Intravenous Thrombolysis For Acute Ischemic 2023

Intravenous REVIEW ARTICLE
Thrombolysis for Acute


CONTINUUM AUDIO
INTERVIEW AVAILABLE
3WZuNYbiUxL+Qx0CJDbgM62RHmPuolEo5N+/X7zoAmdaTwqB+KcSbKRp5behT+Ql0Mk3bty1xhQyZS7k1ah5dNhzzpFEIa7vzF7r
Ischemic Stroke
ONLINE
Downloaded from http://journals.lww.com/continuum by 1dc+NBdzNCtjMFW413F/U85CIXLyZuC9qekkv+z4kRVCS54
By James C. Grotta, MD, FAAN
ABSTRACT
OBJECTIVE: This article reviews the history of IV thrombolysis, its current
indications and implementation, the duality of the “time is brain” versus
“tissue clock” approaches, the impact of endovascular thrombectomy on
Qc4vxUDBJnwzf on 04/11/2023
IV thrombolysis, the emergence of tenecteplase, and future research

directions.
CITE AS:
LATEST DEVELOPMENTS: The growing use of factor Xa inhibitors has increasingly CONTINUUM (MINNEAP MINN)
caused patients with stroke to be excluded from treatment with IV 2023;29(2, CEREBROVASCULAR
DISEASE):425–442.
thrombolysis. Important geographic, socioeconomic, sex, race, and ethnic
disparities have been identified in the implementation of IV thrombolysis Address correspondence to
and need to be overcome. IV thrombolysis substantially improves Dr James Grotta, Memorial
Hermann Hospital - Life Flight,
outcomes when provided within the first golden hour after stroke onset in 18th Floor Sarofim—18.300.2,
patients treated in mobile stroke units, supporting the “time is brain” 6411 Fannin St, Houston, TX
concept and encouraging the possible value of more widespread 77030, james.grotta@
memorialhermann.org.
implementation of the mobile stroke unit approach. At the same time,
other studies have shown that IV thrombolysis can be successful in RELATIONSHIP DISCLOSURE:
patients whose “tissue clock” is still ticking up to 9 hours after stroke onset Dr Grotta has received personal
compensation in the range of
or in patients who awaken with their stroke, as demonstrated by favorable $5000 to $9999 for serving on a
imaging profiles. These considerations, along with the emergence of scientific advisory or data
safety monitoring board for
endovascular thrombectomy, have fostered examination of our care
Haemonetics and Prolong
systems, including the “drip and ship” versus direct to comprehensive or Pharmaceuticals and in the
endovascular thrombectomy stroke center approaches, as well as the range of $10,000 to $49,999 for
serving as a consultant for
possibility of skipping IV thrombolysis in certain patients treated with Frazer Ltd and on a scientific
endovascular thrombectomy. Data suggesting that tenecteplase is at least advisory or data safety
noninferior to alteplase, as well as its more convenient dosing, has led to monitoring board for Acticor
Biotech. The institution of
its increased use. Ongoing studies are evaluating newer thrombolytics and Dr Grotta has received research
adding antithrombotic therapy to IV thrombolysis. support from Chiesi, CSL
Behring, and Genentech.
Dr Grotta has received
IV thrombolysis remains the most common acute stroke
ESSENTIAL POINTS: publishing royalties from
treatment. Advances in acting faster to treat stroke have increased its publications relating to
health care.
efficacy, and advances in imaging have expanded its use. However,
implementing these advances and overcoming disparities in IV UNLABELED USE OF
thrombolysis use remain major challenges. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Grotta reports no disclosure.
© 2023 American Academy

of Neurology.
CONTINUUMJOURNAL.COM 425
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

INTRAVENOUS THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE
INTRODUCTION
T
he benefits of IV thrombolysis for the treatment of acute ischemic
stroke are well established. First, this article will briefly review the
development and approval of recombinant tissue plasminogen
activator (rtPA) followed by the exclusion criteria that have evolved

since the drug’s approval. The increasing use of rtPA is described,
along with the sober reality of substantial disparities in its use. This article
explores the duality of the “time is brain” versus “tissue clock” concepts, which
are more complementary than conflicting, and then summarizes the recent
positive results with ultra-fast treatment on mobile stroke units and with imaging
selection of patients with wake-up stroke or strokes of unknown onset.
Tissue plasminogen activator is a naturally occurring protease that attaches to
fibrin on the surface of a clot and activates plasminogen attached to the fibrin.
Activated plasminogen produces plasmin, the primary enzyme for clot lysis.
Recombinant technology has allowed the manufacturing of several modifications
of tissue plasminogen activator, namely alteplase, reteplase, and tenecteplase,
which vary slightly in their fibrin specificity and half-life. Alteplase was the
first and only recombinant tissue plasminogen activator that was studied
and proven effective for stroke for over 25 years, and so by default has been
equated with the term tissue plasminogen activator or rtPA. Thus, the two terms,
rtPA and alteplase, have been used interchangeably in the literature and in this
review. The emerging use of tenecteplase will be discussed, along with the
current and future effects of endovascular thrombectomy on IV thrombolysis
and future research directions. The terms rtPA and IV thrombolysis will also be
used interchangeably, but for the most part, rtPA will be used when referring
specifically to studies with rtPA, and IV thrombolysis will be used when
referring to the general therapeutic approach of IV thrombolysis.
HISTORY
Prompted by earlier success in animal models, National Institute of Neurological
Disorders and Stroke (NINDS) rtPA pilot studies1,2 were aimed at determining
the upper limit of safety and, although based on relatively small numbers of
patients in each dosing group, chose 0.9 mg/kg with 10% given as a bolus and the
remainder infused over 1 hour. This was 63% to 90% of the cardiac dose
depending on patient weight. Equally important, the pilot studies demonstrated
the feasibility of administering rtPA within 90 minutes of symptom onset, which
was much earlier than in any previous clinical trial. This led to the pivotal NINDS
stroke study,3 which was really two sequential randomized controlled trials of IV
rtPA 0.9 mg/kg versus placebo, with half of patients enrolled within 90 minutes
and half between 90 to 180 minutes of postsymptom onset. The first of these
studies, part 1, was a phase 2b study whose primary outcome was a 4-point
improvement in the 24-hour National Institutes of Health Stroke Scale (NIHSS)
score. While it failed on that primary outcome, all secondary outcomes were
positive, including more substantial improvement at 24 hours and the 90-day
modified Rankin Scale (mRS), Glasgow Outcome Scale, and Barthel Index. Part 2
then confirmed the results of part 1, with the primary outcome being a composite
of all four scales. In the meantime, Mori and colleagues4 conducted a small
randomized trial of a lower dose of rtPA in Japan, and Hacke, Kaste, and Fieschi5
and their European colleagues began ECASS (European Cooperative Acute
Stroke Study),6 a study of a higher dose of rtPA with a 6-hour time window.
426 APRIL 2023

