STATE OF THE ART REVIEW

Management of acute ischemic stroke

BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
Michael S Phipps,1,2 Carolyn A Cronin1
A BST RAC T

1
Stroke is the leading cause of long term disability in developed countries and one
Department of Neurology,
University of Maryland School of of the top causes of mortality worldwide. The past decade has seen substantial
Medicine, Baltimore, MD, USA
2
advances in the diagnostic and treatment options available to minimize the impact
Department of Epidemiology
and Public Health, University of of acute ischemic stroke. The key first step in stroke care is early identification of
Maryland School of Medicine,
Baltimore, MD, USA patients with stroke and triage to centers capable of delivering the appropriate
Correspondence to: M S Phipps treatment, as fast as possible. Here, we review the data supporting pre-hospital and
mphipps@som.umaryland.edu
Cite this as: BMJ 2020;368:l6983 emergency stroke care, including use of emergency medical services protocols for
http://dx.doi.org/10.1136/bmj.l6983 identification of patients with stroke, intravenous thrombolysis in acute ischemic
Series explanation: State of the
Art Reviews are commissioned
stroke including updates to recommended patient eligibility criteria and treatment
on the basis of their relevance
to academics and specialists
time windows, and advanced imaging techniques with automated interpretation
in the US and internationally. to identify patients with large areas of brain at risk but without large completed
For this reason they are written
predominantly by US authors. infarcts who are likely to benefit from endovascular thrombectomy in extended time
windows from symptom onset. We also review protocols for management of patient
physiologic parameters to minimize infarct volumes and recent updates in secondary
prevention recommendations including short term use of dual antiplatelet therapy to
prevent recurrent stroke in the high risk period immediately after stroke. Finally, we
discuss emerging therapies and questions for future research.

Introduction as systems that provide fast but safe care, because

Worldwide, one in six people will have a stroke in their
lifetime, more than 13.7 million have a stroke each year,
and 5.8 million a year die as a consequence (http://
world-stroke.org). Globally, more than 80 million people
have survived a stroke. About 70% of incident strokes
are ischemic (9.5 million), and the rest are intracerebral
hemorrhage or subarachnoid hemorrhage—the
proportion of ischemic strokes in the US is estimated
to be higher, at about 85-87%.1 This review will focus
on the treatment of ischemic stroke, specifically on
treatment in the hyperacute and acute stages.
Acute ischemic stroke (AIS) is defined by the
sudden loss of blood flow to an area of the brain
with the resulting loss of neurologic function. It is
caused by thrombosis or embolism that occludes a
cerebral vessel supplying a specific area of the brain.
During a vessel occlusion, there is a core area where
damage to the brain is irreversible and an area of
penumbra where the brain has lost function owing to
decreased blood flow but is not irreversibly injured.
Evidence based treatments such as intravenous
thrombolysis and endovascular clot retrieval,
which can remove the obstruction and restore blood
flow to the affected areas of the brain, have been
shown to improve outcomes in AIS when applied to
appropriate patients, with substantial advances in
these treatments occurring in the past few years.2-6
Selecting the right patients involves critical clinical
assessment and brain and vascular imaging, as well
the speed at which AIS is treated is directly related to
outcome.4 7-9 Although other vascular causes of acute
brain injury exist, such as intracerebral hemorrhage,
and important management decisions must be made
after the acute stroke phase, this review will focus
only on the management of ischemic stroke in the
hyperacute and acute phases of the disease.
Sources and selection criteria
Both authors independently searched PubMed and
Embase for English language articles published
between 1 January 2000 and 1 September 2019,
using the keyword terms “prehospital scales ischemic
stroke”, “prehospital diversion in AIS”, “imaging in
AIS”, “thrombolysis or alteplase or tenecteplase in
AIS”, “endovascular thrombectomy or mechanical
thrombectomy in AIS”, “intubation versus conscious
sedation or anesthesia in AIS”, “endovascular
devices in AIS”, “blood pressure management in
AIS”, “glucose management in AIS”, “oxygen therapy
in AIS”, “patient position in AIS”, and “antiplatelet
or anticoagulation or antithrombotic therapy for
secondary stroke prevention”. We included articles
of historical importance from the 1990s that include
the pivotal trials for the use of intravenous alteplase.
We also searched the reference lists of high quality
articles and reviews, and we included selected
randomized controlled trials (RCTs), observational
studies, systematic reviews, and meta-analyses

the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983 1

 STATE OF THE ART REVIEW
from these sources. We gave precedence to large
key studies that have informed the guidelines, but
we also reviewed a wider range of recent studies on
topics for which conclusions and evidence are mixed,
controversial, or both. We excluded case reports and
small case series.
Pre-hospital management
A stroke assessment system used by emergency
medical services (EMS), initial management with
a stroke protocol started in the field, and pre-
notification of hospitals all have moderate evidence
from non-randomized studies and are strongly
recommended.10 Regional EMS systems should
develop triage standards and protocols specific
to stroke, using validated instruments, and an
organization of hospitals with different levels of
stroke care should be developed for rapid triage of
the right patient to the right hospital for the right
treatment, in the most efficient way.10
Levels of care
Hospitals have differing capabilities in terms of
treatment of AIS, and an international consensus
exists on levels of care 1 through 3.11 Level 1 stroke
centers have the full spectrum of endovascular
care, do a minimum number of mechanical
thrombectomies, have dedicated neurointensive
care and stroke units, and have full neurosurgical
services. Level 2 requires at least 100 stroke
patients a year, a stroke unit, and a minimum of 50
mechanical thrombectomies, but neurointensive and
neurosurgical care are not required, whereas level 3
requires only a minimum of 50 patients a year and
a stroke unit. Four designations of stroke centers
exist in the US: comprehensive stroke center (CSC),
thrombectomy ready stroke center (TSC), primary
stroke center (PSC), and acute stroke ready hospital
(ASRH).12 All have different capabilities regarding the
care they can provide to patients with acute stroke.
As endovascular therapy for patients with large
vessel occlusion (LVO) is primarily available at TSCs
and CSCs, diversion of patients with suspected LVO
to these centers has become common in an attempt
to decrease time from when the patient was last
known to be well (“last known well”—LKW) to clot
retrieval. However, the benefit of diverting patients to
different level of stroke centers, including bypassing
the closest to go to a higher level of stroke care, is
uncertain.10 13 A large observational study with
almost 1000 patients suggested that patients taken
directly to endovascular centers did better (60%
achieving functional independence—modified
Rankin Scale (mRS) score 0-2) than patients who were
transferred (52.2%; odds ratio 1.38, 95% confidence
interval 1.06 to 1.79); the authors proposed that
a bypass that adds less than 20 minutes would
improve time to endovascular therapy and therefore
outcomes.14 However, although decreasing time to
endovascular therapy is likely to improve outcomes
for some patients, the increased time to intravenous
alteplase in a bypass may be detrimental to others.
2
Guidelines from the American Heart Association and
American Stroke Association (AHA/ASA) recommend
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
direct transport to a CSC if the travel time is less
than 15 minutes more than that to a PSC or ASRH;
however, the evidence is insufficient to show that
benefits at the higher level of stroke care outweigh
the additional time added until evaluation.10 12 A
protocol to randomize patients in Denmark with
likely large vessel ischemic stroke to the nearest PSC
compared with bypass directly to a CSC has recently
been published and may provide stronger evidence
for this process.15
Pre-hospital scales
Several scales exist to assist EMS in identifying
patients with LVO. Identification is the crucial first
step in getting the right patient to the right treatment
more quickly and, as the outcome depends on time
to reperfusion, might improve outcomes.9 About 20
pre-hospital scales exist16; some of the most common
scales used are the Los Angeles Motor Scale (LAMS),17
Cincinnati Prehospital Stroke Severity Scale
(CPSS),18 and Rapid Arterial Occlusion Evaluation
Scale (RACE).19 Many of the scales were designed
initially to identify patients with stroke as opposed
to conditions that mimic stroke, but some were
specifically designed for identification of patients
with stroke with LVO (for example, Vision, Aphasia,
Neglect or VAN).20 However, a recent meta-analysis
found substantial heterogeneity of sensitivity and
specificity among studies.16 The conclusion of this
meta-analysis suggested that the National Institutes
of Health Stroke Scale (NIHSS), LAMS, and VAN had
the best predictive value for LVO but that more testing
in different populations is needed.
Populations in different settings (such as rural
versus urban) may also benefit from different scales;
for example, triage in rural areas may require a more
specific scale given the time and distance a diversion
might entail. Simple modification of the Face-Arm-
Speech-Time (FAST) or the LAMS score might help
to stratify the risk of an LVO, but neither has been
prospectively validated in the pre-hospital setting.21 22
Mobile stroke units
Mobile stroke units (MSUs), have been deployed since
2010 in a few settings as a means for decreasing time
to treatment for patients with stroke, by bringing
the diagnostic tools and treatments to the patient.
These are essentially retrofitted ambulances that
include a small bore computed tomography scanner
and a laboratory unit that are sent to patients with
a potential stroke for evaluation and treatment with
thrombolytics onsite. However, more personnel are
needed to provide thrombolysis onsite, including
often a neurologist, a computed tomography
technician, and a critical care nurse, in addition to
paramedics.23
Most research on MSUs to date has examined the
known metrics of time for treating with thrombolysis
in AIS, such as alarm to treatment time and LKW to
treatment time, and found better times with MSUs,
doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj

but data on the outcomes of these patients compared
with those not seen by the MSU are limited.23 24 In
addition, telemedicine is often used for remote
assessment by a neurologist for these patients, and
telestroke in general has been increasingly used to
provide access to stroke expertise in rural, remote,
and resource poor areas. Telestroke, which is a two
way audiovisual communication between stroke
specialists and physicians with limited neurologist
coverage, has been shown to be safe and effective
in both rural and urban situations.25 However,
although telestroke can improve access and reduce
times, whether clinical outcomes are improved is
not clear,26 so guidelines give a IIa recommendation
for the use of telestroke in decision making for
thrombolytic treatment.10
Imaging in acute stroke
Acute ischemic stroke and intracerebral hemorrhage
cannot be distinguished clinically, and treatment
with thrombolytics is efficacious in the first and
detrimental to the second. Therefore, all patients
with suspected AIS must have emergent brain
imaging, and in most situations a non-contrast head
computed tomography scan is sufficient for initial
management.10 As outcomes are time dependent,
brain imaging should be done as quickly as possible,
ideally within 20 minutes of the patient’s arrival. If
it does not delay intravenous thrombolysis, non-
invasive intracranial vascular imaging should be
done in patients who otherwise meet criteria for
endovascular clot retrieval. This can be done in
combination with the initial imaging study but
should not delay intravenous thrombolysis. One
potential barrier to including computed tomography
angiography (CTA) with the initial imaging is the
concern about contrast induced nephropathy.
However, evidence shows that the risk of doing
CTA before obtaining a creatinine concentration in
patients without known renal failure is low, and many
radiology guidelines recommend that delays should
not occur because of concerns about creatinine.27-31
One measure of early ischemic changes on a non-
contrast computed tomography head scan that has
been used extensively in acute stroke trials is the
Alberta Stroke Program Early CT Score (ASPECTS).
ASPECTS is a prospectively validated score that
gives points for each of 10 middle cerebral artery
(MCA) territory regions that do not show early
ischemic changes. Generally, an ASPECTS of 6-10
was used as an inclusion criterion in acute stroke
endovascular trials, such as ESCAPE, SWIFT PRIME,
and REVASCAT, to select patients with a relatively
small core (that is, irreversible) infarct.
Perfusion imaging, using either computed
tomography or magnetic resonance imaging (MRI),
has been used to select patients for treatment who
are outside typical time windows (4.5 hours for
intravenous alteplase, 6 hours for endovascular
therapy). Perfusion studies use contrast to measure
the amount and timing of blood flow to certain
areas of the brain, which can help to identify areas
the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983
STATE OF THE ART REVIEW
that have been irreversibly damaged or are at risk
of damage if reperfusion is not achieved. Areas
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
that have a very low blood flow have likely been
irreversibly injured, whereas areas that have enough
blood flow but high time to maximum of the residue
function (Tmax) for the blood to reach that area are
at risk but not yet irreversibly injured. The DAWN
and DEFUSE 3 trials (see below) showed improved
outcomes after thrombectomy for patients selected
by specific parameters of the computed tomography
or MRI perfusion study between six and 16-24
hours.5 6 The EXTEND alteplase study used similar
perfusion studies to determine which patients might
safely receive intravenous alteplase in the 4.5-9 hour
window, with improved outcomes for those who
received it.32
Intravenous thrombolytics
The mainstay of AIS management for the past
two decades has been attempted reperfusion of
ischemic tissue with intravenous thrombolysis. The
recommended eligible patients and time frame for
treatment have evolved over that time.
Alteplase
During the 1990s multiple AIS trials with
intravenous alteplase treated patients up to six hours
from LKW; ECASS I used a dose of 1.1 mg/kg, and
ECASS II, ATLANTIS, and ATLANTIS A used 0.9 mg/
kg.33-36 Each trial designated different primary and
secondary endpoints ranging from acute resolution
of symptoms (24 hour NIHSS score 0-1) to long term
functional improvement (three month mRS, Glasgow
Outcome Scale (GOS), or Barthel Index). Some
trials showed a benefit of thrombolytic therapy in
outcomes other than those that had been designated
as the primary outcome for that study, but all failed to
show a significant benefit of treatment in the primary
outcome measure.
The NINDS trials (parts A and B combined for
publication) treated patients up to three hours from
LKW, with a requirement that half the patients had
to be enrolled at less than 90 minutes from LKW.2
NINDS part A analyzed multiple endpoints, finding
benefit of treatment in a global outcome score
derived as a combination of the NIHSS, mRS, GOS,
and Barthel Index at 90 days (odds ratio for good
outcome 2.1; P=0.001). This global outcome measure
was then used as the primary outcome measure for
NINDS part B, which confirmed the increased rate
of good outcome with intravenous alteplase (odds
ratio 1.7; P=0.008). The benefit of treatment was
present despite the increased risk of symptomatic
intracerebral hemorrhage of 6.4% with intravenous
alteplase compared with 0.6% with placebo, and no
difference was seen in three month mortality (17%
v 21%; P=0.30). A meta-analysis in 2004 of patient
level data from all previous studies with intravenous
alteplase for AIS showed that the odds ratio for
favorable outcome crossed 1.0 at 270 minutes (4.5 h)
from LKW.37 This analysis suggested that pushing the
time window for alteplase out to 4.5 hours may be
3
STATE OF THE ART REVIEW
beneficial. A condition of intravenous alteplase being
approved in Europe for use 0-3 hours from onset on
the basis of the NINDS trials was the initiation of the
ECASS III trial to evaluate the 3-4.5 hour treatment
window further. ECASS III randomized 821 patients
to intravenous alteplase or placebo and found that
the chance of favorable outcome (three month mRS
score 0-1) was 45.2% in the placebo arm and 52.4%
in the treatment group.3
Clinical criteria
The Food and Drug Administration (FDA) approved
alteplase for use in the US with the labeling
instructions mirroring the inclusion/exclusion
criteria from the NINDS trials. When alteplase
was approved in Europe for AIS, the approval
included more restrictive exclusion criteria based
on retrospective analysis of data from the previous
studies. The additional exclusion criteria mandated
in Europe were age greater than 80 years, any oral
anticoagulant treatment regardless of international
normalized ratio, a history of both previous stroke
and diabetes, and severe stroke (defined as NIHSS
score >25 or with ischemic changes involving more
than a third of the MCA territory on head computed
tomography). After publication of ECASS III trial
results, the AHA/ASA issued a scientific statement
recommending use of intravenous alteplase 3-4.5
hours from LKW in patients who meet the inclusion/
exclusion criteria used for the ECASS III trial.38
This difference between trials and the subsequent
recommendations for treatment of patients sparked
debate in the stroke community about which patients
should be treated with intravenous alteplase and
whether having different criteria depending on
the treatment time window makes sense. A meta-
analysis of individual patient data from 6756
patients specifically evaluated efficacy of treatment
in different subgroups of patients and concluded that
the proportional benefits of intravenous alteplase
treatment were similar irrespective of age or severity
of stroke.7
The AHA/ASA issued a Scientific Statement in 2016
in which the evidence base for each of the exclusion
criteria was reviewed, concluding that the additional
criteria from ECASS III should not be treated as
strict exclusions to treatment with intravenous
alteplase.39 The FDA prescribing information sheet
for intravenous alteplase (Activase, alteplase) has
also been updated in compliance with new labeling
guidelines and factoring in the evidence base for
exclusion criteria. The patient characteristics listed
as exclusions have decreased significantly (see box
1), with many criteria downgraded to the “Warnings
and precautions” section.39
Patient selection for intravenous thrombolytic
therapy (imaging based criteria)
The DEFUSE trial was a prospective observational
trial that used MRI diffusion weighted imaging (DWI)
and perfusion weighted imaging (PWI) to determine
the imaging characteristics associated with favorable
4
and unfavorable responses to treatment with
intravenous alteplase at three to six hours from
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
LKW.40 This analysis defined a “target mismatch”
profile that identified patients with a favorable
response to reperfusion (<100 mL of DWI lesion with
PWI lesion of 120% or more of the DWI lesion, but
with <100 mL of PWI lesion with >8 s of Tmax delay).
Another observational trial found that the presence of
DWI positive lesions without corresponding lesions
on fluid attenuated inversion recovery (FLAIR)
correlated with patients known to be less than 4.5
hours from symptom onset.41 This DWI to FLAIR
imaging mismatch was used to identify patients
with unknown time of onset for randomization
to intravenous alteplase or placebo in the WAKE-
UP trial.42 A significant benefit of treatment with
intravenous alteplase in these patients was seen, with
a good outcome of mRS 0-1 in 53% of the alteplase
group and 42% in the placebo group (odds ratio 1.61,
95% confidence interval 1.09 to 2.36). The EXTEND
trial used automated perfusion imaging to identify
patients with a target mismatch (<70 mL of core with
perfusion lesion-ischemic core mismatch ratio >1.2)
4.5-9 hours from LKW or waking with symptoms for
randomization to intravenous alteplase or placebo
and showed a benefit in terms of a good outcome
(mRS 0-1) in 35% of the alteplase group versus 29%
of the placebo group (risk ratio 1.44, 95% confidence
interval 1.01 to 2.06).32 This treatment benefit was
confirmed in a meta-analysis combining patient
data from EXTEND and two smaller trials (ECASS
4-EXTEND and EPITHET) using perfusion mismatch
to select patients for randomization to alteplase or
placebo in an extended time window.43 Although the
exact imaging criteria used have varied, the principle
of using imaging based selection criteria rather than
time for patients in extended time windows has also
been used for intra-arterial reperfusion strategies
(see below) and seems to be safe and effective in
identifying the subgroup of patients who have a
slower progression than average from symptom
onset to completed infarction. Using the WAKE-UP
trial criteria of DWI to FLAIR mismatch to select
patients who wake with symptoms for treatment
with intravenous alteplase has received a class IIa
(moderate) recommendation in the 2019 AHA/ASA
guidelines for management of AIS.10
Box 1: Listed contraindications on FDA drug
labeling for Activase (alteplase) use for AIS
• Current intracranial hemorrhage
• Subarachnoid hemorrhage
• Active internal bleeding
• Recent (within 3 months) intracranial or intraspinal
surgery or serious head trauma
• Presence of intracranial conditions that may
increase the risk of bleeding (eg, some neoplasms,
arteriovenous malformations, or aneurysms)
• Bleeding diathesis
• Current severe uncontrolled hypertension
1 AIS=acute ischemic stroke; FDA=Food and Drug Administration
doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj

Tenecteplase, an alternate tissue plasminogen
activator
Tenecteplase is another tissue plasminogen activator,
which has been shown to have higher affinity for
fibrin and a longer half life than alteplase. It is widely
used for acute coronary events and has a lower rate
of systemic hemorrhage than alteplase in that setting.
Between 2012 and 2015 three phase II studies were
published that compared standard dose alteplase (0.9
mg/kg) with variable doses of tenecteplase (0.1, 0.25,
and 0.4 mg/kg) for AIS, with neutral to promising
results.44-46 Published in 2017, NOR-TEST was a
phase III randomized, open label, blinded endpoint
trial comparing tenecteplase 0.4 mg/kg with standard
dose alteplase in AIS.47 This large trial randomized
1100 patients, with a predominance of mild strokes
with a median NIHSS score of 4 (interquartile
range 2-8), and did not show a difference between
tenecteplase and alteplase in the primary outcome
(mRS 0-1 at 90 days in 64% and 63%, respectively)
or in safety (symptomatic intracerebral hemorrhage).
Another study, EXTEND-IA TNK, randomized 202
patients with acute occlusion of the intracranial
internal carotid artery (ICA), basilar artery, or MCA
who were eligible for thrombolysis followed by
mechanical thrombectomy to tenecteplase 0.25 mg/
kg or alteplase 0.9 mg/kg.48 49 Patients then underwent
thrombectomy according to standard protocols. The
primary outcome was based on assessment of the
initial angiogram showing reperfusion of greater than
50% of the involved ischemic territory or absence of
retrievable thrombus. This primary outcome occurred
in 22% of the tenecteplase and 10% of the alteplase
group (P=0.002 for non-inferiority and P=0.03 for
superiority). Symptomatic ICH was not different,
occurring in 1% of each group.
The 2019 AHA/ASA acute stroke management
guidelines gave the following guidance for tenecteplase:
“Tenecteplase administered as a 0.4-mg/kg single IV
bolus has not been proven to be superior or noninferior
to alteplase but might be considered as an alternative
to alteplase in patients with minor neurological
impairment and no major intracranial occlusion.”10
This class IIb recommendation was based primarily on
the largest trial, NOR-TEST. Further support for the use of
tenecteplase in AIS comes from a recent meta-analysis
of all randomized trials comparing tenecteplase and
alteplase for AIS.50 The analysis included 1585 patients
and concluded that tenecteplase was non-inferior to
alteplase in the treatment of AIS, with good outcome
(mRS 0-1) achieved in 57.9% of patients treated with
tenecteplase and 55.4% of those treated with alteplase.
Symptomatic intracerebral hemorrhage occurred in
3% of both groups. As discussed, the optimal dose
of tenecteplase remains unknown as the dosing was
variable, but most patients received the highest dose
(0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/
kg in 68.6%).
Complications of thrombolytic therapy
When treating patients with thrombolytic therapy,
providers must be able to identify and manage the
the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983
STATE OF THE ART REVIEW
two main potential complications of treatment,
intracerebral hemorrhage and angioedema. Hospitals
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
should have protocols for reversal of coagulopathy,
typically with cryoprecipitate or protein complex
concentrate, although no studies have shown that
these interventions are beneficial.51 Angioedema of
the oropharynx can cause airway compromise and
must be recognized and corrected quickly, typically
with steroids, antihistamines, and intubation if
needed. Further recommendations can be found in
the AHA guidelines for management of AIS.10
Mechanical thrombectomy for acute ischemic stroke
Interventions in the less than six hours window
Endovascular treatment for acute stroke with LVO
has revolutionized care for the most severe ischemic
strokes. In 2013 initial trials of endovascular
therapy versus standard care (including intravenous
alteplase) for strokes with LVO (including IMS
III,52 MR RESCUE,53 and SYNTHESIS54) were
disappointing, as they did not show a benefit of
thrombectomy over standard care. However, these
previous studies were limited by lack of vessel
imaging for patient selection, low use of stent
retrievers, low recruitment, and slow recanalization
times.55 Since then, nine studies, seven within the
six hour period and two in a period up to 16-24
hours, have shown dramatically improved functional
outcomes in patients undergoing endovascular
treatment for LVO. The numbers needed to treat for
these studies have tended to be about five for one
patient to go from being dead or dependent to alive
and independent.4 56
The clinical trial MR CLEAN was the first
significantly positive trial to be presented that
showed efficacy of mechanical thrombectomy in AIS.
In this trial, 500 patients less than six hours from
LKW were randomized across 16 medical centers
in the Netherlands to either usual care (including
receiving intravenous alteplase if eligible) or usual
care plus endovascular clot retrieval.56 Eligible
patients included those with a proximal arterial
occlusion in the anterior circulation confirmed
on vessel imaging, and the primary outcome was
functional independence on the modified Rankin
scale (mRS of 0-2) at 90 days. Most devices used in
the treatment arm were stent retrievers, including
Solitaire and Trevo (81.5%). An absolute difference
of 13.5% (95% confidence interval 5.9% to 21.2%)
in the rate of functional independence was seen in
favor of endovascular therapy (32.6% v 19.1%). This
was the only major trial of endovascular treatment
within six hours using mostly stent retrievers that
enrolled to completion.
The other four trials were ongoing at the time
of this trial’s presentation, and the data safety
monitoring boards of these trials were prompted
to do an interim analysis. ESCAPE, EXTEND-IA,
SWIFT PRIME, and REVASCAT were all stopped
early owing to an overwhelming signal in the data
pointing to significant improvement in functional
outcomes with thrombectomy.57-60 A meta-analysis
5
STATE OF THE ART REVIEW
of these five trials in 2016 showed that endovascular
thrombectomy in LVO significantly reduced disability
at 90 days compared with control, with an adjusted
common odds ratio of 2.49 (95% confidence interval
1.76 to 3.53), and estimated that the number needed
to treat to reduce disability by at least one level on the
mRS was 2.6.4 Importantly, pooled treatment with
intravenous alteplase was 83% in the intervention
group and 87% in the usual care group, and the
average time from symptom onset to reperfusion
in the intervention group was 285 minutes (4.75
hours). In addition, four of these trials did not go to
completion, and only between 70 and 316 patients
were enrolled when each study had planned for at
least 500 participants.
THERAPY was another thrombectomy trial that
was stopped early (108 of a planned 692 patients),
comparing aspiration only thrombectomy plus
intravenous alteplase with intravenous alteplase
alone.61 The primary outcome of mRS of 0-2 at 90
days did not differ (38% v 30%; odds ratio 1.4, 0.6 to
3.3). The small numbers make these results difficult
to interpret, but there was no suggestion of harm.
More recently, the HERMES collaboration included
pooled individual data from the five previous
trials, combined with data from THRACE, which
randomized 414 AIS patients less than five hours
from LKW to thrombectomy plus intravenous
alteplase versus intravenous alteplase alone (53%
with mRS of 0-2 at three months with thrombectomy
versus 42% with intravenous alteplase alone),62 and
a smaller study, PISTE.63 Patients were stratified by
laterality of stroke and no significant differences were
seen between right and left hemispheric stroke in the
90 day functional outcome (mRS ≤2: 40.7% v 37.6%;
P=0.19).64 The fact that most of the endovascular
treatment trials were stopped early could raise some
questions about the validity of the findings, but
with multiple trials and combined analyses showing
similar results the evidence is strong that selected
AIS patients with LVO benefit from thrombectomy
less than six hours from LKW. It is estimated that
about 10% of all hospital admissions for acute stroke
would be eligible for thrombectomy on the basis of
the eligibility criteria of these studies.65
Interventions in the greater than six hour window:
DAWN and DEFUSE 3
After the multiple trials showing significantly better
outcomes with endovascular therapy in LVO less than
six hours from LKW, two studies (DAWN and DEFUSE
3) were published that showed large improvement
in functional outcome in patients more than six
hours from LKW at presentation. However, both
trials had strict imaging criteria to select patients
who would be most likely to benefit from delayed
thrombectomy by identifying those without large
areas of established infarct. The trials used software
called RAPID to analyze computed tomography or
magnetic resonance perfusion imaging to identify
core infarction and areas of penumbra or potentially
salvageable tissue (fig 1).
6
The DAWN trial enrolled patients who were
identified six to 24 hours after LKW and had an
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
occlusion of the ICA or the M1 segment of the
proximal MCA.6 Criteria for inclusion included
small core infarct volume and NIHSS score cut-
off depending on age: for patients age 80 or above
and NIHSS score greater than 10, infarct volume
needed to be less than 21 mL; for younger patients
aged under 80, infarct volume had to be less than
31 mL if the NIHSS score was above 10 and 31-50
mL if the NIHSS score was above 20. Mismatch of
infarct core with clinical examinations was used for
inclusion of patients for randomization. The trial was
stopped early owing to an interim analysis showing
pre-specified benefit. In total, 206 patients were
enrolled, 107 in the intervention arm and 99 in the
control arm. The rate of functional independence
was dramatically better in the thrombectomy group
than in the control group (49% v 13% with mRS 0-2
at 90 days). Even patients in the greater than 12 hour
window had dramatic improvement in outcomes
with thrombectomy; however, most of the included
patients had an unwitnessed onset (so actual time
from stroke onset could have been much less than
time from LKW), with only 11.7% witnessed.6
DEFUSE 3 was similar to DAWN but had some
differences in inclusion criteria. Patients were
included if they were six to 16 hours from LKW with
ICA or M1 occlusion, selected with RAPID software.5
In this trial, patients were randomized if their core
infarct was less than 70 mL and the ratio of at risk
ischemic tissue to core infarct volume was 1.8 or
greater. Although the time window was shorter,
about 60% more patients were eligible for DEFUSE
3 than for DAWN.5 This trial was also stopped early
owing to pre-specified stopping rules that showed
impressive benefit; 182 patients were enrolled, 92
in the intervention arm and 90 in the control arm.
In this trial, 36% of cases had witnessed onset. The
percentage of functionally independent patients
was similar to DAWN, with 45% after thrombectomy
and 17% of controls with mRS 0-2 at 90 days. These
two high quality studies together led to the AHA
guidelines designating mechanical thrombectomy
up to 16 hours from onset for carefully selected
patients as a class 1A recommendation.10 A single
center study estimated that about 1.7-2.5% of
all acute stroke admissions would be eligible for
thrombectomy after six hours from LKW on the basis
of DAWN and/or DEFUSE 3 criteria66 (fig 2).
Devices/techniques (stent retrievers, aspiration
catheters)
Although stent retrievers such as Solitaire and Trevo
were used in the main studies that showed efficacy
for thrombectomy after intravenous alteplase versus
alteplase alone,4-6 63 67 other devices and techniques
are also used for thrombectomy that have varying
levels of evidence. Previous devices, including the
Merci device and early Penumbra aspiration catheters
with separators, did not show efficacy in earlier
trials,52-54 and although problems such as patient
doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj

&%)YROXPHPO
0LVPDWFKYROXPHPO
0LVPDWFKUDWLR
Fig 1 | Sample RAPID software output. Cerebral blood flow (CBF) <30%: ischemic core. Time to maximum of residue function (Tmax) >6 seconds:
threshold for critically hypoperfused tissue. Mismatch volume: difference between Tmax >6 s and CBF <30%=estimation of salvageable ischemic
penumbra. Mismatch ratio: ratio of Tmax >6s/CBF <30%. This pattern indicates that a patient with stroke had a target mismatch, which would meet
criteria for mechanical thrombectomy up to 24 hours after last known well
selection likely also affected outcomes of these earlier
trials, stent retrievers have consistently shown better
recanalization rates (see table 1 for explanation of the
Treatment in Cerebral Ischemia (TICI) rating system
for recanalization68) and clinical outcomes.69-71 More
recently, another stent retriever, EMBO-TRAP, has
been evaluated in the single arm prospective study
ARISE II; although not compared directly with other
devices, it showed similar rates of recanalization
(TICI 2B-3 of 80.2% within three passes), functional
independence (mRS 0-2 in 67%), and mortality (9%)
at 90 days as studies involving Solitaire and Trevo.72
An important caveat is that this study had a single arm
with no comparators, so biases may be present, and
concluding that EMBO-TRAP is a safe and effective
option for thrombectomy is difficult; future research
will need to evaluate it against other devices.
The first line use of contact aspiration versus stent
retriever thrombectomy in LVO is evolving as a more
common technique, but evidence to support its use
is mixed. This technique, specifically one called “a
direct aspiration as first pass technique” (ADAPT), has
been studied because observational studies suggested
that it might lead to earlier reperfusion and lower cost
of thrombectomy.73 74 This led to two randomized
clinical trials, ASTER (Contact Aspiration versus Stent
Retriever for Successful Revascularization) in 2017
and COMPASS (Aspiration Thrombectomy Versus
Stent Retriever Thrombectomy as First-Line Approach
for Large Vessel Occlusion) in 2019,75-77 which both
examined the ADAPT technique versus stent retriever
the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983
STATE OF THE ART REVIEW
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
7PD[!VYROXPHPO
within six hours of onset. The ASTER trial was
designed as a superiority trial and the COMPASS trial
as non-inferiority. Both trials studied recanalization
rates within three passes and mRS outcomes at 90
days. ASTER showed recanalization of TICI 2b or
better of 85.4% in the ADAPT arm versus 83.1% in the
stent retriever arm and a 90 day mRS score of 2 or less
in 45.3% versus 50.0% (P=0.38).75 COMPASS showed
TICI of at least 2b in 92% in the ADAPT arm and 89%
in the stent retriever arm (P=0.54) and a 90 day mRS
score of 2 or less in 52% versus 50% (P=0.001 for
non-inferiority). Essentially, the current data support
equivalency of first line aspiration with first line stent
retriever, but not superiority of this technique.
Intubation versus conscious sedation for
mechanical thrombectomy procedure
Controversy continues to exist around the optimal
way to manage anesthesia during endovascular
treatment. Multiple non-randomized and a few
randomized studies have examined different
options, including conscious sedation or general
anesthesia. In general, non-randomized studies
have found that general anesthesia leads to worse
functional outcome and a higher mortality rate,78-83
but some randomized, single center trials including
AnStroke,84 SIESTA,85 and GOLIATH,86 showed no
difference in mortality for general anesthesia versus
conscious sedation, with better functional outcomes
for general anesthesia in SIESTA but no difference in
AnStroke or GOLIATH.
7
STATE OF THE ART REVIEW

,QIRUPDWLRQQHHGHG /DVWNQRZQZHOOWLPH 1,+6WURNH6FDOHVFRUH 3UHVWURNHGLVDELOLW\P56VFRUH

BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
/DVWNQRZQZHOOWLPHWRSUHVHQWDWLRQ

