versus 9 percent). Limitations to the trial include stopping early and lack of efficacy in
unadjusted analyses.
● In the ECASS 4 trial, stopped early for slow recruitment, 119 patients (of a planned 264)
with acute ischemic stroke and salvageable brain tissue identified by MRI were randomly
assigned to treatment with alteplase or placebo between 4.5 and 9 hours after the onset
of symptoms [14]. At 90 days, there was no difference between the alteplase and placebo
groups in the mRS distribution (OR 1.20, 95% CI 0.63-2.27); mortality was nonsignificantly
higher with alteplase (12 versus 7 percent).
A meta-analysis pooled individual patient data (n = 414) from three trials (EXTEND, ECASS 4, and
EPITHET) of intravenous alteplase that used imaging to identify and treat patients with
salvageable brain tissue who had ischemic stroke 4.5 to 9 hours after onset or had wake-up
stroke [15]. There was a higher rate of excellent functional outcome (defined by a mRS score 0
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of 1) at three months for patients assigned to alteplase compared with those assigned to
placebo (36 versus 29 percent, adjusted odds ratio [OR] 1.86, 95% CI 1.15-2.99). Symptomatic
intracerebral hemorrhage was more frequent in the alteplase group (5 versus 0.5 percent), but
this result did not nullify the overall benefit of alteplase. Limitations to this meta-analysis
include small sample size and early stopping of two of the included trials (EXTEND and ECASS 4).
Another meta-analysis of four trials (including Wake-Up Stroke, EXTEND, and ECASS 4) with
individual patient data from over 843 patients reported similar findings [16].
Although this approach seems promising, additional trials are needed to confirm the efficacy
and safety of IVT using imaging selection of patients with a stroke onset time >4.5 hours or an
unknown stroke onset time [17]. Imaging with MRI or CT perfusion appears to be essential to
determine if the cerebral infarction is recent and if there is significant salvageable brain tissue.
Results of the TWIST trial suggest that selecting patients with noncontrast head CT alone (to
exclude hemorrhage or large infarction) is unlikely to identify patients with wake-up stroke who
will benefit from IVT [18].
Risk of intracerebral hemorrhage — Treatment with IVT within 4.5 hours of acute
ischemic stroke onset is associated with an increased early risk of intracerebral hemorrhage,
but this risk is offset by later benefit in the form of reduced disability (see 'Benefit by time to
treatment' above) [4]. In clinical trials of intravenous alteplase, the rates of symptomatic
intracerebral hemorrhage were 5 to 7 percent [4,19], using the National Institute of
Neurological Disorders and Stroke (NINDS) definition. In addition, most community-based
studies of intravenous alteplase have shown similar rates [20-24]. These studies suggest that
IVT can be used safely to treat acute ischemic stroke in routine clinical practice. The number
needed to harm (NNH) with IVT is very high, because most cases of symptomatic intracerebral
hemorrhage occur in patients with severe deficits and poor anticipated prognosis before lysis
[25]. Also, some hemorrhages occur in areas of the brain that are already infarcted and so do
not result in additional measurable deficits. As an example from the NINDS trials, for an
outcome of severely disabled or dead (defined by an mRS score ≥4) with IVT-related
symptomatic hemorrhage, the NNH was 126, and for a worsened outcome (defined by an mRS
score ≥1), the NNH ranged from approximately 30 to 40.
Differences in the criteria used to define symptomatic intracerebral hemorrhage likely account
for much of the variability in the rates of hemorrhage reported in different trials [26]. The
NINDS trial definition of symptomatic intracerebral hemorrhage includes any hemorrhagic
transformation temporally related to any neurologic worsening [19], which may be overly
inclusive because it captures small petechial hemorrhages associated with minimal neurologic
deterioration that are unlikely to have altered long-term functional outcome [27,28]. By
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contrast, the ECASS 2, ECASS-3 and SITS-MOST definitions of symptomatic intracerebral

hemorrhage include only hemorrhage associated with substantial clinical worsening of ≥4
points on the National Institutes of Health Stroke Scale (NIHSS) stroke scale [24,29,30], which
may be more predictive of intracerebral hemorrhages that adversely affect long-term outcome.
As an example, the SITS-MOST study enrolled over 30,000 patients, mainly from Europe, who
were treated with intravenous alteplase at 669 centers [24]. Symptomatic intracerebral
hemorrhage by the NINDS definition occurred in 7.4 percent, and by the SITS-MOST definition
in 1.8 percent. Lower rates have also been reported in other trials using stricter definitions of
symptomatic intracerebral hemorrhage, including ECASS 3 [29].
Several risk assessment methods, including the HAT score, DRAGON score, SEDAN score,
Stroke-Thrombolytic Predictive Instrument, SPAN-100 index, and the SITS SICH risk score, have
been devised to predict the risk of intracerebral hemorrhage and/or prognosis for patients with
acute stroke who are treated with IVT [24,31-39]. However, additional validation studies are
needed to confirm the utility of these methods before they should be used in clinical practice.
Recanalization — Full or partial recanalization up to 24 hours after onset of acute stroke

is associated with a more favorable outcome than persistent occlusion after thrombolysis [40-
44]. In a prospective, multicenter study of 575 patients with acute ischemic stroke and
intracranial arterial occlusion on baseline CT angiography (CTA), the rate of successful
recanalization detected on repeat CTA was greater for patients who received IVT compared with
those who did not (30 versus 13 percent, absolute difference 17 percent, 95% CI 10-26 percent)
[45]. As observed in this and other studies, factors associated with the response to thrombolytic
therapy include location of the symptomatic occlusive thrombus in the arterial tree, and clot-
specific features such as size, composition, and source:
● Clot size and site – Larger clots and more proximal clots (versus more distal location) are
more resistant to thrombolysis [45-50]. As an example, internal carotid artery occlusions
are more resistant than middle cerebral artery occlusions to IVT treatment. This may be
due at least in part to the larger size of clots that lodge in larger vessels [51]. Clot
occluding the cervical internal carotid artery may promote adjacent thrombosis extending
to the intracranial internal carotid artery, resulting in a very long thrombus that is unlikely
to be lysed by IVT alone. In large vessels, in situ thromboses associated with
atherosclerotic lesions may be more resistant to recanalization than fibrin rich embolic
occlusions arising from the heart [52]. In addition, higher residual flow (a measure of
thrombus permeability) of intracranial arteries on baseline angiography is associated with
successful recanalization [45].
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● Clot age and composition – The age and composition of thromboembolic material likely
affect its response to thrombolytic therapy [53,54]. The ability to recanalize in
experimental embolic stroke is related to the amount of red cells in the emboli and
inversely related to the volume of emboli and to the fibrin content and density of the clots
[55]. Thrombolytic drugs are unlikely to disrupt other types of embolic material, such as
calcific plaque and fat.
Other variables affecting outcome — Early recanalization is probably the most

important determinant of good outcome after thrombolysis, but a number of additional
variables may impact neurologic outcome and the risk of intracerebral hemorrhage [56,57].
These include age, sex, stroke severity, availability of collateral blood supply, and early ischemic
change on CT or MRI. However, these factors do not necessarily predict which patients will or
will not benefit from IVT. The only factor known to independently alter response to IVT is time
to treatment. (See 'Benefit by time to treatment' above.)
Whenever possible, the potential risks and benefits of thrombolysis should be discussed
objectively with the patient and/or family or health care proxy prior to initiating treatment. (See
'Issues regarding consent' below.)
● Age – Patients age 80 years or older appear to benefit from IVT despite a higher mortality
rate compared with younger patients. (See 'Age 80 years and older' below.)
● Stroke severity – The severity of neurologic deficit as measured on the NIHSS score
( table 3) is associated with an increased risk of intracerebral hemorrhage [6,58].
However, stroke severity alone cannot be used to select or exclude patients for IVT. A 2014
meta-analysis of individual patient data from 6756 subjects found that the benefit of
alteplase was similar regardless of stroke severity [4].
● Early ischemic changes on CT – The presence of extensive regions of obvious

hypodensity consistent with irreversible injury on initial head CT suggests a longer time
since stroke onset and is an exclusion for use of IVT ( table 1). This finding should be
distinguished from milder early ischemic edema as discussed below. (See 'Early ischemic
changes on neuroimaging' below.)
● Hyperglycemia – Hyperglycemia before reperfusion in patients with acute ischemic stroke

has been associated with diminished neurologic improvement, greater infarct size, and
worse clinical outcome at three months after treatment with IVT [59-61].
● Cerebral microbleeds – Cerebral microbleeds are small chronic hemorrhages that are
best visualized on susceptibility-weighted MRI sequences.
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Meta-analyses published in 2015 [62], 2016 [63], and 2017 [64] found that the presence of
cerebral microbleeds on pretreatment brain MRI was associated with an increased risk of
intracerebral hemorrhage (ICH) in patients treated with IVT for acute ischemic stroke. In
one of these reports, the risk of symptomatic ICH was significantly greater for patients
with a high burden of cerebral microbleeds (>10) compared with patients who had a lower
burden of microbleeds (1 to 10 or 0 to 10) [63]. However, the small number of patients in
the subgroup with >10 microbleeds (n = 15) limits the strength of this conclusion. In
another meta-analysis, the presence of cerebral microbleeds was not associated with
symptomatic ICH but was associated with an increased risk of parenchymal hemorrhage,
and the presence of >5 cerebral microbleeds was associated with poor functional outcome
at three to six months [64].
Since decisions to proceed IVT treatment are usually made based upon CT imaging
without MRI, these results should not affect patient selection or mandate additional
imaging that will prolong the time to treatment.
● Sex – There are conflicting data regarding whether benefit from early IVT of acute
ischemic stroke differs by sex [65-67].
Tenecteplase — Tenecteplase, a type of recombinant tissue plasminogen activator (tPA), is a

