NEUROLOGY GRAND ROUNDS

Challenges and Opportunities ofEndovascular Stroke Therapy

Mayank Goyal, MD,1 Michael D. Hill, MD,1,2 Jeffrey L. Saver, MD,3 and

Marc Fisher, MD4

In light of the results of the recent trials comparing endovascular treatment for acute ischemic stroke compared tothe previous standard of care, endovascular treatment is now the new standard for patients with acute ischemicstroke resulting from proximal vessel occlusion. This is probably the greatest advancement in stroke treatment in twodecades. However, these results, in addition to creating great opportunities for better outcomes for stroke patientsand for future research, have also brought with it new challenges. In this article, we present the key results of the tri-als, as well as future challenges and opportunities.

ANN NEUROL 2016;79:11–17

Endovascular Stroke Treatment Principles

Among the two types of stroke, ischemic and hemor-

rhagic, ischemia is the most common (85% of all

strokes) and ranges in clinical severity from transient

ischemic attack and minor stroke to severe and deadly

resulting from large, proximal vessel occlusion. Anterior

circulation occlusion of the middle cerebral artery stem

with or without occlusion of the top of the internal

carotid artery, typically resulting from an embolus from

the heart or a carotid artery bifurcation atherosclerotic

plaque, is commonest. Fast neurovascular imaging with

brain computed tomography (CT) and CT angiography

(CTA) from aortic arch to vertex is critical for diagnosis

and immediate treatment planning. Severe strokes make

up as much as one quarter of all strokes (200,000

patients annually in North America) and 30-day mortal-

ity in this group is approximately 20%.1 Only half of

stroke victims get to the hospital in time for standard

intravenous thrombolysis with alteplase,2 and when a

large proximal intracranial artery is occluded, alteplase

results in early nutritive reperfusion only one third of the

time.3

Recent data from five randomized, controlled trials

published in the journal provide clear evidence that

among patients with acute ischemic stroke due to large

vessel anterior circulation occlusion endovascular treat-

ment using stent retrievers (with or without tissue plas-

minogen activator [tPA]) dramatically improves patient

outcome.3–7 This is the greatest advance in acute stroke

treatment in 20 years. Treatment was effective and safe

across many different countries, jurisdictions, and health

care systems. The effect size was large and consistent

across all five studies, showing a shift to lower rates of

disability and death on the modified Rankin Scale (mRS;

common odds ratio range: 1.7–3.1) and with an absolute

risk benefit of 13% to 31% in the proportion of patients

achieving an independent functional outcome at 90 days.

There are significant immediate health care implications

and future possibilities that arise from these findings.

Key similarities among the five trials were the con-

firmation of a proximal vascular occlusion, predomi-

nantly with CTA, the inclusion of severe strokes, a

similar age range, and fast treatment by a stroke neurol-

ogy and neurointervention team with a stent retriever

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24528

Received Jun 18, 2015, and in revised form Sep 11, 2015. Accepted for publication Sep 18, 2015.

Address correspondence to: Mayank Goyal, Department of Radiology, Seaman Family MR Research Center, Foothills Hospital, 1403 29th Street North-

west, Calgary, Alberta, Canada, T2N2T9. E-mail:mgoyal@ucalgary.ca

From the 1Department of Radiology and Clinical Neurosciences, Foothills Hospital, Cuming School of Medicine, University of Calgary, Calgary, Alberta,

Canada; 2Department of Community Health Sciences and Medicine, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary,

Calgary, Alberta, Canada; 3Geffen School of Medicine at UCLA, UCLA Comprehensive Stroke Center, Los Angeles, CA; and 4Department of Neurology,

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

VC 2015 American Neurological Association 11

initiated within 6 hours from stroke onset in most

patients. A majority (73–100%) were treated concur-

rently with intravenous alteplase, with onset-to-

reperfusion times within 4 hours and with complete or

near complete reperfusion in a large percentage of

patients (Table). Important differences were the use of

penumbral imaging using CT perfusion technology or

intracranial collateral imaging using multiphase CTA

(mCTA), and the explicit focus on improving workflow

metrics within the trials. The two trials that reported

slower workflow metrics did not demonstrate as large an

effect size. In one trial, there was a protocol-defined

period of 30 minutes after intravenous tPA treatment to

establish that patients had not reperfused with intrave-

nous tPA before enrollment. The trial with the fastest

imaging to reperfusion times showed a mortality benefit.

The common themes from all trials were: (1)

patient selection using brain CT and neurovascular imag-

ing; (2) fast and early treatment; and (3) complete or

near complete reperfusion. All the trials used imaging to

confirm the presence of an acute ischemic stroke (and to

rule out hemorrhage or other stroke mimics) and con-

firm the presence of a target lesion for endovascular

treatment: a proximal vessel occlusion (M1 segment of

the middle cerebral artery [MCA] with or without intra-

cranial internal carotid artery occlusion). Four of the tri-

als (all except for MR CLEAN) used imaging to exclude

patients with well-established regions of large ischemic

core—regions that have already progressed to, or will

progress to, irreversible infarction despite treatment. CT

was used in almost all of the patients because of clear

advantages of availability, access, and relative lack of con-

traindications when compared with magnetic resonance

imaging (MRI).

A noncontrast CT head, followed immediately by a

CTA from aortic arch-to-vertex–based imaging paradigm

is highly effective in making an inclusive diagnosis of

ischemic stroke, confirming the presence of an endovas-

cular target proximal vessel occlusion and defining the

great vessel anatomy for procedural planning. With

attention to the quality of CT acquisition parameters,

very-high-quality brain imaging is available. In the

ESCAPE trial and in a minority of patients in the

REVASCAT trials, a novel technique termed mCTA was

introduced to view and measure the intracranial collateral

circulation.8 This technique can be performed with no

additional contrast, is inexpensive, very fast, adds negligi-

ble additional radiation exposure, is less vulnerable to

patient motion than CT perfusion imaging, and does not

require complex postprocessing. Use of the ASPECTS

score and collateral imaging to exclude patients with

large cores and poor collaterals was an effective, time-

efficient imaging paradigm. CT perfusion imaging was

used in EXTEND-IA and a majority of patients in the

SWIFT PRIME trial. An automated postprocessing

method was used to improve efficiency with a priori

thresholds to determine ischemic core and penumbra.9

There remains debate over the precise computed tomog-

raphy perfusion (CTP) thresholds for patient selection. It

is quite likely that there will be no precise thresholds

given that the thresholds for defining the ischemic core

and penumbra will be dependent on the speed of

recanalization.10

An estimated 1.9 million neurons and 12km of

axons are lost every minute during a MCA occlusion11;

the more rapidly reperfusion is accomplished, the greater

the degree of tissue salvage and the better the clinical

outcome.12–14 Most patients treated in the current trials

were treated early after stroke onset (within the first 6

hours). Some of the trials set aggressive time metrics for

workflow (ESCAPE: start of CT imaging to groin punc-

ture <60 minutes; start of CT imaging to first reperfu-

sion <90 min; SWIFT PRIME: qualifying imaging to

groin puncture <70 min) and successfully met these met-

rics with aggressive training, continuous feedback, and

quality improvement throughout the trial. Replication of

the trial outcomes in clinical routine practice will require

these kinds of rapid treatment times.15

Biologically, the procedural goal is to open the

occluded vessel without complication, achieving complete

or near complete reperfusion defined as Thrombolysis In

Cerebral Ischemia (TICI) 2b or 3 flow.16,17 Patients with

TICI 3 reperfusion (completely normal angiogram) have

the best outcomes. Intracranial complications can include

vessel perforation leading to subarachnoid hemorrhage or

intracerebral hemorrhage (ICH), and embolization of

fragmented thrombus into the distal circulation. Stent

retrievers were the most commonly used devices in these

trials and showed a high degree of efficacy in achieving

reperfusion (TICI 2b/3 range: 58–88%) with exceedingly

low procedural complications.

Challenges of Implementing the TrialResults Into Routine Clinical Practice:The 5Ts

The chain of survival for successful endovascular stroke

treatment needs to be highly efficient (Figure). It is and

will be a challenging problem of logistics, teamwork, and

technology to organize regional systems of care to imple-

ment this therapy.

TransportRegionalized systems of care must route appropriate

patients for endovascular therapy to centers that can

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12 Volume 79, No. 1

perform it as quickly as possible. Training of and tools

for paramedics to determine which patients have a high

likelihood of an acute ischemic stroke diagnosis resulting

from a proximal vessel occlusion are available. Validated

scoring systems (e.g., Los Angeles Motor Score; LAMS)

already exist, but will likely need to be improved.18 Pol-

icy may need to be changed. Telemedicine and video

conferencing between paramedics and physicians and

even patients or their family member and physicians,

now possible with smart phones but obstructed by pri-

vacy policy, could help in timely decision making. Local

geography, weather, and traffic patterns can be incorpo-

rated into transportation optimization algorithms using

geographical information systems (GIS), and effective

communication systems could help optimize decision

making on the route and modality of transportation.

Agreements will need to be made on the destina-

tion hospitals in a given region. It is highly likely that

there exists a volume outcome relationship between

endovascular treatment and favorable stroke outcomes.

TABLE 1. Characteristics, Metrics, and Outcomes of the Five Recent Endovascular Trials

Trial Patients NIHSS (median) IV tPA (%) Onset-to-GroinPuncture(minutes,median)

CT-to-GroinPuncture(minutes,median)

Patient characteristics

Endo Ctrl Endo Ctrl Endo Ctrl Endo only Endo only

MR CLEAN 237 267 17 18 91 87 260 —

ESCAPE 165 150 16 17 73 79 200 51

REVASCAT 103 103 17 17 100 100 269 77

SWIFT PRIME 98 98 17 17 100 100 224 57

EXTEND IA 35 35 17 13 68 78 210 93

Outcomes

% favorablereperfusion

% mRS 0–2 % mortality % symptomatic ICHc

Endo Ctrl Endo Ctrl Endo Ctrl Endo Ctrl

MR CLEAN 59 — 33 19 21 22 6.0 5.2

ESCAPE 72 31b 53 29 10 19a 3.6 2.7

REVASCAT 66 — 44 28 18 16 1.9 1.9

SWIFT PRIME 88 — 60 36 9 12 0 3.0

EXTEND IA 86 — 71 40 9 20 0 6.0

MR CLEAN: Multicenter randomized, clinical trial of endovascular treatment for acute ischemic stroke in the Netherlands trial;ESCAPE: Endovascular treatment for small core and anterior circulation proximal occlusion with emphasis on minimizing CT torecanalization times trial; REVASCAT: Randomized trial of revascularization with Solitaire FR device versus best medical therapyin the treatment of acute stroke due to anterior circulation large vessel occlusion present within eight hours of symptom onset;SWIFT-PRIME: Solitaire with the intention for thrombectomy as primary endovascular treatment trial; EXTEND IA: Extendingthe time for thrombolysis in emergency neurological deficits-intra-arterial trial.Endo: Endovascular therapy was 100% stent retrievers in EXTEND-IA, SWIFT PRIME, and REVASCAT, 97% in MR CLEAN,and 86% in ESCAPE.Control: this was tPA in all patients in some trials and the majority of patients received tPA in the other trials.NIHSS 5 National Institutes of Health Stroke Score; tPA 5 tissue plasminogen activator; CT 5 computed tomography;mRS 5 modified Rankin Scale; ICH 5 intracerebral hemorrhage; TICI 5 Thrombolysis In Cerebral Ischemia.% favorable reperfusion: a TICI 2b/3 score on follow-up imaging indicating 50% to 100% reperfusion.Dash indicates not reported in the primary manuscript.aStatistically significant difference in mortality with endovascular therapy.bDetermined by CT angiogram 2 to 8 hours after randomization.cAs reported in the primary article. PH2 definition used where reported.

Goyal et al: Challenges and Opportunities of Endovascular Stroke Therapy

January 2016 13

The destination hospital must have a team in place that

can deliver the treatment fast and well. Once the possible

destination hospitals are known, the GIS-enabled com-

munication system can help to determine whether a

direct to comprehensive stroke center or a drip-and-ship

approach is optimal. Such decision algorithms will

depend upon the stroke severity, probability of a large

vessel occlusion as a target for endovascular therapy, the

probability of early reperfusion with intravenous tPA,

distances to both a primary stroke center and to a com-

prehensive stroke center, traffic, weathe,r and available

modality of transportation. In particular, the drip and

ship paradigm will necessitate an extreme effort to mini-

mize the time in the primary hospital; indeed, ideally the

patient is never actually moved off the paramedic

stretcher going from the emergency department door to

the CT scanner, receiving intravenous tPA in the scanner,

and immediately leaving the primary hospital for the

comprehensive stroke center. In the future, mobile stroke

ambulances with built-in CT scanners and aided by

FIGURE 1: Flow chart demonstrating sequence of events and strategies to improve workflow. ER 5 emergency room;ABCs 5 airway, breathing, circulation; IV 5 intravenous; mCTA 5 multiphase computed tomography angiography; CTP 5 com-puted tomography perfusion; CT 5 computed tomography; NIHSS 5 National Institutes of Health Stroke Score; tPA 5 tissueplasminogen activator.