ECASS I was published in 1995 before the NINDS studies and failed on its KEY POINTS
primary outcome but was positive in a target population without substantial
● Extensive clinical trial
early ischemic changes on CT. This was followed in 1998 by ECASS II,6 which data and “real world”
included both European and Australian centers and used the 0.9 mg/kg dose of experience support the
rtPA. This study, which included very few patients in the 0- to 3-hour time efficacy and safety of
window, was also negative on its primary outcome (mRS score of 0 or 1 at 90 days) recombinant tissue
plasminogen activator (rtPA)
but was positive on its secondary outcomes (mRS score of 0 to 2). Importantly,
as the primary treatment for
all these studies confirmed the relative safety of rtPA, with symptomatic acute ischemic stroke.
hemorrhage rates of 6% to 9%, depending on the definition. Taken together,
these studies supported the use of rtPA 0.9 mg/kg within 3 hours of symptom ● An improving deficit or
onset, which became the guideline-approved therapy until 2008 when ECASS III low National Institutes of
Health Stroke Scale score
demonstrated better outcomes with rtPA treatment in the 3- to 4.5-hour time does not exclude a patient
window.7 Subsequent meta-analyses and pooled analyses in thousands of from receiving rtPA if, after a
randomly assigned patients confirmed the effectiveness and safety of rtPA8,9 as careful neurologic history
well as a clear relation between time elapsed from symptom onset to treatment and examination, the
stroke-related deficit would
and decay of efficacy.10,11 In the 0- to 90-minute time window, the number be disabling if it persisted
needed to treat for one patient to benefit from rtPA treatment was 3.6, and the without treatment.
number needed to harm was 65; in the time windows of 90 to 180 minutes and
181 to 270 minutes, these numbers were 4.3 and 38, and 5.9 and 30, respectively.12 ● While rtPA is approved by
the US Food and Drug
Administration (FDA) for
INDICATIONS AND CONTRAINDICATIONS FOR INTRAVENOUS only up to 3 hours after
THROMBOLYSIS symptom onset, data and
The initial US Food and Drug Administration (FDA)-approved rtPA package guidelines support its use for
up to 4.5 hours after
insert essentially repeated the same inclusion and exclusion criteria that were used
symptom onset.
in the NINDS rtPA study. In practice, however, as clinicians became more
comfortable using rtPA, these criteria have evolved. TABLE 2-113-16 lists the most ● The use of factor Xa
current inclusion and exclusion criteria in the guidelines and package insert. For inhibitors is an increasing
instance, many patients had treatment delayed or not administered because of the cause of exclusion from
treatment with IV
initial exclusion of “rapidly improving neurologic deficit.”17 This exclusion is no thrombolysis.
longer listed, and the patient should be treated as soon as possible as long as the
deficit would be considered “disabling” if it persisted. What is disabling, of course,
can be a matter of judgment. While there is no lower NIHSS score cutoff, data
suggest that patients with an NIHSS score of less than 5 whose deficit is not
disabling will usually recover without rtPA treatment, and a study in such patients
was stopped early without showing a trend for better outcome with treatment.18
However, clinicians should complete a thorough examination to detect disabling
signs. For instance, an isolated mild aphasia might disable a person whose work or
social life involves substantial speaking or conversation. Weakness in the hand and
truncal ataxia are not measured on the NIHSS but may be disabling (CASE 2-1).
The biggest change in the inclusion criteria for intravenous thrombolysis occurred
after ECASS III, in which benefits were demonstrated from rtPA treatment up to
4.5 hours after symptom onset. While the FDA package insert still lists 3 hours as
the cutoff, American Heart Association guidelines accept rtPA treatment up to
4.5 hours after symptom onset, and this is the practice for most clinicians.19 While
there was an initial warning about treatment in patients older than 80 years, this has
been removed from the guidelines based on data demonstrating the benefit of
treatment in older adults, assuming no other contraindications.
On the other hand, clinical experience has led to additional contraindications
(eg, aortic arch dissection) in the guidelines that were not in the initial list. An
emerging common reason for exclusion is use of a factor Xa inhibitor. Since there

is no point-of-care test available to determine if patients are anticoagulated,

current practice is to withhold rtPA treatment within 48 hours of the last dose
unless a coagulation assay confirms normal coagulation.
CURRENT USE OF INTRAVENOUS THROMBOLYSIS

The most recent data suggest that rtPA is administered to approximately 12% of
patients with acute ischemic stroke in the United States.20 The most common
reason for exclusion is that patients often arrive too late to the emergency
department for treatment to occur within 4.5 hours of symptom onset. Several
factors have led to increased use of rtPA among patients who do present within
4.5 hours of symptom onset: the development and certification of designated
stroke centers with preferential emergency medical services (EMS) triage to
their emergency departments, increased training and availability of vascular
neurologists, education of nonstroke specialty clinicians about rtPA use, and
the use of telemedicine to extend rtPA treatment expertise to nonstroke
centers. This last development, also referred to as “telestroke,” has made a
TABLE 2-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen

Activatora
American Heart Association Guideline 201914 US Food and Drug Administration (FDA) Package Insert 201515
Indicationsb
Diagnosis of ischemic stroke with disabling neurologic Same

deficit (regardless of severity)
Symptom onsetc within 4.5 hours Within 3 hours
Wake-up stroke with diffusion-weighted imaging FLAIR Not contemplated

mismatch on MRId
Age ≥18 years Warning for age >77 years with risk factors for intracranial
hemorrhage
Contraindications
Severe head trauma within 3 months Same
Ischemic stroke within 3 months Removede
Previous intracranial hemorrhage Warning for recent intracranial hemorrhage (contraindicated if

active intracranial hemorrhage)
Suspected subarachnoid hemorrhage Same
Suspected infective endocarditis Not listed
Suspected aortic arch dissection Not listed
Recent intracranial or intraspinal surgery (within 3 months) Same
Intracranial intraaxial neoplasm Not listed
Gastrointestinal malignancy or gastrointestinal bleeding Warning

within previous 21 days
CONTINUED ON PAGE 429
428 APRIL 2023

particular impact,21 and it has been estimated that as many patients in the United
States are currently treated by telestroke as by primary treatment by the emergency
department staff. Despite these advances, the fact that only 12% of patients with
acute ischemic stroke receive rtPA indicates opportunities for improvement.
One solution is community education emphasizing the recognition of stroke
symptoms and the need to call 911 when they occur.22 Community education has
been only modestly successful. Going forward, such education programs need to
be complemented by efforts to remove financial and other disincentives to
activating 911 and to alter our emergency systems of care, which might include
wider use of mobile stroke units that can provide treatment at the home and have
been shown to increase the rate of rtPA treatment.23,24 In the future, home
telemedicine may quickly and accurately identify acute stroke symptoms, and
early warning devices used in the home may detect physiologic changes and
encourage the patient or bystander to call for help.
The last several years have seen increased focus on disparities in the use of IV
thrombolysis between the sexes and among various geographic regions,
CONTINUED FROM PAGE 428
American Heart Association Guideline 201914 US Food and Drug Administration (FDA) Package Insert 201515
Active internal bleeding Same
Systolic blood pressure (BP) >185 mm Hg or diastolic BP Contraindicated for severe uncontrolled hypertension (BP
>110 mm Hg that cannot be lowered safely values removede); warning for BP >175/110 mm Hg
Bleeding diathesis Same (laboratory values removede)
International normalized ratio (INR) >1.7
Heparin within 48 hours with abnormal activated partial

thromboplastin time
Low-molecular-weight heparin full treatment dose within

previous 24 hours
Platelets <100,000/mm3
Current use of direct thrombin inhibitor or factor Xa