modified version of alteplase, the only approved tPA for treating acute ischemic stroke.
Tenecteplase differs from human tPA by having three amino acid substitutions. Because of the
modifications, tenecteplase is more fibrin-specific and has a longer duration of action
compared with alteplase.
The single bolus dosing of tenecteplase is far easier to give in an emergency department and
translates into faster door-to-needle times compared with alteplase [68].
Although not licensed in the US for IVT in acute ischemic stroke treatment, there is moderate-
to high-quality evidence that intravenous tenecteplase, given in a single bolus at 0.25 mg/kg
(maximum 25 mg), has similar efficacy and safety outcomes compared with alteplase, including
rates of excellent functional outcome, symptomatic intracerebral hemorrhage, and mortality at
90 days [68-80]. As an example, the EXTEND-IA TNK trial found that tenecteplase led to better
functional outcomes compared with alteplase and higher rates of reperfusion of the involved
ischemic territory [70]. Furthermore, in an analysis of pooled individual patient data from
several trials and a registry of patients with large vessel occlusion who were treated with
intravenous thrombolysis, tenecteplase treatment (n = 492) compared with alteplase treatment
(n = 401) was associated with higher rates of prethrombectomy reperfusion, which in turn was
associated with improved outcomes [81].
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However, higher doses of tenecteplase (≥0.4 mg/kg) should not be used for IVT because such
doses may be associated with harm, although the evidence is inconsistent. In the original NOR-
TEST trial, most of the 1100 patients had minor strokes (the median NIHSS score was 4), and the
tenecteplase group, treated with 0.4 mg/kg, had similar safety and efficacy outcomes compared
with the alteplase group [69]. However, the NOR-TEST 2, part A trial was stopped early, after
enrolling only 204 patients, due to higher numbers of symptomatic intracranial hemorrhage in
the tenecteplase group [82]. NOR-TEST 2 included patients with moderate to severe ischemic
stroke (the median NIHSS was 11) who were within 4.5 hours of the time last known well; the
patients were randomly assigned to tenecteplase 0.4 mg/kg or alteplase 0.9 mg/kg. At three
months, compared with the alteplase group, the tenecteplase group showed a trend toward an
increased rate of symptomatic intracranial hemorrhage (6 versus 1 percent, OR 6.57, 95% CI
0.78-55.62). Furthermore, the tenecteplase group had a lower rate of a favorable outcome,
defined as an mRS score of 0 to 1 (32 versus 51 percent, OR 0.45, 95% CI 0.25-0.80), and a
higher rate of mortality (16 versus 5 percent, OR 3.56, 95% CI 1.24-10.21).
Mechanical thrombectomy (MT) — Mechanical thrombectomy is indicated for patients with

acute ischemic stroke due to a large artery occlusion in the anterior circulation who meet
eligibility criteria and can be treated within 24 hours of the time last known to be well (ie, at
neurologic baseline), regardless of whether they receive IVT for the same ischemic stroke event.
(See "Mechanical thrombectomy for acute ischemic stroke".)
Patient selection for MT is discussed in detail separately. (See "Mechanical thrombectomy for
acute ischemic stroke", section on 'Patient selection'.)
IVT followed by MT — Treatment with IVT prior to MT, known as bridging therapy, is
recommended for most patients who are candidates for both reperfusion therapies. Patients
with ischemic stroke from large vessel occlusion should receive IVT without delay, if eligible,
even if MT is being considered [83]. Mechanical thrombectomy treatment should then be
started as quickly as possible [84,85], and should not be delayed to assess the response to IVT.
Potential advantages of IVT before MT include complete or partial lysis of the thrombus causing
the large vessel occlusion (the target of MT), lysis of thrombotic emboli in distal vessels beyond
the reach of MT, and faster resolution of brain ischemia [86]. Potential disadvantages of giving
IVT first include a delay in the time to the start of the MT procedure, an increased risk of
symptomatic brain hemorrhage, and partial lysis of the large vessel thrombus that allows it to
travel to more distal vessels beyond the reach of MT.
MT alone (without preceding IVT) is an alternative strategy, but the available data, while
inconsistent, have not proven the efficacy of this approach compared with the combination of
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IVT and MT for improved clinical outcomes or safety [87-96]. However, the preponderance of
the evidence seems to favor bridging therapy over MT alone.
RAPID EVALUATION
All adult patients with a clinical diagnosis of acute ischemic stroke should be rapidly screened
for treatment with intravenous thrombolysis (IVT). Simultaneously, patients with suspected
acute ischemic stroke involving the anterior circulation should be evaluated for mechanical
thrombectomy (MT). (See "Mechanical thrombectomy for acute ischemic stroke".)
Prehospital recognition and management — Emergency medical responders should identify

patients with a suspected stroke, preferably using a validated stroke screening tool (see "Use
and utility of stroke scales and grading systems", section on 'Stroke diagnosis'), and transport
them rapidly to the nearest medical facility that can provide urgent stroke care with the
capability to treat with IVT, or IVT and MT.
The use of mobile stroke units (MSUs) offers the potential for more rapid identification and
treatment of acute ischemic stroke [97,98]. MSUs are ambulances equipped with point-of-care
laboratory testing and a CT scanner; they are staffed by medical personnel trained to diagnose
and treat patients in the ambulance using thrombolytic therapy and to make triage decisions
for mechanical thrombectomy, in conjunction with telemedicine communication to hospital
stroke experts. However, MSUs are expensive, and availability is limited to only a few
metropolitan areas throughout the world.
The potential benefit of MSUs for improving outcome from acute ischemic stroke is illustrated
by two prospective, nonrandomized controlled studies. One was a multicenter study from the
United States of 1047 patients who were within 4.5 hours after stroke symptom onset; patients
were assigned by week of enrollment to receive MSU or standard emergency medical services
(EMS) care [99]. Among patients eligible for intravenous thrombolysis, the rate of thrombolysis
was higher in the MSU group compared with the EMS group (97.1 versus 79.5 percent), and the
median time to thrombolysis was shorter (72 versus 108 minutes). At 90 days, the proportion of
patients with no or minimal disability (ie, a score of 0 to 1 on the modified Rankin Scale [mRS])
was greater in the MSU group (55.0 versus 44.4 percent), while mortality was lower (8.9 versus
11.9 percent). The rate of symptomatic intracerebral hemorrhage in each group was 2 percent.
In a similar prospective study of over 1500 patients from Berlin, Germany, dispatch of an MSU
compared with EMS was associated with a shorter median time to treatment with thrombolysis
(50 versus 70 minutes) and a lower level of global disability at 90 days [100]. In a 2022 meta-
analysis that included these two nonrandomized studies, MSU use was associated with higher
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rates of excellent outcome, defined by an mRS score of 0 to 1 at 90 days, compared with usual
care (adjusted odds ratio [OR] 1.64, 95% CI 1.27-2.13) [101].
Further confirmation of clinical benefit along with evidence of cost-effectiveness will be needed
before widespread use of MSUs can be considered. Other unproven strategies to reduce time to
treatment with MT are being explored, including direct transport to a thrombectomy-capable
center [102], and even flying the thrombectomy intervention clinical team to the local stroke
center [103].
In-hospital timeline — A door-to-needle time of ≤60 minutes is the benchmark for achieving
rapid treatment with IVT [83]. The following in-hospital timeline is suggested as a goal for all
patients with acute ischemic stroke who are eligible for treatment with IVT:
● Evaluation by physician – 10 minutes elapsed from arrival

● Stroke or neurologic expertise contacted (ie, stroke team) – ≤15 minutes elapsed
● Head CT or MRI scan – ≤25 minutes elapsed
● Interpretation of neuroimaging scan – ≤45 minutes elapsed
● Start of IVT – ≤60 minutes elapsed
Although IVT is the first priority, evaluation and preparation for possible MT should proceed
during and after IVT. Patients with suspected infarction involving the anterior circulation should
have cerebral angiography (eg, CT angiography [CTA] or magnetic resonance angiography
[MRA]) as soon as possible to determine whether they have a proximal intracranial large artery
occlusion that might also benefit from MT. However, IVT should not be delayed by angiography
or MT.
The administration of IVT for acute ischemic stroke, including dosing, monitoring, and
complications, is reviewed in detail separately. (See "Intravenous thrombolytic therapy for acute
ischemic stroke: Therapeutic use".)
Investigations — Diagnostic neuroimaging is essential before considering reperfusion therapy

for acute ischemic stroke. The only other test that is mandatory for all patients before initiation
of IVT is blood glucose. In most cases, the results of routine laboratory tests including
coagulation parameters and platelet count are not required to proceed with IVT. Thrombolytic
therapy with alteplase (or tenecteplase) should not be delayed while results are pending unless
one of the following conditions is present [83]:
● Clinical suspicion of a bleeding abnormality or thrombocytopenia

