ARTICLE

Indications for Mechanical Thrombectomy for

Acute Ischemic Stroke
Current Guidelines and Beyond
Ashutosh P. Jadhav, MD, PhD, Shashvat M. Desai, MD, and Tudor G. Jovin, MD Correspondence
Dr. Jadhav
®
Neurology 2021;97:S126-S136. doi:10.1212/WNL.0000000000012801 jadhav.library@gmail.com

Abstract
Purpose of the Review
This article reviews recent breakthroughs in the treatment of acute ischemic stroke, mainly
focusing on the evolution of endovascular thrombectomy, its impact on guidelines, and the
need for and implications of next-generation randomized controlled trials.

Recent Findings
Endovascular thrombectomy is a powerful tool to treat large vessel occlusion strokes and
multiple trials over the past 5 years have established its safety and efficacy in the treatment of
anterior circulation large vessel occlusion strokes up to 24 hours from stroke onset.

Summary
In 2015, multiple landmark trials (MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, and
EXTEND IA) established the superiority of endovascular thrombectomy over medical man-
agement for the treatment of anterior circulation large vessel occlusion strokes. Endovascular
thrombectomy has a strong treatment effect with a number needed to treat ranging from 3 to
10. These trials selected patients based on occlusion location (proximal anterior occlusion:
internal carotid or middle cerebral artery), time from stroke onset (early window: up to 6–12
hours), and acceptable infarct burden (Alberta Stroke Program Early CT Score [ASPECTS] ≥6
or infarct volume <50 mL). In 2017, the DAWN and DEFUSE-3 trials successfully extended the
time window up to 24 hours in appropriately selected patients. Societal and national throm-
bectomy guidelines have incorporated these findings and offer Class 1A recommendation to a
subset of well-selected patients. Thrombectomy ineligible stroke subpopulations are being
studied in ongoing randomized controlled trials. These trials, built on encouraging data from
pooled analysis of early trials (HERMES collaboration) and emerging retrospective data, are
studying large vessel occlusion strokes with mild deficits (National Institutes of Health Stroke
Scale <6) and large infarct burden (core volume >70 mL).

From the Department of Neurosurgery (A.P.J.), Barrow Neurological Institute, Phoenix, AZ; HonorHealth Research Institute (S.M.D.), Scottsdale, AZ; and Cooper Neurologic Institute
(T.G.J.), Camden, NJ.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