KRXUV !KRXUVDQGKRXUV !KRXUV

&7KHDG&7$KHDGDQGQHFN 1,+6WURNH6FDOHƝ &7KHDGDQGDGPLW

$1' DFXWHVWURNHSURWRFRO
SUHVWURNHGLVDELOLW\P56Ɯ

,IKRXUVFKHFNFULWHULDIRUW3$ ,I!DQGKRXUV <HV 1R

<HV 1R &7KHDG&7$5$3,'SURWRFRO

1,+6WURNH6FDOHƝ &KHFNLI&7$VKRZV/92DQGLVFKHPLFFRUHP/$1'
$1' PLVPDWFKUDWLR!$1'SHQXPEUDYROXPH!P/
*LYHW3$67$7 SUHVWURNHGLVDELOLW\P56Ɯ
$1'
ODUJHYHVVHORFFOXVLRQ

1R <HV <HV 1R

$GPLWDFXWHVWURNHSURWRFRO &DOOVHQGHQGRYDVFXODUWUHDWPHQW $GPLWDFXWHVWURNHSURWRFRO

Fig 2 | Sample algorithm for acute management of ischemic stroke. This type of algorithm is institution specific; this example flowchart is based
on the guidelines for acute ischemic stroke treatment but may not be applicable to all institutions. CT=computed tomography; CTA=computed
tomography angiography; LVO=large vessel occlusion; mRS=modified Rankin Scale; NIH=National Institutes of Health; tPA=alteplase

A recent meta-analysis of these three trials suggests
better outcomes with general anesthesia.87 However,
a pre-planned sub-study of DEFUSE 3 published in
2019 that examined the outcomes of patients who
underwent general anesthesia versus conscious
sedation, found significantly better functional
independence (mRS ≤2) in patients who underwent
conscious sedation, with no difference in mortality or
symptomatic intracerebral hemorrhage.88 A pooled
analysis of trials in the HERMES collaborative found
that use of general anesthesia was associated with
worse functional outcomes at 90 days compared
with conscious sedation or non-general anesthesia,
but with no difference in mortality or symptomatic
intracerebral hemorrhage.89
The drawback of many of these studies, including
the last two, is that the decision to use general
anesthesia or conscious sedation was left up to the
treating team, and some locations did all general
anesthesia and others did all conscious sedation.
Multiple comparisons have been done to adjust
for different factors, but at this point definitively
saying that general anesthesia or conscious sedation
is better for outcomes is still difficult. It is also
important to recognize that the trials were designed
to avoid blood pressure extremes, that the rate of
conversion from conscious sedation to general
anesthesia was high (between 6.3% and 15.6%), that
no significant difference was seen in time to groin
puncture (although it was a little longer with general

Table 1 | Modified Treatment in Cerebral Ischemia (TICI) scale

TICI grade Definition
Grade 0 No perfusion
Grade 1 Antegrade reperfusion past the initial occlusion, but limited distal branch filling with little or slow distal reperfusion
Grade 2A Antegrade reperfusion of less than half of the occluded target artery previously ischemic territory
Grade 2B Antegrade reperfusion of more than half of the occluded target artery previously ischemic territory
Grade 2C Complete antegrade reperfusion of the previously occluded target artery ischemic territory, with presence of visualized
occlusion in one or more distal branches
Grade 3 Complete antegrade reperfusion of the previously occluded target artery ischemic territory, with absence of visualized
occlusion in all distal branches
Adapted from Zaidat et al, 2013.68

8 doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj


anesthesia), that no significant difference was seen in
time to recanalization after groin puncture (although
it was a little longer with conscious sedation), and
that assessment of pneumonia outcomes was limited,
although these are important when considering
intubation as an intervention.
The 2019 AHA/ASA guidelines conclude that
“It is reasonable to select an anesthetic technique
during endovascular therapy for AIS on the basis
of individualized assessment of patient risk factors,
technical performance of the procedure, and other
clinical characteristics.”10
Management of physiological factors
Blood pressure management in acute stroke
Management of blood pressure in AIS must balance
multiple factors including elevated pressures
improving tissue perfusion but also increasing the
risk of hemorrhage or secondary damage to already
infarcted areas of brain. With these competing factors,
the optimal blood pressure for any given patient will
vary depending on whether the patient has been
treated with thrombolytic therapy or embolectomy,
as well as the patency of major vessels and perfusion
status of the brain, if these factors are known.
Some trials have evaluated blood pressure
management in the acute phase. The recent RIGHT-2
trial had EMS personnel randomize patients in
the ultra-acute period and start treatment using
glyceryl trinitrate or placebo; it found no difference
in functional outcome or death.90 A meta-analysis
of 13 RCTs of antihypertensive agents started
between 15 hours and three days after onset of
AIS also had neutral results for both likelihood of
death or dependency at three months and recurrent
vascular events.91 The 2019 AHA/ASA acute stroke
guidelines recommend: “In patients with BP
≥220/120 mm Hg who did not receive IV alteplase
or EVT and have no comorbid conditions requiring
acute antihypertensive treatment, the benefit of
initiating or reinitiating treatment of hypertension
within the first 48 to 72 hours is uncertain. It might
be reasonable to lower BP by 15% during the first 24
hours after onset of stroke.”10
The protocols for the thrombolytic trials instructed
that blood pressure should be controlled to below
180/105 mm Hg after thrombolytic treatment. This
protocol had not been compared with alternate blood
pressure goals until the recent ENCHANTED trial,92 in
which patients eligible for thrombolytic therapy were
randomized to standard goal systolic pressure (<180
mm Hg) or intensive management (goal 130-140 mm
Hg). Fewer hemorrhages occurred in the intensive
therapy group, but no difference was seen in three
month mRS (however, the mean systolic blood
pressure was not very different between the groups
despite different goals (144.3 v 149.8 mm Hg)).
Most patients enrolled in mechanical thrombectomy
trials were also eligible for and treated with intravenous
alteplase, so blood pressure was controlled as per
post-alteplase guidelines (<180/105 mm Hg). Debate
remains regarding whether blood pressure should
the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983
STATE OF THE ART REVIEW
be lowered further post-thrombectomy if reperfusion
is achieved. The DAWN trial protocol recommended
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
systolic pressure below 140 mm Hg for 24 hours after
reperfusion. A single site observational study of patients
undergoing mechanical thrombectomy stratified
by maximum blood pressure in the 24 hours post-
thrombectomy: permissive hypertension (<180/105
mm Hg for patients treated with intravenous alteplase
or <220/110 mm Hg for those not treated), moderate
blood pressure goal (<160/90 mm Hg), or intensive
blood pressure goal (<140/90 mm Hg).93 This study
did not find a difference in symptomatic intracerebral
hemorrhage but did find that high maximum blood
pressure levels were independently associated with
increased likelihood of three month mortality and
functional dependence (mRS >2). As this was a non-
randomized study, the maximum blood pressure
achieved could be associated with poor outcomes but
not causative. A survey of 58 StrokeNet institutions
showed variability in current practice patterns for
blood pressure management post-thrombectomy.94
Systolic blood pressure goals for patients with full
recanalization varied widely: 120-139 mm Hg in
36%, 140-159 mm Hg in 21%, and below 180 mm Hg
in 28%. For patients with unsuccessful reperfusion,
blood pressure goals were generally higher, with 43%
of respondents accepting any value below 180 mm Hg
and 10% accepting below 220 mm Hg.
Patient positioning
In addition to permissive blood pressure, positioning
patients fully supine (that is, with the head of the
bed flat) is another strategy that has been proposed
to increase cerebral perfusion in the acute stroke
setting. Small studies evaluating physiologic
outcome parameters have shown that positioning
patients fully supine improves cerebral blood
flow velocities and cerebral blood volume in some
patients with AIS, especially those with poor cerebral
autoregulation.95-99 This potential advantage to
perfusion brings with it the potential increased risk
of aspiration. The HeadPoST trial published in 2017
assigned 11 093 patients to either lying flat or lying
with the head elevated at least 30 degrees, with
positioning started soon after hospital admission and
maintained for 24 hours.100 No difference was seen
between the groups in disability outcomes at 90 days.
A critique of the HeadPoST protocol was published
questioning the validity of the results.101 The main
concerns were inclusion of all types of strokes, as the
authors felt that minor strokes would be unlikely to
benefit from the intervention, and the intervention
being started too late to be beneficial (median time to
intervention initiation was 14 hours from LKW and
seven hours from hospital admission). Although no
evidence based recommendation on head positioning
exists that can be applied to all patients with AIS,
certain patients with disrupted autoregulation and
tenuous penumbral perfusion may benefit from
positioning with head of the bed flat, especially in
the hyperacute stages before definitive reperfusion
strategies are started.
9
STATE OF THE ART REVIEW
Blood sugar management
Persistent hyperglycemia in the acute stroke period
has been associated with poor outcomes. However,
whether tighter control of blood glucose would be
beneficial was unclear. The SHINE trial randomized
patients to receive either intensive glucose control
for 72 hours post-stroke (target 80-130 mg/dL with
intravenous insulin infusion) or standard therapy
with sliding scale insulin targeted to 80-179 mg/
dL.102 The study was stopped for futility at the fourth
planned interim analysis after 82% (1151/1400) of
the planned maximum number of patients had been
enrolled. The primary endpoint of favorable three
month outcome was reached in 20.5% of patients in
the intensive treatment group and 21.6% of patients
in the standard treatment group (relative risk 0.97;
P=0.55). Severe hypoglycemia occurred in 2.6%
of patients in the intensive group and none in the
standard treatment group.
Oxygen management
The AHA/ASA guidelines recommend supplemental
oxygen to maintain O2 saturation above 94%. Some
debate has taken place about whether all patients
should be treated with supplemental oxygen in the
acute stroke setting. The Stroke Oxygen Study (SO2S)
investigated this in 8003 non-hypoxic patients
with acute stroke within 24 hours of admission by
randomizing them to continuous nasal cannula
oxygen, nocturnal nasal cannula oxygen, or control
(oxygen only if clinically indicated) for 72 hours.103
No difference was seen between the groups in
likelihood of a good outcome, and no subgroups
were identified that benefited from oxygen.
Acute antithrombotic management for secondary
prevention
Management has two main objectives when patients
present with acute ischemic stroke or transient
ischemic attack (TIA): to minimize disability from the
acute event and decrease the likelihood of another
stroke. The risk of recurrent stroke is highest soon
after presentation, when presumably the factors
leading to the current event are still in play (for
example, ruptured atherosclerotic plaque with
thrombus). Therefore, secondary stroke prevention
strategies will be most successful if implemented
as soon as possible. Two RCTs published in 1997
formed the basis of the standard of care treatment
of acute stroke patients with aspirin for secondary
stroke prevention, the International Stroke Trial (IST)
and the Chinese Acute Stroke Trial (CAST).104 105 Both
studies randomized patients as soon as possible
after onset (within 48 hours for CAST) to aspirin
(162 mg and 300 mg, respectively) or placebo. In
total, 40 541 patients were randomized and the
results analyzed together indicated that treatment
with aspirin prevented about 10 deaths or recurrent
strokes per 1000 patients treated during the first few
weeks. The IST also randomized patients to heparin
or placebo and concluded that “Patients allocated to
heparin had significantly fewer recurrent ischaemic
10
strokes within 14 days (2.9% vs 3.8%) but this was
offset by a similar-sized increase in haemorrhagic
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
strokes (1.2% vs 0.4%), so the difference in death or
non-fatal recurrent stroke (11.7% vs 12.0%) was not
significant.”
Two recent RCTs have re-examined this topic to
determine whether dual antiplatelet therapy with
aspirin and clopidogrel is superior to aspirin alone in
preventing recurrent stroke soon after the presenting
stroke or TIA. The CHANCE trial randomized 5170
patients in China presenting with TIA or minor
stroke within 24 hours from onset to either aspirin
75 mg or aspirin 75 mg and clopidogrel (300 mg load
and then 75 mg per day) for 21 days.106 Analysis at
90 days found that stroke occurred in 8.2% of the
dual antiplatelet group compared with 11.7% of
the aspirin group (hazard ratio 0.68; P<0.001). No
difference was seen between the groups in the rate
of moderate to severe hemorrhage or in intracerebral
hemorrhage.
The POINT trial randomized 4881 patients at 269
international sites (with 82.8% enrolled in the US)
to either aspirin (dose 50 mg to 325 mg) or aspirin
and clopidogrel (600 mg load followed by 75 mg
daily for 90 days) within 12 hours from onset.107
The Data Safety Monitoring Board stopped the trial
early after 84% of the planned patients had been
enrolled when the determination was made that
the dual antiplatelet group had both a lower risk of
major ischemic events (5.0% v 6.5%) and a higher
risk of major hemorrhage (0.9% v 0.4%) at 90 days.
Interestingly, most of the ischemic events occurred
within the first week after the initial event, whereas
the risk of hemorrhagic events remained relatively
constant throughout the trial period. A recent BMJ
Rapid Recommendations Panel did a meta-analysis
of RCTs examining dual versus single antiplatelet
agents started acutely after presentation with
ischemic stroke or TIA.108 The panel recommended
starting dual antiplatelet therapy within 24 hours
of onset of TIA or minor stroke symptoms and
continuing for 10-21 days on the basis of the finding
that this practice reduces non-fatal recurrent stroke
(ischemic or hemorrhagic) by 1.9% while increasing
moderate to major extracranial bleeding by 0.2% and
having no effect on all cause mortality, myocardial
infarction, or recurrent TIA.
Emerging treatments
Emerging treatments in the area of AIS management
include research into expanding indications
for thrombectomy, stem cell therapy, and
neuroprotection. As advanced imaging is increasingly
being used to select patients who will most benefit
from thrombectomy, a question remains as to
whether even patients with less favorable imaging
characteristics would also derive more benefit than
risk from thrombectomy.109  110 Recently initiated
trials, including TELSA, SELECT 2, TENSION, and IN
EXTREMIS (https://clinicaltrials.gov/) aim to establish
the effectiveness of thrombectomy versus medical
management in patients with moderate to large infarcts
doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj

established on non-contrast computed tomography of
the head (ASPECTS111 of 2-5 for TESLA and 3-5 for
the others). These studies may help us to understand
whether we can offer more for patients presenting
with larger established infarcts than we currently do.
In addition, whether patients with low severity (low
NIHSS score) and LVO should get thrombectomy is
unclear; some analyses of cohorts have reported either
benefit of thrombectomy or no difference between
those that received thrombectomy and best medical
care.112 113 A second part of IN EXTREMIS (called
MOSTE or Minor Stroke Therapy Evaluation) and
the Endovascular Therapy for Low NIHSS Ischemic
Strokes (ENDOLOW) are planned randomized trials
that will attempt to answer this question.
Time to reperfusion continues to predict outcome
in endovascular treatment, so the possibility of
direct triage to the angiography suite is potentially
desirable. Small series of patients have examined
“one stop imaging” with a direct-to-angiography suite
for imaging with the flat panel detector computed
tomography and decision making about intravenous
alteplase and thrombectomy taking place there, with
the goal of avoiding time in a separate computed
tomography scan.114 115 If the quality of the flat panel
detector computed tomography to detect hemorrhage,
ischemic changes, and LVO is confirmed, this
might be an option to significantly reduce time at
endovascular capable centers. Another potential time
saver for patients eligible for thrombectomy might
be to bypass intravenous alteplase to go directly to
endovascular treatment. Ongoing studies, such as
SWIFT DIRECT, are examining whether bridging
with thrombolysis plus thrombectomy is superior to
thrombectomy alone and, if not, whether time saved
by going directly to thrombectomy could potentially
improve outcomes.
The use of stem cells in recovery from stroke has
been tested for decades in animal models, and more
recently in humans, but now interest exists in testing
stem cell treatments in the acute phase, with the
hope of early recovery of neurologic function. A 2019
Cochrane Database review of randomized trials in
stem cell transplantation in ischemic stroke identified
seven trials involving 401 participants, and overall
stem cell transplantation was associated with better
clinical outcome when measured by NIHSS but not
by mRS or other measures of disability.116 The two
larger trials with 60 or more patients did not show
any benefit, whereas the smaller trials did show a
small benefit, and there were no safety concerns.
The authors’ conclusions were that there is currently
“insufficient evidence to support or refute the use of
stem cell transplantation to treat ischemic stroke”
and that more research is “urgently needed.”116
Even less evidence exists in the acute phase, but a
search of clinicaltrials.gov using key words “acute
stroke” and “stem cells” retrieves 17 either recently
completed or ongoing trials worldwide. Intravenous
or intra-arterial injection of stem cells might be a
promising treatment for acute stroke in the future but
is of uncertain value at this time.
the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983
STATE OF THE ART REVIEW
Neuroprotection in ischemic stroke has been
studied extensively, resulting from an interest in
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
extending the time neurons can survive ischemia
until recanalization or other forms of reperfusion
can be achieved. An ideal neuroprotectant would
have few adverse effects and would be easy to use
in the earliest setting of stroke, either onsite or at
least pre-hospital. Unfortunately, after more than
1000 published experiments and more than 100
clinical trials, although multiple animal studies have
showed promising results, no data in humans have
shown efficacy.117 The AHA/ASA 2019 guidelines
recommend against the use of neuroprotective
agents, as class III (no benefit), level of evidence A
(highest quality).10 Nevertheless, research continues
to find agents or strategies that could provide
neuroprotection in AIS, and the most promising
efforts at this point seem to be intra-arterial delivery
of drugs, stem cells, and local hypothermia.118
Guidelines
Multiple stroke organizations worldwide
periodically review the available literature and
produce updated guidelines for the management
of acute ischemic stroke. The Royal College of
Physicians in the UK last updated the National
Clinical Guidelines for Stroke in 2016, which can
be found online at https://www.strokeaudit.org/
Guideline/Guideline-Home.aspx. The Canadian
Stroke Best Practice Recommendations for AIS
treatment were updated in 2018 and are available as
online modules at https://www.strokebestpractices.
ca/recommendations/acute-stroke-management/
acute-ischemic-stroke-treatment and also published
in the International Journal of Stroke.119 The
Australian Stroke Foundation states that its Clinical
Guidelines for Stroke Management are “living
guidelines,” which are updated as new evidence
emerges and can be found at https://informme.org.
au/en/Guidelines/Clinical-Guidelines-for-Stroke-
Management. The most frequently cited stroke
guidelines are published in Stroke by the American
Heart Association and American Stroke Association.
The most recent update to the Guidelines for the
Early Management of Acute Ischemic Stroke was
published in 2019.10 The format of the AHA/ASA
guidelines has evolved in recent years to more
clearly link the recommendation statements to the
supporting scientific evidence and to clearly indicate
the class (strength) of recommendation and the level
(quality) of evidence.
Guidelines from these different organizations are
mostly very similar to each other. Where differences
exist, they are typically in the strength of the
recommendation made about newly published
data, with some guideline committees endorsing
new protocols, whereas others require a higher level
of data before making a strong recommendation.
Practitioners are encouraged to look for updated
guidelines periodically, as they will continue to be
updated as the dynamic field of acute stroke care
continues to evolve.
11
STATE OF THE ART REVIEW
RESEARCH QUESTIONS
• What are the best systems of care and protocols that
can help emergency medical services to identify
patients with large vessel occlusion and to determine
to which level of stroke center to triage a patient?
• Is endovascular thrombectomy efficacious in
patients with acute ischemic stroke who have larger
established core infarcts? What about those with low
National Institutes of Health Stroke Scale scores and
large vessel occlusion?
• What is the best method of patient sedation during
endovascular therapy (general anesthesia versus
conscious sedation)? Would certain patients benefit
from one approach versus the other?
• What is the optimal blood pressure management
during endovascular therapy and after successful
recanalization of large vessel occlusion?
• Is stem cell therapy effective for stroke recovery?
Conclusions
Management of AIS has undergone many changes
in the past few years, with more patients receiving
treatment to minimize long term disability. A
critical advance has been the establishment of
organized regional stroke systems of care that can
quickly identify patients with stroke in the field
GLOSSARY OF ABBREVIATIONS
• ADAPT—a direct aspiration as first pass technique
• AHA/ASA—American Heart Association/American
Stroke Association
• AIS—acute ischemic stroke
• ASPECTS—Alberta Stroke Program Early CT Score
• ASRH—acute stroke ready hospital
• CPSS—Cincinnati Prehospital Stroke Severity Scale
• CSC—comprehensive stroke center
• CTA—computed tomography angiography
• DWI—diffusion weighted imaging
• EMS—emergency medical services
• FAST—Face-Arm-Speech-Time
• FDA—Food and Drug Administration
• FLAIR—fluid attenuated inversion recovery
• GOS—Glasgow Outcome Scale
• ICA—internal carotid artery
• LAMS—Los Angeles Motor Scale
• LKW—last known well
• LVO—large vessel occlusion
• MCA—middle cerebral artery
• MRI—magnetic resonance imaging
• mRS—modified Rankin Scale
• MSU—mobile stroke unit
• NIHSS—National Institutes of Health Stroke Scale
• PSC—primary stroke center
• PWI—perfusion weighted imaging
• RACE—Rapid Arterial Occlusion Evaluation Scale
• RCT—randomized controlled trial
• TIA—transient ischemic attack
• TICI—Treatment in Cerebral Ischemia
• Tmax—time to maximum of the residue function
• TSC—thrombectomy ready stroke center
12
PATIENT INVOLVEMENT
BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
A patient treated for his acute ischemic stroke reviewed
the draft of this manuscript and made suggestions and
edits on the content and presentation of the article,
specifically for the language (including spelling out
acronyms), the inclusion of graphics, and the inclusion
of clear summaries and recommendations
and use decision support to get patients to the
appropriate centers that can provide state of the
art care for their condition. This includes doing
the necessary clinical and imaging evaluation and
interpretation of those results by clinicians with
expertise in determining patients’ eligibility for rapid
administration of intravenous thrombolytic therapy
and endovascular thrombectomy. The devices
available for endovascular thrombectomy continue
to be improved, and the appropriate procedural and
subacute management of patients continue to be
refined. Presentation with acute stroke is also the
time to begin acute measures aimed at preventing
additional strokes in this high risk population.
Appropriate application of the available treatments
is crucial to optimizing outcomes of patients with
stroke.
Contributors: MSP and CAC both did the literature search and
prepared the initial draft of the manuscript. Both authors were
substantially involved in the conception, drafting, and editing of the
manuscript. Both authors have given final approval of the manuscript
and are accountable for all portions of the manuscript. MSP is the
guarantor.
Competing interests: We have read and understood the BMJ policy
on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer
reviewed.
1  Benjamin EJ, Muntner P, Alonso A, et al, American Heart Association
Council on Epidemiology and Prevention Statistics Committee
and Stroke Statistics Subcommittee. Heart Disease and Stroke
Statistics-2019 Update: A Report From the American Heart
Association. Circulation 2019;139:e56-528. doi:10.1161/
CIR.0000000000000659 
2  National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group. Tissue plasminogen activator for acute
ischemic stroke. N Engl J Med 1995;333:1581-7. doi:10.1056/
NEJM199512143332401 
3  Hacke W, Kaste M, Bluhmki E, et al, ECASS Investigators. Thrombolysis
with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J
Med 2008;359:1317-29. doi:10.1056/NEJMoa0804656 
4  Goyal M, Menon BK, van Zwam WH, et al, HERMES collaborators.
Endovascular thrombectomy after large-vessel ischaemic stroke:
a meta-analysis of individual patient data from five randomised
trials. Lancet 2016;387:1723-31. doi:10.1016/S0140-
6736(16)00163-X 
5  Albers GW, Marks MP, Kemp S, et al, DEFUSE 3 Investigators.
Thrombectomy for Stroke at 6 to 16 Hours with Selection by
Perfusion Imaging. N Engl J Med 2018;378:708-18. doi:10.1056/
NEJMoa1713973 
6  Nogueira RG, Jadhav AP, Haussen DC, et al, DAWN Trial Investigators.
Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between
Deficit and Infarct. N Engl J Med 2018;378:11-21. doi:10.1056/
NEJMoa1706442 
7  Emberson J, Lees KR, Lyden P, et al, Stroke Thrombolysis Trialists’
Collaborative Group. Effect of treatment delay, age, and stroke
severity on the effects of intravenous thrombolysis with alteplase for
acute ischaemic stroke: a meta-analysis of individual patient data
from randomised trials. Lancet 2014;384:1929-35. doi:10.1016/
S0140-6736(14)60584-5 
8  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;311:1632-40. doi:10.1001/jama.2014.3203 
doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj
 STATE OF THE ART REVIEW