ANNALS of Neurology

14 Volume 79, No. 1

telemedicine consultation may allow even more sophisti-

cated triage decisions to be made in the field.19 Given

the efficacy of the treatment, it is critical that there be a

strong collective effort to get the correct patient to the

correct hospital to be treated by the correct team in the

most efficient fashion.

TeamworkAll the current trials were performed at centers with

experienced endovascular teams and well-established

processes to allow not only patient evaluation and imag-

ing, but also safe and fast endovascular management

using modern devices. The endovascular management of

acute stroke is a team sport that requires interaction and

cooperation among multiple physicians, allied health pro-

fessionals, technicians, and hospital administrators.20

There is a need both for resources to organize these

teams and also the creation of hospital cultures of team-

work. National and local guidelines will evolve to define

the standard-of-care and workflow metrics for team orga-

nization and delivery of endovascular acute stroke ther-

apy. Accreditation standards must include and recognize

the need for this kind of teamwork.

TechnologyThis new standard of care will spark an entire new cycle

of innovation to further improve the available technology

for performing acute stroke interventions. Device

improvements to safely increase the effective reperfusion

rate and to improve fast access to the intracranial circula-

tion are needed. Technological advances and innovation

will not be limited to neurointervention devices. New

technologies may help in decision making regarding tri-

age and transportation. There is an evolving small group

examining the use of CT-equipped ambulances19; further

miniaturization of CT may be possible. New understand-

ing of stroke imaging and automation of algorithms for

image processing will lead to refinement or patient selec-

tion and better resource use. Endovascular patient simu-

lators are needed to aid in training.

Training and TechniqueThe success of any interventional procedure is a combi-

nation of appropriate technology and the skill of the

operator. In endovascular stroke treatment, there is the

added challenge of working against time and upon a rela-

tively sick and uncooperative patient. As a disease domi-

nantly of the elderly, tortuosity of the blood vessels,

presence of stenosis along the access pathway resulting

from atherosclerotic disease, and presence of other

comorbidities introduce technical challenges. Finally, the

intracranial circulation is fragile; it is unsupported by

strong fibrous tissue or fascia as elsewhere in the body

and instead rests in the delicate pia arachnoid.

The current trials were limited to a few high-

volume centers with proven expertise. To spread the ben-

efit of this treatment, there is a need for additional quali-

fied centers with additional trained personnel. The

penetration of this treatment to some of the most popu-

lous parts of the world where the incidence of stroke is

high is still in its infancy. The need for training in neu-

rointervention will be aided by patient simulators. Train-

ing of residents and fellows is impacted by the need for

efficiency where the staff neurointerventionist is limited

in providing adequate training opportunities owing to

the focus on efficiency, that is, the need to open the

occluded vessel as quickly as possible. Though neuroin-

tervention training will build upon a base of intracranial

aneurysm treatment, it must be expanded and improved

to deal with the realities of treating awake patients at

speed to replicate and further improve outcome com-

pared to the current trials. The use of simulation has

great potential in exposing trainees to the real-life chal-

lenging scenarios in a practice environment. Finally,

training guidelines will need to be adapted to define

what constitutes adequate training,

Training is not limited to the actual neurointerven-

tion procedure, but includes all aspects of stroke patient

care from prehospital evaluation and transport, acute

neurological evaluation, and treatment and neurocritical

care management of the patient after successful reperfu-

sion. We hope and recommend that professional soci-

eties, hospitals, and accreditation bodies allocate

sufficient time and resources for improved training and

certification along the entire chain of acute stroke care.

Immediate Opportunities: What’s Next?