inhibitor with abnormal coagulation testsf
CT showing acute hemorrhage Same
CT showing extensive hypodensity (eg, >1/3 of the cerebral Removede

hemisphere)
CT = computed tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
a
Reprinted with permission from Rabinstein AA, Continuum.13 © 2020 American Academy of Neurology.
b
In other situations listed in the guideline, the risk and benefit need to be individually assessed. Some of these situations include major extracranial
trauma or major surgery within the previous 14 days, intradural arterial dissection, untreated giant intracranial aneurysm, intracranial arteriovenous
malformation, multiple cerebral microbleeds on MRI (count >10), recent but not concomitant anterior wall ST-elevation myocardial infarction,
pregnancy, and early puerperium.
c
Last known well.
d
Evidence also exists that perfusion imaging can be used to select candidates with stroke presenting upon wake up or between 4.5 and 9 hours of
last known well,16 but these studies were published after the evidence review for the 2019 American Heart Association guidelines.
e
The term removed is used to denote a change compared with the previous version of the package insert (2009).
f
Activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, factor Xa activity assays.

socioeconomic groups, ethnicities, and races.20 Clearly, IV thrombolysis is rarely

implemented in developing regions of the world where the drug is prohibitively
expensive and appropriate emergency diagnostic and medical care is not
available. Even in the developed world, IV thrombolysis is less frequent in rural
areas, and among women and Black and Hispanic people, although no evidence
suggests that the benefit of IV thrombolysis differs among these groups

(FIGURE 2-125). Continued efforts are needed to address and overcome these
disparities in access to IV thrombolysis.
TIME WINDOWS FOR INTRAVENOUS THROMBOLYSIS

Because of the aforementioned relationship between shorter time to rtPA bolus
from symptom onset (or time last known well) and reduced disability at 90 days,
“time is brain” has been the mantra for acute stroke treatment with rtPA
(FIGURE 2-2). Ample preclinical and clinical data support this notion; a seminal
study in primates demonstrated that the middle cerebral artery can be occluded
for up to an hour without causing infarction.26 This is because residual cerebral
blood flow provided by collateral circulation can maintain the ischemic region in
a penumbral state where tissue is threatened and will eventually die if flow is not
restored.27 Over the next minutes to hours, if the artery remains occluded,
penumbral tissue will become infarcted and a “core” of irreversible damage
grows to incorporate the entire threatened territory. Based on rodent models that
showed that infarction becomes complete after 3 hours,26,28 and the 3-hour time
window of the successful NINDS stroke study,3 the “time window” for
FDA-approved rtPA treatment was established at 3 hours between symptom
onset or last time known well, with better results seen with earlier treatment.10,11
CASE 2-1 A 65-year-old man, employed as a construction worker, was evaluated

by a mobile stroke unit at his job after experiencing symptoms of a
stroke. During his 9:30 AM coffee break that morning, his colleagues
noticed that he was having difficulty speaking. His coworkers had
reported having a normal conversation with him when he arrived at work
at 8:00 AM. The patient was evaluated on scene by the mobile stroke unit
team at 9:55 AM. His National Institutes of Health Stroke Scale score was
4 (for answering one question erroneously), and he presented with mild
aphasia, facial asymmetry, and slight pronator drift of his right arm. After
obtaining a normal CT scan on the mobile stroke unit and discussing risks
and benefits with the patient, recombinant tissue plasminogen activator
(rtPA) IV bolus was administered at 10:10 AM, followed by the 1-hour
infusion. He was transported to the emergency department, where his CT
angiography was found to be normal. Over the next 2 hours, the patient’s
aphasia improved, and he was back to normal after 24 hours. Subsequent
MRI showed no acute infarct.
COMMENT This case shows that IV thrombolysis can be beneficial in patients with
relatively mild but disabling deficits, and that such treatment can
completely avert the stroke.
430 APRIL 2023

FIGURE 2-1
Racial and geographic disparities in the use of IV thrombolysis. IV thrombolysis use in
Black (A), Hispanic (C), and Asian/Pacific Islander (PI) (E) patients compared with White
patients, stratified by geographic region, and corresponding color-coded US maps
(B, D, and F, respectively).
CI = confidence interval; NIS = National Inpatient Sample; OR = odds ratio.
Reprinted with permission from Suolang D, et al, Stroke.25 © 2021, Wolters Kluwer Health.

FIGURE 2-2
Time window versus tissue window. A, Relation between time from symptom onset and
treatment with recombinant tissue plasminogen activator (rtPA) and odds ratio of excellent
outcome. Efforts such as stroke teams, telemedicine, and mobile stroke units are used to
treat patients faster in the first hours after onset (left side of plot), whereas imaging of
ischemic core (B, purple) and hypoperfusion (B, green) can guide treatment in the later time
window (right side of plot).
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale.
The “time is brain” concept has been further demonstrated in studies of mobile
stroke units, which deliver rtPA treatment on scene and increase the proportion
of patients treated in the first “golden hour” after last time known well.23,24
Treatment in this time frame is rare with usual care in the emergency
department,11 but is 10 times more likely with a mobile stroke unit.29 Faster
treatment, coupled with higher rates of treatment than in the emergency
department, results in significantly better clinical outcome with mobile stroke
unit treatment compared with standard management by EMS.29,30 With
treatment in the first hour, approximately 60% of patients will recover to an mRS
score of 0 or 1 (eg, no disability) by 90 days compared with approximately 40%
with treatment at 3 hours (FIGURES 2-3A and 2-3B29) (CASE 2-2). The better
results occurring within the first hour of treatment are probably not only because
of the absence of an irreversibly damaged “core,” but also because fresher clots
are more porous with a higher ratio of red blood cells to platelets, and thereby are
more easily lysed by rtPA compared with more mature clots.31
While time is of unquestionable importance in delivering rtPA, the
development of penumbral imaging using positron emission tomography (PET),
MRI, and CT perfusion32-34 has shown that some patients are slow progressors (ie,
their collateral flow or other less obvious cytoprotective features delay the
incorporation of penumbral regions into infarcted core). Hence, the positive
results of ECASS III, the third International Stroke Trial, and a pooled analysis of
all randomized data showed the benefit of rtPA treatment up to 4.5 hours if
extensive ischemic changes are not already present on CT scanning.7,8,35 More
dramatically, studies in patients who awaken from their stroke or who have
uncertain time of onset up to 9 hours from last time known well have
432 APRIL 2023

demonstrated as much benefit as KEY POINTS
earlier treatment, provided
● Use of emergency
substantial irreversible ischemic department telestroke,
damage is not present on bringing stroke treatment
imaging.36,37 This has fostered to the patient’s home
the concept of the “tissue clock” via mobile stroke

units, improved
that is unique to each patient

telecommunication, and
and becomes more important other devices will help
with time elapsed from last time increase the use of IV
known well. The tissue clock can thrombolysis.
be read on each patient using
● There are many
MRI or CT perfusion techniques disparities in the availability
demonstrating a favorable ratio and use of IV thrombolysis,
of penumbral tissue volume and overcoming them is an
compared with irreversibly important priority for
improving stroke outcomes.
damaged ischemic core volume.
The tissue clock concept opens ● The sooner IV

the window of treatment to thrombolysis is delivered
substantially more patients after symptom onset, the
better the outcome; if
(CASE 2-3).
treatment can be given in
the first golden hour via
INTERACTION WITH mobile stroke units or by
ENDOVASCULAR expedited emergency
department care, two-thirds
THROMBECTOMY
of patients will recover with
While not the subject of this no disability.
article, endovascular
thrombectomy has transformed ● Advanced imaging reveals
the field of acute stroke treatment that the temporal
progression of stroke is
FIGURE 2-3 because of its powerful benefit on different in each patient;
Increased frequency of “golden hour” treatment outcomes in patients with large outcomes with treatment
by mobile stroke units results in better outcome.
vessel occlusions.38 While patients out to 9 hours after symptom
A, Distribution of time from symptom onset to onset in imaging-selected
recombinant tissue plasminogen activator (rtPA) with large vessel occlusions are a
patients may result in
bolus in patients treated by a mobile stroke unit critical population to identify and comparable benefit to
versus standard management by emergency transport to endovascular earlier treatment.
medical services. B, Relation of time from
thrombectomy centers because of
symptom onset and recovery to modified Rankin
Scale score of 0 or 1 at 90 days in patients treated the substantial benefits they
with rtPA in the BEST-MSU (BEnefits of Stroke receive from endovascular
Treatment Delivered Using a Mobile Stroke Unit) thrombectomy, most patients with
study showing increasing benefit with treatment acute stroke who qualify for rtPA
in the first hour.
Reprinted from Grotta JC, et al, N Engl J Med.29 do not have large vessel occlusions
© 2021 Massachusetts Medical Society. that are accessible by endovascular
thrombectomy.39 Therefore, IV
thrombolysis with rtPA or any
other systemic lytic that may replace it will not disappear from the acute stroke
treatment armamentarium and will remain the most frequent treatment for the
largest proportion of patients with stroke.
For the foreseeable future, there will be more primary stroke centers able to
carry out IV thrombolysis than comprehensive or thrombectomy-capable centers
able to deliver endovascular thrombectomy. Therefore, in managing patients
with acute stroke, systems of care need to balance the need to administer IV

thrombolysis as soon as possible to those who qualify, and at the same time,
identify patients with large vessel occlusion and expedite their triage to the
nearest endovascular thrombectomy center. This has led to the “drip and ship”
concept, where patients stop first at the nearest primary stroke center for IV
thrombolysis, get screened for large vessel occlusions, and if one is found, they
are sent to the endovascular thrombectomy center. The alternative approach is to

use various prehospital screening tools to identify potential patients with large
vessel occlusions and deliver them directly to the endovascular thrombectomy
center for both IV thrombolysis and endovascular thrombectomy. A recent study
carried out in Catalonia, Spain, where relatively long distances separate the
primary and endovascular thrombectomy centers, showed that these approaches
are equivalent.40 It is likely that the optimal solution will depend on local
distribution of available resources. Mobile stroke units are also a logical solution
since they are essentially a primary stroke center on wheels that can deliver IV
thrombolysis and screen the patient for large vessel occlusions, thereby obviating
the need to choose between a drip and ship or direct to endovascular
thrombectomy center approach.
CASE 2-2 A 65-year-old man with a history of treated hypertension was noted by
his wife to suddenly stop speaking and slump over to the right at 10:35 AM
as they were sitting having coffee. She immediately called 911, which
dispatched an emergency medical services (EMS) first responder and
medic and the mobile stroke unit. EMS arrived on scene at 10:50 AM and,
recognizing a severe stroke (Los Angeles Motor Scale = 5), began
transport to the nearest comprehensive stroke center and inserted two
IV lines. The mobile stroke unit rendezvoused with the EMS part way
between the scene and the nearest stroke center at 11:12 AM.
The patient was awake and attentive with a blood pressure of 175/80 mm
Hg and a regular rate and rhythm, but had global aphasia, gaze to the left,
no response to threat in the right visual field, right facial weakness, right
hemiplegia, no response to pain on the right, and a National Institutes of
Health Stroke Scale (NIHSS) score of 25 measured by the mobile stroke unit
nurse in concert with the telemedicine-based vascular neurologist. The
patient was transferred into the mobile stroke unit where a CT scan was
performed, and images were uploaded to a web-based picture archiving
and communications system and immediately read by the telemedicine-
based vascular neurologist. Based on an estimated weight of 113 kg (250 lb),
the patient was administered an IV recombinant tissue plasminogen
activator (rtPA) bolus of 9 mg at 11:22 AM (47 minutes after symptom onset)
followed immediately by an rtPA infusion of 81 mg over 60 minutes. While
still in the mobile stroke unit, CT angiography was then carried out using the
second IV line for the contrast (FIGURE 2-4). The CT angiography images were
read by the vascular neurologist and showed a lack of opacification of the
left distal internal carotid artery and middle cerebral artery at 11:27 AM.
The endovascular physician on call was called by the vascular
neurologist, and the mobile stroke unit began transport and arrived at the
emergency department at 11:46 AM. The patient was taken directly to the
434 APRIL 2023

Some patients may qualify for endovascular thrombectomy but not for IV
thrombolysis, or IV thrombolysis may be relatively ineffective in some
candidates for thrombectomy. For instance, patients taking factor Xa inhibitors
are excluded from IV thrombolysis according to current guidelines41 but may be
safely treated with endovascular thrombectomy. The more common situation
where IV thrombolysis may be skipped is when the patient directly presents to

the endovascular thrombectomy center. Several studies have examined outcomes

in patients with large vessel occlusions presenting directly to the endovascular
center emergency department who were randomly assigned to receive rtPA or not,
prior to endovascular thrombectomy, with conflicting results.42-44 While rtPA is
relatively ineffective in dissolving a large vessel occlusion, it can do so in 10% to 30%
of cases,45 particularly if administered in the first hour after last time known well
and given 30 to 60 minutes to work. A recent meta-analysis of patients presenting to
nonendovascular thrombectomy centers with large vessel occlusions showed that
outcomes were better if rtPA was given prior to transfer to the endovascular center
than if it was skipped.46 Therefore, current practice is not to skip rtPA unless the
patient presents directly to the endovascular thrombectomy center, has an
endovascular suite; skin puncture occurred at 11:56 AM, and reperfusion with
thrombolysis in cerebral infarction grade 3 flow was established at 12:26 PM.
At 24 hours after symptom onset, the NIHSS score was 3 for mild right
facial weakness, right arm pronator drift, and speech hesitancy.
FIGURE 2-4
Imaging of the patient in CASE 2-2. A, CT angiography from the mobile stroke unit showing
occluded distal left internal carotid artery. B, Arteriogram showing the distal internal
carotid artery occlusion.
This case illustrates how a mobile stroke unit can achieve treatment within COMMENT
the first hour after symptom onset by beginning rtPA treatment on the
scene and identify and triage an appropriate thrombectomy candidate to
the appropriate stroke center.

