Review Article

Treatment of Acute
Address correspondence to
Dr Alejandro Rabinstein, Mayo
Clinic, Department of
Neurology, W8B, 200 First St
SW, Rochester, MN 55905,
rabinstein.alejandro@mayo.edu.
Relationship Disclosure:
Ischemic Stroke
Dr Rabinstein serves as an Alejandro A. Rabinstein, MD, FAAN
associate editor for
Neurocritical Care; on the
editorial boards of Continuum:
Lifelong Learning in Neurology, ABSTRACT
the Journal of Stroke and
Cerebrovascular Diseases, Purpose of Review: This article provides an update on the state of the art of the
Neurology, and Stroke; and on emergency treatment of acute ischemic stroke with particular emphasis on the
the scientific advisory board of alternatives for reperfusion therapy.
Portola Pharmaceuticals, Inc.
Dr Rabinstein receives research/ Recent Findings: The results of several randomized controlled trials consistently
grant support from DJO Global, and conclusively demonstrating that previously functional patients with disabling
Inc, and royalties from Elsevier, strokes from a proximal intracranial artery occlusion benefit from prompt recanaliza-
Oxford University Press, and
UpToDate, Inc. tion with mechanical thrombectomy using a retrievable stent have changed the
Unlabeled Use of landscape of acute stroke therapy. Mechanical thrombectomy within 6 hours of
Products/Investigational symptom onset should now be considered the preferred treatment for these patients
Use Disclosure:
Dr Rabinstein reports
along with IV thrombolysis with recombinant tissue plasminogen activator (rtPA) within
no disclosure. the first 4.5 hours for all patients who do not have contraindications for systemic
* 2017 American Academy thrombolysis. Patients who are ineligible for IV rtPA can also benefit from mechanical
of Neurology. thrombectomy. Collateral status and time to reperfusion are the main determinants
of outcome.
Summary: Timely successful reperfusion is the most effective treatment for patients
with acute ischemic stroke. Systems of care should be optimized to maximize the
number of patients with acute ischemic stroke able to receive reperfusion therapy.

Continuum (Minneap Minn) 2017;23(1):62–81.

INTRODUCTION treatments are the most effective in-

Over the past 2 decades, the thera-
peutic approach to acute ischemic
stroke has been deeply transformed.
Long gone is the nihilism of former
times, now replaced by the excite-
ment of proven treatment options that
can reverse ischemia and bring back
function to patients who were otherwise
destined to death or severe disabil-
ity. The wide adoption of IV thrombol-
ysis that began 20 years ago has recently
been followed with clear evidence
that the addition of endovascular treat-
ment with mechanical thrombectomy
can further improve outcomes in pa-
tients with severe neurologic defi-
cits from a proximal intracranial vessel
occlusion.
This article primarily focuses on
reperfusion strategies because these
terventions for acute ischemic stroke.
However, the treatment of acute
stroke also includes adequate hemo-
dynamic management, monitoring
and management of ischemic brain
edema, and early recognition of and
therapy for systemic complications
(such as infections, cardiac arrhyth-
mias, heart failure, and venous throm-
boembolism) in a stroke unit staffed
by specially trained personnel. The
management of acute ischemic stroke
starts with the prompt recognition of
the diagnosis in the field, and atten-
tion is currently aimed at optimizing
the time to reperfusion in the emer-
gency department and the angio-
graphic suite. However, what happens
in the stroke unit or intensive care
unit after hospitalization is also very

62 ContinuumJournal.com February 2017

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important to maximize the chances of
good recovery. Comprehensive guide-
lines offer useful advice in these addi-
tional areas.1
PRINCIPLES OF ACUTE
STROKE CARE
The three main principles of acute
stroke care are: (1) achieve timely
recanalization of the occluded artery
and reperfusion of the ischemic tis-
sue, (2) optimize collateral flow, and
(3) avoid secondary brain injury.
Recanalization and reperfusion are
the mainstay of acute stroke treatment
and can reduce infarct size and re-
verse neurologic deficits. Recanaliza-
tion is defined by the degree of
reopening of the occluded artery.
Reperfusion is measured by the de-
gree of flow reaching the previously
hypoperfused brain region. Opening
the occluded artery works because, in
most cases, when the occlusion oc-
curs, an area of brain tissue becomes
hypoperfused but is initially not in-
farcted. This tissue represents the
ischemic penumbra that can be sal-
vaged if adequate blood flow is
promptly reestablished. Advanced
brain imaging with CT perfusion or
magnetic resonance (MR) diffusion/
perfusion can visualize this tissue at
risk (penumbra imaging).2 Chemical
thrombolysis with recombinant tissue
plasminogen activator (rtPA), also
known as alteplase, and mechanical
embolectomy with a retrievable stent
are the two evidence-based strategies
to achieve reperfusion.
Collateral flow is responsible for
keeping the ischemic penumbra via-
ble. It provides enough flow to pre-
vent critical ischemia and infarction
but not sufficient flow to maintain
normal cellular function. This explains
why the acute neurologic deficits
exceed what would be expected for
the established infarct core at the time
Continuum (Minneap Minn) 2017;23(1):62–81
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
of presentation and why neurologic h Prompt reperfusion
function can improve after reperfu- is the most effective
sion. This collateral flow, however, is treatment for
often tenuous and can sustain viability patients with acute
only for a limited period of time. Thus, ischemic stroke.
without recanalization, the ischemic h The three principles of
penumbra is destined to progress to acute stroke therapy are
infarction. Collateral flow can be pro- to achieve recanalization
tected by avoiding blood pressure drops of the occluded vessel
and supported by the administration (and reperfusion of the
of IV fluids. The value of keeping the ischemic tissue), to
head of the bed flat for patients with optimize collateral flow,
acute ischemic stroke is being investi- and to avoid secondary
gated in the ongoing Head Position in brain injury.
Stroke Trial (HeadPoST) and should be h The ischemic penumbra
weighed against the risk of aspiration.3 is the region of
Hemodynamic augmentation with va- hypoperfused brain that
sopressors may be beneficial in well- can still be viable with
prompt recanalization
selected cases (such as patients with
of the occluded artery.
cervical internal carotid artery occlusion
without tandem intracranial occlusion), h Collateral flow is
but the safety and efficacy of this strat- responsible for
the temporary
egy is otherwise unknown. Invasive in-
preservation of the
terventions to improve collateral flow
ischemic penumbra.
remain investigational.
Despite promising results in basic h No neuroprotective
agent has been proven
and translational experiments, numer-
to be beneficial for
ous neuroprotective agents have failed
acute ischemic stroke in
to improve outcomes in clinical trials. clinical trials.
Yet, avoidance of secondary insults is a
form of neuroprotection. Hypoglyce-
mia can exacerbate energy failure and
should be strictly averted. Hyperglyce-
mia might also be deleterious; so far,
we know that it correlates with worse
outcomes after an ischemic stroke but
do not have proof that its correction
improves outcomes.4 The Stroke Hy-
perglycemia Insulin Network Effort
(SHINE) trial is a randomized controlled
trial comparing tight glycemic control
with IV insulin to maintain a glucose
level between 80 mg/dL and 130 mg/dL
versus standard glycemic control using
subcutaneous insulin dosed according
to a sliding scale to keep the glucose
level lower than 180 mg/dL in patients
with acute ischemic stroke within
12 hours of symptom onset.5 It is
ContinuumJournal.com 63
 Acute Ischemic Stroke
KEY POINTS
h IV thrombolysis with
rtPA and endovascular
thrombectomy with
a retrievable stent
are both solidly
established treatments
for appropriate
candidates with acute
ischemic stroke.
h Time to reperfusion is a
major determinant of
outcome in acute
ischemic stroke.
h Randomized
placebo-controlled trials
have demonstrated that
IV thrombolysis with
rtPA is beneficial for
patients with acute
ischemic stroke up to
4.5 hours from
symptom onset.
h Some previously cited
contraindications for IV
thrombolysis have been
revisited, thus expanding
the pool of patients
who can be considered
good candidates for
this treatment.
64 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
hoped that this trial will answer the
question whether tight glycemic control
is safe and beneficial after an acute is-
chemic stroke. Fever is associated with
worse clinical results; thus, treating fever
may be beneficial.6 The value of hypo-
thermia continues to be investigated.
Preventing infections (which notably
includes dysphagia assessment before
any oral intake) and early recurrent
strokes are additional priorities in the
care of the patient with acute stroke.
ACUTE REPERFUSION
TREATMENTS
There is incontrovertible evidence
that IV thrombolysis with rtPA and
endovascular thrombectomy with a
retrievable stent improve neurologic
outcomes in patients with acute ische-
mic stroke. Both treatments should
be administered as quickly as possi-
ble after stroke onset, can be com-
bined, and are safe in appropriately
selected candidates.
IV thrombolysis and mechanical
thrombectomy can produce reperfu-
sion injury after recanalization. Re-
perfusion injury can manifest with
hemorrhage and edema. It is more
severe when the area of established
infarction is larger. Good patient se-
lection (ie, absence of a large ischemic
core) and prompt treatment are cru-
cial to avoid this complication.
Intravenous Thrombolysis
IV thrombolysis with rtPA is proven to
be effective in improving functional
outcomes after an ischemic stroke up
to 4.5 hours after symptom onset.1,7Y9
Randomized controlled trials8,9 fol-
lowed by large observational studies
confirming the rates of recovery noted
in these trials10 and meta-analyses7
support this therapeutic indication
(Figure 3-111). The US Food and Drug
Administration (FDA) has only ap-
proved rtPA for use within 3 hours of
stroke onset, but regulatory agencies
in most other countries (including
those in the European Union) have
approved its administration within
4.5 hours of stroke onset.
The initial evaluation of a patient
with a possible acute stroke in the
emergency department should focus
on establishing whether the patient is
eligible for reperfusion therapy. Nec-
essary information includes the time
the patient was last known to be well,
medical conditions or recent surgery
that could contraindicate thrombolysis,
neurologic examination to calculate the
National Institutes of Health Stroke
Scale (NIHSS) score, a capillary glucose
level, blood pressure, and brain imaging
(CT scan with or without a CT angio-
gram depending on whether endovas-
cular therapy is being considered).
Recently, the indications and contra-
indications for IV rtPA have been re-
visited in a scientific statement of the
American Heart Association (AHA)12
and modified by the FDA in the pack-
age insert for the drug (Table 3-113).
As a result, more patients can be con-
sidered for IV thrombolysis in clinical
practice. IV thrombolysis should not be
withheld because of advanced age, and
mild but disabling deficits justify treat-
ment. Individualized clinical judgment
is necessary when deciding whether to
recommend thrombolysis to patients
with weaker indications (such as non-
disabling deficits) or relative contrain-
dications. The safety and efficacy of
IV thrombolysis in pediatric patients
(younger than 18 years of age) is not
well established.
IV rtPA infused within 3 hours of
symptom onset increases the chances
of functional independence at 3 months
by one-third.7,8 The benefit is time de-
pendent and much stronger when the
drug is administered within the first
90 minutes after symptom onset (esti-
mated number necessary to treat to help
February 2017
 KEY POINT
h Benefit from IV
thrombolysis is much
greater in the first
90 minutes from
symptom onset.

FIGURE 3-1 Results of meta-analysis of individual data from major randomized trials of IV
recombinant tissue plasminogen activator (rtPA) (alteplase) for acute ischemic
stroke showing that thrombolysis increases the chances of achieving a modified
Rankin Scale score of 0 to 1 (no symptoms or mild symptoms with no disability) at 90 days.
Notice that the benefit is time dependent and no longer significant when the drug is
administered more than 4.5 hours after symptom onset. Treatment is beneficial in patients older
than 80 years, and the benefit is fairly consistent across all degrees of initial stroke severity.
CI = confidence interval; NIHSS = National Institutes of Health Stroke Scale.
Reprinted with permission from Emberson J, et al, Lancet Neurol.11 B 2014 Emberson et al. thelancet.com/journals/
lancet/article/PIIS0140-6736(14)60584-5/fulltext.

one more patient achieve functional
independence is 3.6 within the first
90 minutes and 4.3 between 91 and
180 minutes) 14 (Case 3-1). Older
patients and those with a very severe
stroke at presentation have worse
prognosis15 but can still benefit from
IV rtPA. The benefit is less robust
for patients treated between 3 and
4.5 hours, but rtPA is still beneficial in
this extended window (number neces-
sary to treat 5.9).9,14
The standard dose of IV rtPA for
acute ischemic stroke is 0.9 mg/kg,
with 10% administered as a bolus and
the remainder infused over 1 hour.
The total dose should not exceed
90 mg. The phase 3 Enhanced Control
of Hypertension and Thrombolysis
Stroke Study (ENCHANTED) enrolled
3310 predominantly Asian patients to
receive either 0.9 mg/kg or 0.6 mg/kg
of IV rtPA within 4.5 hours of stroke
onset.16 The reduced dose was inferior
to the standard dose for the end point
of death or any degree of disability at
90 days, although it was associated with
a lower risk of symptomatic intracere-
bral hemorrhage (which was low in
both treatment groups).
No other thrombolytic agent has
been approved for use in ischemic
stroke. In emergency departments of
medical centers with more limited
capabilities, patients can receive the
bolus of rtPA and then be transferred
to a primary stroke center or compre-
hensive stroke center while the rest of
the dose of the drug is being infused
(the drip-and-ship strategy).
Hemorrhage is the most dangerous
complication after thrombolysis. The

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 Acute Ischemic Stroke

TABLE 3-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen Activator

American Heart Association
Guideline 20131
Indications
Diagnosis of ischemic stroke with
measurable neurologic deficit
Symptom onseta within 4.5 hours Same
Age Q18 years
Contraindications
Severe head trauma within
3 months
Ischemic stroke within 3 months
Arterial puncture at
noncompressible site within
7 days
Previous intracranial
hemorrhage
Suspected subarachnoid
hemorrhage
Intracranial neoplasm,
arteriovenous malformation
(AVM), or aneurysm
Recent intracranial or
intraspinal surgery
(within 3 months)
Active internal bleeding
Systolic blood pressure (BP)
9185 mm Hg or diastolic BP
9110 mm Hg
Bleeding diathesis
International normalized
ratio (INR) 91.7
Heparin within 48 hours with
abnormal activated partial
thromboplastin time
3 testsc are normal)
Platelets G100,000/mm
Current use of direct thrombin
inhibitor or factor Xa inhibitor
c
with abnormal coagulation tests
American Heart Association
Scientific Statement 201512
Same
Same
Same
Risk increased, but degree is unclear
Risk uncertain
Same
Same
Probably recommended if
extraaxial neoplasm is present; not
recommended if intraaxial neoplasm
is present; risk unclear for AVM;
probably recommended if unruptured
unsecured aneurysm G10 mm is
present, but risk unclear if greater size
Same
Same
Same, but treatment recommended
if BP can be lowered safely
Consider case by case in patients
with history of bleeding diathesis;
not recommended if INR 91.7,
low-molecular-weight heparinoid
within 24 hours, direct thrombin
inhibitor or factor Xa inhibitor
within 48 hours (unless coagulation
US Food and Drug Administration
(FDA) Package Insert 201513
Same
Within 3 hours
Warning for age 977 years with risk
factors for intracranial hemorrhage
Contraindicated
Removedb
Not listed
Warning for recent intracranial
hemorrhage (contraindicated if
active intracranial hemorrhage)
Contraindicated
Contraindicated
Contraindicated
Contraindicated
Contraindicated for severe uncontrolled
hypertension (BP values removedb);
warning for BP 9175/110 mm Hg
Contraindicated for bleeding
diathesis (laboratory
values removedb)
Continued on page 67

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 American Heart Association
Guideline 20131
Contraindications (continued)
Blood glucose G50 mg/dL
CT showing hypodensity 91/3
of the cerebral hemisphere
Relative contraindications
Minor stroke (typically
National Institutes of Health
Stroke Scale [NIHSS] score G5)
Rapidly improving symptoms
Pregnancy
Seizure at onset with
postictal residual deficits
Major extracranial trauma
within 14 days
Major surgery within 14 days
Gastrointestinal or genitourinary Consider rtPA if no structural
surgery within 21 days
Acute myocardial infarction
within 3 months
Additional contraindications for
3- to 4.5-hour window
Age 980 years
Warfarin use (regardless
of INR)
NIHSS 925
Previous strokeor diabetes mellitus rtPA probably recommended
American Heart Association US Food and Drug Administration
Scientific Statement 201512 (FDA) Package Insert 201513
Consider recombinant tissue Removedb
plasminogen activator (rtPA) if deficits
still present after glucose normalization
Same Removedb
rtPA should be administered to patients Removedb
with mild but disabling symptoms
within 3 hours of onset; possible risk and
benefit should be weighed in patients
with nondisabling symptoms
rtPA should be administered if Not listed
symptoms are still disabling
rtPA may be considered in moderate Warning (Category C)
to severe stroke when anticipated
benefit outweighs the anticipated
risk of uterine bleeding
rtPA administration is reasonable Removedb
if residual deficits are thought
to be caused by a stroke
rtPA can be considered Warning for recent trauma
rtPA can be considered in carefully Warning for recent surgery
selected cases
Warning
bleeding lesions
Administer rtPA (stroke dose) if concurrent Not listed
stroke and acute myocardial infarction
(MI); it is also reasonable to give rtPA
after recent MI unless it was a STEMI
involving the left anterior myocardium
rtPA recommended
rtPA probably recommended if INR G1.7 FDA has not approved rtPA for
use after 3 hours
Risk and benefit uncertain

CT = computed tomography; STEMI = ST-segment elevation myocardial infarction.

a
Last known well.
b
The term removed is used to denote a change compared with the previous version of the package insert (2009).
c
Activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, factor Xa activity assays.

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 Acute Ischemic Stroke

KEY POINT
h Most cases of
symptomatic intracerebral
Case 3-1
A 54-year-old woman presented with the sudden onset of left-sided
hemorrhage are caused
weakness and dysarthria. Her husband promptly called 911, and the
by reperfusion injury
patient arrived by ambulance to the emergency department 15 minutes
causing hemorrhagic
after symptom onset. Her National Institutes of Health Stroke Scale (NIHSS)
transformation of an
score was 6. Noncontrast CT scan showed no hemorrhage, acute ischemic
already severe stroke.
changes, or hyperdense vessel sign. She had no contraindications for
thrombolysis. IV rtPA was started 32 minutes after symptom onset. Within
the following 2 hours, the patient improved remarkably, and the following
day she had no residual symptoms.
Comment. The benefit from IV thrombolysis for patients with acute
ischemic stroke is highly dependent on time to administration.
Administration of the bolus within 60 to 90 minutes affords maximal
chances of improvement. In order to treat patients within this short time
window, it is essential to optimize the efficiency of early evaluation, CT
scanning, and drug delivery. In the United States, stroke centers are
expected to be able to consistently administer IV rtPA within 60 minutes of
patient arrival to the emergency department.

reported rates of symptomatic intrace- consists of control of hypertension (sys-

rebral hemorrhage (sICH) have varied
(between 1.9% and 6.4%), depending
on its definition and the design of the
study.17 However, most cases of sICH
are caused by reperfusion injury and
worsen strokes that were already
severe and destined to be disabling.
Hemorrhagic transformation of a large
infarction can increase the risk of
death, but sICH rarely negates what
would have otherwise been a good
recovery. In fact, the number needed
to harm for IV rtPA has been estimated
to be 126 for the combined end point
of disability or death.18 The risk of
sICH is increased with old age, diabe-
tes mellitus, severe hyperglycemia,
uncontrolled hypertension, and larger
hypodensity on baseline CT scan.19
The risk of sICH might also be higher
in patients with cerebral microbleeds,
although this association is not entirely
certain.20
When sudden neurologic decline
occurs during rtPA infusion, the infu-
sion should be immediately stopped
and a CT scan should be obtained
emergently. Whenever postthrom-
bolysis sICH is diagnosed, treatment
tolic target 140 mm Hg to 160 mm Hg)
and reversal of the fibrinolytic effect
with cryoprecipitate (10 units) or an
antifibrinolytic agent (tranexamic acid
10 mg/kg to 15 mg/kg IV over 20 minutes
or (-aminocaproic acid 5 g IV followed
by an infusion of 1 g/h if necessary).
Additional cryoprecipitate may be given
if the serum fibrinogen level remains
below 150 mg/dL.21
Orolingual angioedema is a rare but
potentially serious complication of
rtPA administration. The risk is higher
in patients previously taking angiotensin-
converting enzyme inhibitors. It is typ-
ically asymmetric and tends to involve
the hemiparetic side. The most severe
cases can compromise airway patency;
thus careful monitoring is indispens-
able. Treatment consists of a combina-
tion of diphenhydramine (50 mg IV),
ranitidine (50 mg IV), and dexametha-
sone (10 mg IV).
While IV thrombolysis is the stan-
dard of care for eligible patients with
acute ischemic stroke, this treatment
has limitations. In addition to its short
time window and contraindication in
patients with increased bleeding risk,

68 ContinuumJournal.com February 2017

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IV rtPA often fails to recanalize proxi-
mal artery occlusions caused by large
clots. These are the most disabling
strokes, and strong evidence now
exists that these patients should be
considered for endovascular therapy.
Mechanical Thrombectomy
Although endovascular recanalization
treatment for selected patients with
severe acute ischemic stroke has been
practiced in many centers for decades,
the publication of several recent pos-
itive trials has catapulted this therapy
to the status of evidence-based treat-
ment for patients with large intracra-
nial artery occlusion. Previous trials
had failed to show a benefit from
endovascular therapy because of
suboptimal inclusion criteria (by not
requiring proof of a proximal intracra-
nial artery occlusion before randomi-
zation), longer time to intervention,
and use of less effective reperfusion
devices.22Y24 Instead, the six positive
trials25Y30 shared the requirement of
CT angiogram for patient screen-
ing (only patients with documented
internal carotid artery or proximal
middle cerebral artery occlusions could
be entered into the studies), empha-
sized the importance of prompt inter-
vention, and almost exclusively used
retrievable stents to achieve reper-
fusion, devices that have been solidly
proven to be more effective than
their predecessors.31,32
The main characteristics of the ran-
domized controlled trials establishing
the benefit of mechanical throm-
bectomy are summarized in Table 3-2.
All of them enrolled patients with
severe neurologic deficits and good
prestroke functional status who pres-
ented mostly within 6 hours of symp-
tom onset (Table 3-3). Major early
ischemic changes on the baseline
CT scan were a reason for exclusion.
The great majority of patients in
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KEY POINTS
both arms were treated with IV rtPA. h Six recent randomized
The results were unequivocal: patients controlled trials have
treated with mechanical thrombectomy conclusively proven that
had high rates of reperfusion and endovascular therapy
much better functional outcomes at with mechanical
90 days. thrombectomy improves
When taken in combination, these functional outcomes in
trials demonstrated that between three patients with acute
and seven patients must be treated to stroke from a proximal
help one additional patient regain func- intracranial artery
occlusion (internal
tional independence,33 which is par-
carotid artery, M1 or M2
ticularly remarkable considering the
segments) when the
severity of the symptoms upon pre- intervention is performed
sentation (Case 3-2). Furthermore, within 6 hours of
since the benefit conferred by mechan- symptom onset.
ical thrombectomy spanned through
h Candidates for
the entire range of functional outcome, endovascular stroke
the number necessary to treat to therapy are patients
reduce disability by one level on the with severe neurologic
modified Rankin Scale was only 2.6. symptoms, no major
This benefit was confirmed across ischemic changes
multiple subgroups (including patients on the baseline CT scan,
older than 80 years and those with very good prestroke
severe strokes as indicated by a base- functional status, and
line NIHSS score higher than 20).33 early presentation.
Mechanical thrombectomy was also h Mechanical
proven to be quite safe, with a pooled thrombectomy can be
rate of sICH of 4.4% across all patients attempted when IV
treated in the intervention arms of thrombolysis does not
the five trials.33 Few emergency treat- result in rapid clinical
improvement and also
ments in medicine have shown this
in patients who are
degree of success.
ineligible for IV rtPA.
The dramatic benefit observed in
these trials relied on very high reper-
fusion rates using retrievable stents.
These devices are deployed at the
level of the occlusive clot, capture
the clot in their mesh, and are then
retrieved along with the clot. Inter-
ventions in these trials were prompt
and typically performed by experi-
enced specialists. Delays to treatment
were minimized, and consequently
the times to reperfusion were rela-
tively short. In fact, those trials with
shorter average time to reperfusion
showed the greatest clinical benefit.34
Some unanswered questions still
exist regarding the best application of
ContinuumJournal.com 69
 Acute Ischemic Stroke