● Current or recent use of anticoagulants (eg, heparin, warfarin, direct oral anticoagulants
[DOACs])
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● Use of anticoagulants is not known
Potential exclusions to treatment — Exclusion criteria for IVT are listed in the table
( table 1); these criteria have evolved with time as experience with IVT has increased. Several
clinical issues may complicate the decision to use reperfusion therapy for acute ischemic stroke.
Among these are rapidly improving stroke symptoms and early ischemic changes on
neuroimaging.
Patients on anticoagulants — Current anticoagulant use with evidence of anticoagulant

effect by laboratory tests is a contraindication to IVT.
● Coagulation tests – For patients without recent use of oral anticoagulants or heparin,
treatment with IVT can be started before availability of coagulation test results if there is
no reason to suspect a coagulopathy (ie, patients not on anticoagulant therapy who have
no known liver disease, hematologic disease, or advanced kidney disease). In such cases,
alteplase treatment should be discontinued if the international normalized ratio (INR),
prothrombin time (PT), or activated partial thromboplastin time (aPTT) are excessively
elevated ( table 1). For patients with inadequate historical information, IVT should not
be started until the aPTT and either the PT or the INR are available.
Preliminary data suggest that normal coagulation parameters can be predicted on arrival
to the emergency department by assessing three questions [104]:
• Is the patient taking an oral anticoagulant?

• Is the patient taking heparin or low molecular weight heparin?
• Is the patient on hemodialysis?
In a retrospective study from 2006 (prior to the advent of direct oral anticoagulants) that
included 299 patients, "no" answers to all three questions predicted normal range PT and
aPTT with a sensitivity of 100 percent, suggesting that this simple screen may permit
earlier treatment with alteplase in selected patients with acute stroke [104]. Other data
suggest that unsuspected coagulopathy is rarely detected among patients evaluated for
IVT [105].
● Patients on DOACs – Accumulating evidence suggests that recent use of a DOAC is not
associated with an increased risk of symptomatic intracerebral hemorrhage following IVT
[106,107]. Nevertheless, DOAC use remains a contraindication to IVT unless laboratory
tests such as aPTT, INR, platelet count, ecarin clotting time, thrombin time, or appropriate
direct factor Xa activity assays are normal or the patient has not received a DOAC dose for
more than 48 hours, assuming normal renal function [83].
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● DOAC reversal – DOAC reversal may provide an option to safely treat with thrombolysis,
although this approach is not yet established as safe [108]. An observational cohort study
identified 51 patients treated with idarucizumab for dabigatran reversal prior to
thrombolysis and found that idarucizumab-treated patients had similar rates of
symptomatic intracerebral hemorrhage, early neurologic improvement, and mortality
compared with patients not treated with idarucizumab [109].
Rapidly improving stroke symptoms — Rapidly improving stroke symptoms (RISS) should be
considered an exclusion for reperfusion therapy only for patients who improve to the degree
that any remaining deficits are nondisabling [110]. The decision regarding use of IVT or MT
should be made based upon monitoring neurologic deficits for no longer than the time needed
to prepare and begin treatment; treatment should not be delayed by continued monitoring for
improvement.
Disabling versus nondisabling stroke deficits — Qualifying patients who have an acute
ischemic stroke causing a persistent neurologic deficit that is potentially disabling, despite
improvement of any degree while being evaluated, should be treated urgently with IVT and/or
MT as appropriate. Any of the following should be considered disabling deficits [110]:
● Complete hemianopia: ≥2 on the National Institutes of Health Stroke Scale (NIHSS)

question 3 ( table 3)
● Severe aphasia: ≥2 on NIHSS question 9 ( table 3)
● Visual extinction: ≥1 on NIHSS question 11 ( table 3)
● Any weakness limiting sustained effort against gravity: ≥2 on NIHSS question 5 or 6
( table 3)
● Any deficits that lead to a total NIHSS >5 (calculator 1)
● Any remaining deficit considered potentially disabling by the patient, family, or the
treating practitioner
For patients with an NIHSS score of 0 to 5, a clearly disabling deficit has also been defined as
one that would prevent the patient from performing basic activities of daily living (ie, bathing,
walking, toileting, and eating) or returning to work [111].
Whether IVT is beneficial for patients with mild, nondisabling ischemic stroke is unknown, and
data are limited. The PRISMS trial enrolled patients with acute ischemic stroke within three
hours of symptom onset who had an NIHSS score of 0 to 5 and deficits judged not clearly
disabling; there was no difference in the rate of a favorable functional outcome (defined as a
modified Rankin Scale score of 0 or 1 at 90 days) for patients assigned to treatment with IVT or
to aspirin (78.2 versus 81.5 percent) [111]. However, the trial was stopped very early solely
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because of slow recruitment, having enrolled only 313 of a planned 948 subjects, and therefore
its findings are not definitive.
Early ischemic changes on neuroimaging — Minor ischemic changes on CT are not a

contraindication to treatment; these include subtle or small areas of hypodensity, loss of gray-
white distinction, obscuration of the lentiform nucleus, or the presence of a hyperdense artery
sign ( image 1).
We suggest withholding thrombolytic therapy with alteplase for patients with extensive regions
of obvious hypodensity consistent with irreversible injury on initial head CT ( table 1),
although there are few data to determine a threshold of ischemic severity or extent that
modifies treatment response to alteplase [112].
Patient selection for MT is reviewed separately. (See "Mechanical thrombectomy for acute
ischemic stroke", section on 'ASPECTS method'.)
Issues regarding consent — Alteplase is an approved therapy for acute ischemic stroke
because of substantial evidence of safety and efficacy. Consent is not required to administer
alteplase as an emergent therapy for an otherwise eligible adult patient with a disabling acute
ischemic stroke if patient or surrogate consent is not possible [83]. In such cases, the need for
informed consent is outweighed by the need for urgent intervention, and the patient can be
treated under the principle of presumption of consent. Furthermore, given the lack of clinical
equipoise (the benefit of alteplase clearly outweighs the harms), shared decision-making is not
appropriate [113].
Whether to proceed to thrombolysis in an individual patient should be based upon a brief

discussion of the risks and benefits with the patient and family or health care proxy, if possible.
However, neurologic deficits caused by acute stroke often preclude the ability of the patient to
participate in the decision.
Explaining benefits and risks — Procedures for informed decision-making and informed
consent vary among different centers; we explain the risks and benefits of alteplase as follows
[113]:
"There is a treatment for your stroke called alteplase that must be given within 4.5 hours after
the stroke started. It is a 'clot-buster' drug. Getting alteplase reduces your risk of being
disabled. People who get alteplase for stroke have a better chance of recovering without
disability and getting back to the activities they enjoy compared to people who do not receive
the treatment. All medicines have some risk. With alteplase, there is a risk of serious bleeding.
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However, time is important as well. We know that the sooner we start treatment with alteplase,
the greater the chance that patients will have a good outcome."
Some patients will accept any risk, including an increased risk of intracranial bleeding, for an
increased chance of avoiding severe permanent disability. Others are more risk averse and
prefer to accept disability, especially if there is a chance of recovery over time.
Need for transfer to stroke center — Most hospitals in more economically developed
countries are able to treat acute ischemic stroke with IVT. In situations where local stroke
expertise is not routinely or immediately available, accumulating data suggest that the decision
to administer IVT can be guided safely and effectively via telemedicine (telestroke) [114].
By contrast, MT is not as widely available. Transfer to an expert stroke center may be necessary
for patients with acute ischemic stroke in the anterior circulation who present to medical
facilities that lack resources and expertise to deliver MT. However, eligible patients can receive
standard treatment with IVT if they present to hospitals where thrombectomy is not an option,
and those with qualifying anterior circulation strokes can then be transferred to stroke centers
where intra-arterial thrombectomy is available, a strategy called "drip and ship" [115,116].
Screening of patients for transfer is aided by the ability of networked hospitals to share brain
and neurovascular imaging studies via cloud computing, which allows the stroke center hub to
read a CTA (or MRA) done locally and thereby determine whether the patient has a large vessel
occlusion, a key requirement for MT.
Reducing delay — Inordinate treatment delay can occur during any of the steps involved in
reperfusion therapy, including emergency department triaging, initial telephone triage by the
stroke physician, physician evaluation, neuroimaging, obtaining and waiting for results of blood
and laboratory tests, obtaining consent, treating hypertension that would otherwise exclude
the use of IVT (ie, systolic blood pressure ≥185 mmHg or diastolic ≥110 mmHg), and delivery of
alteplase from the pharmacy to the bedside. Expedited stroke protocols may reduce treatment
delays and improving patient outcomes. Such protocols may include the following features
[117,118]:
● Prehospital notification by emergency medical personnel/ambulance of a patient with a