CASE 2-3 A 71-year-old woman presented to the emergency department after

waking up at 9:30 AM with left-sided weakness. She had a history of
hypertension and hypothyroidism, and was last known well at 1:30 AM
when she got up to use the bathroom. The patient’s National Institutes of
Health Stroke Scale (NIHSS) score was 14, and her examination
demonstrated left hemiparesis and sensory loss, right gaze preference,
and visual neglect. Head CT was negative for acute hemorrhage or signs
of early ischemic change. CT angiography showed a subocclusive right
middle cerebral artery clot, and CT perfusion showed a 79 mL area of
decreased perfusion with no infarction “core” (FIGURE 2-5).
After obtaining informed consent, the patient was given a recombinant
tissue plasminogen activator (rtPA) bolus at 10:37 AM per the “wake-up”
protocol. The patient rapidly improved and thus did not receive
thrombectomy, and by 24 hours after symptom onset her NIHSS score was 4
and MRI showed a small area of infarction in the right corona radiata.
FIGURE 2-5
Imaging of the patient in CASE 2-3. CT perfusion study showing decreased tissue perfusion
in the right middle cerebral artery territory (green) but no area where flow was reduced
to a level predicting irreversible damage (infarct). Please refer to the legend of
FIGURE 2-2 for a depiction of a region with decreased perfusion (green) versus a region
with irreversible damage (purple). For the software used in these images, the area of
decreased perfusion is defined as the volume of brain tissue having a greater than
6-second delay in the arrival of the maximal dye bolus, whereas the area of irreversible
damage (“infarct core”) is defined as the volume of brain tissue with a calculated cerebral
blood flow of less than 30%, both compared to the homologous region of the contralateral
hemisphere. Note the absence of any purple infarct core in this figure.
COMMENT This case illustrates the use of perfusion imaging to identify a patient who
could be safely and effectively treated with IV thrombolysis beyond
4.5 hours from the time they were last known well.
436 APRIL 2023

approachable clot, and the thrombectomy team is immediately available. Even in KEY POINTS
those circumstances, it is possible that endovascular thrombectomy will not be
● Regional systems of care
successful, and the patient would be deprived of any treatment if IV thrombolysis must balance the need to
were skipped. administer IV thrombolysis
as soon as possible to those
TENECTEPLASE AND OTHER APPROACHES who qualify while also

identifying and expediting
Tenecteplase is under evaluation as an alternative to rtPA for acute stroke

triage of patients with large
treatment and has a class 2b recommendation in patients with acute stroke due to vessel occlusion to the
large vessel occlusion.14,47-50 Tenecteplase has a longer half-life and is given as an nearest endovascular
IV bolus without infusion.51 This provides important logistic advantages; thrombectomy center.
specifically, it is not necessary to insert a dedicated IV line for the infusion. This
● IV thrombolysis can
may lead to faster time between entering the emergency department to needle dissolve 20% to 30% of large
time but, more importantly, provides a therapeutic blood level after the bolus vessel occlusion clots and
without requiring the continuous 1-hour infusion needed with rtPA. In our should not be withheld in
experience, when rtPA bolus and infusion are started by the mobile stroke unit patients meeting treatment
criteria except in rare
and the patient is then handed off to the emergency department stroke team for circumstances.
completion of the infusion, the rtPA infusion is delayed or interrupted 8% of the

time, usually because of technical difficulties with the IV or suspicion of bleeding ● Compared with rtPA,
or other adverse effects. Such delays will reduce the blood level of rtPA below the tenecteplase is more
convenient, delivers the full
therapeutic range without rebolusing.52 Finally, EMS agencies may be reluctant to
dose faster, and produces
transfer patients from a primary stroke center to an endovascular thrombectomy comparable outcomes, but
center with a rtPA infusion running in the drip and ship scenario. Tenecteplase is not yet approved by the
may have advantages over rtPA beyond logistics. It is more fibrin specific and FDA for IV thrombolysis.
therefore may achieve superior clot lysis, as was demonstrated in at least one study
of large vessel occlusions,51 and may also be associated with fewer bleeding
complications. Several studies of tenecteplase versus rtPA are ongoing and should
provide a definitive answer about best dose and relative efficacy. However, the
best evidence to date, based on two large, randomized comparisons53,54 and three
different meta-analyses of studies,55-57 shows that tenecteplase is “noninferior” to
rtPA, meaning their outcomes and safety are similar. Other thrombolytics are also
under evaluation.58
Other investigational approaches focus on achieving more complete lysis
than intravenous thrombolysis alone by adding an antithrombotic agent during
the thrombolytic infusion. Concomitant heparin has been associated with
increased bleeding, but GP2b3a receptor antagonists and thrombin inhibitors
have proven safe in phase 2 studies59,60 and are under evaluation in an ongoing
phase 3 study.61
THE FUTURE OF IV THROMBOLYSIS

The “time is brain” and “tissue clock” concepts will continue to be the focus of IV
thrombolysis. Regarding the former concept, this will include efforts to
streamline our emergency department pathways and prehospital triage systems.
Mobile stroke units have the potential to provide an important quantum leap in
speeding care if financial and logistic issues can be solved. These include
appropriate reimbursement so that mobile stroke unit programs can be fiscally
sustainable. Models of the best method of deploying mobile stroke units in
regions with sparse or concentrated stroke centers need to be developed. Also, we
need to reduce patient disincentives for calling 911, and use artificial intelligence
and other technology to screen 911 calls to make mobile stroke unit dispatch more
efficient. More research on devices to help with early detection of stroke might

increase the number of patients who call for help immediately after symptom
onset. Regarding the tissue clock, more widespread dissemination of imaging to
community hospitals where most patients with stroke seek care may detect more
patients who may benefit from IV thrombolysis in the late time window.
However, this improved imaging access should be combined with efforts to
simplify the required imaging protocol. In addition, studies should refine the
risks versus benefits of extending the time window even further and in certain
subpopulations, such as those with significant preexisting disability. It will be
important to develop public health messaging that alerts patients with stroke and
their caregivers to the potential of late treatment without diluting the imperative
to call 911 immediately after symptoms occur.
Another focus of IV thrombolysis research will be how to improve clot lysis
and reperfusion beyond what we now achieve with rtPA and tenecteplase. There
are two targets: increasing immediate recanalization and reversing “no reflow” in
the microcirculation. Studies using continuous transcranial Doppler insonation
of middle cerebral artery clots after rtPA show that the clots may start to dissolve
and fragment but then the artery may reocclude (FIGURE 2-6).62 The newer
FIGURE 2-6
Recanalization and reocclusion after IV thrombolysis in a representative case of a middle
cerebral artery occlusion. The top panel shows the transcranial Doppler signal with signal
loss at the time of occlusion, reappearance of signal with clot fragmentation, and signal
dampening with reocclusion (white arrow). This is associated with clinical improvement
(decrease) and then deterioration (increase) on the National Institutes of Health Stroke Scale
(middle panel). The lower panel shows the pre–recombinant tissue plasminogen activator
(rtPA) noncontrast CT scan, the timetable of events, the post-rtPA noncontrast CT scan
done after the patient had clinical deterioration, and the digital subtraction angiogram
showing persistent occlusion of the right middle cerebral artery as predicted by the
transcranial Doppler.
CT = computed tomography; DSA = digital subtraction angiography; TPA = tissue plasminogen activator.
Reprinted from Alexandrov and Grotta, Neurology.62 © 2002, American Academy of Neurology.
438 APRIL 2023

thrombolytics and linking thrombolytics with antithrombotic agents, as already KEY POINT
mentioned, may prevent such reocclusion and could be the next step in achieving
● Research is ongoing to
improved recanalization. In addition, inadequate reperfusion due to distal study the wider
embolization and impaired microcirculatory flow may exist despite excellent implementation of mobile
recanalization of the proximal occlusion. A recent study showed that infusing stroke units in speeding up
rtPA intraarterially distal to the site of occlusion after successful endovascular the delivery of IV
thrombolysis to patients
thrombectomy results in improved clinical oucome63 and supports the
with stroke.
importance of “no reflow.” Longer-lasting thrombolytics or linking IV
thrombolysis with antithrombotic drugs may be effective for improving
reperfusion as well as increasing recanalization.
CONCLUSION
IV thrombolysis will remain the most common acute stroke treatment. Exciting
advances in speeding up treatment have increased its efficacy, and advances in
imaging have expanded its use. Newer thrombolytics and antithrombotic agents
may improve recanalization and reperfusion after IV thrombolysis. However,

developing the systems of care to implement these advances and overcoming
disparities in IV thrombolysis utilization remain major challenges.
REFERENCES
1 Brott TG, Haley EC, Levy DE, et al. Urgent therapy 7 Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis
for stroke. part I. pilot study of tissue with alteplase 3 to 4.5 hours after acute ischemic
plasminogen activator administered within stroke. N Engl J Med 2008;359(13):1317-1329.
90 minutes. Stroke 1992;23(5):632-640. doi:10.1161/ doi:10.1056/NEJMoa0804656
01.str.23.5.632
8 Emberson J, Lees KR, Lyden P, et al. Effect of
2 Haley EC, Levy DE, Brott TG, et al. Urgent treatment delay, age, and stroke severity on the
therapy for stroke. part II. pilot study of tissue effects of intravenous thrombolysis with
plasminogen activator administered 91-180 minutes alteplase for acute ischaemic stroke: a
from onset. Stroke 1992;23(5):641-645. doi:10.1161/01. meta-analysis of individual patient data from
str.23.5.641 randomised trials. Lancet 2014;384(9958):
1929-1935. doi:10.1016/S0140-6736(14)60584-5
3 National Institute of Neurological Disorders and
Stroke rt-PA Stroke Study Group. Tissue 9 Ingall TJ, O’Fallon WM, Asplund K, et al. Findings
plasminogen activator for acute ischemic stroke. from the reanalysis of the NINDS tissue
N Engl J Med 1995;333(24):1581-1587. doi:10.1056/ plasminogen activator for acute ischemic stroke
NEJM199512143332401 treatment trial. Stroke 2004;35(10):2418-2424. doi:
10.1161/01.STR.0000140891.70547.56
4 Mori E, Yoneda Y, Tabuchi M, et al. Intravenous
recombinant tissue plasminogen activator in 10 Marler JR, Tilley BC, Lu M, et al. Early stroke
acute carotid artery territory stroke. Neurology treatment associated with better outcome: the
1992;42(5):976-982. doi:10.1212/wnl.42.5.976 NINDS rt-PA stroke study. Neurology 2000;55(11):
1649-1655. doi:10.1212/wnl.55.11.1649
5 Hacke W, Kaste M, Fieschi C, et al. Intravenous
thrombolysis with recombinant tissue 11 Kim JT, Fonarow GC, Smith EE, et al. Treatment
plasminogen activator for acute hemispheric with tissue plasminogen activator in the golden
stroke. The European Cooperative Acute Stroke hour and the shape of the 4.5-hour time-benefit
Study (ECASS). JAMA 1995;274(13):1017-1025. curve in the national United States Get With The
PMID: 7563451 Guidelines-Stroke population. Circulation 2017;
135(2):128-139. doi:10.1161/CIRCULATIONAHA.
6 Hacke W, Kaste M, Fieschi C, et al. Randomised
116.023336
double-blind placebo-controlled trial of
thrombolytic therapy with intravenous alteplase 12 Lansberg MG, Schrooten M, Bluhmki E, Thijs VN,
in acute ischaemic stroke (ECASS II). second Saver JL. Treatment time-specific number
European-Australasian acute stroke study needed to treat estimates for tissue
investigators. Lancet 1998;352(9136):1245-1251. plasminogen activator therapy in acute stroke
doi:10.1016/s0140-6736(98)08020-9 based on shifts over the entire range of the
modified Rankin Scale. Stroke 2009;40(6):
2079-2084. doi:10.1161/STROKEAHA.108.540708