S126 Copyright © 2021 American Academy of Neurology

Copyright © 2021 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Reperfusion Hypothesis
Cerebral ischemia occurs when a blood vessel hypoperfuses
the target tissue. The target tissue subsequently undergoes
irreversible damage in a time dependent fashion with dead
tissue referred to as “core” and at-risk tissue referred to as
“penumbra.” The reperfusion hypothesis posits that the
penumbra is salvageable tissue that can be rescued with ex-
peditious and complete restoration of blood flow. Conversely,
failure to restore blood flow inevitably results in the surrender
of penumbral tissue to irreversible damage and expansion of
the core. Early attempts to both intravenously and intra-
arterially reinstate perfusion established proof of concept but
safety and efficacy required further refinement. After numer-
ous negative thrombolysis trials, the results of the NINDS tpa
trial in 1995 demonstrated the superiority of IV tPA over
placebo in patients presenting within 3 hours of symptoms.1
This prompted the Food and Drug Administration (FDA) to
approve the use of IV tPA up to 3 hours in 1996. While
subsequent studies such as the ECASS3 trial in 2008 further
demonstrated the benefit of IV tPA over placebo in patients
presenting within 3–4.5 hours of symptoms,2 the FDA did not
find this data sufficient to grant supplemental biological
license and the current on-label indication for IV tPA remains
restricted to 3 hours.3
While the intravenous approach is more easily administrable
and therefore more broadly available, the limited therapeutic
time window as well as low efficacy13 for large vessel oc-
clusions prompted interest in an endovascular approach.
The Prolyse in Acute Cerebral Thromboembolism (PRO-
ACT I) trial enrolled patients presenting with a middle ce-
rebral artery (MCA) occlusion within 6 hours of symptoms
onset. Patients were randomized to local intra-arterial in-
fusion of thrombolysis (r-proUK) vs saline. The trial was
halted early due to the approval of IV tPA, however analysis
revealed higher rates of recanalization with r-proUK (57.7%)
vs placebo (14.3%). This landmark study was the first ran-
domized controlled trial investigating the benefit of an intra-
arterial approach for acute ischemic stroke and laid the
groundwork for future investigations.14
Based on the encouraging results of PROACT I, the PRO-
ACT II study randomized a larger set of patients with MCA
occlusions presenting within 6 hours of symptoms onset to
receive a local infusion of r-proUK vs placebo over a 2-hour
period.15 Both groups received low dose intravenous heparin
(in PROACT I and II). Once again, higher rates of re-
canalization were noted in the lytic cohort and while there
were higher rates of symptomatic hemorrhage in the treat-
ment population, there was improved outcomes in the
r-proUK group (40%) compared to the placebo group (25%).
Despite the positive primary outcome, the FDA ultimately did
not approve the use of r-proUK due to the small study sample
size. In the first AHA/ASA acute ischemic stroke guidelines in
1994,16 intra-arterial therapy was considered investigational
with level E evidence but in 2003,17 the results of PROACT II
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were extrapolated to alteplase based on consensus as sup-
ported by case series data.
An additional study conducted in Japan from 2002 to 2005
compared the efficacy of intra-arterial urokinase vs placebo for
patients presenting within 6 hours of symptoms. This study
was halted after the approval of IV tpa in Japan. Good out-
comes were more frequent in the treatment arm; however, the
results did not reach statistical significance due to limited
sample size.18 In clinical practice terms, the results of these
studies were extrapolated to tPA and this led to increased use
of intra-arterial therapy, particularly in patients who did not
respond to or qualify for IV tpa.
First Generation Technique Trials
To some extent, the promising experience with PROACT II
and MELT likely led to some loss of equipoise among prac-
titioners and thereby created barriers to conducting further
randomized controlled trials. Nonetheless, the PROACT II
introduced several important concepts relevant to future
study design including the utilization of dichotomized mod-
ified Rankin Scale (mRS) of 0–2 as a primary end-point for an
acute ischemic stroke trial as well as expanding the treatment
time window from 3 hours to 6 hours.15
Given lingering concerns of hemorrhagic complications associ-
ated with lytics, the development of mechanical devices for clot
disruption and retrieval became of high interest. Several classes of
devices were developed including lasers, ultrasonography, an-
gioplasty and micro-snares. In 2004, FDA cleared the Merci
retriever which consisted of a memory-shaped nitinol wire with
helical loops that was delivered to the thrombus via micro-
catheter navigation. Approval was based on a single arm, pro-
spective study of patients who presented within 8 hours of