possible stroke
● Blast paging of all relevant hospital stroke personnel, including CT technicians
● In-person triage of all code strokes without telephone triage; the stroke physician on-call
proceeds immediately to the bedside
● Direct transfer of the patient, without fully undressing, from triage onto the CT scanner
table via the ambulance stretcher
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● No delays pending formal neuroimaging interpretation; the on-call stroke physician reads
the brain CT or MRI scan
● Unmixed alteplase is available at the bedside during the evaluation
● No delays pending electrocardiogram (ECG), coagulation tests, chest radiograph, or stool
guaiac unless specifically indicated
● No delays pending written consent; verbal consent is obtained if the patient is able to
consent or if family members or health care proxy are nearby
While an expedited evaluation might increase the risk of giving IVT in cases of stroke mimics,
data suggest that the intracranial hemorrhage rate in patients who later are diagnosed with a
stroke mimic is approximately 1 percent [119,120].
TREATMENT BY TIME FROM SYMPTOM ONSET
"Time is brain." The sooner intravenous thrombolysis (IVT) treatment with alteplase is initiated
after ischemic stroke, the more likely it is to be beneficial [121-123]. Eligible patients should
start treatment as quickly as possible within the appropriate 3- or 4.5-hour time window from
stroke onset; treatment should not be delayed until the end of the time window.
Mechanical thrombectomy (MT) is also time-dependent, with clear benefit for patients with
acute ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior
circulation who are treated within 6 hours of symptom onset. Beyond 6 hours, MT may be an
option at specialized stroke centers using imaging-based selection of patients with anterior
circulation stroke who have symptom onset 6 to 24 hours before treatment. (See "Mechanical
thrombectomy for acute ischemic stroke".)
Less than 3 hours — For eligible patients with acute ischemic stroke causing a potentially
disabling neurologic deficit, we recommend IVT with intravenous alteplase (or intravenous
tenecteplase) when treatment is initiated within 3 hours of the time last known well. Patients in
this time window should also be evaluated to determine if they are candidates for MT. (See
'Benefit by time to treatment' above.)
3 to 4.5 hours — The benefit of alteplase extends to 4.5 hours, as discussed above. For
otherwise eligible patients who cannot be treated in less than 3 hours, we suggest (ie, a weak
recommendation) IVT with alteplase provided that treatment is initiated within 3 to 4.5 hours of
the time last known well. Patients in this time window should also be evaluated to determine if
they are candidates for MT. (See 'Benefit by time to treatment' above.)
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There are additional exclusion criteria ( table 1) for IVT in the 3- to 4.5-hour time window (age
>80 years old, an National Institutes of Health Stroke Scale (NIHSS) score >25, a combination of
previous stroke and diabetes, and oral anticoagulant use regardless of INR). However, we do
not consider these as absolute contraindications to IVT in the 3- to 4.5-hour time window, given
evidence that alteplase is still beneficial in patients who would otherwise be excluded by these
criteria [4,112,124,125]. The additional exclusions from 3 to 4.5 hours were made to satisfy
safety concerns from the European regulatory agency and were employed to select patients for
treatment in the ECASS 3 trial [29], which established the benefit of IVT in the 3- to 4.5-hour
time window.
4.5 to 6 hours — Patients within 4.5 to 6 hours from stroke symptom onset should not
routinely receive IVT because harm may exceed benefit, but they should be evaluated to
determine if they are candidates for MT. (See 'Benefit by time to treatment' above.)
6 to 24 hours — Patients beyond 6 hours from ischemic stroke symptom onset are not eligible
for treatment with IVT. However, MT is an option at specialized stroke centers using imaging-
based selection of patients with anterior circulation stroke who have were last known to be well
at 6 to 24 hours before treatment. This is discussed in detail separately. (See "Mechanical
thrombectomy for acute ischemic stroke", section on 'Benefit of later treatment'.)
Beyond 24 hours — Patients beyond 24 hours from ischemic stroke symptom onset generally
are not eligible for treatment with IVT or MT. Limited retrospective data suggest possible
benefit for selected patients treated with MT beyond 24 hours of last known well, but
confirmation from prospective trials is needed [126].
Unwitnessed stroke onset and "wake-up" stroke — When the exact time of stroke onset is
not known, it is defined as the last time the patient was known to be normal. For patients
whose stroke symptoms are first noted upon awakening from sleep, the last time known to be
normal may be the time they went to bed (if the patient can report this reliably) or the last time
seen normal by a friend or family member. Such patients are not ordinarily eligible for IVT
unless the time last known to be normal is less than 4.5 hours. However, imaging-based criteria
(ie, MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated
inversion recovery [FLAIR] negative) is an option at expert stroke centers to select patients with
wake-up stroke or unknown stroke onset time for IVT. (See 'Benefit with imaging selection of
patients' above.)
Imaging-based selection of patients for treatment with MT who were last known to be normal 6
to 24 hours before treatment is an option at specialized stroke centers. (See "Mechanical
thrombectomy for acute ischemic stroke", section on 'Benefit of later treatment'.)
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SPECIAL POPULATIONS
Different clinical presentations and patient populations may affect the decision to use
intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) for acute ischemic stroke, as
discussed below.
Posterior circulation stroke — All eligible patients with acute ischemic stroke should be
treated with IVT, including those with stroke in the posterior circulation. Mechanical
thrombectomy is beneficial for select patients with acute ischemic stroke caused by a proximal
intracranial arterial occlusion in the anterior circulation, but trials that established the benefit of
MT largely excluded patients with posterior circulation infarcts. However, endovascular
interventions for vertebrobasilar occlusions, including MT, may be treatment options stroke
centers with appropriate expertise. (See "Mechanical thrombectomy for acute ischemic stroke",
section on 'Posterior circulation stroke'.)
Age 80 years and older — Patients age 80 years or older appear to benefit from IVT despite a
higher mortality rate compared with younger patients. Therefore, we do not consider age to be
a contraindication to IVT treatment for otherwise eligible patients. However, age >80 years is a
relative contraindication in the 3- to 4.5-hour time window. (See '3 to 4.5 hours' above.)
A 2014 meta-analysis of individual patient data from 6756 subjects (including more than 1700
subjects older than age 80 years) found that benefit of alteplase was similar regardless of
patient age [4]. In a prespecified secondary analysis of individual participant data (n = 6756)
from a 2016 meta-analysis of nine trials of alteplase versus control for acute ischemic stroke,
the increased risk of intracerebral hemorrhage with alteplase in the first seven days after
treatment did not differ by age [6].
Older age is not an exclusion for MT [127]. (See "Mechanical thrombectomy for acute ischemic
stroke", section on 'Patient selection'.)
Prestroke disability or dementia — Treatment decisions regarding IVT or MT for patients with
significant prestroke disability or dementia should be individualized using shared decision-
making that incorporates patient values and preferences [128]. Such patients were largely
excluded from randomized trials of reperfusion therapies for acute ischemic stroke. However,
observational data suggest that patients with disability or dementia at baseline may still benefit
from reperfusion for acute stroke, despite an overall worse prognosis and possibly higher
mortality [128].
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Pregnancy — Although pregnancy has been considered a relative contraindication to the use of
thrombolysis for acute stroke, IVT can be given in pregnancy after careful discussion of the
potential risks and benefits. The use of thrombolytic therapy in pregnancy is discussed
separately. (See "Cerebrovascular disorders complicating pregnancy", section on 'Acute
ischemic stroke'.)
Children — Safety and efficacy data for reperfusion therapy of acute ischemic stroke are lacking
in patients younger than 18 years of age. However, IVT and MT may be options for some
children, particularly adolescents (age ≥13 years), with acute ischemic stroke on neuroimaging
who are evaluated and treated at pediatric stroke centers. (See "Ischemic stroke in children:
Management and prognosis", section on 'Reperfusion with thrombolysis and thrombectomy'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Stroke in adults".)
SUMMARY AND RECOMMENDATIONS
● Goals and options for reperfusion – The immediate goal of reperfusion therapy for acute
ischemic stroke is to restore blood flow to the regions of brain that are ischemic but not
yet infarcted. Intravenous thrombolysis (IVT) is the mainstay of reperfusion therapy for
acute ischemic stroke. Mechanical thrombectomy (MT) is indicated for patients with acute
ischemic stroke caused by an intracranial large artery occlusion in the proximal anterior
circulation. (See 'Reperfusion therapies' above.)
● Benefit of reperfusion therapy
• IVT improves functional outcome at three to six months for appropriately selected
patients when given within 4.5 hours of ischemic stroke onset. (See 'Alteplase' above
and 'Tenecteplase' above.)
• MT improves functional outcome at three months for appropriately selected patients if

treatment is started within 24 hours from the time the patient was last known well.
(See "Mechanical thrombectomy for acute ischemic stroke", section on 'Efficacy of
mechanical thrombectomy'.)
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● Evaluation – All adult patients with a clinical diagnosis of acute ischemic stroke should be
rapidly evaluated for treatment with IVT. Simultaneously, patients with suspected acute
ischemic stroke involving the anterior circulation should be evaluated for MT. (See 'Rapid
evaluation' above.)
● Patient selection
• For IVT – Eligibility criteria for treatment with IVT are outlined in the table ( table 1).
For eligible patients with acute ischemic stroke causing a potentially disabling
neurologic deficit, we recommend IVT with alteplase, provided that treatment is
initiated within 3 hours of the time last known well (Grade 1A). For otherwise eligible
patients who cannot be treated in less than 3 hours, we suggest IVT, provided that
treatment is initiated within 3 to 4.5 hours of the time last known well (Grade 2A). For
patients with wake-up stroke or unknown stroke onset time, imaging-based criteria (ie,
MRI showing an acute ischemic lesion that is diffusion positive and fluid-attenuated
inversion recovery [FLAIR] negative) is an option at expert stroke centers to determine
eligibility for IVT. (See 'Less than 3 hours' above and '3 to 4.5 hours' above and
'Unwitnessed stroke onset and "wake-up" stroke' above.)
• For MT – Intra-arterial mechanical thrombectomy is recommended for patients with

ischemic stroke caused by a large artery occlusion in the proximal anterior circulation
who can start treatment within 24 hours of the time last known well. Indications and
eligibility criteria for MT are discussed in detail elsewhere. (See "Mechanical
thrombectomy for acute ischemic stroke", section on 'Patient selection'.)
● IVT administration – The administration of IVT for acute ischemic stroke, including
dosing, monitoring, and complications, is reviewed in detail separately. (See "Intravenous
thrombolytic therapy for acute ischemic stroke: Therapeutic use".)
● MT procedure – Procedural details for MT are discussed in detail elsewhere. (See

"Mechanical thrombectomy for acute ischemic stroke", section on 'Procedure'.)
Use of UpToDate is subject to the Terms of Use.
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66. Meseguer E, Mazighi M, Labreuche J, et al. Outcomes of intravenous recombinant tissue

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67. Hametner C, MacIsaac RL, Kellert L, et al. Sex and Stroke in Thrombolyzed Patients and
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68. Warach SJ, Dula AN, Milling TJ, et al. Prospective Observational Cohort Study of
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70. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus Alteplase before
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73. Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Alteplase for Acute
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76. Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for
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78. Potla N, Ganti L. Tenecteplase vs. alteplase for acute ischemic stroke: a systematic review.
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80. Wang Y, Li S, Pan Y, et al. Tenecteplase versus alteplase in acute ischaemic cerebrovascular
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81. Yogendrakumar V, Beharry J, Churilov L, et al. Tenecteplase Improves Reperfusion across
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82. Kvistad CE, Næss H, Helleberg BH, et al. Tenecteplase versus alteplase for the management
of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-
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83. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of
Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early
Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the
American Heart Association/American Stroke Association. Stroke 2019; 50:e344.
84. Jahan R, Saver JL, Schwamm LH, et al. Association Between Time to Treatment With
Endovascular Reperfusion Therapy and Outcomes in Patients With Acute Ischemic Stroke
Treated in Clinical Practice. JAMA 2019; 322:252.
85. Kunz WG, Hunink MG, Almekhlafi MA, et al. Public health and cost consequences of time
delays to thrombectomy for acute ischemic stroke. Neurology 2020; 95:e2465.
86. Saver JL, Adeoye O. Intravenous Thrombolysis Before Endovascular Thrombectomy for
Acute Ischemic Stroke. JAMA 2021; 325:229.
87. Yang P, Zhang Y, Zhang L, et al. Endovascular Thrombectomy with or without Intravenous
Alteplase in Acute Stroke. N Engl J Med 2020; 382:1981.
88. Wang Y, Wu X, Zhu C, et al. Bridging Thrombolysis Achieved Better Outcomes Than Direct
Thrombectomy After Large Vessel Occlusion: An Updated Meta-Analysis. Stroke 2021;
52:356.
89. Zi W, Qiu Z, Li F, et al. Effect of Endovascular Treatment Alone vs Intravenous Alteplase Plus
Endovascular Treatment on Functional Independence in Patients With Acute Ischemic
Stroke: The DEVT Randomized Clinical Trial. JAMA 2021; 325:234.
90. Suzuki K, Matsumaru Y, Takeuchi M, et al. Effect of Mechanical Thrombectomy Without vs
With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute
Ischemic Stroke: The SKIP Randomized Clinical Trial. JAMA 2021; 325:244.
91. LeCouffe NE, Kappelhof M, Treurniet KM, et al. A Randomized Trial of Intravenous Alteplase
before Endovascular Treatment for Stroke. N Engl J Med 2021; 385:1833.
92. Douarinou M, Gory B, Consoli A, et al. Impact of Strategy on Clinical Outcome in Large
Vessel Occlusion Stroke Successfully Reperfused: ETIS Registry Results. Stroke 2022; 53:e1.
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93. Fischer U, Kaesmacher J, Strbian D, et al. Thrombectomy alone versus intravenous alteplase
plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised
non-inferiority trial. Lancet 2022; 400:104.
94. Mitchell PJ, Yan B, Churilov L, et al. Endovascular thrombectomy versus standard bridging
thrombolytic with endovascular thrombectomy within 4·5 h of stroke onset: an open-label,
blinded-endpoint, randomised non-inferiority trial. Lancet 2022; 400:116.
95. Trifan G, Biller J, Testai FD. Mechanical Thrombectomy vs Bridging Therapy for Anterior
Circulation Large Vessel Occlusion Stroke: Systematic Review and Meta-analysis. Neurology
2022; 98:e1361.
96. Smith EE, Zerna C, Solomon N, et al. Outcomes After Endovascular Thrombectomy With or
Without Alteplase in Routine Clinical Practice. JAMA Neurol 2022; 79:768.
97. Harris J. A review of mobile stroke units. J Neurol 2021; 268:3180.
98. Fassbender K, Merzou F, Lesmeister M, et al. Impact of mobile stroke units. J Neurol
Neurosurg Psychiatry 2021.
99. Grotta JC, Yamal JM, Parker SA, et al. Prospective, Multicenter, Controlled Trial of Mobile
Stroke Units. N Engl J Med 2021; 385:971.
100. Ebinger M, Siegerink B, Kunz A, et al. Association Between Dispatch of Mobile Stroke Units
and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin. JAMA 2021;
325:454.
101. Turc G, Hadziahmetovic M, Walter S, et al. Comparison of Mobile Stroke Unit With Usual
Care for Acute Ischemic Stroke Management: A Systematic Review and Meta-analysis. JAMA
Neurol 2022; 79:281.
102. Pérez de la Ossa N, Abilleira S, Jovin TG, et al. Effect of Direct Transportation to
Thrombectomy-Capable Center vs Local Stroke Center on Neurological Outcomes in
Patients With Suspected Large-Vessel Occlusion Stroke in Nonurban Areas: The RACECAT
Randomized Clinical Trial. JAMA 2022; 327:1782.
103. Hubert GJ, Hubert ND, Maegerlein C, et al. Association Between Use of a Flying
Intervention Team vs Patient Interhospital Transfer and Time to Endovascular
Thrombectomy Among Patients With Acute Ischemic Stroke in Nonurban Germany. JAMA
2022; 327:1795.
104. Gottesman RF, Alt J, Wityk RJ, Llinas RH. Predicting abnormal coagulation in ischemic
stroke: reducing delay in rt-PA use. Neurology 2006; 67:1665.
105. Rost NS, Masrur S, Pervez MA, et al. Unsuspected coagulopathy rarely prevents IV
thrombolysis in acute ischemic stroke. Neurology 2009; 73:1957.
3/30/23, 5:07 PM 115775
106. Shahjouei S, Tsivgoulis G, Goyal N, et al. Safety of Intravenous Thrombolysis Among

Patients Taking Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis. Stroke
2020; 51:533.
107. Kam W, Holmes DN, Hernandez AF, et al. Association of Recent Use of Non-Vitamin K
Antagonist Oral Anticoagulants With Intracranial Hemorrhage Among Patients With Acute
Ischemic Stroke Treated With Alteplase. JAMA 2022; 327:760.
108. Seiffge DJ, Meinel T, Purrucker JC, et al. Recanalisation therapies for acute ischaemic stroke
in patients on direct oral anticoagulants. J Neurol Neurosurg Psychiatry 2021; 92:534.
109. Barber PA, Wu TY, Ranta A. Stroke reperfusion therapy following dabigatran reversal with
idarucizumab in a national cohort. Neurology 2020; 94:e1968.
110. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et
al. Review, historical context, and clarifications of the NINDS rt-PA stroke trials exclusion
criteria: Part 1: rapidly improving stroke symptoms. Stroke 2013; 44:2500.
111. Khatri P, Kleindorfer DO, Devlin T, et al. Effect of Alteplase vs Aspirin on Functional Outcome
for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The
PRISMS Randomized Clinical Trial. JAMA 2018; 320:156.
112. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific Rationale for the Inclusion
and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for
Healthcare Professionals From the American Heart Association/American Stroke
Association. Stroke 2016; 47:581.
113. Skolarus LE, O'Brien A, Meurer WJ, Zikmund Fisher BJ. Getting the Gist Across Is Enough for
Informed Consent for Acute Stroke Thrombolytics. Stroke 2019; 50:1595.
114. Kepplinger J, Barlinn K, Deckert S, et al. Safety and efficacy of thrombolysis in telestroke: A
systematic review and meta-analysis. Neurology 2016; 87:1344.
115. Sheth KN, Smith EE, Grau-Sepulveda MV, et al. Drip and ship thrombolytic therapy for acute
ischemic stroke: use, temporal trends, and outcomes. Stroke 2015; 46:732.
116. Deguchi I, Mizuno S, Kohyama S, et al. Drip-and-Ship Thrombolytic Therapy for Acute
Ischemic Stroke. J Stroke Cerebrovasc Dis 2018; 27:61.
117. Sattin JA, Olson SE, Liu L, et al. An expedited code stroke protocol is feasible and safe.
Stroke 2006; 37:2935.
118. Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke thrombolysis delays to 25
minutes in Melbourne in only 4 months. Neurology 2013; 81:1071.
119. Keselman B, Cooray C, Vanhooren G, et al. Intravenous thrombolysis in stroke mimics:

results from the SITS International Stroke Thrombolysis Register. Eur J Neurol 2019;
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26:1091.
120. Tsivgoulis G, Zand R, Katsanos AH, et al. Safety of intravenous thrombolysis in stroke
mimics: prospective 5-year study and comprehensive meta-analysis. Stroke 2015; 46:1281.
121. Strbian D, Soinne L, Sairanen T, et al. Ultraearly thrombolysis in acute ischemic stroke is
associated with better outcome and lower mortality. Stroke 2010; 41:712.
122. Ebinger M, Winter B, Wendt M, et al. Effect of the use of ambulance-based thrombolysis on
time to thrombolysis in acute ischemic stroke: a randomized clinical trial. JAMA 2014;
311:1622.
123. Fonarow GC, Zhao X, Smith EE, et al. Door-to-needle times for tissue plasminogen activator
administration and clinical outcomes in acute ischemic stroke before and after a quality
improvement initiative. JAMA 2014; 311:1632.
124. Cronin CA, Shah N, Morovati T, et al. No increased risk of symptomatic intracerebral
hemorrhage after thrombolysis in patients with European Cooperative Acute Stroke Study
(ECASS) exclusion criteria. Stroke 2012; 43:1684.
125. Hill MD, Coutts SB. Alteplase in acute ischaemic stroke: the need for speed. Lancet 2014;
384:1904.
126. Sarraj A, Kleinig TJ, Hassan AE, et al. Association of Endovascular Thrombectomy vs Medical
Management With Functional and Safety Outcomes in Patients Treated Beyond 24 Hours of
Last Known Well: The SELECT Late Study. JAMA Neurol 2023; 80:172.
127. McDonough RV, Ospel JM, Campbell BCV, et al. Functional Outcomes of Patients ≥85 Years
With Acute Ischemic Stroke Following EVT: A HERMES Substudy. Stroke 2022; 53:2220.
128. Ganesh A, Fraser JF, Gordon Perue GL, et al. Endovascular Treatment and Thrombolysis for
Acute Ischemic Stroke in Patients With Premorbid Disability or Dementia: A Scientific
Statement From the American Heart Association/American Stroke Association. Stroke 2022;
53:e204.
Topic 115775 Version 40.0
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GRAPHICS
Eligibility criteria for the treatment of acute ischemic stroke with

intravenous thrombolysis (recombinant tissue plasminogen activator or
tPA)
Inclusion criteria
Clinical diagnosis of ischemic stroke causing measurable neurologic deficit
Onset of symptoms <4.5 hours before beginning treatment; if the exact time of stroke onset is not
known, it is defined as the last time the patient was known to be normal or at neurologic baseline
Age ≥18 years
Exclusion criteria
Patient history
Ischemic stroke or severe head trauma in the previous three months
Previous intracranial hemorrhage
Intra-axial intracranial neoplasm
Gastrointestinal malignancy
Gastrointestinal hemorrhage in the previous 21 days
Intracranial or intraspinal surgery within the prior three months
Clinical
Symptoms suggestive of subarachnoid hemorrhage
Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mmHg)
Active internal bleeding
Presentation consistent with infective endocarditis
Stroke known or suspected to be associated with aortic arch dissection
Acute bleeding diathesis, including but not limited to conditions defined under 'Hematologic'
Hematologic
Platelet count <100,000/mm 3 *
Current anticoagulant use with an INR >1.7 or PT >15 seconds or aPTT >40 seconds*
Therapeutic doses of low molecular weight heparin received within 24 hours (eg, to treat VTE
and ACS); this exclusion does not apply to prophylactic doses (eg, to prevent VTE)
Current use (ie, last dose within 48 hours in a patient with normal renal function) of a direct
thrombin inhibitor or direct factor Xa inhibitor with evidence of anticoagulant effect by
laboratory tests such as aPTT, INR, ECT, TT, or appropriate factor Xa activity assays
3/30/23, 5:07 PM 115775
Head CT
Evidence of hemorrhage
Extensive regions of obvious hypodensity consistent with irreversible injury
Warnings ¶
Only minor and isolated neurologic signs or rapidly improving symptoms Δ
Serum glucose <50 mg/dL (<2.8 mmol/L) ◊
Serious trauma in the previous 14 days §
Major surgery in the previous 14 days ¥
History of gastrointestinal bleeding (remote) or genitourinary bleeding ‡
Seizure at the onset of stroke with postictal neurologic impairments †
Pregnancy**
Arterial puncture at a noncompressible site in the previous seven days ¶¶
Large (≥10 mm), untreated, unruptured intracranial aneurysm ¶¶
Untreated intracranial vascular malformation ¶¶
Additional warnings for treatment from 3 to 4.5 hours from symptom onset ΔΔ
Age >80 years
Oral anticoagulant use regardless of INR
Severe stroke (NIHSS score >25)
Combination of both previous ischemic stroke and diabetes mellitus
ACS: acute coronary syndrome; aPTT: activated partial thromboplastin time; ECT: ecarin clotting
time; INR: international normalized ratio; PT: prothrombin time; NIHSS: National Institutes of Health
Stroke Scale; tPA: intravenous alteplase; TT: thrombin time; VTE: venous thromboembolism.
* Although it is desirable to know the results of these tests, thrombolytic therapy should not be
delayed while results are pending unless (1) there is clinical suspicion of a bleeding abnormality or
thrombocytopenia, (2) the patient is currently on or has recently received anticoagulants (eg,
heparin, warfarin, a direct thrombin inhibitor, or a direct factor Xa inhibitor), or (3) use of
anticoagulants is not known. Otherwise, treatment with intravenous tPA can be started before
availability of coagulation test results but should be discontinued if the INR, PT, or aPTT exceed the
limits stated in the table, or if platelet count is <100,000 mm 3 .
¶ With careful consideration and weighting of risk-to-benefit, patients may receive intravenous
alteplase despite one or more warnings.
Δ Patients who have a persistent neurologic deficit that is potentially disabling, despite improvement
of any degree, should be treated with tPA in the absence of other contraindications. Any of the
following should be considered disabling deficits:
Complete hemianopia: ≥2 on NIHSS question 3, or
Severe aphasia: ≥2 on NIHSS question 9, or
3/30/23, 5:07 PM 115775
Visual or sensory extinction: ≥1 on NIHSS question 11, or

Any weakness limiting sustained effort against gravity: ≥2 on NIHSS question 5 or 6, or
Any deficits that lead to a total NIHSS >5, or
Any remaining deficit considered potentially disabling in the view of the patient and the
treating practitioner using clinical judgment
◊ Patients may be treated with intravenous alteplase if glucose level is subsequently normalized.
§ The potential risks of bleeding with alteplase from injuries related to the trauma should be
weighed against the anticipated benefits of reduced stroke-related neurologic deficits.
¥ The increased risk of surgical site bleeding with alteplase should be weighed against the
anticipated benefits of reduced stroke-related neurologic deficits.
‡ There is a low increased risk of new bleeding with alteplase in the setting of past gastrointestinal
or genitourinary bleeding. However, alteplase administration within 21 days of gastrointestinal
bleeding is not recommended.
† Alteplase is reasonable in patients with a seizure at stroke onset if evidence suggests that residual
impairments are secondary to acute ischemic stroke and not to a postictal phenomenon.
** Alteplase can be given in pregnancy when the anticipated benefits of treating moderate or severe
stroke outweigh the anticipated increased risks of uterine bleeding.
¶¶ The safety and efficacy of administering alteplase is uncertain for these relative exclusions.
ΔΔ Although these were exclusions in the trial showing benefit in the 3 to 4.5 hour window,
intravenous alteplase appears to be safe and may be beneficial for patients with these criteria,
including patients taking oral anticoagulants with an INR <1.7.
Adapted from:
1. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J
Med 2008; 359:1317.
2. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with
intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke
Association. Stroke 2009; 40:2945.
3. Re-examining Acute Eligibility for Thrombolysis (TREAT) Task Force:, Levine SR, Khatri P, et al. Review, historical context,
and clarifications of the NINDS rt-PA stroke trials exclusion criteria: Part 1: rapidly improving stroke symptoms. Stroke
2013; 44:2500.
4. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for
intravenous alteplase in acute ischemic stroke: A statement for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2016; 47:581.
5. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic
Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for
Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019; 50:e344.
Graphic 71462 Version 26.0
3/30/23, 5:07 PM 115775
Modified Rankin Scale
Score Description
0 No symptoms at all
1 No significant disability despite symptoms; able to carry out all usual duties and activities
2 Slight disability; unable to carry out all previous activities, but able to look after own affairs
without assistance
3 Moderate disability; requiring some help, but able to walk without assistance
4 Moderately severe disability; unable to walk without assistance and unable to attend to own
bodily needs without assistance
5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention
6 Dead
Reproduced with permission from: Van Swieten JC, Koudstaa PJ, Visser MC, et al. Interobserver agreement for the assessment
of handicap in stroke patients. Stroke 1988; 19:604. Copyright © 1988 Lippincott Williams & Wilkins.
3/30/23, 5:07 PM 115775
Stroke treatment delay and outcome
Relation of stroke onset to start of treatment (OTT) with treatment effect after adjustment for
prognostic variables assessed by A) day 90 modified Rankin score 0-1 versus 2-6 (interaction
p=0.0269, n=3530 [excluding EPITHET data p=0.0116, n=3431]); B) global test that
incorporates modified Rankin score 0-1 versus 2-6, Barthel Index score 95-100 versus 90 or
lower and NIHSS score 0-1 versus 2 or more (interaction p=0.0111, n=3535 [excluding
EPITHET data p=0.0049, n=3436]); C) mortality (interaction p=0.0444, n=3530 [excluding
EPITHET data p=0.0582, n=3431]); and D) parenchymal hemorrhage type 2 (interaction
p=0.4140, n=3531 [excluding EPITHET data p=0.4578, n=3431]). Thus, for parenchymal
hemorrhage type 2, the fitted line is not statistically distinguishable from a horizontal line.
For each graph, the adjusted odds ratio is shown with the 95% CIs. CIs from the models will
differ from those shown in the tables because the model uses data from all patients treated
within 0-360 min whereas the categorized analyses in the tables are based on subsets of
patients: the modeled CIs are deemed to be more reliable.
%: percent.
Lees, KR, Bluhmki, E, von Kummer, R, et al. Time to treatment with intravenous alteplase and outcome in stroke: an
updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010; 375:1695. Illustration used
3/30/23, 5:07 PM 115775
with permission of Elsevier Inc. All rights reserved.
3/30/23, 5:07 PM 115775
National Institutes of Health Stroke Scale (NIHSS)
Administer stroke scale items in the order listed. Record performance in each category after each
subscale exam. Do not go back and change scores. Follow directions provided for each exam
technique. Scores should reflect what the patient does, not what the clinician thinks the patient can
do. The clinician should record answers while administering the exam and work quickly. Except where
indicated, the patient should not be coached (ie, repeated requests to patient to make a special
effort).
Instructions Scale definition Score
1a. Level of consciousness: The 0 = Alert; keenly responsive.

investigator must choose a response if a full
1 = Not alert; but arousable by minor
evaluation is prevented by such obstacles as
stimulation to obey, answer, or respond.
an endotracheal tube, language barrier,
orotracheal trauma/bandages. A 3 is scored 2 = Not alert; requires repeated stimulation
only if the patient makes no movement to attend, or is obtunded and requires _____
(other than reflexive posturing) in response strong or painful stimulation to make
to noxious stimulation. movements (not stereotyped).
3 = Responds only with reflex motor or

autonomic effects or totally unresponsive,
flaccid, and areflexic.
1b. Level of consciousness questions: The 0 = Answers both questions correctly.

patient is asked the month and his/her age.
1 = Answers one question correctly.
The answer must be correct - there is no
partial credit for being close. Aphasic and 2 = Answers neither question correctly.
stuporous patients who do not comprehend
the questions will score 2. Patients unable
to speak because of endotracheal
_____
intubation, orotracheal trauma, severe
dysarthria from any cause, language
barrier, or any other problem not secondary
to aphasia are given a 1. It is important that
only the initial answer be graded and that
the examiner not "help" the patient with
verbal or non-verbal cues.
1c. Level of consciousness commands: 0 = Performs both tasks correctly. _____

The patient is asked to open and close the
1 = Performs one task correctly.
eyes and then to grip and release the non-
paretic hand. Substitute another one step 2 = Performs neither task correctly.
command if the hands cannot be used.
Credit is given if an unequivocal attempt is
made but not completed due to weakness.
If the patient does not respond to
command, the task should be demonstrated
3/30/23, 5:07 PM 115775
to him or her (pantomime), and the result

scored (ie, follows none, one or two
commands). Patients with trauma,
amputation, or other physical impediments
should be given suitable one-step
commands. Only the first attempt is scored.
2. Best gaze: Only horizontal eye 0 = Normal.

movements will be tested. Voluntary or
1 = Partial gaze palsy; gaze is abnormal in
reflexive (oculocephalic) eye movements will
one or both eyes, but forced deviation or
be scored, but caloric testing is not done. If
total gaze paresis is not present.
the patient has a conjugate deviation of the
eyes that can be overcome by voluntary or 2 = Forced deviation, or total gaze paresis
reflexive activity, the score will be 1. If a not overcome by the oculocephalic
patient has an isolated peripheral nerve maneuver.
paresis (cranial nerves III, IV or VI), score a
_____
1. Gaze is testable in all aphasic patients.
Patients with ocular trauma, bandages, pre-
existing blindness, or other disorder of
visual acuity or fields should be tested with
reflexive movements, and a choice made by
the investigator. Establishing eye contact
and then moving about the patient from
side to side will occasionally clarify the
presence of a partial gaze palsy.
3. Visual: Visual fields (upper and lower 0 = No visual loss.

quadrants) are tested by confrontation,
1 = Partial hemianopia.
using finger counting or visual threat, as
appropriate. Patients may be encouraged, 2 = Complete hemianopia.
but if they look at the side of the moving 3 = Bilateral hemianopia (blind including
fingers appropriately, this can be scored as cortical blindness).
normal. If there is unilateral blindness or
enucleation, visual fields in the remaining _____
eye are scored. Score 1 only if a clear-cut
asymmetry, including quadrantanopia, is
found. If patient is blind from any cause,
score 3. Double simultaneous stimulation is
performed at this point. If there is
extinction, patient receives a 1, and the
results are used to respond to item 11.
4. Facial palsy: Ask - or use pantomime to 0 = Normal symmetrical movements. _____

encourage - the patient to show teeth or
1 = Minor paralysis (flattened nasolabial
raise eyebrows and close eyes. Score
fold, asymmetry on smiling).
symmetry of grimace in response to
noxious stimuli in the poorly responsive or 2 = Partial paralysis (total or near-total
non-comprehending patient. If facial paralysis of lower face).
3/30/23, 5:07 PM 115775
trauma/bandages, orotracheal tube, tape or 3 = Complete paralysis of one or both sides

other physical barriers obscure the face, (absence of facial movement in the upper
these should be removed to the extent and lower face).
possible.
5. Motor arm: The limb is placed in the 0 = No drift; limb holds 90 (or 45) degrees
appropriate position: extend the arms for full 10 seconds.
(palms down) 90 degrees (if sitting) or 45
1 = Drift; limb holds 90 (or 45) degrees, but
degrees (if supine). Drift is scored if the arm
drifts down before full 10 seconds; does not
falls before 10 seconds. The aphasic patient
hit bed or other support.
is encouraged using urgency in the voice
and pantomime, but not noxious 2 = Some effort against gravity; limb
stimulation. Each limb is tested in turn, cannot get to or maintain (if cued) 90 (or 45)
beginning with the non-paretic arm. Only in degrees, drifts down to bed, but has some
_____
the case of amputation or joint fusion at the effort against gravity.
shoulder, the examiner should record the 3 = No effort against gravity; limb falls.
score as untestable (UN), and clearly write
4 = No movement.
the explanation for this choice.
UN = Amputation or joint fusion,
explain:________________
5a. Left arm
5b. Right arm
6. Motor leg: The limb is placed in the 0 = No drift; leg holds 30-degree position
appropriate position: hold the leg at 30 for full 5 seconds.
degrees (always tested supine). Drift is
1 = Drift; leg falls by the end of the 5-
scored if the leg falls before 5 seconds. The
second period but does not hit bed.
aphasic patient is encouraged using
urgency in the voice and pantomime, but 2 = Some effort against gravity; leg falls to
not noxious stimulation. Each limb is tested bed by 5 seconds, but has some effort
in turn, beginning with the non-paretic leg. against gravity.
Only in the case of amputation or joint 3 = No effort against gravity; leg falls to _____
fusion at the hip, the examiner should bed immediately.
record the score as untestable (UN), and
4 = No movement.
clearly write the explanation for this choice.
UN = Amputation or joint fusion,
explain:________________
6a. Left leg
6b. Right leg
7. Limb ataxia: This item is aimed at finding 0 = Absent. _____

evidence of a unilateral cerebellar lesion.
1 = Present in one limb.
Test with eyes open. In case of visual defect,
ensure testing is done in intact visual field. 2 = Present in two limbs.
The finger-nose-finger and heel-shin tests UN = Amputation or joint fusion,
are performed on both sides, and ataxia is explain:________________
3/30/23, 5:07 PM 115775
scored only if present out of proportion to

weakness. Ataxia is absent in the patient
who cannot understand or is paralyzed.
Only in the case of amputation or joint
fusion, the examiner should record the
score as untestable (UN), and clearly write
the explanation for this choice. In case of
blindness, test by having the patient touch
nose from extended arm position.
8. Sensory: Sensation or grimace to 0 = Normal; no sensory loss.

pinprick when tested, or withdrawal from
1 = Mild-to-moderate sensory loss; patient
noxious stimulus in the obtunded or
feels pinprick is less sharp or is dull on the
aphasic patient. Only sensory loss
affected side; or there is a loss of superficial
attributed to stroke is scored as abnormal
pain with pinprick, but patient is aware of
and the examiner should test as many body
being touched.
areas (arms [not hands], legs, trunk, face) as
needed to accurately check for hemisensory 2 = Severe to total sensory loss; patient is
loss. A score of 2, "severe or total sensory not aware of being touched in the face, arm,
loss," should only be given when a severe or and leg. _____
total loss of sensation can be clearly
demonstrated. Stuporous and aphasic
patients will, therefore, probably score 1 or
0. The patient with brainstem stroke who
has bilateral loss of sensation is scored 2. If
the patient does not respond and is
quadriplegic, score 2. Patients in a coma
(item 1a=3) are automatically given a 2 on
this item.
9. Best language: A great deal of 0 = No aphasia; normal. _____

information about comprehension will be
1 = Mild-to-moderate aphasia; some
obtained during the preceding sections of
obvious loss of fluency or facility of
the examination. For this scale item, the
comprehension, without significant
patient is asked to describe what is
limitation on ideas expressed or form of
happening in the attached picture, to name
expression. Reduction of speech and/or
the items on the attached naming sheet and
comprehension, however, makes
to read from the attached list of sentences.
conversation about provided materials
Comprehension is judged from responses
difficult or impossible. For example, in
here, as well as to all of the commands in
conversation about provided materials,
the preceding general neurological exam. If
examiner can identify picture or naming
visual loss interferes with the tests, ask the
card content from patient's response.
patient to identify objects placed in the
hand, repeat, and produce speech. The 2 = Severe aphasia; all communication is
intubated patient should be asked to write. through fragmentary expression; great
The patient in a coma (item 1a=3) will need for inference, questioning, and
automatically score 3 on this item. The guessing by the listener. Range of
information that can be exchanged is
3/30/23, 5:07 PM 115775
examiner must choose a score for the limited; listener carries burden of
patient with stupor or limited cooperation, communication. Examiner cannot identify
but a score of 3 should be used only if the materials provided from patient response.
patient is mute and follows no one-step
3 = Mute, global aphasia; no usable speech
commands.
or auditory comprehension.
10. Dysarthria: If patient is thought to be 0 = Normal.

normal, an adequate sample of speech
1 = Mild-to-moderate dysarthria; patient
must be obtained by asking patient to read
slurs at least some words and, at worst, can
or repeat words from the attached list. If the
be understood with some difficulty.
patient has severe aphasia, the clarity of
articulation of spontaneous speech can be 2 = Severe dysarthria; patient's speech is
so slurred as to be unintelligible in the _____
rated. Only if the patient is intubated or has
other physical barriers to producing speech, absence of or out of proportion to any
the examiner should record the score as dysphasia, or is mute/anarthric.
untestable (UN), and clearly write an UN = Intubated or other physical barrier,
explanation for this choice. Do not tell the explain:________________
patient why he or she is being tested.
11. Extinction and inattention (formerly 0 = No abnormality.

neglect): Sufficient information to identify
1 = Visual, tactile, auditory, spatial, or
neglect may be obtained during the prior
personal inattention or extinction to
testing. If the patient has a severe visual
bilateral simultaneous stimulation in one of
loss preventing visual double simultaneous
the sensory modalities.
stimulation, and the cutaneous stimuli are
normal, the score is normal. If the patient 2 = Profound hemi-inattention or
extinction to more than one modality; _____
has aphasia but does appear to attend to
both sides, the score is normal. The does not recognize own hand or orients to
presence of visual spatial neglect or only one side of space.
anosognosia may also be taken as evidence
of abnormality. Since the abnormality is
scored only if present, the item is never
untestable.
_____
Adapted from: Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non-
neurologists in the context of a clinical trial. Stroke 1997; 28:307.
3/30/23, 5:07 PM 115775
Early ischemic changes on noncontrast head CT scan
Findings of EIC in a 59-year-old man who presented with acute left hemiparesis. (A and B) NCCT 3.5 hours
after symptom onset shows hypodensity and cortical swelling with sulcal effacement. There is loss of gray-
white matter differentiation in the right frontal operculum, right temporal operculum, right insular cortex,
and right frontoparietal lobes (arrowheads).
CT: computed tomography; EIC: early ischemic changes; NCCT: noncontrast-enhanced computed
tomography.
From: Prakkamakul S, Yoo AJ. ASPECTS CT in Acute Ischemia: Review of Current Data. Top Magn Reson Imaging 2017; 26:103. DOI:
10.1097/RMR.0000000000000122. Copyright © 2017. Reproduced with permission from Wolters Kluwer Health. Unauthorized
reproduction of this material is prohibited.
3/30/23, 5:07 PM 115775
Contributor Disclosures
Jamary Oliveira-Filho, MD, MS, PhD No relevant financial relationship(s) with ineligible companies to
disclose. Owen B Samuels, MD No relevant financial relationship(s) with ineligible companies to
disclose. José Biller, MD, FACP, FAAN, FAHA No relevant financial relationship(s) with ineligible companies
to disclose. Jonathan A Edlow, MD, FACEP No relevant financial relationship(s) with ineligible companies
to disclose. Alejandro A Rabinstein, MD Consultant/Advisory Boards: AstraZeneca[Secondary stroke
prevention];Novo Nordisk[Stroke risk]. Other Financial Interest: Boston Scientific [Adverse event
adjudication committee member for stroke risk reduction device in patients with atrial fibrillation]. All of
the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Approach To Reperfusion Therapy For Acute Ischemic Stroke

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Official reprint from UpToDate®

Approach to reperfusion therapy for acute ischemic

Mechanical thrombectomy is reviewed in detail elsewhere. (See "Mechanical thrombectomy for

but no corresponding hyperintensity on FLAIR [12]. Nearly 90 percent of enrolled patients

contrast, the ECASS 2, ECASS-3 and SITS-MOST definitions of symptomatic intracerebral

Recanalization — Full or partial recanalization up to 24 hours after onset of acute stroke

Other variables affecting outcome — Early recanalization is probably the most

● Early ischemic changes on CT – The presence of extensive regions of obvious

● Hyperglycemia – Hyperglycemia before reperfusion in patients with acute ischemic stroke

Tenecteplase — Tenecteplase, a type of recombinant tissue plasminogen activator (tPA), is a

Mechanical thrombectomy (MT) — Mechanical thrombectomy is indicated for patients with

Prehospital recognition and management — Emergency medical responders should identify

● Evaluation by physician – 10 minutes elapsed from arrival

Investigations — Diagnostic neuroimaging is essential before considering reperfusion therapy

● Clinical suspicion of a bleeding abnormality or thrombocytopenia

● Use of anticoagulants is not known

Patients on anticoagulants — Current anticoagulant use with evidence of anticoagulant

• Is the patient taking an oral anticoagulant?

● Complete hemianopia: ≥2 on the National Institutes of Health Stroke Scale (NIHSS)

Early ischemic changes on neuroimaging — Minor ischemic changes on CT are not a

Whether to proceed to thrombolysis in an individual patient should be based upon a brief

● Prehospital notification by emergency medical personnel/ambulance of a patient with a

TREATMENT BY TIME FROM SYMPTOM ONSET

SOCIETY GUIDELINE LINKS

SUMMARY AND RECOMMENDATIONS

● Benefit of reperfusion therapy

• MT improves functional outcome at three months for appropriately selected patients if

• For MT – Intra-arterial mechanical thrombectomy is recommended for patients with

● MT procedure – Procedural details for MT are discussed in detail elsewhere. (See

Use of UpToDate is subject to the Terms of Use.

40. Neumann-Haefelin T, du Mesnil de Rochemont R, Fiebach JB, et al. Effect of incomplete

a magnetic resonance imaging study. Stroke 2004; 35:109.

66. Meseguer E, Mazighi M, Labreuche J, et al. Outcomes of intravenous recombinant tissue

79. Tsivgoulis G, Katsanos AH, Christogiannis C, et al. Intravenous Thrombolysis with

106. Shahjouei S, Tsivgoulis G, Goyal N, et al. Safety of Intravenous Thrombolysis Among

119. Keselman B, Cooray C, Vanhooren G, et al. Intravenous thrombolysis in stroke mimics:

Eligibility criteria for the treatment of acute ischemic stroke with

Age ≥18 years

Ischemic stroke or severe head trauma in the previous three months

Previous intracranial hemorrhage

Intra-axial intracranial neoplasm

Gastrointestinal hemorrhage in the previous 21 days

Intracranial or intraspinal surgery within the prior three months

Symptoms suggestive of subarachnoid hemorrhage

Active internal bleeding

Presentation consistent with infective endocarditis

Stroke known or suspected to be associated with aortic arch dissection

Platelet count <100,000/mm 3 *

Extensive regions of obvious hypodensity consistent with irreversible injury

Serum glucose <50 mg/dL (<2.8 mmol/L) ◊

Serious trauma in the previous 14 days §

Major surgery in the previous 14 days ¥

History of gastrointestinal bleeding (remote) or genitourinary bleeding ‡

Seizure at the onset of stroke with postictal neurologic impairments †

Arterial puncture at a noncompressible site in the previous seven days ¶¶

Large (≥10 mm), untreated, unruptured intracranial aneurysm ¶¶

Untreated intracranial vascular malformation ¶¶

Age >80 years