13 Rabinstein AA. Update on treatment of acute 24 Ebinger M, Winter B, Wendt M, et al. Effect of the
ischemic stroke. Continuum (Minneap Minn) use of ambulance-based thrombolysis on time to
2020;26(2):268-286. doi:10.1212/ thrombolysis in acute ischemic stroke: a
CON.0000000000000840 randomized clinical trial. JAMA 2014;311(16):
1622-1631. doi:10.1001/jama.2014.2850
14 Powers WJ, Rabinstein AA, Ackerson T, et al.
Guidelines for the early management of patients 25 Suolang D, Chen BJ, Wang NY, Gottesman RF,
with acute ischemic stroke: 2019 update to the Faigle R. Geographic and regional variability
2018 guidelines for the early management of in racial and ethnic disparities in stroke
acute ischemic stroke: a guideline for healthcare thrombolysis in the United States. Stroke
professionals from the American Heart 2021;52(12):e782-e787. doi:10.1161/
Association/American Stroke Association. Stroke STROKEAHA.121.035220
2019;50(12):e344-e418. doi:10.1161/
26 Jones TH, Morawetz RB, Crowell RM, et al.
STR.0000000000000211
Thresholds of focal cerebral ischemia in awake
15 ACTIVASE (alteplase). Prescribing information. monkeys. J Neurosurg 1981;54(6):773-782.
gene.com/download/pdf/activase_prescribing. doi:10.3171/jns.1981.54.6.0773
pdf. Accessed February 24, 2023.
27 Astrup J, Siesjö BK, Symon L. Thresholds in
16 Rabinstein AA. Treatment of acute ischemic cerebral ischemia - the ischemic penumbra.
stroke. Continuum (Minneap Minn) 2017;23(1, Stroke 1981;12(6):723-725. doi:10.1161/01.str.
Cerebrovascular Disease):62-81. doi:10.1212/ 12.6.723
CON.0000000000000420
28 Kaplan B, Brint S, Tanabe J, et al. Temporal
17 Balucani C, Levine SR, Khoury JC, et al. Acute thresholds for neocortical infarction in rats
ischemic stroke with very early clinical subjected to reversible focal cerebral ischemia.
improvement: a national institute of neurological Stroke 1991;22(8):1032-1039. doi:10.1161/01.
disorders and stroke recombinant tissue str.22.8.1032
plasminogen activator stroke trials exploratory
29 Grotta JC, Yamal JM, Parker SA, et al.
analysis. J Stroke Cerebrovasc Dis 2016;25(4):
Prospective, multicenter, controlled trial of
894-901. doi:10.1016/j.
mobile stroke units. N Engl J Med 2021;385(11):
jstrokecerebrovasdis.2015.10.028
971-981. doi:10.1056/NEJMoa2103879
18 Khatri P, Kleindorfer DO, Devlin T, et al. Effect of
30 Ebinger M, Siegerink B, Kunz A, et al. Association
alteplase vs aspirin on functional outcome for
between dispatch of mobile stroke units and
patients with acute ischemic stroke and minor
functional outcomes among patients with acute
nondisabling neurologic deficits: the PRISMS
ischemic stroke in Berlin. JAMA 2021;325(5):
randomized clinical trial. JAMA 2018;320(2):
454-466. doi:10.1001/jama.2020.26345
156-166. doi:10.1001/jama.2018.8496
31 Jolugbo P, Ariëns RAS. Thrombus composition
19 Demaerschalk BM, Kleindorfer DO, Adeoye OM,
and efficacy of thrombolysis and thrombectomy
et al. Scientific rationale for the inclusion and
in acute ischemic stroke. Stroke 2021;52(3):
exclusion criteria for intravenous alteplase in
1131-1142. doi:10.1161/STROKEAHA.120.032810
acute ischemic stroke: a statement for
healthcare professionals from the American 32 Baron JC, Bousser MG, Comar D, Soussaline F,
Heart Association/American Stroke Association. Castaigne P. Noninvasive tomographic study of
Stroke 2016;47:581-641. doi:10.1161/ cerebral blood flow and oxygen metabolism in
STR.0000000000000086 vivo. Potentials, limitations, and clinical
applications in cerebral ischemic disorders. Eur
20 Otite FO, Patel S, Sharma R, et al. Trends in
Neurol 1981;20(3):273-284. doi:10.1159/000115247
incidence and epidemiologic characteristics of
cerebral venous thrombosis in the United States. 33 Albers GW, Thijs VN, Wechsler L, et al. Magnetic
Neurology 2020;95(16):e2200-e2213. doi:10.1212/ resonance imaging profiles predict clinical
WNL.0000000000010598 response to early reperfusion: the diffusion and
perfusion imaging evaluation for understanding
21 Levine SR, Gorman M. “Telestroke”: the
stroke evolution (DEFUSE) study. Ann Neurol
application of telemedicine for stroke. Stroke
2006;60(5):508-517. doi:10.1002/ana.20976
1999;30(2):464-469. doi:10.1161/01.str.30.2.464
34 Lansberg MG, Cereda CW, Mlynash M, et al.
22 Morgenstern LB, Bartholomew LK, Grotta JC,
Response to endovascular reperfusion is not
et al. Sustained benefit of a community and
time-dependent in patients with salvageable
professional intervention to increase acute
tissue. Neurology 2015;85(8):708-714. doi:10.1212/
stroke therapy. Arch Intern Med 2003;163(18):
WNL.0000000000001853
2198-2202. doi:10.1001/archinte.163.18.2198
35 IST-3 collaborative group, Sandercock P,
23 Walter S, Kostpopoulos P, Haass A, et al. Bringing
Wardlaw JM, et al. The benefits and harms of
the hospital to the patient: first treatment of
intravenous thrombolysis with recombinant
stroke patients at the emergency site. PLoS One
tissue plasminogen activator within 6 h of acute
2010;5(10):e13758. doi:10.1371/journal.
ischaemic stroke (the third international stroke
pone.0013758
trial [IST-3]): a randomised controlled trial.
Lancet 2012;379(9834):2352-2363. doi:10.1016/
S0140-6736(12)60768-5
440 APRIL 2023

36 Thomalla G, Simonsen CZ, Boutitie F, et al. 46 Katsanos AH, Sarraj A, Froehler M, et al.
MRI-guided thrombolysis for stroke with Intravenous thrombolysis initiated before
unknown time of onset. N Engl J Med 2018;379(7): transfer for endovascular stroke thrombectomy:
611-622. doi:10.1056/NEJMoa1804355 a systematic review and meta-analysis.
Neurology Published online December 29, 2022:
37 Campbell BCV, Ma H, Ringleb PA, et al. Extending
10.1212/WNL.0000000000206784. doi:10.1212/
thrombolysis to 4·5-9 h and wake-up stroke using
WNL.0000000000206784
perfusion imaging: a systematic review and

meta-analysis of individual patient data. 47 Kheiri B, Osman M, Abdalla A, et al. Tenecteplase
Lancet 2019;394(10193):139-147. doi:10.1016/S0140- versus alteplase for management of acute

6736(19)31053-0 ischemic stroke: a pairwise and network
meta-analysis of randomized clinical trials.
38 Goyal M, Menon BK, van Zwam WH, et al.
J Thromb Thrombolysis 2018;46(4):440-450.
Endovascular thrombectomy after large-vessel
doi:10.1007/s11239-018-1721-3
ischaemic stroke: a meta-analysis of individual
patient data from five randomised trials. Lancet 48 Burgos AM, Saver JL. Evidence that tenecteplase
2016;387(10029):1723-1731. doi:10.1016/S0140- Is noninferior to alteplase for acute ischemic
6736(16)00163-X stroke: meta-analysis of 5 randomized trials.
Stroke 2019;50(8):2156-2162. doi:10.1161/
39 Reeves M, Khoury J, Alwell K, et al. Distribution of
STROKEAHA.119.025080
National Institutes of Health stroke scale in the
Cincinnati/Northern Kentucky Stroke Study. 49 Campbell BCV, Mitchell PJ, Churilov L, et al.
Stroke 2013;44(11):3211-3213. doi:10.1161/ Effect of intravenous tenecteplase dose on
STROKEAHA.113.002881 cerebral reperfusion before thrombectomy in