symptoms onset and were ineligible for IV tpa. Recanalization
was achieved in 46% of patients and good outcomes were more
frequent in the patients who experienced successful re-
canalization (46% vs 10%, p < 0.0001).19 Since the data was not a
randomized comparison to a medical therapy, the FDA granted
the 510K-pathway for clearance as a device for clot removal in
acute ischemic stroke, however not for a clinical indication for
reduced disability. Modelled after the reimbursement for cra-
niectomy, the device company was successfully able to negotiate
a diagnosis-related group reimbursement through the Centers
for Medicare & Medicaid Services. The 510-k pathway was
successfully pursued in 2007 for a second class of devices:
reperfusion catheters with aspiration pump. This was based on
the results of the single arm prospective pivotal Penumbra trial
which enrolled patients who were ineligible or refractory to IV
tpa presenting within 8 hours of symptoms onset.20 The use of
mechanical thrombectomy was supported by a class II level B
recommendation by the AHA/ASA.21
While intra-arterial therapy became increasingly available,
there was no high-quality data to suggest that this approach
S127
 Table 1 Frequency of Baseline mRS, ASPECT, and Site of Occlusion by Trial
Trial Baseline mRS, mRS 0–2
MR CLEAN 95.8
ESCAPE N/A
REVASCAT N/A
SWIFT PRIME mRS 0–1: 98.4
EXTEND-IA N/A
HERMES N/A
DAWN mRS 0–1: 100
DEFUSE-3 mRS 0–2: 100
was any more efficacious than medical therapy. Given the
associated cost and variable availability, EVT was offered
sporadically and the use of mechanical thrombectomy as of
2013 was only supported by a class II level B recommendation
by the AHA/ASA.21 Three randomized controlled trials (IMS
III, SYNTHESIS, MR RESCUE) were conducted to address
the question of whether EVT as stand-alone or adjunctive
therapy would lead to superior outcomes over IVT in patients
presenting with acute ischemic stroke.22-24 While all the
studies had slightly different trial designs, a majority of pa-
tients were treated with first generation technology (intra-
arterial alteplase, Merci retriever, Penumbra reperfusion
catheter) with resultant low rates of recanalization. Additional
trial limitations included: inclusion of patients without proven
occlusion (lack of surgical target lesion in approximately 8% of
patients) and established infarct (minimal salvageable tissue)
as well as slow work flow. Furthermore, there was often failure
to randomize all consecutive eligible patients, likely reflecting
provider lack of equipoise. While the results were disap-
pointing, the lessons learned galvanized efforts to design a
second wave of trials focused primarily on more efficacious
devices, appropriate patient selection and streamlined
workflow.
Stent Retriever Devices
In order to appropriately test the reperfusion hypothesis, a
basic prerequisite is that vessel recanalization is achieved with
complete (TICI3) or near complete recanalization (TICI2b).
A major limitation of the first-generation devices was
low efficacy with recanalization. For example, successful re-
canalization after thrombectomy in the IMS3 trial was only
44% and even less in the MR RESCUE trial (27%). The rates of
recanalization in the SYNTHESIS trial were not reported.22-24
Given the relatively low efficacy of intra-arterial thrombolysis
with LVO,14,15 the MERCI retriever and first-generation Pen-
umbra aspiration catheters, continued interest remained in
further refining the mechanical thrombectomy approach. In
cases where vessels could not be recanalized with available
technologies, practitioners began resorting to angioplasty and
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Stroke burden Occlusion location, % ICA/MCA-M1
ASPECTS ≥5: 94.4 91.6
ASPECTS ≥6: 97.2 97.2
N/A 91.2
ASPECTS ≥8: 76.7 90.3
N/A 85.7
ASPECTS ≥6: 90.5 90.8
Core <51 mL: 100 97.6
Core <70 mL: 100 99.5
intra-cranial stent placement as salvage methods. While there
was technical success in opening the vessel, the need for sub-
sequent dual anti-platelets to preserve implant patency com-
plicates routine use of this approach given concerns for
hemorrhagic complications. Nonetheless, the general principle
of radially displacing the whole length of thrombus against the
vessel wall while simultaneously incorporating the clot in the
stent struts prompted the development of a new class of stent-
like devices termed stent retrievers. Importantly, stent re-
trievers are subsequently withdrawn from the intra-cranial
vasculature after clot engagement without significant vessel
disruption and abrogate the need for dual antiplatelets.
The Solitaire Flow Restoration device is a self-expanding stent
retriever that was compared to the predicate Merci retriever
device in the SWIFT study.25 Rates of recanalization (TIMI 2
or 3) were significantly higher with the Solitaire device (61%
vs 24%). A second stent retriever device, the Trevo retriever,
was similarly compared against the Merci retriever device.
Rates of recanalization (TICI 2 or higher) were significantly
higher with the Trevo device (86% vs 60%).26 Superior
