Opinion
EDITORIAL
Endovascular Thrombectomy for Ischemic Stroke
The Second Quantum Leap in Stroke Systems of Care?
Steven Warach, MD, PhD; S. Claiborne Johnston, MD, PhD
In 2015, the publication of 5 clinical trials1-5 established the ef-
ficacy of endovascular thrombectomy for reducing disability
from large artery ischemic stroke, with each trial demonstrat-
ing the same superiority of
thrombectomy compared
Related article page 1279
with standard care. Endovas-
cular stroke therapymost recently with the use of stent re-
trievers to rapidly recanalize the artery during stent deploy-
ment and complete the thrombectomy by withdrawing the
stent that had engaged the clot during stent deployment
had been practiced prior to that time, despite uncertainty about
its uses and benefits. After nearly 2 decades since intrave-
nous tissue plasminogen activator (IV tPA) became the first
proven therapy for ischemic stroke, the findings from these
trials indicated that major changes in stroke management and
stroke systems of care were about to occur.
The US Food and Drug Administration approval of IV tPA in
1996 has arguably benefitted a greater percentage of patients with
stroke than the small minority of patients with ischemic stroke
who have received the drug.6 The concept of stroke as a treat-
able emergency was a major shift in clinical practice. Following
tPA approval, in-hospital stroke code teams were formed, primary
and comprehensive stroke centers were developed and prolif-
erated, and vascular neurology emerged as a discrete specialty.
Although stroke centers were developed to maximize the
number of patients treated with tPA and minimize delays to
initiation of tPA treatment, these centers had the broader ben-
efit of holding hospitals to evidence-based standards for in-
patient management across the spectrum of cerebrovascular
diseases. Out-of-hospital emergency medical systems (EMSs)
developed stroke protocols and guidelines to transport pa-
tients to the stroke centers where they were most likely to re-
ceive tPA with the shortest delays. Public education cam-
paigns for the recognition of stroke signs and urgency of calling
911 are now more common on billboards and public service an-
nouncements. Telestroke programs were developed to direct
stroke thrombolysis decisions at hospitals without the in-
house expertise. Large stroke registries created to track tPA sta-
tistics and performance metrics, have yielded a wealth of in-
sights about stroke risk factors, demographics, prevention, and
outcomes unrelated to tPA7.
The effects of thrombectomy in reducing disability and re-
storing functional independence were remarkably robust and
consistent across 5 independent trials, notwithstanding trial
differences in time-to-treatment windows and imaging selec-
tion criteria.1-5 The practice guideline8 that was derived based
on these studies recommends thrombectomy for patients at
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the intersection of the 5 trials: patients who are free from dis-
ability prior to the stroke, have occlusion of the internal ca-
rotid artery or proximal middle cerebral artery, received treat-
ment with tPA within 4.5 hours from of onset according to
guidelines from professional medical societies, have clinical
severity of 6 or greater on the National Institutes of Health
Stroke Scale, have a small infarct core defined as a score of 6
or greater on Alberta Stroke Program Early Computed Tomog-
raphy score (ASPECTS), and can have the procedure (arterial
puncture) initiated less than 6 hours from symptom onset. The
guidelines also include recommendations about the need to
optimize systems of care to increase access and reduce times
to treatment, without a specific prescription for how to do so.
Will the evidence supporting effective thrombectomy
transform the way stroke is assessed and managed beyond the
application of the thrombectomy procedure, just as occurred
with tPA 20 years ago? The profound effect of early time to
treatment suggests that systems must change substantially to
achieve the maximum benefit for the most patients.
The Highly Effective Reperfusion Evaluated in Multiple En-
dovascular Stroke Trials (HERMES) collaboration9 pooled indi-
vidual patient data from the 5 positive trials to investigate effi-
cacy in subgroups too small to be conclusive in the individual
trials. The study results showed no heterogeneity of the treat-
ment effect across prespecified subgroups and a number needed
to treat with thrombectomy of 2.6 patients to achieve a reduc-
tion in disability of at least 1 level on the modified Rankin score.9
In this issue of JAMA, the report by Saver and colleagues10
further defines the relationships of treatment times to benefit
from the HERMES collaboration, and quantifies the inverse re-
lationship of workflow delays with treatment benefit. With re-
spect to the organization of stroke services, understanding of
timing is among the most important factors in improving out-
comes. The authors pooled data from 1287 patients enrolled in
the 5 thrombectomy trials,1-5 including 634 assigned to receive
endovascular thrombectomy plus medical therapy and 653 as-
signed to receive medical therapy alone. The time from symp-
tom onset to randomization was approximately 3 hours (196
minutes). Among patients who received endovascular throm-
bectomy, the time from symptom onset to arterial puncture was
nearly 4 hours (238 minutes), and time from symptom onset to
reperfusion was nearly 5 hours (286 minutes).
The authors found that the degree of benefit, measured as
the degree of disability (modified Rankin Scale score) at 3
months, was greater at earlier time to initiation of treatment and
at earlier time to achieving substantial reperfusion. Overall ef-
ficacy significantly declined for every hour delay from symp-
(Reprinted) JAMA September 27, 2016 Volume 316, Number 12 1265
 Opinion Editorial

tom onset to arterial puncture and for every hour delay from
symptom onset to the achievement of substantial reperfusion.
However, the benefit of thrombectomy extended to as long as
7 hours and 18 minutes from symptom onset to the time of pro-
cedure initiation. Expansion of the time window would make
the benefit of this treatment accessible to more patients, albeit
at the tail of the efficacy curve. These data have important im-
plications for how stroke services should be organized, includ-
ing the time at which thrombectomy should not be attempted.
The potential benefit of earlier times to thrombectomy that
could be achieved by reducing workflow delays will require
substantial system changes. Organizations that certify stroke
centers may attempt to help improve outcomes by requiring
endovascular-capable stroke centers to meet aggressive goals,
such as 60 minutes from hospital arrival to arterial puncture
and 90 minutes from hospital arrival to achievement of sub-
stantial reperfusion.11
To enable more patients with ischemic stroke to have ac-
cess to endovascular thrombectomy, interfacility transfers to
endovascular-capable stroke centers must increase, and trans-
fers must be accomplished with the utmost of speed. If the re-
ferring facilities are linked to receiving facilities by video tele-
communication and routinely include vascular imaging
(CT angiography) for assessing eligibility for thrombectomy by
the receiving team, redundant assessments and delays may be
eliminated at the receiving hospital (where the patients could
be transported directly to the angiography suite), potentially
saving an estimated 30 to 45 minutes based on the workflow
times observed by Saver and colleagues. The authors also es-
timated from the magnitude of the outcomes observed in the
HERMES analysis that for every 1000 patients achieving sub-
stantial endovascular reperfusion, 15 minutes faster emer-
gency department doorto-reperfusion time would result in
39 patients having a less-disabled outcome at 3 months, in-
cluding 25 who would achieve functional independence. An
hour faster to reperfusion was estimated to benefit an addi-
tional 15.6% of patients successfully treated.
The biggest opportunities to improve outcomes through
time reductions may involve the EMS system, but these op-
portunities also pose the biggest challenges. In the HERMES
collaborative data, symptom onsetto-reperfusion time was de-
layed 2 hours for patients transferred between facilities com-
pared with those transported directly to the treating facility,10
suggesting a potential benefit for an additional 12.8% of treated
patients if the interhospital transfer was replaced by direct
transport to the endovascular capable center. Another impor-
tant consideration is among all patients with acute stroke symp-
toms, only a small fraction, estimated at less than 5%, may be
candidates for endovascular thrombectomy therapy.12
Throughout the country EMS directors and personnel are
debating the best protocols to triage patients directly to endo-
vascular capable facilities: Which out-of-hospital stroke scale
to use for identifying large artery occlusions? Would telemedi-
cine directed by a remote stroke physician be a better triage tech-
nique? Should primary stroke centers be bypassed to transport
patients to comprehensive centers, even if it means delaying the
start of IV tPA? How much delay in bypass is acceptable? How
much of a delay to start IV tPA would eliminate the benefit of
earlier thrombectomy? Would a mobile stroke unit with CT an-
giography and out-of-hospital tPA administration be the best
way to triage to comprehensive stroke centers for thrombec-
tomy? There is no consensus and there has been no organiza-
tion with the authority to choose, promulgate, and enforce stan-
dardized EMS transport protocols on a national scale, despite
much discussion and debate about these issues. These ques-
tions are testable, and clinical trials comparing EMS strategies
for stroke triage and treatment are feasible.13
The next major clinical trials in acute stroke therapeutics may
be the testing of out-of-hospital strategies to improve outcomes
with thrombectomy by substantially reducing times to reperfu-
sion (eg, NCT02795962). In the meantime, communities in the
United States and in other developed countries will be evaluat-
ing new triage approaches, as previously occurred in the success-
ful evolution of care for trauma and acute coronary syndrome.

ARTICLE INFORMATION
Author Affiliations: Dell Medical School, University
of Texas at Austin, Austin.
Corresponding Author: S. Claiborne Johnston, MD,
PhD, Dell Medical School, University of Texas at
Austin, 110 Inner Campus Dr, Austin, TX 78705 (clay
.johnston@austin.utexas.edu).
Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
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