patients with large vessel occlusion ischemic
40 Abilleira S, Pérez de la Ossa N, Jiménez X, et al.
stroke: the EXTEND-IA TNK part 2 randomized
Transfer to the local stroke center versus direct
clinical trial. JAMA 2020;323(13):1257-1265.
transfer to endovascular center of acute stroke
doi:10.1001/jama.2020.1511
patients with suspected large vessel occlusion in
the Catalan territory (RACECAT): study protocol 50 Warach SJ, Dula AN, Milling TJ. Tenecteplase
of a cluster randomized within a cohort trial. thrombolysis for acute ischemic stroke. Stroke
Int J Stroke 2019;14(7):734-744. doi:10.1177/ 2020;51(11):3440-3451. doi:10.1161/
1747493019852176 STROKEAHA.120.029749
41 Czap AL, Grotta J. Complexities of reperfusion 51 Benedict CR, Refino CJ, Keyt BA, et al. New
therapy in patients with ischemic stroke variant of human tissue plasminogen activator
pretreated with direct oral anticoagulants: to (TPA) with enhanced efficacy and lower
treat or not, and how? JAMA Neurology 2021; incidence of bleeding compared with
78(5):517-518. doi:10.1001/jamaneurol.2021.0290 recombinant human TPA. Circulation 1995;92(10):
3032-3040. doi:10.1161/01.cir.92.10.3032
42 LeCouffe NE, Kappelhof M, Treurniet KM, et al. A
randomized trial of intravenous alteplase before 52 Smith C, Al-Nuaimi Y, Wainwright J, et al. The
endovascular treatment for stroke. N Engl J Med influence of bolus to infusion delays on plasma
2021;385(20):1833-1844. doi:10.1056/ tissue plasminogen activator levels. Int J Stroke
NEJMoa2107727 2014;9(7):939-942. doi:10.1111/j.1747-4949.
2012.00924.x
43 Suzuki K, Matsumaru Y, Takeuchi M, et al. Effect
of mechanical thrombectomy without vs with 53 Menon BK, Buck BH, Singh, et al. Intravenous
intravenous thrombolysis on functional outcome tenecteplase compared with alteplase for acute
among patients with acute ischemic stroke: the ischaemic stroke in Canada (AcT): a pragmatic,
SKIP randomized clinical trial. JAMA 2021;325(3): multicentre, open-label, registry-linked,
244-253. doi:10.1001/jama.2020.23522 randomised, controlled, non-inferiority trial.
Lancet 2022;400:161-169. doi:10.1016/S0140-
44 Zi W, Qiu Z, Li F, et al. Effect of endovascular
6736(22)01054-6
treatment alone vs intravenous alteplase plus
endovascular treatment on functional 54 Wang Y, Li S, Pan Y, et al. Tenecteplase versus
independence in patients with acute ischemic alteplase in acute ischaemic cerebrovascular
stroke: the DEVT randomized clinical trial. JAMA events (TRACE-2): a phase 3, multicentre,
2021;325(3):234-243. doi:10.1001/jama.2020.23523 open-label, randomised controlled, non-
inferiority trial. Lancet 2023;401:645-654.
45 Czap AL, Parker S, Yamal J, et al. Immediate doi:10.1016/S0140-6736(22)02600-9
recanalization of large-vessel occlusions by
tissue plasminogen activator occurs in 28% of 55 Requiao LE, Oliveira RS, Reis LS, et al. Short-Term
patients treated in a mobile stroke unit. Stroke: Efficacy Outcomes of Tenecteplase versus
Vascular and Interventional Neurology 2022;2(2): Alteplase for Acute Ischemic Stroke: A Meta-
e000101. doi:10.1161/SVIN.121.000101 Analysis of 5 Randomized Trials. Neurol India
2022;70:1454-1459. doi:10.4103/0028-3886.355108
56 Ma P, Zhang Y, Chang L, et al. Tenecteplase vs.
alteplase for the treatment of patients with
acute ischemic stroke: a systematic review and
meta-analysis. J Neurol 2022;269:5262-5271. doi:
10.1007/s00415-022-11242-4

57 Katsanos AH, Psychogios K, Turc G, et al. Off- 60 Adeoye O, Sucharew H, Khoury J, et al. Combined
Label Use of Tenecteplase for the Treatment of approach to lysis utilizing eptifibatide and
Acute Ischemic Stroke: A Systematic Review and recombinant tissue-type plasminogen activator
Meta-analysis. JAMA Netw Open 2022 Mar 1;5(3): in acute ischemic stroke-full dose regimen
e224506. doi: 10.1001/jamanetworkopen. Stroke trial. Stroke 2015;46(9):2529-2533.
2022.4506. PMID: 35357458; PMCID: PMC8972028. doi:10.1161/STROKEAHA.115.010260
doi:10.1001/jamanetworkopen.2022.4506
61 Deeds SI, Barreto A, Elm J, et al. The multiarm

58 Gusev EI, Martynov MY, Nikonov AA, et al. optimization of stroke thrombolysis phase 3
Non-immunogenic recombinant staphylokinase acute stroke randomized clinical trial: Rationale

versus alteplase for patients with acute and methods. Int J Stroke 2021;16(7):873-880.
ischaemic stroke 4·5 h after symptom onset in doi:10.1177/1747493020978345
Russia (FRIDA): a randomised, open label,
62 Alexandrov AV, Grotta JC. Arterial reocclusion in
multicentre, parallel-group, non-inferiority trial.
stroke patients treated with intravenous tissue
Lancet Neurol 2021;20(9):721-728. doi:10.1016/
plasminogen activator. Neurology 2002;59(6):
S1474-4422(21)00210-6
862-867. doi:10.1212/wnl.59.6.862
59 Barreto AD, Ford GA, Shen L, et al. Randomized,
63 Renú A, Millán M, San Román L, et al. Effect of
multicenter trial of ARTSS-2 (argatroban with
intra-arterial alteplase vs placebo following
recombinant tissue plasminogen activator for
successful thrombectomy on functional
acute stroke). Stroke 2017;48(6):1608-1616.
outcomes in patients with large vessel occlusion
doi:10.1161/STROKEAHA.117.016720
acute ischemic stroke: the CHOICE randomized
clinical trial. JAMA 2022;327(9):826-835.

doi:10.1001/jama.2022.1645
442 APRIL 2023

Intravenous Thrombolysis For Acute Ischemic 2023

Uploaded by

Copyright:

Available Formats

You might also like

Intravenous Thrombolysis For Acute Ischemic 2023

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Intravenous Thrombolysis For Acute Ischemic 2023

Uploaded by

Copyright:

Available Formats

Intravenous REVIEW ARTICLE

Thrombolysis for Acute

By James C. Grotta, MD, FAAN

IV thrombolysis, the emergence of tenecteplase, and future research

© 2023 American Academy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

activator (rtPA) followed by the exclusion criteria that have evolved

426 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

is no point-of-care test available to determine if patients are anticoagulated,

CURRENT USE OF INTRAVENOUS THROMBOLYSIS

TABLE 2-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen

Diagnosis of ischemic stroke with disabling neurologic Same

Symptom onsetc within 4.5 hours Within 3 hours

Wake-up stroke with diffusion-weighted imaging FLAIR Not contemplated

Severe head trauma within 3 months Same

Ischemic stroke within 3 months Removede

Previous intracranial hemorrhage Warning for recent intracranial hemorrhage (contraindicated if

Suspected subarachnoid hemorrhage Same

Suspected infective endocarditis Not listed

Suspected aortic arch dissection Not listed

Recent intracranial or intraspinal surgery (within 3 months) Same

Intracranial intraaxial neoplasm Not listed

Gastrointestinal malignancy or gastrointestinal bleeding Warning

CONTINUED ON PAGE 429

428 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CONTINUED FROM PAGE 428

Bleeding diathesis Same (laboratory values removede)

International normalized ratio (INR) >1.7

Heparin within 48 hours with abnormal activated partial

Low-molecular-weight heparin full treatment dose within

Current use of direct thrombin inhibitor or factor Xa

CT showing acute hemorrhage Same

CT showing extensive hypodensity (eg, >1/3 of the cerebral Removede

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

socioeconomic groups, ethnicities, and races.20 Clearly, IV thrombolysis is rarely

suggests that the benefit of IV thrombolysis differs among these groups

disparities in access to IV thrombolysis.

TIME WINDOWS FOR INTRAVENOUS THROMBOLYSIS

CASE 2-1 A 65-year-old man, employed as a construction worker, was evaluated

430 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

432 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

the concept of the “tissue clock” via mobile stroke

that is unique to each patient

The tissue clock concept opens ● The sooner IV

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

are sent to the endovascular thrombectomy center. The alternative approach is to

thrombectomy center approach.

434 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

where IV thrombolysis may be skipped is when the patient directly presents to

the endovascular thrombectomy center. Several studies have examined outcomes

patient presents directly to the endovascular thrombectomy center, has an