clinical outcomes were observed in the stent retriever arm of
both studies. The use of stent retriever devices over the Merci
retriever for clot retrieval were supported by a class I level A
recommendation by the 2013 AHA/ASA guidelines.21 Given
the results of the SWIFT study and the TREVO2 study, both
devices were cleared by the FDA in 2014. Similar to the Merci
and Penumbra devices, the stent retriever devices were ini-
tially cleared for clot removal but not for reducing clinical
disability.
Early Time Window Trials
Given the improved recanalization rates, a new set of trials,
predominantly employing the Solitaire and Trevo devices,
studied the benefit of EVT therapy over medical therapy alone.
MR CLEAN was a randomized controlled trial performed in
the Netherlands that studied 500 patients presenting within 6
hours of symptoms onset related to an intra-cranial anterior
circulation occlusion.8 Patients were randomized to receive
Neurology.org/N
Figure 1 Rates of Recanalization (TICI≥2B) and mRS 0–2 at 90 Days in Early Window Trials
standard medical management (including IV tpa) alone vs
adjunctive EVT. At 24 hours, 75.4% of the patients in the
intervention had absence of residual occlusion as compared to
32.9% of the patients in the control group. Importantly, the
primary end-point of mRS 0–2 at 90 days was higher in the
treatment group (32.6% vs 19.1%) and the follow up infarct
volume was smaller by 19 cc on average. This study was the first
to demonstrate the benefit of EVT over usual care (including
IV tpa).
The favorable results of MR CLEAN compared to IMS III
have been attributed to several important study design con-
siderations. In terms of patient selection, MR CLEAN re-
quired the documentation of an intra-cranial occlusion
whereas initially the use of CTA was not routine during the
enrollment of IMS III and vessel status was unknown in 47%
of the patients.22 Of patients that underwent mechanical
thrombectomy, nearly all cases (190 out of 195) used stent
retrievers. In addition, a major concern of IMS III had been
the slow enrollment (1–2 patients per center per year) which
was attributed in part to treatments being offered outside the
context of a clinical trial. This enrollment bias was minimized
in MR CLEAN as all centers offering EVT participated in the
trial and after policy changes in 2013, insurance re-
imbursement was only provided for patients being treated in
the context of the clinical trial.
After the results of MR CLEAN were presented at the World
Stroke Conference in the October of 2014, several ongoing
EVT trials were either halted due to lack of equipoise or
examined at a pre-specified interim analysis. In short order,
the results of EXTEND-IA, ESCAPE, SWIFT PRIME and
REVASCAT similarly confirmed the benefit of EVT over
medical therapy.4-7 These trials were all published in 2015 and
based on these cumulative results, the AHA/ASA guidelines
were revised and supported a class I level A recommendation
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for patients with baseline good functional status (mRS 0–1)
and treatment initiation within 6 hours of disabling stroke
(NIHSS≥6) due to an anterior circulation proximal occlusion
(internal carotid artery, MCA segment 1) and small infarct
(Alberta Stroke Program Early CT Score [ASPECTS] of 6 or
better) should receive IV tpa and undergo stent retriever
thrombectomy.27 In addition, the FDA expanded clearance
for stent retrievers from simply clot removal to also reducing
disability. The stent retrievers are the first and only class of
neurothrombectomy devices cleared for clinical indication.
The rationale for these specific criteria was based on the AHA/
ASA Level of Evidence grading algorithm requiring more than one
positive trial specifying the various criteria to warrant a level A
recommendation: baseline mRS 0–1 (SWIFT PRIME, REVAS-
CAT), treatment within 6 hours (SWIFT PRIME, EXTEND-IA),
ASPECTS 6 or better (SWIFT PRIME, ESCAPE) and NIHSS 6
or higher (ESCAPE, REVASCAT). Furthermore, a majority of
the trials either excluded or minimally included occlusions in-
volving or distal to the MCA segment 2 (MCA-M2). Table 1
provides trial specific inclusion criteria and Figure 1 provides a
figure including the rates of recanalization and rates of functional
independence in the intervention arm of early window throm-
bectomy trials.
Late Time Window Trials
While the ESCAPE trial randomized patients up to 12 hours
and the REVASCAT trial enrolled patients treatable within 8
hours of time last seen well, very few patients were available
from the 2015 clinical trials to determine the benefit of EVT in
patients presenting beyond 6 hours of symptoms onset. In-
deed, in the MR CLEAN study, benefit was no longer sta-
tistically significant if reperfusion occurred after 6 hours and
19 minutes of symptoms onset. A meta-analyses of the 5 trials
was conducted as part of the HERMES collaboration (MR
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 Table 2 AHA/ASA Guidelines
Reference Treatment Recommendation Source

Adams et al. (1994)16 IA STK or UKN Level V Case series

49
Adams et al. (1996) IA STK or UKN Level V Case series

17
Adams et al. (2003) IA thrombolysis Grade IB (0–6h) PROACT2

Adams et al. (2005)50 IA thrombolysis Grade IB (0–6h) PROACT2

Adams et al. (2007)51 IA thrombolysis Grade IB (0–6h) PROACT2

21
Jauch et al. (2013) IA thrombolysis Grade IB (0–6h) PROACT2, MELT

Mechanical thrombectomy Grade IIB Merci, Penumbra

SWIFT, TREVO2

27
Powers et al. (2015) Mechanical thrombectomy Grade IA (0–6h, M1/ICA) MR CLEAN, REVASCAT, ESCAPE, SWIFT PRIME, EXTEND IA

37
Powers et al. (2018) Mechanical thrombectomy Grade IA (0–6h, M1/ICA) MR CLEAN, REVASCAT, ESCAPE, SWIFT PRIME, EXTEND IA

Mechanical thrombectomy Grade IA (6–24h, M1/ICA) DAWN, DEFUSE 3

IA-Intraarterial.

CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVAS-
CAT) and similarly demonstrated that there was no addi-
tional clinical benefit of mechanical thrombectomy after
7.3 hours.28 The benefit of reperfusion therapy is time de-
pendent with the every 30-minute delay in reperfusion leading
to a 26% decrease in good outcome in the REVASCAT trial.29
Indeed, time has become well recognized as a treatment effect
modifier for both IV and IA therapy and much of the stroke
systems of care have evolved around the principle of
streamlining workflow and reducing time delays. Nonetheless,
it has also been long recognized that a subset of patients
benefits from perfusion therapy even at late time windows and
EVT has been offered off label routinely. In a single center
analyses of patients treated with EVT between 2012 to 2015,
126 patients were treated outside of the AHA/ASA guidelines
top tier recommendation and of those, 58% were treated
beyond 6 hours.30 The physiologic basis for this approach has
been predicated on the clinical observation that patients
presenting after similar duration of symptoms onset will have
variable established infarct31,32 and therefore a tissue based
paradigm has been increasingly adopted in favor of a purely
time based paradigm.33,34
late time window patients.10,35 Patients were selected based
on severe clinical deficit (high NIHSS) in the setting of a small
established infarct (small core). This clinical-core mismatch
paradigm successfully identified patients who benefited from
EVT in the late time window and the trial was halted after a
pre-specified interim analysis. Rate of functional in-
dependence at 90 days was 49% in the EVT group as com-
pared with 13% in the control group.10
In 2012, the results of the DEFUSE-2 study demonstrated
comparable rates of good outcomes after EVT in patients
presenting within 6 hours vs beyond 6 hours as long as a target
mismatch was identified on perfusion imaging.36 The target
mismatch paradigm served as the basis for patient selection in
the DEFUSE-3 trial.11 Similar to the DAWN trial, the
DEFUSE-3 trial enrolled patients in the late time window
(6–16 hours) with stent retrievers used in a majority of the
cases (75%). After the DAWN trial results were presented in
the May of 2017, the DEFUSE-3 trial was halted due to lack of
equipoise and an early interim analysis at the time confirmed
benefit of EVT over medical therapy in patients selected based
on a tissue paradigm. Good outcomes in the treatment arm
were 45% compared to 17% in the medical arm.11

In 2011, a multi-center study of 237 patients presenting with
an anterior circulation occlusion treated beyond 8 hours of
symptoms onset and selected based on perfusion imaging
revealed rates of good outcomes comparable to those treated
in the early time window with comparable safety profile.34
This “pre-DAWN” cohort of patients served as the rationale
for a prospective trial comparing the benefit of EVT vs usual
care in patients presenting between 6-24 hours. The DAWN
trial was a multi-center study specifically comparing the
benefit of Trevo thrombectomy to medical management in
Together, the results of the DAWN and DEFUSE-3 trials
significantly expanded the time window in which acute stroke
therapy could be offered. In 2018, the AHA/ASA guidelines
were revised and supported a Class I level A recommendation
for patients presenting in the 6–16 hours time window and
class IIA level B-R recommendation for patients presenting in
the 16–24 hours time window with baseline good functional
status and disabling stroke (NIHSS≥6) due to an anterior
circulation proximal occlusion (internal carotid artery, middle
cerebral artery segment 1) and tissue at risk (as defined by trial

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Table 3 Estimated Endovascular Thrombectomy Eligibility per Current and Projected Thrombectomy Eligibility Criteria
Population based
Comprehensive stroke center eligibility (per Total numbers in United States
eligibility43,44 (among all 100,000 person (extrapolation based on
Criteria Eligibility per AHA/ASA acute ischemic stroke), % years) 680,000 acute strokes in US)

0-6-hour AHA/ASA Yes. Eligible per AHA/ASA 12 18 81,600

criteria

6-24-hour AHA/ASA 4 6 27,200

criteria

0–24 hours AHA/ASA 7 11 108,800

criteria

0-6 Applying 0-6-hour No. Potentially Eligible per meta- 11 17 74,800

criteria to 6-24-hour analyses and/or retrospective data
criteria (0–24 hours) but pending RCT confirmation

Including MCA-M2 4 6 27,200

occlusions (0–24 hours)

Including Basilar 4 6 27,200

artery occlusion

Including Large Core 3.5 5 23,800

Strokes (0–24 hours)

Including Low NIHSS 3.5 5 23,800

stroke patients (0–24
hours)

Including all above 21.3 33 144,840

(0–24 hours and
beyond 24 hours)