TABLE 3-2 Summary of the Main Trials Evaluating Mechanical Thrombectomy With
Retrievable Stents for Acute Ischemic Stroke

Study MR CLEAN25 ESCAPE26 EXTEND-IA27

Size (intervention 500 (233 versus 267) 315 (165 versus 150) 70 (35 versus 35)
versus control)
Age, median (years) 65.8 versus 65.7 71 versus 70 68.6 versus 70.2
a
Time to randomization 6 hours 12 hours 6 hours
Image to puncture
G60 minutes
Clinical selection Any age Any age Any age
NIHSS Q2 Any NIHSS (disabling Any NIHSS
symptoms)
Barthel Index990 Premorbid mRS G2
b
Imaging selection CTA (+/- CTP) CT ASPECTS 6Y10 with good CTA/CTP (core G70 mL)
collaterals 950% of MCA
Any ASPECTS

NIHSS, median 17 versus 18 16 versus 17 17 versus 13

ASPECTS, median 9 9 versus 9 Not reported
IV rtPA, % 87.1 versus 90.6 72.7 versus 78.7 100 versus 100
Onset to groin puncture, 260 185 210
median (minutes)
Onset to reperfusion, Not reported 241 248
median (minutes)
M1 occlusion, % 66.1 versus 62 68.1 versus 71.4 57 versus 51
TICI 2bY3, % 58.7 72.4 86
mRS -0Y2 at 90 days, % 32.6 versus 19.1 53 versus 29.3 71 versus 40
OR 1.7 OR 1.8 OR 4.2
(95% CI 1.2Y2.3) (95% CI 1.4Y2.4) (95% CI 1.4Y12)
mRS 0Y2 at 90 days, NNT 7.1 4.2 3.2
sICH, % 6 versus 5.2 3.6 versus 2.7 0 versus 6
+/- = with or without; ASPECTS = Alberta Stroke Program Early CT Score; CI = confidence interval; CT = computed tomography;
CTA = computed tomography angiography; CTP = computed tomography perfusion; ESCAPE = Endovascular Treatment for Small
Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times; EXTEND-IA = Extending the
Time for Thrombolysis in Emergency Neurological DeficitsVIntra-Arterial; ICA = internal carotid artery; IV= intravenous; MCA = middle cerebral
artery; MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands;
MRA = magnetic resonance angiography; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NNT = number
needed to treat; OR = odds ratio; REVASCAT = Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy
in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset;
rtPA = recombinant tissue plasminogen activator; sICH = symptomatic intracerebral hemorrhage; SWIFT PRIME = Solitaire With the Intention
for Thrombectomy as Primary Endovascular Treatment; THRACE = The Contribution of Intra-arterial Thrombectomy in Acute Ischemic
Stroke in Patients Treated With Intravenous Thrombolysis; TICI = thrombolysis in cerebral infarction.
a
84% within 6 hours.
b
67% of MR CLEAN subjects and 81% of SWIFT PRIME subjects had CT perfusion.

70 ContinuumJournal.com February 2017

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 SWIFT PRIME28 REVASCAT29 THRACE30
196 (98 versus 98) 206 (103 versus 103) 414 (204 versus 208)

65 versus 66.3 65.7 versus 67.2 66 versus 68

6 hours 3.7 hours 4.5 hours
Image to puncture Onset to groin puncture
G90 minutes 5 hours
Age 18Y80 years Age 18Y80 years Age 18Y80 years
NIHSS Q8 NIHSS Q6 NIHSS 10Y25

Premorbid mRS G2 Premorbid mRS G2

CTA (+/- CTP)b CTA CTA or MRA

ASPECTS 6Y10 ASPECTS 7Y10 Any ASPECTS

No cervical ICA occlusion
17 versus 17 17 versus 17 18 versus 17
9 versus 9 7 versus 8 Median not reported
100 versus 100 68.0 versus 77.7 100 versus 100
224 269 250

250 355 303

67 versus 77 64.7 versus 64.4 86 versus 79

88 65.7 69
60.2 versus 35.5 43.7 versus 28.2 53 versus 42
OR 1.7 OR 2.1 OR 1.55
(95% CI 1.2Y2.3) (95% CI 1.1Y4.0) (95% CI 1.05Y2.30)
4.0 6.3 9.1
1 versus 3 1.9 versus 1.9 2 versus 2

Continuum (Minneap Minn) 2017;23(1):62–81 ContinuumJournal.com 71

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

 Acute Ischemic Stroke

KEY POINTS
h Careful assessment of
brain imaging is
necessary to exclude
a large established
infarction (core).
h The optimal radiologic
method to select
candidates for
endovascular therapy is
not yet established, but
the Alberta Stroke
Programs Early CT
Score, evaluation of
collaterals on CT
angiography, and CT
perfusion or MRI
diffusion/perfusion are
all available options.
TABLE 3-3 Candidates for
Acute Endovascular
Stroke Therapy
b Age Q18 years
b NIHSS score Q6
b Time from symptom onset
to groin puncture G6 hours
b Good prestroke functional
status
b ASPECTS score Q6 on baseline
CT scan
b Presence of proximal
intracranial artery occlusion
ASPECTS = Alberta Stroke Program Early
CT Score; CT = computed tomography;
NIHSS = National Institutes of Health
Stroke Scale.
mechanical thrombectomy for pa-
tients with acute ischemic stroke. In
particular, the best imaging modal-
ity to select patients for the inter-
vention remains to be determined.
All trials excluded patients with an
Alberta Stroke Program Early CT Score
(ASPECTS) lower than 6 on baseline
CT scan. The ASPECTS provides an ex-
pedient method to quantify the extent
of early ischemic damage (Figure 3-335).36
However, the noncontrast CT scan is
not sensitive for the visualization of
early ischemia. One of the trials used
multiphase CT angiography to evaluate
collateral vessels,26 and another re-
quired a CT perfusion showing a
limited infarct core and evidence of
penumbra before randomization.27
Furthermore, many patients in trials
that did not require CT perfusion by
protocol had this imaging before in-
clusion in the study because that was
the prevailing practice in the enrolling
center.25,28 CT perfusion can provide
more reliable assessment of the is-
chemic region, but its acquisition re-
quires additional time. MRI diffusion/
perfusion is broadly considered the
most accurate method to determine
the ischemic core and the extent of the
penumbra, but this technique is less
available. New software packages
promise to accelerate the time re-
quired to obtain perfusion imaging.
Yet, at this time, it is unclear if the
additional time needed to obtain these
images is justified.37 Figure 3-438 illus-
trates the current work flow in the

Case 3-2
A 62-year-old man without past medical history collapsed in his bathroom. The noise alerted his son,
who found his father on the ground, unable to move the right side of his body and mute. He
immediately called an ambulance. Paramedics in the field noted a blood pressure of 180/100 mm Hg
and an irregularly irregular pulse. In the emergency department, the patient had a fluctuating level of
alertness, forced left gaze deviation, a right visual field deficit, global aphasia with mutism, right
hemiplegia, and severe right hypoesthesia. His National Institutes of Health Stroke Scale (NIHSS) score
was 22. Noncontrast head CT scan showed a hyperdense left middle cerebral artery sign, but his
Alberta Stroke Program Early CT Score (ASPECTS) was 10 (Figure 3-2A). CT angiogram showed a flow
gap in the left middle cerebral artery with good collateral flow distal to it (Figure 3-2B). IV
thrombolysis was started 55 minutes after symptom onset, and the patient was taken to the angiographic
suite for endovascular therapy. Groin puncture took place 67 minutes after symptom onset. Initial
injection of contrast into the left internal carotid artery showed that this vessel was occluded at the top of
its supraclinoid segment (Figure 3-2C). Complete recanalization with full reperfusion was rapidly
achieved with mechanical thrombectomy using a retrievable stent (Figure 3-2D). The patient began
improving on the angiographic table and continued to improve overnight. By the next morning, his
NIHSS score was 3. Repeat CT scan showed a small infarction in the left lenticular nucleus (Figure 3-2E).
At 3 months, the patient had full function and no residual symptoms.
Continued on page 74

72 ContinuumJournal.com February 2017

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 Continued from page 73

FIGURE 3-2 Imaging of the patient in Case 3-2. A, CT scan of the brain showing hyperdensity in the left middle cerebral
artery consistent with acute thrombus (arrow). B, CT angiogram showing a focal area of left middle cerebral
artery occlusion (arrow) with good collateral flow in the vessels distal to the occlusion. C, Digital subtraction
angiogram demonstrating occlusion of the distal segment of the left internal carotid artery as well as intact collaterals
supplying the peripheral middle cerebral artery branches. D, Full recanalization and reperfusion after mechanical
thrombectomy. E, Repeat CT scan showing a small residual infarction in the left basal ganglia (arrow).

Comment. Thanks to technologic advances, endovascular therapy with mechanical thrombectomy is

highly effective in achieving reperfusion in patients with proximal intracranial artery occlusions. It is
usually combined with IV thrombolysis. However, endovascular recanalization is also beneficial in
patients with contraindications for IV rtPA. Adequate patient selection (in this case, the patient had
no evidence of ischemic changes on CT scan and good collaterals on CT angiogram) and prompt
intervention are crucial to optimize the chances of therapeutic success.

evaluation and treatment of acute is-
chemic stroke.
A growing body of evidence sug-
gests that interventions performed
under conscious sedation have better
outcomes than those performed un-
der general anesthesia. This finding
was first reported in retrospective
studies39 and subsequently confirmed
in a subanalysis of the Multicenter
Randomized Clinical Trial of Endovas- KEY POINT
cular Treatment for Acute Ischemic h Endovascular
Stroke in the Netherlands (MR CLEAN) interventions for acute
stroke should be
trial.40 It is becoming increasingly clear
performed under
that most interventions can be safely
conscious sedation
completed using conscious sedation. whenever possible.
An appropriately powered large ran-
domized trial will be necessary to
conclusively determine if conscious
sedation should be preferred over

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

 Acute Ischemic Stroke

FIGURE 3-3 The Alberta Stroke Program Early CT Score

(ASPECTS) is designed to quantify the severity
of brain parenchymal changes in acute stroke.
The 10 areas are depicted on this illustration. A normal CT scan
is represented by an ASPECTS of 10. One point is subtracted for
each of the 10 regions when any evidence of early ischemic
change exists. Thus, the lower the ASPECTS, the larger the
extent of the ischemic damage.
Reprinted from Puetz V, et al, Int J Stroke.35 B 2009 World Stroke Organization.
wso.sagepub.com/content/4/5/354.abstract.

FIGURE 3-4 Graphic illustrating the sequence of steps in contemporary acute stroke therapy. IV thrombolysis should be given to
all patients without contraindications within 60 minutes of their arrival to the emergency department. The use of
perfusion imaging is considered optional at this time. Ideally, the time from the qualifying scan to the groin
puncture in candidates for endovascular therapy should be shorter than 60 minutes.
CT = computed tomography; DSA = digital subtraction angiography; IV = intravenous; rtPA = recombinant tissue plasminogen activator.
Reprinted with permission from Rabinstein AA, Nat Rev Neurol.38 B 2016 Alejandro A. Rabinstein. nature.com/nrneurol/journal/v12/n2/full/nrneurol.2015.241.html.

74 ContinuumJournal.com February 2017

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general anesthesia during endovascular
stroke therapy.
Perhaps the main question is
whether the outcomes observed in
the randomized trials can be repli-
cated in daily practice. To achieve this
goal, triaging mechanisms must be
refined and expertise must become
more readily available. Organization
and implementation of stroke net-
works around comprehensive stroke
centers with 24/7 neurointerventional
capability must become a priority. In
turn, neurointerventional centers will
have to prove compliance with strict
metrics of efficiency and safety.
SPECIAL SITUATIONS
Special clinical situations remain for
which the evidence is insufficient to
determine the best course of action.
Until more definite data become avail-
able, these cases should be approached
considering individual factors and what
is known from collective experience.
Wake-up Strokes
Patients whose neurologic deficits are
first noticed upon their awakening
represent a particular challenge to
the clinician. The same applies to
those with unclear time of onset (such
as when the patient is aphasic and the
onset of symptoms was not witnessed).
These situations constitute formal con-
traindications for IV rtPA, but it is widely
agreed that some of these patients may
benefit from reperfusion therapy. When
the baseline CT scan shows no evidence
of a large established infarction, it is
likely that advanced imaging with CT
perfusion or MR diffusion/perfusion
may identify those patients who can be
safely treated and can improve after
successful recanalization (Case 3-3).
Observational studies support this ap-
proach,41,42 which is currently being
tested in the DWI or CTP Assess-
ment With Clinical Mismatch in the
Continuum (Minneap Minn) 2017;23(1):62–81
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KEY POINTS
Triage of Wake-Up and Late Presenting h Patients with wake-up
Strokes Undergoing Neurointervention strokes and those with
(DAWN),43 PerfusiOn Imaging Selec- stroke of unknown time
tion of Ischemic STroke Patients for of onset might benefit
EndoVascular ThErapy (POSITIVE),44 from acute reperfusion
Diffusion and Perfusion Imaging Eval- if a large infarct core can
uation for Understanding Stroke Evo- be reliably excluded.
lution 3 (DEFUSE 3),45 and A Phase IIa h It is prudent not to
Safety Study of Intravenous Thrombol- administer IV thrombolysis
ysis With Alteplase in MRI-Selected in patients taking the
Patients (MR WITNESS)46 trials. novel oral anticoagulants
(dabigatran, rivaroxaban,
Intravenous Thrombolysis apixaban, edoxaban)
in Patients Taking because readily available
tests in the emergency
Newer Anticoagulants
department cannot
IV rtPA can be administered within quantify the degree of
3 hours of symptom onset to patients active anticoagulation.
taking warfarin whose international
normalized ratio (INR) is 1.7 or less.
However, no adequate safety data
with the newer anticoagulants (the
direct thrombin inhibitor dabigatran
and the factor Xa inhibitors riva-
roxaban, apixaban, and edoxaban)
exist. Readily available laboratory stud-
ies cannot quantify the degree of anti-
coagulation. Thus, it is most prudent
to withhold thrombolysis in patients
taking these agents.12 However, patients
with proximal intracranial artery occlu-
sion may benefit from mechanical
thrombectomy.
Minor and Rapidly
Improving Deficits
Although thrombolysis is often with-
held because the symptoms are
considered mild or patients appear
to be rapidly improving, several ob-
servational studies have shown that
up to one-third of patients who are
otherwise eligible for thrombolysis
but do not receive it for these reasons
are disabled at 3 months.47 Thus, one
must be very careful when assess-
ing these patients. IV rtPA might be
justified when the NIHSS score is low
but the symptoms are nonetheless dis-
abling for the patient (eg, hemianopia
ContinuumJournal.com 75
 Acute Ischemic Stroke

Case 3-3
A 74-year-old woman with a history of atrial fibrillation on aspirin woke up with speech difficulties
and right-sided weakness. She was feeling well when she had gone to bed the night before. Her
husband called an ambulance, and upon arrival to the emergency department, she had a National
Institutes of Health Stroke Scale (NIHSS) score of 15. CT scan of the brain was unremarkable, but CT
angiogram showed occlusion of the left middle cerebral artery with good collateral flow (Figure 3-5A).
CT perfusion demonstrated a large mismatch between the cerebral blood flow (Figure 3-5B) and
the cerebral blood volume (Figure 3-5C) throughout the entire left middle cerebral artery territory.
Consequently, the patient was taken to the angiographic suite and underwent successful recanalization
of the left middle cerebral artery by means of a retrievable stent (Figures 3-5D and 3-5E). She experienced
great clinical improvement over the subsequent 3 days. Follow-up CT scan is shown in Figure 3-5F. At
3 months, she had regained full function.

FIGURE 3-5 Imaging of the patient in Case 3-3. A, CT angiogram showing occlusion of the left middle cerebral artery (arrow);
collateral flow distal to the occlusion was satisfactory. B, Cerebral blood flow image of the CT perfusion
disclosing hypoperfusion throughout the left middle cerebral artery distribution. C, Cerebral blood volume
image of the CT perfusion showing no definite areas of established infarction. D, Digital subtraction angiogram confirming
the presence of an occlusive/subocclusive clot in the proximal left middle cerebral artery. E, Angiographic run after full
reperfusion following treatment with a retrievable stent. F, On follow-up CT scan 24 hours later, a relatively small infarction in
comparison with the initial region of hypoperfusion in the left basal ganglia and internal capsule is seen (arrow).

Comment. Wake-up strokes and strokes of unclear time of onset are particularly problematic because
these cases were not included in the trials supporting IV thrombolysis or mechanical thrombectomy.
Yet, patients with small infarct core and large penumbra can be good candidates for acute reperfusion
therapy. This is one of the situations in which the use of penumbral imaging (CT perfusion or MR
diffusion/perfusion) can be invaluable to identify good candidates for treatment. Ongoing trials should
be able to establish the best strategy for treatment of stroke with uncertain time of onset.