9  Saver JL, Goyal M, van der Lugt A, et al, HERMES Collaborators. Time 26  Zhang D, Shi L, Ido MS, et al. Impact of Participation in a Telestroke
to Treatment With Endovascular Thrombectomy and Outcomes Network on Clinical Outcomes. Circ Cardiovasc Qual Outcomes

BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
From Ischemic Stroke: A Meta-analysis. JAMA 2016;316:1279-88. 2019;12:e005147. doi:10.1161/CIRCOUTCOMES.118.005147 
doi:10.1001/jama.2016.13647  27  Ehrlich ME, Turner HL, Currie LJ, Wintermark M, Worrall BB,
10  Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Southerland AM. Safety of Computed Tomographic Angiography
Early Management of Patients With Acute Ischemic Stroke: 2019 in the Evaluation of Patients With Acute Stroke: A Single-
Update to the 2018 Guidelines for the Early Management of Acute Center Experience. Stroke 2016;47:2045-50. doi:10.1161/
Ischemic Stroke: A Guideline for Healthcare Professionals From STROKEAHA.116.013973 
the American Heart Association/American Stroke Association. 28  Lima FO, Lev MH, Levy RA, et al. Functional contrast-enhanced CT
Stroke 2019;50:e344-418. doi:10.1161/STR.0000000000000211  for evaluation of acute ischemic stroke does not increase the risk of
11  Pierot L, Jayaraman MV, Szikora I, et al, Asian-Australian Federation contrast-induced nephropathy. AJNR Am J Neuroradiol 2010;31:817-
of Interventional and Therapeutic Neuroradiology (AAFITN), 21. doi:10.3174/ajnr.A1927 
Australianand New Zealand Society of Neuroradiology (ANZSNR), 29  Hopyan JJ, Gladstone DJ, Mallia G, et al. Renal safety of CT
American Society of Neuroradiology (ASNR), Canadian Society angiography and perfusion imaging in the emergency evaluation
of Neuroradiology (CSNR), European Society of Minimally of acute stroke. AJNR Am J Neuroradiol 2008;29:1826-30.
Invasive Neurological Therapy (ESMINT), European Society of doi:10.3174/ajnr.A1257 
Neuroradiology (ESNR), European Stroke Organization (ESO), 30  Ang TE, Bivard A, Levi C, et al. Multi-modal CT in acute stroke: wait
Japanese Society for NeuroEndovascular Therapy (JSNET), The for a serum creatinine before giving intravenous contrast? No!Int J
French Society of Neuroradiology (SFNR) Ibero-Latin American Stroke 2015;10:1014-7. doi:10.1111/ijs.12605 
Society of Diagnostic and Therapeutic Neuroradiology (SILAN), 31  ACR–ASNR–SIR–SNIS Practice parameter for the performance of
Society of NeuroInterventional Surgery (SNIS), Society of Vascular endovascular embolectomy and revascularization in acute stroke.
and Interventional Neurology (SVIN), World Stroke Organization 2018. https://www.acr.org/-/media/ACR/Files/Practice-Parameters/
(WSO), World Federation of Interventional Neuroradiology (WFITN). Acute-Stroke.pdf?la=en.
Standards of practice in acute ischemic stroke intervention: 32  Ma H, Campbell BCV, Parsons MW, et al, EXTEND Investigators.
international recommendations. J Neurointerv Surg 2018;10:1121- Thrombolysis Guided by Perfusion Imaging up to 9 Hours after
6. doi:10.1136/neurintsurg-2018-014287  Onset of Stroke. N Engl J Med 2019;380:1795-803. doi:10.1056/
12  Adeoye O, Nyström KV, Yavagal DR, et al. Recommendations for NEJMoa1813046 
the Establishment of Stroke Systems of Care: A 2019 Update. 33  Hacke W, Kaste M, Fieschi C, et al, The European Cooperative
Stroke 2019;50:e187-210. doi:10.1161/STR.0000000000000173  Acute Stroke Study (ECASS). Intravenous thrombolysis
13  Benoit JL, Khatri P, Adeoye OM, et al. Prehospital Triage of Acute with recombinant tissue plasminogen activator for acute
Ischemic Stroke Patients to an Intravenous tPA-Ready versus hemispheric stroke. JAMA 1995;274:1017-25. doi:10.1001/
Endovascular-Ready Hospital: A Decision Analysis. Prehosp Emerg jama.1995.03530130023023 
Care 2018;22:722-33. doi:10.1080/10903127.2018.1465500  34  Hacke W, Kaste M, Fieschi C, et al, Second European-Australasian
14  Froehler MT, Saver JL, Zaidat OO, et al, STRATIS Investigators. Acute Stroke Study Investigators. Randomised double-blind placebo-
Interhospital Transfer Before Thrombectomy Is Associated With controlled trial of thrombolytic therapy with intravenous alteplase
Delayed Treatment and Worse Outcome in the STRATIS Registry in acute ischaemic stroke (ECASS II). Lancet 1998;352:1245-51.
(Systematic Evaluation of Patients Treated With Neurothrombectomy doi:10.1016/S0140-6736(98)08020-9 
Devices for Acute Ischemic Stroke). Circulation 2017;136:2311-21. 35  Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP,
doi:10.1161/CIRCULATIONAHA.117.028920  Hamilton S. Recombinant tissue-type plasminogen activator
15  Behrndtz A, Johnsen SP, Valentin JB, et al. TRIAGE-STROKE: (Alteplase) for ischemic stroke 3 to 5 hours after symptom
Treatment strategy In Acute larGE vessel occlusion: Prioritize onset. The ATLANTIS Study: a randomized controlled trial.
IV or endovascular treatment-A randomized trial. Int J Stroke Alteplase Thrombolysis for Acute Noninterventional Therapy
2019;1747493019869830. doi:10.1177/1747493019869830  in Ischemic Stroke. JAMA 1999;282:2019-26. doi:10.1001/
16  Vidale S, Agostoni E. Prehospital stroke scales and large vessel jama.282.21.2019 
occlusion: A systematic review. Acta Neurol Scand 2018;138:24-31. 36  Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase)
doi:10.1111/ane.12908  0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-
17  Kim JT, Chung PW, Starkman S, et al, FAST-MAG Trial (Field blind, placebo-controlled, multicenter study. Thromblytic therapy in
Administration of Stroke Therapy–Magnesium) Nurse-Coordinators acute ischemic stroke study investigators. Stroke 2000;31:811-6.
and Investigators. Field Validation of the Los Angeles Motor doi:10.1161/01.STR.31.4.811 
Scale as a Tool for Paramedic Assessment of Stroke Severity. 37  Hacke W, Donnan G, Fieschi C, et al, ATLANTIS Trials Investigators,
Stroke 2017;48:298-306. doi:10.1161/STROKEAHA.116.015247  ECASS Trials Investigators, NINDS rt-PA Study Group Investigators.
18  Katz BS, McMullan JT, Sucharew H, Adeoye O, Broderick JP. Design Association of outcome with early stroke treatment: pooled
and validation of a prehospital scale to predict stroke severity: analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials.
Cincinnati Prehospital Stroke Severity Scale. Stroke 2015;46:1508- Lancet 2004;363:768-74. doi:10.1016/S0140-6736(04)15692-4 
12. doi:10.1161/STROKEAHA.115.008804  38  Del Zoppo GJ, Saver JL, Jauch EC, Adams HPJrAmerican Heart
19  Pérez de la Ossa N, Carrera D, Gorchs M, et al. Design and validation Association Stroke Council. Expansion of the time window for
of a prehospital stroke scale to predict large arterial occlusion: the treatment of acute ischemic stroke with intravenous tissue
rapid arterial occlusion evaluation scale. Stroke 2014;45:87-91. plasminogen activator: a science advisory from the American Heart
doi:10.1161/STROKEAHA.113.003071  Association/American Stroke Association. Stroke 2009;40:2945-8.
20  Teleb MS, Ver Hage A, Carter J, Jayaraman MV, McTaggart RA. Stroke doi:10.1161/STROKEAHA.109.192535 
vision, aphasia, neglect (VAN) assessment-a novel emergent large 39  Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al, American
vessel occlusion screening tool: pilot study and comparison with Heart Association Stroke Council and Council on Epidemiology
current clinical severity indices. J Neurointerv Surg 2017;9:122-6. and Prevention. Scientific Rationale for the Inclusion and Exclusion
doi:10.1136/neurintsurg-2015-012131  Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A
21  Scheitz JF, Abdul-Rahim AH, MacIsaac RL, et al, SITS Scientific Statement for Healthcare Professionals From the American Heart
Committee. Clinical Selection Strategies to Identify Ischemic Stroke Association/American Stroke Association. Stroke 2016;47:581-641.
Patients With Large Anterior Vessel Occlusion: Results From SITS-ISTR doi:10.1161/STR.0000000000000086 
(Safe Implementation of Thrombolysis in Stroke International Stroke 40  Albers GW, Thijs VN, Wechsler L, et al, DEFUSE Investigators.
Thrombolysis Registry). Stroke 2017;48:290-7. doi:10.1161/ Magnetic resonance imaging profiles predict clinical response
STROKEAHA.116.014431  to early reperfusion: the diffusion and perfusion imaging
22  Vidale S, Arnaboldi M, Frangi L, Longoni M, Monza G, Agostoni E. evaluation for understanding stroke evolution (DEFUSE) study. Ann
The Large ARtery Intracranial Occlusion Stroke Scale: A New Tool Neurol 2006;60:508-17. doi:10.1002/ana.20976 
With High Accuracy in Predicting Large Vessel Occlusion. Front 41  Thomalla G, Cheng B, Ebinger M, et al, STIR and VISTA Imaging
Neurol 2019;10:130. doi:10.3389/fneur.2019.00130  Investigators. DWI-FLAIR mismatch for the identification of
23  Calderon VJ, Kasturiarachi BM, Lin E, Bansal V, Zaidat OO. patients with acute ischaemic stroke within 4·5 h of symptom
Review of the Mobile Stroke Unit Experience Worldwide. Interv onset (PRE-FLAIR): a multicentre observational study. Lancet
Neurol 2018;7:347-58. doi:10.1159/000487334  Neurol 2011;10:978-86. doi:10.1016/S1474-4422(11)70192-2 
24  Helwig SA, Ragoschke-Schumm A, Schwindling L, et al. Prehospital 42  Thomalla G, Simonsen CZ, Boutitie F, et al, WAKE-UP Investigators.
Stroke Management Optimized by Use of Clinical Scoring vs Mobile MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N
Stroke Unit for Triage of Patients With Stroke: A Randomized Clinical Engl J Med 2018;379:611-22. doi:10.1056/NEJMoa1804355 
Trial. JAMA Neurol 2019. doi:10.1001/jamaneurol.2019.2829  43  Campbell BCV, Ma H, Ringleb PA, et al, EXTEND, ECASS-4, and
25  Kepplinger J, Barlinn K, Deckert S, Scheibe M, Bodechtel U, Schmitt J. EPITHET Investigators. Extending thrombolysis to 4.5-9 h and
Safety and efficacy of thrombolysis in telestroke: A systematic review wake-up stroke using perfusion imaging: a systematic review and
and meta-analysis. Neurology 2016;87:1344-51. doi:10.1212/ meta-analysis of individual patient data. Lancet 2019;394:139-47.
WNL.0000000000003148  doi:10.1016/S0140-6736(19)31053-0 

the bmj | BMJ 2020;368:l6983 | doi: 10.1136/bmj.l6983 13

STATE OF THE ART REVIEW

44  Haley ECJr, Thompson JLP, Grotta JC, et al, Tenecteplase in Stroke 66  Jadhav AP, Desai SM, Kenmuir CL, et al. Eligibility for Endovascular
Investigators. Phase IIB/III trial of tenecteplase in acute ischemic Trial Enrollment in the 6- to 24-Hour Time Window: Analysis of a

BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
stroke: results of a prematurely terminated randomized clinical trial. Single Comprehensive Stroke Center. Stroke 2018;49:1015-7.
Stroke 2010;41:707-11. doi:10.1161/STROKEAHA.109.572040  doi:10.1161/STROKEAHA.117.020273 
45  Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus 67  Campbell BC, Hill MD, Rubiera M, et al. Safety and Efficacy of
tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a Solitaire Stent Thrombectomy: Individual Patient Data Meta-Analysis
phase 2, randomised, open-label, blinded endpoint study. Lancet of Randomized Trials. Stroke 2016;47:798-806. doi:10.1161/
Neurol 2015;14:368-76. doi:10.1016/S1474-4422(15)70017-7  STROKEAHA.115.012360 
46  Parsons M, Spratt N, Bivard A, et al. A randomized trial of 68  Zaidat OO, Yoo AJ, Khatri P, et al, Cerebral Angiographic
tenecteplase versus alteplase for acute ischemic stroke. N Engl J Revascularization Grading (CARG) Collaborators, STIR
Med 2012;366:1099-107. doi:10.1056/NEJMoa1109842  Revascularization working group, STIR Thrombolysis in Cerebral
47  Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus Infarction (TICI) Task Force. Recommendations on angiographic
alteplase for management of acute ischaemic stroke (NOR-TEST): revascularization grading standards for acute ischemic stroke: a
a phase 3, randomised, open-label, blinded endpoint trial. Lancet consensus statement. Stroke 2013;44:2650-63. doi:10.1161/
Neurol 2017;16:781-8. doi:10.1016/S1474-4422(17)30253-3  STROKEAHA.113.001972 
48  Campbell BCV, Mitchell PJ, Churilov L, et al, EXTEND-IA TNK 69  Saver JL, Jahan R, Levy EI, et al, SWIFT Trialists. Solitaire flow
Investigators. Tenecteplase versus Alteplase before Thrombectomy restoration device versus the Merci Retriever in patients with acute
for Ischemic Stroke. N Engl J Med 2018;378:1573-82. doi:10.1056/ ischaemic stroke (SWIFT): a randomised, parallel-group, non-
NEJMoa1716405  inferiority trial. Lancet 2012;380:1241-9. doi:10.1016/S0140-
49  Campbell BC, Mitchell PJ, Churilov L, et al, EXTEND-IA TNK Investigators. 6736(12)61384-1 
Tenecteplase versus alteplase before endovascular thrombectomy 70  Broussalis E, Trinka E, Hitzl W, Wallner A, Chroust V, Killer-Oberpfalzer
(EXTEND-IA TNK): A multicenter, randomized, controlled study. Int J M. Comparison of stent-retriever devices versus the Merci
Stroke 2018;13:328-34. doi:10.1177/1747493017733935  retriever for endovascular treatment of acute stroke. AJNR Am J
50  Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Neuroradiol 2013;34:366-72. doi:10.3174/ajnr.A3195 
Alteplase for Acute Ischemic Stroke. Stroke 2019;50:2156-62. 71  Deng L, Qiu S, Wang L, Li Y, Wang D, Liu M. Comparison of Four Food
doi:10.1161/STROKEAHA.119.025080  and Drug Administration-Approved Mechanical Thrombectomy
51  Yaghi S, Willey JZ, Cucchiara B, et al, American Heart Association Devices for Acute Ischemic Stroke: A Network Meta-Analysis. World
Stroke Council; Council on Cardiovascular and Stroke Nursing; Council Neurosurg 2019;127:e49-57. doi:10.1016/j.wneu.2019.02.011 
on Clinical Cardiology; and Council on Quality of Care and Outcomes 72  Zaidat OO, Bozorgchami H, Ribó M, et al. Primary Results of the
Research. Treatment and Outcome of Hemorrhagic Transformation Multicenter ARISE II Study (Analysis of Revascularization in Ischemic
After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Stroke With EmboTrap). Stroke 2018;49:1107-15. doi:10.1161/
Statement for Healthcare Professionals From the American Heart STROKEAHA.117.020125 
Association/American Stroke Association. Stroke 2017;48:e343-61. 73  Jindal G, Serulle Y, Miller T, et al. Stent retrieval thrombectomy in acute
doi:10.1161/STR.0000000000000152  stoke is facilitated by the concurrent use of intracranial aspiration
52  Broderick JP, Palesch YY, Demchuk AM, et al, Interventional catheters. J Neurointerv Surg 2017;9:944-7. doi:10.1136/
Management of Stroke (IMS) III Investigators. Endovascular neurintsurg-2016-012581 
therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J 74  Turk AS, Turner R, Spiotta A, et al. Comparison of endovascular
Med 2013;368:893-903. doi:10.1056/NEJMoa1214300  treatment approaches for acute ischemic stroke: cost effectiveness,
53  Kidwell CS, Jahan R, Gornbein J, et al, MR RESCUE Investigators. A trial technical success, and clinical outcomes. J Neurointerv
of imaging selection and endovascular treatment for ischemic stroke. Surg 2015;7:666-70. doi:10.1136/neurintsurg-2014-011282 
N Engl J Med 2013;368:914-23. doi:10.1056/NEJMoa1212793  75  Lapergue B, Blanc R, Gory B, et al, ASTER Trial Investigators.
54  Ciccone A, Valvassori L, Nichelatti M, et al, SYNTHESIS Expansion Effect of Endovascular Contact Aspiration vs Stent Retriever on
Investigators. Endovascular treatment for acute ischemic stroke. N Revascularization in Patients With Acute Ischemic Stroke and
Engl J Med 2013;368:904-13. doi:10.1056/NEJMoa1213701  Large Vessel Occlusion: The ASTER Randomized Clinical Trial.
55  Alberts MJ, Shang T, Magadan A. Endovascular Therapy for Acute JAMA 2017;318:443-52. doi:10.1001/jama.2017.9644 
Ischemic Stroke: Dawn of a New Era. JAMA Neurol 2015;72:1101-3. 76  Gory B, Lapergue B, Blanc R, et al, ASTER Trial Investigators. Contact
doi:10.1001/jamaneurol.2015.1743  Aspiration Versus Stent Retriever in Patients With Acute Ischemic
56  Berkhemer OA, Fransen PS, Beumer D, et al, MR CLEAN Investigators. Stroke With M2 Occlusion in the ASTER Randomized Trial (Contact
A randomized trial of intraarterial treatment for acute ischemic stroke. Aspiration Versus Stent Retriever for Successful Revascularization).
N Engl J Med 2015;372:11-20. doi:10.1056/NEJMoa1411587  Stroke 2018;49:461-4. doi:10.1161/STROKEAHA.117.019598 
57  Goyal M, Demchuk AM, Menon BK, et al, ESCAPE Trial Investigators. 77  Turk AS3rd, Siddiqui A, Fifi JT, et al. Aspiration thrombectomy versus
Randomized assessment of rapid endovascular treatment of stent retriever thrombectomy as first-line approach for large vessel
ischemic stroke. N Engl J Med 2015;372:1019-30. doi:10.1056/ occlusion (COMPASS): a multicentre, randomised, open label,
NEJMoa1414905  blinded outcome, non-inferiority trial. Lancet 2019;393:998-1008.
58  Campbell BC, Mitchell PJ, Kleinig TJ, et al, EXTEND-IA Investigators. doi:10.1016/S0140-6736(19)30297-1 
Endovascular therapy for ischemic stroke with perfusion-imaging 78  Wan TF, Xu R, Zhao ZA, Lv Y, Chen HS, Liu L. Outcomes of
selection. N Engl J Med 2015;372:1009-18. doi:10.1056/ general anesthesia versus conscious sedation for Stroke
NEJMoa1414792  undergoing endovascular treatment: a meta-analysis. BMC
59  Saver JL, Goyal M, Bonafe A, et al, SWIFT PRIME Investigators. Stent- Anesthesiol 2019;19:69. doi:10.1186/s12871-019-0741-7 
retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. 79  Abou-Chebl A, Lin R, Hussain MS, et al. Conscious sedation
N Engl J Med 2015;372:2285-95. doi:10.1056/NEJMoa1415061  versus general anesthesia during endovascular therapy for acute
60  Jovin TG, Chamorro A, Cobo E, et al, REVASCAT Trial Investigators. anterior circulation stroke: preliminary results from a retrospective,
Thrombectomy within 8 hours after symptom onset in ischemic stroke. multicenter study. Stroke 2010;41:1175-9. doi:10.1161/
N Engl J Med 2015;372:2296-306. doi:10.1056/NEJMoa1503780  STROKEAHA.109.574129 
61  Mocco J, Zaidat OO, von Kummer R, et al, THERAPY Trial 80  Jumaa MA, Zhang F, Ruiz-Ares G, et al. Comparison of safety
Investigators*. Aspiration Thrombectomy After Intravenous Alteplase and clinical and radiographic outcomes in endovascular acute
Versus Intravenous Alteplase Alone. Stroke 2016;47:2331-8. stroke therapy for proximal middle cerebral artery occlusion with
doi:10.1161/STROKEAHA.116.013372  intubation and general anesthesia versus the nonintubated state.
62  Bracard S, Ducrocq X, Mas JL, et al, THRACE investigators. Mechanical Stroke 2010;41:1180-4. doi:10.1161/STROKEAHA.109.574194 
thrombectomy after intravenous alteplase versus alteplase alone 81  John N, Mitchell P, Dowling R, Yan B. Is general anaesthesia preferable
after stroke (THRACE): a randomised controlled trial. Lancet to conscious sedation in the treatment of acute ischaemic stroke with
Neurol 2016;15:1138-47. doi:10.1016/S1474-4422(16)30177-6  intra-arterial mechanical thrombectomy? A review of the literature.
63  Muir KW, Ford GA, Messow CM, et al, PISTE Investigators. Neuroradiology 2013;55:93-100. doi:10.1007/s00234-012-1084-y 
Endovascular therapy for acute ischaemic stroke: the Pragmatic 82  Brinjikji W, Murad MH, Rabinstein AA, Cloft HJ, Lanzino G, Kallmes DF.
Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, Conscious sedation versus general anesthesia during endovascular
controlled trial. J Neurol Neurosurg Psychiatry 2017;88:38-44. acute ischemic stroke treatment: a systematic review and meta-analysis.
doi:10.1136/jnnp-2016-314117  AJNR Am J Neuroradiol 2015;36:525-9. doi:10.3174/ajnr.A4159 
64  Almekhlafi MA, Hill MD, Roos YM, et al. Stroke Laterality Did Not 83  Just C, Rizek P, Tryphonopoulos P, Pelz D, Arango M. Outcomes
Modify Outcomes in the HERMES Meta-Analysis of Individual of General Anesthesia and Conscious Sedation in Endovascular
Patient Data of 7 Trials. Stroke 2019;50:2118-24. doi:10.1161/ Treatment for Stroke. Can J Neurol Sci 2016;43:655-8. doi:10.1017/
STROKEAHA.118.023102  cjn.2016.256 
65  McMeekin P, White P, James MA, Price CI, Flynn D, Ford GA. 84  Löwhagen Hendén P, Rentzos A, Karlsson JE, et al. General Anesthesia
Estimating the number of UK stroke patients eligible for Versus Conscious Sedation for Endovascular Treatment of Acute
endovascular thrombectomy. Eur Stroke J 2017;2:319-26. Ischemic Stroke: The AnStroke Trial (Anesthesia During Stroke).
doi:10.1177/2396987317733343  Stroke 2017;48:1601-7. doi:10.1161/STROKEAHA.117.016554 