criteria) to undergo stent retriever thrombectomy.37 While
the treatment time window studied in trials has been limited
to 24 hours, it appears that even patients presenting beyond
24 hours who otherwise meet DAWN criteria may be safely
treated with comparable clinical outcomes to those treated
within 24 hours.38-40
Treatment Eligibility Based on
Current Guidelines
Given the time-sensitive nature of stroke intervention along
with the complex infrastructure required to triage, treat and
manage large vessel occlusions, the landscape of acute stroke
has evolved dramatically with the eventual goal of offering all
eligible patients this ground-breaking advancement.12 Para-
mount to allocating the appropriate resources involves un-
derstanding the number of patients that harbor large vessel
occlusions and furthermore, how many of those would qualify
for class IA treatment. Estimating the frequency of large vessel
occlusions is primarily complicated by the definition that is
applied as well as the population mix examined. In a recent
meta-analysis of 16 studies examining the incidence of large
vessel occlusions, the authors identified 9 different classifica-
tion schemes. The prevalence ranged from 7.3% to 60.6%
with a mean prevalence of 31.1% across all studies.41 While all
definitions include ICA and MCA-M1 occlusions, there was
variable inclusion of basilar occlusions or distal occlusions
(MCA-M2, MCA-M3, ACA-A1, ACA-A2, PCA-P1, PCA-
P2). Nonetheless, such data provides some estimate for the
burden of disease that must now be considered as systems of
care are being re-aligned and optimized.
The number of patients eligible for thrombectomy based on
current guidelines has been addressed in several studies. In
one analysis of 318 patients presenting with acute ischemic
stroke over a one-year period, 7% of patients were eligible for
EVT based on guideline criteria within the early time window.
At a population level, this was estimated to be 11 potential
EVT cases per 100,000 person-years.42 A single comprehen-
sive stroke center analysis of 2,667 patients presenting with
acute stroke revealed that 2.7% of all patients were EVT eli-
gible based on DAWN or DEFUSE3 criteria.43 Importantly,
42% of all patients presenting in the 6–24 hours time window
with anterior circulation large vessel occlusion were EVT
eligible.43,44 In a nutshell, 93 in 100 acute ischemic strokes and
1 in 2 acute ischemic strokes with anterior LVO currently do
not meet top tier criteria for thrombectomy. Given the dis-
proportionate impact of LVO strokes on morbidity and
mortality, thrombectomy should be offered to all eligible
patients and reasons for ineligibility must be addressed.
Reasons for treatment ineligibility can be broadly divided into
site of occlusion (distal occlusion or posterior circulation
occlusion), low NIHSS (<6), large core (ASPECTS <6 or
core >70 cc) and poor clinical baseline (mRS >1). In one
analysis of 445 patients with large vessel occlusion, reasons for
EVT ineligibility included: low NIHSS in 22% of patients,

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 Figure 2 Digital Subtraction Angiography Demonstrating Right MCA-M3 Occlusion
large stroke burden in 21% of patients, poor baseline in 20% of
patients, MCA-M2 site of occlusion in 23% of patients and
vertebrobasilar site of occlusion in 24% of patients.44 Table 2
provides a concise tabulation of evolution of AHA/ASA
guidelines over last 25 years. Certain population subgroups
have not been tested in clinical trials and are currently under
investigation, hence an analysis of potential need for throm-
bectomy is required. Based on the study conducted by Desai
et al.,44 Table 3 provides approximate estimation of current
and projected thrombectomy eligible patients at a compre-
hensive stroke center in the United States and overall in the
United States.
Treatment for Medium
Vessel Occlusions
Given the efficacy of IV tpa for smaller clot burden and hence
more distal occlusions,13 a majority of the EVT trials either
under-sampled or excluded MCA-M2 occlusions. An impor-
tant consideration in this population is the anatomical vari-
ability of how much territory the occluded vessel supplies,
particularly as it pertains to whether the occlusion is in the
proximal or distal MCA-M2 or in a dominant or non-
dominant MCA-M2 as well as what topographic regions the
MCA-M2 supplies and how many MCA-M2 branches are
present. Such heterogeneity has important implications for
determining the risk/benefit profile of EVT. Given the paucity
of high-quality data, the 2019 AHA/ASA guidelines have
issued a class IIB recommendation for EVT in patients with a
causative occlusion of the M2 or M3 portion of the MCAs.3
However, numerous single arm studies, non-randomized
case-controlled studies and pooled meta-analyses of the EVT
trials support the safety and efficacy of EVT for MCA-M2
occlusions.
In a meta-analysis of 12 studies with 1,080 patients un-
dergoing MCA-M2 thrombectomy, good outcomes were
noted in 59% of patients with 16% mortality and 10% sICH
rates.45 A patient level meta-analysis of the early time window
trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME,
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THRACE,9 EXTEND IA, and PISTE) identified 130 patients
with MCA-M2 occlusions. A majority were in the proximal
location (proximal n = 116 vs distal n = 14). There were
higher rates of good outcomes in the EVT group (58.2% vs
39.7%), particularly in those with proximal occlusions.46 The
2019 Society for Neuro-interventional Surgery guidelines
have issued a class IA recommendation for thrombectomy in
the MCA-M2 location.47 Furthermore, the feasibility of a
randomized controlled trial in this population may be limited
by lack of clinical equipoise by practitioners.
The issue of occlusions even more distal than the M2 location
including the M3 location or occlusions in the anterior and
posterior cerebral artery is even less studied. Figure 2 dem-
onstrates a digital subtraction angiogram of 76 years old
woman presenting with an acute ischemic stroke (NIHSS
score of 9) and harboring a right MCA-M3 occlusion. Several
case series have demonstrated the safety and feasibility of clot
retrieval in both the anterior and posterior medium sized
vessels however the benefit of this approach over the medical
arm is poorly understood. With the development of small
stent retrievers (“baby” Trevo, Tiger-13), larger size micro-
catheters (3 MAX, Headway-27) as well as adjunctive local
intra-arterial thrombolytic infusion, there is increasing interest
in testing the benefit EVT in this population.
Treatment for Mildly
Disabling Strokes
It has long been recognized that while stroke severity is a
strong predictor of clinical outcome, a subset of patients with
low NIHSS can do poorly with approximately of 30%–35% of
patients having poor clinical outcome at 90 days. A majority of
patients treated in the EVT trials had an NIHSS of 6 or higher
and so there is limited data on this low NIHSS population. In
a patient-level pooled analysis of the early time window trials
(MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, EX-
TEND IA), the direction of effect favored EVT for the 177
patients with an NIHSS of 0–10, however the result was not
significant and specific results on patients with an NIHSS of
Neurology.org/N
Figure 3 Non-contrast CT Head Showing ASPECTS Score of 4 in a Stroke Patient With a Left Carotid Artery Occlusion

0–5 were not reported.28 Several single center case series have
demonstrated the safety and feasibility of EVT for patients
with an NIHSS <6, however a recent multi-center study of
251 patients with large vessel occlusion in the setting of a low
NIHSS managed with EVT vs medical therapy revealed no
significant difference between the 2 groups.48 Likely the low
NIHSS population is a heterogeneous group in which addi-
tional testing may be necessary to identify the higher risk
population. Parameters such as elevated blood pressures,
position dependent clinical stability, large perfusion deficit,
and presence of motor or language symptoms may help
identify the particularly vulnerable population. The benefit of
EVT vs medical therapy will be investigated in the ENDO-
LOW52 and MOSTE trials.53
Treatment for Large Core Patients
Similar to stroke severity on presentation, infarct burden is a
strong predictor of clinical outcomes in the acute ischemic
stroke. Early data suggested that at a threshold of 70 cc,54
there was no benefit appreciated after EVT and a majority of
the trials set an upper threshold of 50–70cc or ASPECTS of 6.
In a patient level meta-analysis of the early time window trials
(MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME,

Figure 4 CT Perfusion Imaging of a Patient With Large Vessel Occlusion With Large Baseline Core Volume (101 mL) and
Presence of Substantial Mismatch (Tmax >6 Seconds Volume- 157 mL)

Neurology.org/N Neurology | Volume 97, Number 20, Supplement 2 | November 16, 2021 S133
Copyright © 2021 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 THRACE, EXTEND IA, and PISTE), benefit after EVT was
appreciated in patients with an ASPECTS of 6–10 as well as
ASPECTS of 3–5 but not in patients with an ASPECTS of
0–2.28,55 Sample size was small in the low ASPECTS groups
but importantly no signal of harm was noted in the large core
populations. However, risks of reperfusion injury following
recanalization of large stroke are important and several studies
identify an increased incidence of post thrombectomy pa-
renchymal hemorrhage amongst large burden strokes.
Figure 3 demonstrates a non-contrast CT head-based AS-
PECTS score of 4 for a 56 years old woman presenting as an
acute ischemic stroke with a NIHSS score of 24, time from
stroke onset approximately 3 hours, and occlusion of the left
internal carotid artery. Multiple additional retrospective and
prospective studies of non-randomized have similarly con-
firmed the safety and feasibility of treating patients with large
baseline infarct. The benefit of EVT is likely higher in younger
patients, who are able to achieve functional recovery at larger
infarct thresholds. The benefit of EVT vs medical therapy,
amongst patients with large baseline infarct core and presence
of substantial mismatch, will be investigated in the TEN-
SION,56 TESLA57 and LASTE53 trials. Figure 4 demonstrates
a CT perfusion map of an acute ischemic stroke patient har-
boring an acute left MCA-M1 occlusion with a NIHSS score
of 22 and time from last known well of 6 hours. Baseline
infarct volume is 101 mL (CBF <30%) and Tmax >6 seconds
volume is 157 mL.
Treatment in Advanced Age and Poor
Baseline Patients
While advanced age is a treatment effect modifier for out-
comes after acute ischemic stroke, age per se is not con-
sidered a contra-indication for EVT. In multiple trials (MR
CLEAN, EXTEND-IA, ESCAPE, DEFUSE-3), there was
no upper age cutoff for trial inclusion. In a patient level
meta-analysis of the early time window trials (MR CLEAN,
ESCAPE, REVASCAT, SWIFT PRIME, THRACE, EX-
TEND IA, and PISTE58) of outcomes by age, the adjusted
treatment effect was highest in patients with age 80 and
higher. This likely reflects the particularly poor natural
history of untreated large vessel occlusion in the advanced
age population. A single center study of 30 nonagenarians
undergoing thrombectomy demonstrated that a final in-
farct volume of <10 cc is a strong predictor of “return to
home.”59
While age per se should not be considered a contra-indication
for EVT, patients with poor baseline functional status and
cognitive impairment were categorically excluded from all the
EVT trials. Registry or single center studies of patients with
pre-stroke disability have demonstrated that 20%–27% of
patients will return to their baseline disability.60 Depending
on individual patient and patient family preferences, treat-
ment in these populations may be considered outside of
guideline criteria.
S134 Neurology | Volume 97, Number 20, Supplement 2 | November 16, 2021
Copyright © 2021 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Special Populations
Although numerous trials have now demonstrated the benefit
of EVT across numerous sub-groups, a majority of the trials
excluded patients based on features related to demographics
(age <18, pregnant), features that may compromise life ex-
pectancy (active cancer) or features that may increase the
procedural risks (history of aortic dissection, intra-cranial
aneurysm, endocarditis, thrombocytopenia, coagulopathy or
underlying non-atherosclerotic vasculopathy). Multiple case
series have demonstrated the safety and feasibility of EVT in
these populations61-63 however efficacy will be difficult to
demonstrate in the setting of a high quality randomized
controlled trial given the rarity of these populations. This
challenge highlights the importance of maintaining pro-
spective multicenter registries of both treated and untreated
large vessel occlusions irrespective of treatment eligibility.
Conclusion
Acute ischemic stroke care has evolved dramatically as this year
marks the 26th anniversary of the NINDS tpa trial and the 6th
anniversary of the early time window trials. While the general
concept of flow restoration is intuitive, the generation of high-
quality data proving the benefit of IV therapy and subsequently
EVT has been less straight forward and has required attention
to appropriate patient selection, rapid work flow and effective
treatments. High quality science ultimately informs societal
guidelines and tilts organizations and policies to appropriate
resources to maximize treatment opportunities. In the absence
of high-quality data, treatments will continue to be offered off-
label with provider and institutional variability. Irrespective of
practice patterns, it is critical to maintain prospective registries
and enroll patients in high quality clinical trials when possible.
Study Funding
No targeted funding reported.
Disclosure
The authors report no disclosures relevant to the manuscript.
Go to Neurology.org/N for full disclosures.
Publication History
Received by Neurology May 21, 2020. Accepted in final form
March 5, 2021.
Appendix Authors
Name Location Contribution
Ashutosh Department of Drafting/revision of the
P. Jadhav, Neurosurgery, Barrow manuscript for content,
MD, PhD Neurological Institute, including medical writing for
Phoenix, AZ content; major role in the
acquisition of data; study
concept or design; analysis or
interpretation of data
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 20. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial:
safety and effectiveness of a new generation of mechanical devices for clot
Appendix (continued)
removal in intracranial large vessel occlusive disease. Stroke. 2009; 40(8):
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M. Desai, Institute, Scottsdale, AZ manuscript for content, 22. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous
MD including medical writing for t-PA versus t-PA alone for stroke. N Engl J Med. 2013; 368(10): 893-903.
content; major role in the 23. Ciccone A, Valvassori L, Nichelatti M, et al. Endovascular treatment for acute is-
acquisition of data; study chemic stroke. N Engl J Med. 2013; 368(10): 904-913.
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Tudor G. Cooper Neurologic Institute, Drafting/revision of the Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-
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 Indications for Mechanical Thrombectomy for Acute Ischemic Stroke: Current
Guidelines and Beyond
Ashutosh P. Jadhav, Shashvat M. Desai and Tudor G. Jovin
Neurology 2021;97;S126-S136
DOI 10.1212/WNL.0000000000012801

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