76 ContinuumJournal.com February 2017

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


in a professional driver). Improving
deficits that are still disabling at the time
of the neurologic evaluation may simi-
larly warrant thrombolysis. The value of
IV rtPA within 3 hours of symptom
onset in patients with mild (NIHSS
score of 5 or less) or rapidly improving
deficits is being investigated in the
Phase IIIB, Double-Blind, Multicenter
Study to Evaluate the Efficacy and Safety
of Alteplase in Patients With Mild Stroke:
Rapidly Improving Symptoms and Neu-
rologic Deficits (PRISMS) trial.48
Posterior Circulation Strokes
Randomized trials of IV thrombolysis
and mechanical thrombectomy (ex-
cept for very few patients enrolled
in The Contribution of Intra-arterial
Thrombectomy in Acute Ischemic
Stroke in Patients Treated With Intra-
venous Thrombolysis [THRACE] trial)30
have been restricted to patients
with anterior circulation strokes. Yet,
clinical experience with treating pos-
terior circulation infarctions with these
therapies exists. Basilar artery occlu-
sions can be devastating unless recan-
alization is achieved. Registry data
indicate that IV rtPA49 and mechanical
thrombectomy50 can result in func-
tional independence at 3 months in
30% to 40% of cases; these rates of
favorable outcome are clearly greater
than those reported without reper-
fusion therapy.51 The value of endo-
vascular therapy for acute basilar
occlusion is currently being investi-
gated in the Basilar Artery International
Cooperation Study (BASICS).52 Even
among patients who are treated with
reperfusion strategies, mortality re-
mains high (30% to 35%).49,50 There-
fore, many consider extending the
therapeutic window for IV thromboly-
sis beyond 4.5 hours and for mechan-
ical thrombectomy far beyond 6 hours
in patients with basilar artery occlusion
who do not have a large established
Continuum (Minneap Minn) 2017;23(1):62–81
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KEY POINTS
pontine or cerebellar infarction to be h Patients with mild or
reasonable. rapidly improving
strokes who present
FUTURE DIRECTIONS within the time window
Current efforts are focused on increas- for IV thrombolysis and
ing the efficiency of systems of care and still have disabling
investigating new strategies for acute symptoms at the time of
stroke therapy. The common objective the evaluation should
is to increase the number of patients probably be offered
with acute ischemic stroke who can treatment with rtPA.
regain perfusion of the ischemic tissue h Although patients with
before infarction is established. basilar artery occlusion
Mobile stroke units are rapidly were not included in the
gaining acceptance. These are special randomized controlled
ambulances equipped with a portable trials of IV thrombolysis
or mechanical
CT scanner and digital technology to
thrombectomy, these
enable telecommunication with a
patients should be
stroke specialist. They have been shown treated with acute
to allow safe initiation of IV throm- reperfusion therapies
bolysis while en route to the stroke because of their dismal
center.53 This option, although expen- prognosis if recanalization
sive, can be a very welcome solution cannot be achieved.
for some heavily populated urban com- h Mobile stroke units have
munities. Dispatchers and paramedics been shown to provide
must receive specific stroke education a safe way to start
to optimize the efficiency and safety of thrombolysis in the
these mobile units. prehospital setting.
Ways to extend the therapeutic win-
dow (beyond 4.5 hours for IV therapy
and 6 hours for mechanical thrombec-
tomy) are being actively investigated.
Using more fibrin-specific fibrinolytic
agents has been considered a promis-
ing option for years. Trials using
desmoteplase showed no benefit,54
but tenecteplase is still being studied.55
Radiologic identification of patients
with better collateral flow resulting
in persistently salvageable tissue is
broadly considered a reasonable,
albeit still unproven, approach. Se-
lection of candidates using perfusion
imaging modalities is being tested in
ongoing trials (DAWN, DEFUSE 3, and
MR WITNESS).43,45,46
Collateral flow augmentation is an-
other proposed strategy. In current
practice, this is sometimes attempted
with vasopressors. Evidence is restricted
ContinuumJournal.com 77
 Acute Ischemic Stroke
to small case series and one pilot
feasibility study.56 Yet, hemodynamic
augmentation with vasopressors can
occasionally work, in particular in pa-
tients with proximal vessel occlusions
who are not deemed candidates for
endovascular recanalization or in
whom the recanalization attempt was
unsuccessful. Mechanical techniques
for collateral recruitment (such as ex-
ternal counterpulsation and intraaortic
inflation devices) have been shown
feasible and safe, but their efficacy
remains to be proven.57
The evolution of emergency treat-
ment for acute ST-segment elevation
myocardial infarction can inform the
future of acute stroke therapy from a
proximal artery occlusion. Fibrinolysis
followed by endovascular therapy was
initially a common practice but was
later abandoned after randomized tri-
als demonstrated that proceeding di-
rectly to the endovascular intervention
was a superior strategy. Once systems
of care are optimized to guarantee fast
access to the angiographic suite for
patients with acute stroke, it will be
necessary to perform a trial comparing
IV thrombolysis followed by mechan-
ical thrombectomy versus primary
mechanical thrombectomy for patients
with severe stroke and proven proximal
artery occlusion.
CONCLUSION
Acute ischemic stroke is a medical
emergency in which every minute
counts. Achievement of reperfusion
can reverse neurologic deficits, even
if severe, and allow patients to regain
function. Two reperfusion strategies
are now proven: IV rtPA and mechan-
ical thrombectomy. They are both safe
and effective for the right candidates.
Patient selection is crucial to optimize
outcomes, but the attitude of the
clinician should be that treatment
78 ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
should be given unless a solid contra-
indication exists.
At this juncture, efforts should be
concentrated on refining systems of
care to allow more patients to have
access to reperfusion treatment. Ex-
panding the number of candidates for
intervention will require continuous
education of the community to recog-
nize signs of stroke, improving the
initial triage of patients with stroke,
and speeding evaluation and treat-
ment in the hospital. Ongoing trials
are also evaluating the possibility of
extending the therapeutic window by
using advanced imaging modalities to
identify patients in whom good collat-
erals have preserved tissue viability for
a longer time. Collateral augmentation
strategies and ultra-early administra-
tion of neuroprotective agents may
provide additional treatment venues
in the future.
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