The success of recent trials has shown the commitment

of all components of the stroke community to work

toward the common goal of providing definitive evidence

in support of a new treatment. This commitment,

momentum, and cooperation can be used to answer

ongoing related questions related to maximizing the ben-

efits of acute stroke therapy. Many clear questions arise

as natural extensions of the inclusion/exclusion criteria of

the recent trials: (1) Does acute ischemic stroke resulting

from M2 (second-order branch) branch of MCA occlu-

sion also benefit from endovascular treatment?; (2) Can

the results of the current trials be extrapolated to the pos-

terior circulation, pediatric populations, and patients in

later time windows beyond 6 hours from stroke onset

with a favorable imaging profile?; (3) In a patient under-

going endovascular treatment, is intravenous alteplase

necessary?; and (4) What imaging and/or clinical criteria

Goyal et al: Challenges and Opportunities of Endovascular Stroke Therapy

January 2016 15

define absence of benefit (or potentially even harm) such

that endovascular treatment should not be offered? For

example, what is the lower limit of the CT ASPECTS

score or upper limit of the ischemic core volume on CT

perfusion where endovascular therapy is no longer effec-

tive? Trials and pooled analyses are being designed that

will soon be underway to answer many of these

questions.

The Future: The Human FocalIschemia-Reperfusion Model

We now have a focal ischemia-reperfusion MCA occlu-

sion “model” in humans. This is the very model that has

been so extensively explored in the preclinical setting.21,22

The human model was lacking at the time many of the

previous neuroprotection drugs were undergoing clinical

testing. Similarly, studies of stroke imaging using MRI or

multimodal CT to assess imaging predictors of tissue fate

have been confounded by a lack of reperfusion in a sub-

stantial proportion of patients. There is now a very excit-

ing opportunity to reassess what exactly acute imaging

means, to provide definitive guidance to clinicians mak-

ing treatment decisions. Even more enticing is the oppor-

tunity to re-explore adjuvant treatments for stroke.

We envision a rebirth of pharmacological stroke

treatment in which a neuroprotective agent can be used

to prevent infarct growth until the vessel is being opened

using endovascular thrombectomy. Even more exciting

would be the possibility that such an agent could be

administered in the field or in the ambulance by para-

medics. Such a drug would slow the trajectory of infarc-

tion such that the proportion of patients who arrive at

the comprehensive stroke with a favorable imaging pro-

file would rise dramatically, thereby increasing the num-

ber of patients who could benefit from fast reperfusion

therapies. In stroke animal models, it has been observed

that neuroprotective drugs or gases could slow down or

stop the evolution of the ischemic core for several

hours.23–25 If this was feasible in humans, many patients

who now could not get to an endovascular center in time

would become appropriate candidates for this highly

effective therapy. The implementation success of the

FAST-MAG trial, with a median onset-to-treatment time

of 45 minutes, shows the feasibility of such an approach

to prehospital neuroprotective treatment.26 Neuroprotec-

tive agents given after reperfusion was achieved could tar-

get multiple mechanisms including reperfusion injury,

blood–brain barrier breakdown, and hemorrhage risk.

It is an exciting time in the world of acute ischemic

stroke with dramatic recent advances and boundless

opportunities for further progress in the near future.

There is much to be done to build upon the recent suc-

cesses to maximize outcomes in as many patients as pos-

sible. Time is brain.

Author Contributions

M.G. came up with the idea and wrote the first draft.

M.D.H., J.L.S., and M.F. provided critical input and

revisions to the document. All authors had complete

access to the final version and have approved it.

Potential Conflicts of Interest

Dr Hill was one of the PIs of the ESCAPE trial. Dr

Saver was one of the PIs for the SWIFT PRIME trial.

Dr Goyal is one of the PIs of ESCAPE and SWIFT

PRIME. ESCAPE was partially funded by Covidien

through a grant to the University of Calgary. SWIFT

PRIME was fully funded by Covidien. Dr Goyal has a

consulting agreement with Covidien to assist with design

and conduct of the trial and also for teaching engage-

ments. Dr Goyal has a patent (pending) regarding meth-

ods for diagnosing (licensed to GE Healthcare) and a

patent (pending) related to packaging for stroke interven-

tion to improve efficiency. Dr Saver is an employee of

the University of California. The University of California

(UC) Regents receive funding for Dr Saver’s services as a

scientific consultant regarding trial design and conduct to

Medtronic/Covidien, Stryker, Neuravia, BrainsGate,

Pfizer, Squibb, Boehringer Ingelheim (prevention only),

ZZ Biotech, and St. Jude Medical. Dr Saver has served

as an unpaid site investigator in multicenter trials run by

Lundbeck for which the UC Regents received payments

on the basis of clinical trial contracts for the number of

subjects enrolled. Dr Saver serves as an unpaid consultant

to Genentech advising on the design and conduct of the

PRISMS trial; neither the UC nor Dr Saver received any

payments for this voluntary service. The UC has patent

rights in retrieval devices for stroke.

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