14 doi: 10.1136/bmj.l6983 | BMJ 2020;368:l6983 | the bmj

 STATE OF THE ART REVIEW

85  Schönenberger S, Uhlmann L, Hacke W, et al. Effect of Conscious 102  Johnston KC, Bruno A, Pauls Q, et al, Neurological Emergencies
Sedation vs General Anesthesia on Early Neurological Improvement Treatment Trials Network and the SHINE Trial Investigators. Intensive

BMJ: first published as 10.1136/bmj.l6983 on 13 February 2020. Downloaded from http://www.bmj.com/ on 17 February 2020 by guest. Protected by copyright.
Among Patients With Ischemic Stroke Undergoing Endovascular vs Standard Treatment of Hyperglycemia and Functional Outcome in
Thrombectomy: A Randomized Clinical Trial. JAMA 2016;316:1986- Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical
96. doi:10.1001/jama.2016.16623  Trial. JAMA 2019;322:326-35. doi:10.1001/jama.2019.9346 
86  Simonsen CZ, Yoo AJ, Sørensen LH, et al. Effect of General 103  Roffe C, Nevatte T, Sim J, et al, Stroke Oxygen Study Investigators and
Anesthesia and Conscious Sedation During Endovascular Therapy the Stroke OxygenStudy Collaborative Group. Effect of Routine Low-
on Infarct Growth and Clinical Outcomes in Acute Ischemic Dose Oxygen Supplementation on Death and Disability in Adults With
Stroke: A Randomized Clinical Trial. JAMA Neurol 2018;75:470-7. Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial.
doi:10.1001/jamaneurol.2017.4474  JAMA 2017;318:1125-35. doi:10.1001/jama.2017.11463 
87  Schönenberger S, Hendén PL, Simonsen CZ, et al. Association 104  CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST:
of General Anesthesia vs Procedural Sedation With Functional randomised placebo-controlled trial of early aspirin use in 20,000
Outcome Among Patients With Acute Ischemic Stroke Undergoing patients with acute ischaemic stroke. Lancet 1997;349:1641-9.
Thrombectomy: A Systematic Review and Meta-analysis. doi:10.1016/S0140-6736(97)04010-5 
JAMA 2019;322:1283-93. doi:10.1001/jama.2019.11455  105  International Stroke Trial Collaborative Group. The International
88  Powers CJ, Dornbos D3rd, Mlynash M, et al. Thrombectomy with Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin,
Conscious Sedation Compared with General Anesthesia: A DEFUSE 3 both, or neither among 19435 patients with acute ischaemic stroke.
Analysis. AJNR Am J Neuroradiol 2019;40:1001-5. doi:10.3174/ajnr. Lancet 1997;349:1569-81. doi:10.1016/S0140-6736(97)04011-7 
A6059  106  Wang Y, Wang Y, Zhao X, et al, CHANCE Investigators. Clopidogrel with
89  Campbell BCV, van Zwam WH, Goyal M, et al, HERMES collaborators. aspirin in acute minor stroke or transient ischemic attack. N Engl J
Effect of general anaesthesia on functional outcome in patients Med 2013;369:11-9. doi:10.1056/NEJMoa1215340 
with anterior circulation ischaemic stroke having endovascular 107  Johnston SC, Easton JD, Farrant M, et al, Clinical Research
thrombectomy versus standard care: a meta-analysis of individual Collaboration, Neurological Emergencies Treatment Trials Network,
patient data. Lancet Neurol 2018;17:47-53. doi:10.1016/S1474- and the POINT Investigators. Clopidogrel and Aspirin in Acute
4422(17)30407-6  Ischemic Stroke and High-Risk TIA. N Engl J Med 2018;379:215-25.
90  Bath PM, Scutt P, Anderson CS, et al, RIGHT-2 Investigators. doi:10.1056/NEJMoa1800410 
Prehospital transdermal glyceryl trinitrate in patients with ultra-acute 108  Prasad K, Siemieniuk R, Hao Q, et al. Dual antiplatelet therapy with
presumed stroke (RIGHT-2): an ambulance-based, randomised, aspirin and clopidogrel for acute high risk transient ischaemic
sham-controlled, blinded, phase 3 trial. Lancet 2019;393:1009-20. attack and minor ischaemic stroke: a clinical practice guideline.
doi:10.1016/S0140-6736(19)30194-1  BMJ 2018;363:k5130. doi:10.1136/bmj.k5130 
91  Lee M, Ovbiagele B, Hong KS, et al. Effect of Blood Pressure Lowering 109  Campbell BCV, Majoie CBLM, Albers GW, et al, HERMES collaborators.
in Early Ischemic Stroke: Meta-Analysis. Stroke 2015;46:1883-9. Penumbral imaging and functional outcome in patients with anterior
doi:10.1161/STROKEAHA.115.009552  circulation ischaemic stroke treated with endovascular thrombectomy
92  Anderson CS, Huang Y, Lindley RI, et al, ENCHANTED Investigators and versus medical therapy: a meta-analysis of individual patient-
Coordinators. Intensive blood pressure reduction with intravenous level data. Lancet Neurol 2019;18:46-55. doi:10.1016/S1474-
thrombolysis therapy for acute ischaemic stroke (ENCHANTED): 4422(18)30314-4 
an international, randomised, open-label, blinded-endpoint, 110  Román LS, Menon BK, Blasco J, et al, HERMES collaborators.
phase 3 trial. Lancet 2019;393:877-88. doi:10.1016/S0140- Imaging features and safety and efficacy of endovascular stroke
6736(19)30038-8  treatment: a meta-analysis of individual patient-level data. Lancet
93  Goyal N, Tsivgoulis G, Pandhi A, et al. Blood pressure levels Neurol 2018;17:895-904. doi:10.1016/S1474-4422(18)30242-4 
post mechanical thrombectomy and outcomes in large vessel 111  Barber PA, Demchuk AM, Zhang J, Buchan AM. Validity and reliability
occlusion strokes. Neurology 2017;89:540-7. doi:10.1212/ of a quantitative computed tomography score in predicting
WNL.0000000000004184  outcome of hyperacute stroke before thrombolytic therapy.
94  Mistry EA, Mayer SA, Khatri P. Blood Pressure Management after ASPECTS Study Group. Alberta Stroke Programme Early CT Score.
Mechanical Thrombectomy for Acute Ischemic Stroke: A Survey of Lancet 2000;355:1670-4. doi:10.1016/S0140-6736(00)02237-6 
the StrokeNet Sites. J Stroke Cerebrovasc Dis 2018;27:2474-8. 112  Nagel S, Bouslama M, Krause LU, et al. Mechanical Thrombectomy
doi:10.1016/j.jstrokecerebrovasdis.2018.05.003  in Patients With Milder Strokes and Large Vessel Occlusions.
95  Wojner-Alexander AW, Garami Z, Chernyshev OY, Alexandrov AV. Stroke 2018;49:2391-7. doi:10.1161/STROKEAHA.118.021106 
Heads down: flat positioning improves blood flow velocity in acute 113  Sarraj A, Hassan A, Savitz SI, et al. Endovascular Thrombectomy for
ischemic stroke. Neurology 2005;64:1354-7. doi:10.1212/01. Mild Strokes: How Low Should We Go?Stroke 2018;49:2398-405.
WNL.0000158284.41705.A5  doi:10.1161/STROKEAHA.118.022114 
96  Hargroves D, Tallis R, Pomeroy V, Bhalla A. The influence of 114  Brehm A, Tsogkas I, Maier IL, et al. One-Stop Management with
positioning upon cerebral oxygenation after acute stroke: a pilot Perfusion for Transfer Patients with Stroke due to a Large-Vessel
study. Age Ageing 2008;37:581-5. doi:10.1093/ageing/afn143  Occlusion: Feasibility and Effects on In-Hospital Times. AJNR Am J
97  Olavarría VV, Arima H, Anderson CS, et al. Head position and Neuroradiol 2019;40:1330-4. doi:10.3174/ajnr.A6129 
cerebral blood flow velocity in acute ischemic stroke: a systematic 115  Psychogios MN, Behme D, Schregel K, et al. One-Stop Management
review and meta-analysis. Cerebrovasc Dis 2014;37:401-8. of Acute Stroke Patients: Minimizing Door-to-Reperfusion Times.
doi:10.1159/000362533  Stroke 2017;48:3152-5. doi:10.1161/STROKEAHA.117.018077 
98  Truijen J, Rasmussen LS, Kim YS, et al. Cerebral autoregulatory 116  Boncoraglio GB, Ranieri M, Bersano A, Parati EA, Del Giovane C. Stem
performance and the cerebrovascular response to head-of-bed cell transplantation for ischemic stroke. Cochrane Database Syst
positioning in acute ischaemic stroke. Eur J Neurol 2018;25:1365- Rev 2019;5:CD007231.
e117. doi:10.1111/ene.13737  117  Patel RAG, McMullen PW. Neuroprotection in the Treatment of
99  Olavarría VV, Lavados PM, Muñoz-Venturelli P, et al. Flat-head Acute Ischemic Stroke. Prog Cardiovasc Dis 2017;59:542-8.
positioning increases cerebral blood flow in anterior circulation doi:10.1016/j.pcad.2017.04.005 
acute ischemic stroke. A cluster randomized phase IIb trial. Int J 118  Griauzde J, Ravindra VM, Chaudhary N, Gemmete JJ, Pandey
Stroke 2018;13:600-11. doi:10.1177/1747493017711943  AS. Neuroprotection for ischemic stroke in the endovascular
100  Anderson CS, Arima H, Lavados P, et al, HeadPoST Investigators era: A brief report on the future of intra-arterial therapy. J Clin
and Coordinators. Cluster-Randomized, Crossover Trial of Head Neurosci 2019;69:289-91. doi:10.1016/j.jocn.2019.08.001 
Positioning in Acute Stroke. N Engl J Med 2017;376:2437-47. 119  Boulanger JM, Lindsay MP, Gubitz G, et al. Canadian Stroke
doi:10.1056/NEJMoa1615715  Best Practice Recommendations for Acute Stroke Management:
101  Alexandrov AW, Tsivgoulis G, Hill MD, et al. HeadPoST: Rightly Prehospital, Emergency Department, and Acute Inpatient Stroke
positioned, or flat out wrong?Neurology 2018;90:885-9. Care, 6th Edition, Update 2018. Int J Stroke 2018;13:949-84.
doi:10.1212/WNL.0000000000005481  doi:10.1177/1747493018786616

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe