Extra Acute Ischemic Stroke

EXTRA!
JUNE 2019 :: STROKE
Current Advances in Emergency

Department Care of Acute Ischemic Stroke
Part 1: Intravenous Thrombolysis
AUTHOR
Spyridoula Tsetsou, MD
Neurocritical Care Fellow, Icahn School of Medicine at Mount Sinai, New York, NY
Part 2: Endovascular Therapy

AUTHORS
Mohsen Nouri, MD
Clinical Fellow of Endovascular Surgical Neuroradiology, Cerebrovascular Center, Icahn School of Medicine at Mount
Sinai, New York, NY
Pramath Kakodkar, MD
School of Medicine, National University of Ireland, Galway, Ireland
Hazem Shoirah, MD
Assistant Professor, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY
PEER REVIEWER
Rhonda Cadena, MD
Associate Professor, Departments of Neurology, Neurosurgery, and Emergency Medicine, University of North
Carolina, Chapel Hill, NC
EDITOR-IN-CHIEF
Cappi Lay, MD
Assistant Professor, Director of Emergency Critical Care, Departments of Emergency Medicine and Neurocritical Care,
Icahn School of Medicine at Mount Sinai, New York, NY
Prior to beginning this activity, see "CME Information" on page 50.

This supplement is eligible for 4 Stroke CME credits
and 2 Pharmacology CME credits
Current Advances in
Emergency Department
Care of Acute Ischemic
Stroke
Table of Contents
Part 1: Intravenous Thrombolysis in Acute Ischemic Stroke......................... 3
Part 1 CME Questions..................................................................................... 21
Part 2: Endovascular Therapy in Acute Ischemic Stroke.............................. 23
Part 2 CME Questions..................................................................................... 43
Answer Key....................................................................................................... 46
Abbreviation List.............................................................................................. 48
Abbreviations of Clinical Trials....................................................................... 48
CME Information............................................................................................. 50
Emergency Medicine Practice EXTRA • June 2019 2 Copyright © 2019 EB Medicine. All rights reserved.
Part 1:
Intravenous Thrombolysis
in Acute Ischemic Stroke
AUTHOR
Spyridoula Tsetsou, MD
Neurocritical Care Fellow, Icahn School of Medicine at Mount Sinai, New York, NY
Introduction
Stroke is the fifth leading cause of death in the United States and an impor-
tant cause of long-term disability.1 Approximately 795,000 people suffer from
stroke each year (610,000 primary strokes and 185,000 recurrent strokes),1 with
ischemic stroke representing the vast majority of all stroke types (87%).2 The
cornerstone of acute ischemic stroke treatment relies on rapid clearance of an
offending thrombus in the cerebrovascular system.3 Advanced neuroimaging
and clinical trials, together with continuous adjustments of inclusion/exclu-
sion criteria, have helped emergency clinicians to rapidly and more accurately
identify the patients who will benefit from acute stroke treatment.
Alteplase (recombinant tissue plasminogen activator [rt-PA]) was the first

drug approved by the United States Food and Drug Administration (FDA)
for treatment of acute ischemic stroke. rt-PA is a protease derived by
recombinant DNA technology that activates fibrin-bound plasminogen,
leading to plasmin formation and the disintegration of fibrin clots.4,5 In
1995, the National Institute of Neurological Disorders and Stroke (NINDS)
Recombinant Tissue Plasminogen Activator trial showed that patients suf-
fering from ischemic stroke who received intravenous (IV) rt-PA in a dose
of 0.9 mg/kg within 3 hours of symptom onset had a more favorable out-
come at 3 months than those who received placebo (odds ratio [OR] 1.7;
95% confidence interval [CI], 1.2 to 2.6; P = .008).6 Since then, other studies
and randomized controlled trials have confirmed the safety and efficacy of
IV thrombolysis (IVT).7-12
In 2008, the ECASS III study13 showed a statistically significant benefit in

selected patients treated with IV rt-PA between 3 hours and 4.5 hours from
symptom onset. Additional studies have supported the use of IVT in a
time window as late as 4.5 hours after symptom onset.14-16 The IST-3 trial
attempted to extend the time window for IVT administration beyond the
4.5-hour time window, but was unable to show a meaningful improvement
in outcome beyond that time point.17 However, the recently published
EXTEND trial reveals promising results for extending the time window up
to 9 hours, in selected populations.18 The benefit of IVT in favorable neuro-
logic outcome has been demonstrated to persist at both 3 and 12 months
after stroke occurrence.6,19
Inclusion and Exclusion of Intravenous Thrombolysis:

A Changing Landscape
The American Heart Association (AHA) recently published updated guide-
lines for stroke management. Table 1, page 5, summarizes the updated
2018 AHA indications and contraindications for treatment with IVT.20 Ev-
ery patient presenting with symptoms of acute stroke within 4.5 hours of
last known well or usual state should be triaged for potential IVT. Patients
should be evaluated with computed tomography (CT) scan of the brain
and systolic blood pressure (SBP) should be maintained at < 185 mm Hg
and diastolic blood pressure (DBP) at < 110 mm Hg.21,22 Every eligible pa-
tient should receive IVT without delay. Changes and adjustments of inclu-
sion/exclusion criteria (in order to minimize the risk of any complication)
have been made and are discussed in following sections.
Hematologic Disorders and Previous Antithrombotic Treatment

IV rt-PA is contraindicated in patients with known thrombocytopenia or co-
agulopathy. If platelets < 100,000/mm3, international normalized ratio (INR)
> 1.7, activated partial thromboplastin time (aPTT) > 40 sec, or prothrombin
time (PT) > 15 sec, IVT should not be given. However, in patients without
known thrombocytopenia or coagulopathy, IVT administration should not be
delayed by laboratory measurements of platelet count or coagulation studies.
The risk of harm from IVT in patients taking direct thrombin inhibitors or direct
factor Xa inhibitors is not well established. These patients should have specific
laboratory tests sent to determine the safety of IVT administration (aPTT for
all anticoagulants; thrombin time for dabigatran; and direct factor Xa activity
assays for apixaban, rivaroxaban, and edoxaban). With the exception of aPTT,
these tests may be time-consuming, depending on different stroke centers’
laboratory capacity; however, these tests should be performed routinely, if in-
dicated. If a patient has not taken the drug in the last 48 hours (or if they have,
but the confirmatory tests are normal), IVT can be considered, if indicated.20
For patients who have received a therapeutic dose of low-molecular-weight

heparin (LMWH) within the previous 24 hours, IVT should not be adminis-
tered. Prior antiplatelet therapy (as monotherapy or as a drug combination of
aspirin and clopidogrel) is not a contraindication for IVT.23 Abciximab (glyco-
protein IIB/IIIA inhibitor) should not be administered concurrently with IV rt-PA
outside of a clinical trial setting.
Table 1. Eligibility Criteria and Exclusion Criteria
for Intravenous Thrombolysis20
Eligibility Criteria
0-3 Hours 3-4.5 Hours*
• Age ≥ 18 years • Age ≤ 80 years
• Acute-onset stroke symptoms (severe, • No history of both diabetes mellitus and prior
moderate, or mild, but disabling) stroke
• NIHSS score ≤ 25
• Not taking any oral anticoagulation agents
Exclusion Criteria
• Intracranial hemorrhage on CT or MRI
• CT evidence of obvious hypodensity
• Ischemic stroke within prior 3 months
• Severe head trauma within prior 3 months
• Intracranial or spinal surgery within prior 3 months
• History of intracranial hemorrhage
• Symptoms suggestive of subarachnoid hemorrhage
• Gastrointestinal bleeding event within 21 days of the stroke event
• Platelets < 100,000/mm3; INR > 1.7; aPTT > 40 sec; PT > 15 sec
• Treatment dose of LMWH within the last 24 hours
• Warfarin use with INR > 1.7
• NOAC [DOAC] use, unless normal laboratory result (thrombin time for dabigatran; direct factor
Xa activity assays for apixaban, rivaroxaban, and edoxaban) or if not taken > 48 hours (if normal
renal function)
• Clinical suspicion of infective endocarditis
• Known or suspected aortic arch dissection
• Intra-axial intracranial neoplasm
• Giant unruptured or unsecured aneurysm
• High burden of cerebral microbleeds (> 10) demonstrated on MRI (if MRI available)
Relative Exclusion Criteria
(Individualized decisions should be made)
• Pre-existing disability or dementia; individual considerations should be taken, as thrombolytic
therapy for acute therapy may be reasonable in this population
• Seizures at onset, unless stroke is proven
• Lumbar puncture within previous 7 days
• Arterial puncture in a noncompressible vessel within previous 7 days
• Major trauma not involving the head within previous 14 days
• Major surgery within previous 14 days (discuss bleeding risk with surgeon)
• Active menstruation with history of menorrhagia
• Intracranial arterial dissection (unknown risk, not well established)
• Intracranial aneurysm, unruptured or unsecured, small to moderate size (< 10 mm)
• Intracranial vascular malformations
• Extra-axial intracranial neoplasm
• Systemic malignancy with < 6 months’ life expectancy
*Time window not currently approved by the United States Food and Drug Administration.
Abbreviations: aPTT, activated partial thromboplastin time; CT, computed tomography; DOAC,
direct oral anticoagulant; INR, international normalized ratio; LMWH, low-molecular-weight
heparin; MRI, magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale;
NOAC, novel oral anticoagulant; PT, prothrombin time; PTT, partial thromboplastin time.
Seizures
Seizure at onset of acute stroke is not a contraindication for IVT as long as
residual symptoms are due to stroke and not secondary to postictal phe-
nomenon (Class of Recommendation IIa). (See Table 2 for AHA Class of
Recommendation definitions noted in this section.)
Table 2. American Heart Association Definitions of

Classification of Recommendations20
Classification
• Class I Strong. Benefit >>> Risk
• Class IIa Moderate. Benefit >> Risk
• Class IIb Weak. Benefit ≥ Risk
Minor Stroke
Patients with a low NIHSS score due to mild symptoms should be given
IVT within 3 hours of onset if there is no contraindication, as long as their
symptoms are considered disabling (Class of Recommendation I). How-
ever, if they present in the 3- to 4.5-hour window, the evidence supporting
IVT administration is weaker (Class of Recommendation IIb); treatment
should be offered if the risks do not outweigh the benefits.
MDCalc calculator for NIH Stroke Scale/Score (NIHSS):

www.mdcalc.com/nih-stroke-scale-score-nihss
Cerebral Microbleeds
The presence of cerebral microbleeds increases the risk of intracerebral
hemorrhage and a worse outcome after IVT; however, it remains unclear
whether these negative effects outweigh the benefit of IVT. In the absence
of any randomized controlled trials, AHA proposes that, if brain magnetic
resonance imaging (MRI) is available and reveals a small number of cerebral
microbleeds (1-10), IVT may be considered (Class of Recommendation IIb).20
Glucose Disorders
Hypoglycemia and hyperglycemia can mimic acute stroke symptoms, but
if there is high suspicion for a vascular cause and the patient’s symptoms
persist despite correction of abnormal glucose levels, IVT should be ad-
ministered unless indicated otherwise.
Myocardial Infarction and Other Cardiological Disorders

History of myocardial infarction (MI) in the 3 months prior to the stroke was
previously considered a relative contraindication to IVT, mainly due to the
theoretical risk of cardiac wall rupture and tamponade.24 The overall risk
of these complications is approximately 1% in patients treated with IVT
for acute MI.25 The 2018 AHA guidelines state that, in cases of MI in the
prior 3 months, IVT for acute ischemic stroke is reasonable if the recent MI
was a non–ST-segment elevation myocardial infarction (NSTEMI) or STEMI
involving the right or inferior myocardium, and may be reasonable in the
case of a STEMI involving the left anterior myocardium.20
In the absence of any evidence-based data, AHA recommends IVT at the

appropriate cerebral dose followed by percutaneous coronary angioplasty
and stenting, if indicated, in patients with concomitant presentation of
acute ischemic stroke and acute MI.20 The risk of hemopericardium or
other complications in patients receiving IVT for acute ischemic stroke
with concomitant pericarditis is not well established;26 it is currently rec-
ommended to consider IVT in case of major ischemic stroke that can be
expected to cause severe disability. Similarly, due to the lack of litera-
ture suggesting any clear benefit of IVT in cases of acute ischemic stroke
and left atrial or left ventricular thrombus, cardiac myxoma, and pupillary
fibroelastoma, it is currently recommended to consider IVT only in case of
major ischemic stroke expected to cause severe disability.20 In all of the
above cases, urgent cardiology consultation is strongly recommended.
Additional Recommendations
For patients aged > 80 years presenting in the 3- to 4.5-hour window
who are taking warfarin (with INR ≤ 1.7) and have had previous stroke or
diabetes, IVT administration may be safe, even though evidence is weak
(Class of Recommendation IIb). Treatment should be offered if the risks
do not outweigh the benefits. Similarly, patients (regardless of age) pre-
senting with severe stroke symptoms (NIHSS score > 25) will benefit from
IVT within the 3-hour window (Class of Recommendation I). On the other
hand, it is uncertain whether they will benefit from IVT if they present in
the 3- to 4.5-hour window (Class of Recommendation IIb), as the risk of
hemorrhagic transformation might outweigh the benefits.
Intravenous Thrombolysis in Clinical Practice

The FDA-approved dose of IV rt-PA is 0.9 mg/kg, with a maximum dose
of 90 mg. Ten percent of the total dose is given as a bolus over 1 minute,
and the remaining 90% in an infusion over 60 minutes.1 Administration of
IV rt-PA should not be delayed, since maximum benefit is linked to time
of administration.27 Ideally, the patient should receive IV rt-PA within 30
minutes of hospital arrival.28,29
A 2014 meta-analysis27 including data from 6756 patients from 9 trials (with
participants randomized to alteplase administration within 3-6 hours of
symptom onset vs placebo/control) showed that, in those stroke patients
receiving IVT within 3 hours of symptom onset, the number needed to
treat to produce 1 additional patient with a good 3-month functional
outcome (modified Rankin Scale [mRS] score of 0-1) was 10, when the drug
was given within 60 minutes of symptom onset. The number needed to
treat increased to 20 when drug administration was delayed until between
180 to 270 minutes after onset of symptoms.
MDCalc calculator for Modified Rankin Scale for Neurologic Disability:

www.mdcalc.com/modified-rankin-scale-neurologic-disability
After the stroke code is activated, it is recommended to discuss the ben-

efits and potential harms of IVT with the patient or next of kin (in case of
the patient’s incapacity) in order to obtain consent as quickly as possible.
However, thrombolytic treatment in acute ischemic stroke is the standard
of care,30 and in case of a patient’s incapacity and absence of next of kin,
the stroke team can proceed to IVT administration, if indicated, without
expending additional time attempting to contact family members for
consent. After IV rt-PA administration, the patient should be admitted to
a stroke unit or intensive care unit for frequent blood pressure monitor-
ing and neurological assessment. Blood pressure and NIHSS score should
be recorded every 15 minutes during and after IV rt-PA infusion and for
the following 2 hours; then every 30 minutes for 6 hours; and then hourly
until 24 hours after thrombolysis treatment.22 SBP should be maintained at
< 180 mm Hg and DBP at < 105 mm Hg,20 with antihypertensive medica-
tions, if required. A follow-up CT or MRI scan at 24 hours post treatment
should be obtained prior to starting antithrombotic medication.
If the patient develops new headache, vomiting, acute hypertension, or a

rapidly worsening neurologic examination, IV rt-PA infusion (if still ongo-
ing) should be stopped immediately and an urgent noncontrast head CT
should be obtained.
Intravenous Thrombolysis Complications

There are 2 major complications that can occur after IVT administration: (1)
hemorrhagic transformation and (2) orolingual edema. Clinicians manag-
ing patients who have received IVT should be aware of these complica-
tions and be able to rapidly recognize and treat these conditions, as they
can eliminate IVT efficacy or even increase early mortality rate.
Hemorrhagic Transformation
Radiological Classification
Hemorrhagic transformation after IVT is classified into 4 categories.31
Parenchymal hemorrhage is associated with worse outcomes31-33 and early
mortality.8,27 (See Figure 1, page 10.)
1. Hemorrhagic infarct (HI) 1: small petechial hemorrhage along the mar-
gins of the infarct.
2. HI 2: confluent petechiae within the infarcted area but without mass
effect.
3. Parenchymal hemorrhage (PH)1: hematoma occupying ≤ 30% of the
infarcted area with some slight mass effect.
4. PH 2: hematoma occupying > 30% of the infarcted area with a substan-
tial mass effect and tissue distortion.
Clinical Implications of Hemorrhagic Transformation

Symptomatic hemorrhagic transformation can occur in 2.6% to 6.4% of
patients receiving IVT, based on different studies.6,13,14,31,33 Patients with a
higher NIHSS score and presence of early ischemic signs and/or hypoden-
sity on initial head CT scored < 7 with the Alberta Stroke Program Early CT
Score (ASPECTS) are traditionally considered to be at high risk.34,35 In order
to better predict the individual risk of hemorrhagic transformation in each
patient, several scores have been created, combining epidemiological,
clinical, and radiological data (eg, HAT,36 SEDAN,37 SITS,38 TURN39); how-
ever, these scores have been only moderately accurate.40
MDCalc calculator for Alberta Program Early CT Score (ASPECTS):

www.mdcalc.com/alberta-stroke-program-early-ct-score-aspects
A recent trial testing a lower dose of IV rt-PA (0.6 mg/kg) did not have a
significantly lower rate of symptomatic hemorrhage, and was inferior to
the standard dose of 0.9 mg/kg in reducing death at 90 days.41
If symptomatic hemorrhagic transformation occurs within 24 hours after

IVT administration, stop the infusion immediately if it is still ongoing.
Laboratory studies, including complete blood cell (CBC) count, PT, aPTT,
fibrinogen level, and type and cross-match should be sent. The AHA
recommends the immediate administration of 10 units of cryoprecipitate
over 10 to 30 minutes (plus 1 extra unit if fibrinogen < 200 mg/dL) and IV
tranexamic acid (1 gram infused over 10 minutes) or IV E-aminocaproic
acid (4 to 5 g over 1 hour, followed by 1g/hour) until bleeding is con-
trolled.20 Hematology and neurosurgery consults should be obtained
and further discussion for possible hematoma evacuation and decom-
pression should take place when the anticipated benefits outweigh the
anticipated risks.42-44
Figure 1. Types of Hemorrhagic Transformation
HI 1 HI 2
PH 1 PH 2
HI 1: small petechial hemorrhage (punctuate hyperdensities, red arrow)

HI 2: confluent petechiae (confluent hyperdensity, red arrow)
PH 1: hematoma occupying ≤ 30% (red arrow) of the infarcted area with some slight mass effect
(compression of the left lateral ventricle frontal horn, blue arrow)
PH 2: hematoma occupies > 30% (red arrow) of the infarcted area with a substantial mass effect
and tissue distortion (compression of the right lateral ventricle frontal horn with midline shift, blue
arrow)
Abbreviations: HI, hemorrhagic infarct; PH, parenchymal hemorrhage.
Marco Fiorelli, Stefano Bastianello, Rüdiger von Kummer, et al. Hemorrhagic transformation within
36 hours of a cerebral infarct. Stroke. Volume 30, Issue 11. Pages 2280-2284. With permission of
the American Stroke Association. https://www.ahajournals.org/doi/full/10.1161/01.STR.30.11.2280
Extracranial hemorrhage has been reported in 0.4% to 1.5% of patients,
and management strategies aimed at replacing intravascular volume with-
out active reversal of the rt-PA is generally recommended as long as the
patient remains hemodynamically stable. In the presence of hemodynamic
instability or the inability to control bleeding, aggressive resuscitation and
the above-mentioned reversal should be initiated.45
Orolingual Angioedema
Orolingual angioedema occurs in 1% to 5% of patients after receiving
IVT.46-48 Most of the cases are mild and self-limited. The airway should
always be assessed and prophylactic intubation considered because, in
rare cases, the pharyngeal edema can be severe enough to cause airway
obstruction. The underlying pathophysiologic mechanism remains unclear.
Initial medical management includes IV glucocorticoids and antihista-
mines. In case of worsening angioedema, epinephrine should be adminis-
tered, either intramuscularly (in lateral thigh) or by nebulizer. Epinephrine
could also be administered subcutaneously; however, the absorption will
be delayed and unpredictable. In refractory cases, icatibant, a selective
bradykinin B2 receptor antagonist, or plasma-derived C1 esterase inhibitor
(successfully used in hereditary angioedema and angiotensin-converting-
enzyme [ACE] inhibitor-related angioedema) can be considered.49 ACE
inhibitors should be avoided, as concomitant administration is strongly
associated with this entity.47 Table 3 describes the 2018 AHA recommen-
dations on managing orolingual angioedema.
Table 3. Management of Orolingual Angioedema

Post Intravenous Thrombolysis20
• Maintain airway; initiate endotracheal intubation, if necessary

• Discontinue IV rt-PA (if still infusing) and ACE inhibitors
• Administer
l
Methylprednisolone 125 mg IV
l
Diphenhydramine 50 mg IV
l
Ranitidine 50 mg IV or famotidine 20 mg IV
• If further increase in angioedema, administer:
l
Epinephrine (0.1%) 0.3 mL IM or 0.5 mL by nebulizer, if worsening angioedema
l
Icatibant (selective bradykinin B2 receptor antagonist) 3 mL (30 mg) subcutaneously in
abdominal area (maximum 3 injections in 24 hours)
• Consider plasma-derived C1 esterase inhibitor (20 IU/kg), which has been used successfully in
hereditary angioedema and ACE-inhibitor-related angioedema
• Provide supportive care
Abbreviations: ACE, angiotensin-converting enzyme; IM, intramuscular; IU, international unit; IV,
intravenous; rt-PA, recombinant tissue plasminogen activator.
“Wake-up” Stroke – Changing the Paradigm
Besides delayed arrival at the hospital, the most common reason for stroke
patients not receiving IVT is an unknown time of symptom onset. In up to 30%
of patients, the time of acute stroke symptom onset is not known, usually due
to symptoms being recognized only after awakening from sleep.50,51 Patients
who wake up with stroke symptoms and aphasic patients without a witness to
the onset of symptoms create a dilemma for the emergency clinician trying
to administer IVT within the acceptable time window.52,53 While mechanical
thrombectomy is an option for patients up to 24 hours after symptom onset,
depending on the results of specialized perfusion imaging,54,55 the time win-
dow for the use of IVT has not been extended in the same manner.
Michel et al published a pilot CT perfusion-guided trial in 2012 that empha-

sized the safety of IVT, based on CT perfusion imaging of patients who were
suffering stroke of unknown onset time, but who had been seen well at some
point in the prior 24 hours.52 In 2018, Thomalla et al published a multicenter
trial exploring IVT in patients with unknown time of onset of acute stroke,
guided by an MRI mismatch between diffusion-weighted imaging and FLAIR
(fluid-attenuated inversion recovery) imaging in the region of ischemia.56 The
treatment group showed significantly better functional outcome at 3 months
(53.3% in the treatment group versus 41.8% in placebo group; adjusted OR,
1.61; 95% CI, 1.09 - 2.36; P = .02). Symptomatic hemorrhagic transformation
(defined by SITS-MOST) was increased in the treatment group, at 2% versus
0.4% in the placebo group, without affecting mortality (OR 4.95; 95% CI, 0.57
- 42.87; P = .15). Despite promising results, the trial was stopped early due
to funding cessation. Recent data from the EXTEND trial support alteplase
administration up to 9 hours after symptom onset if salvageable brain tissue is
present on CT perfusion or MRI perfusion-diffusion, with a number needed to
treat of 17.18 Similar to the Thomalla trial, the treatment group suffered from
higher rates of symptomatic hemorrhage (6.2% vs 0.9%; adjusted risk ratio
7.22; 95% CI, 0.97-53.5; P = .05).
Despite these promising results pointing to the possibility of extending

the time window for IV rt-PA in select groups of patients, current guide-
lines have not yet implemented perfusion imaging to select patients for
IVT administration outside of the standard time windows.
New Thrombolysis Agents and Techniques

Tenecteplase, an rt-PA, has been studied extensively and appears to have
a similar profile of safety and efficacy when compared to alteplase.57-60 Until
recently, the largest tenecteplase trial included primarily patients with minor
stroke (NIHSS median score of 4) without major intracranial vessel occlusion.60
The 2018 AHA guidelines stated that tenecteplase at a single bolus dose of
0.4 mg/kg can be considered as an alternative to alteplase in patients with
minor neurological deficit and no large-vessel occlusion.20 However, in 2018,
Campbell et al published the results of a randomized controlled trial com-
paring the effect of tenecteplase and alteplase before mechanical throm-
bectomy in acute ischemic stroke with large-vessel occlusion.61 Interestingly,
tenecteplase administration at a dose of 0.25 mg/kg (maximum 25 mg) before
mechanical thrombectomy within 4.5 hours of symptom onset was associ-
ated with statistically significant better reperfusion results and better 90-day
functional outcome than alteplase. Despite these promising results, the study
was relatively underpowered (n = 202) and concerned only patients with large-
vessel occlusion who were eligible for IVT.
There is no proven benefit to using any other fibrinolytic agent (such as

streptokinase62-64 or desmoteplase65-68) in the setting of acute ischemic
stroke, outside of a clinical trial. Combination treatments, such as a re-
duced dose of IV alteplase with eptifibatide69 or sonothrombolysis with
IVT70 have not shown benefit and are currently not recommended.
Conclusion
IVT with alteplase (rt-PA) has dramatically changed acute stroke manage-
ment. Although the opportunity for treatment is restricted to a narrow
time window, since the late 1990s, IVT has contributed to the improvement
of functional outcome in thousands of patients suffering from acute stroke.
While continuous research to explore different pharmacological options
and expanding the time window is ongoing, emergency clinicians should
be aware that the earlier the treatment is given, the more likely it is that
the patient will benefit.
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14. Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase
3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study.
Lancet. 2008;372(9646):1303-1309. (Prospective study; 12,529 patients)
15. Bluhmki E, Chamorro A, Davalos A, et al. Stroke treatment with al-
teplase given 3.0-4.5 h after onset of acute ischaemic stroke (ECASS
III): additional outcomes and subgroup analysis of a randomised con-
trolled trial. Lancet Neurol. 2009;8(12):1095-1102. (Randomized dou-
ble-blind controlled trial; 418 patients)
16. Ahmed N, Wahlgren N, Grond M, et al. Implementation and outcome
of thrombolysis with alteplase 3-4.5 h after an acute stroke: an updated
analysis from SITS-ISTR. Lancet Neurol. 2010;9(9):866-874. (Observa-
tional study; 23,942 patients)
17. IST Collaborative Group, Sandercock P, Wardlaw JM, et al. The ben-
efits and harms of intravenous thrombolysis with recombinant tissue
plasminogen activator within 6 h of acute ischaemic stroke (the Third
International Stroke Trial [IST-3]): a randomised controlled trial. Lancet.
2012;379(9834):2352-2363. (Multicenter randomized open-treatment
trial; 3035 patients)
18. Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by
perfusion imaging up to 9 hours after onset of stroke. N Engl J Med.
2019;380(19):1795-1803. (Multicenter randomized placebo-controlled
19. Fischer U, Mono ML, Zwahlen M, et al. Impact of thrombolysis on
stroke outcome at 12 months in a population: the Bern stroke project.
Stroke. 2012;43(4):1039-1045. (Prospective study; 807 patients)
20. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 guidelines for the
early management of patients with acute ischemic stroke: a guideline
for healthcare professionals from the American Heart Association/
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21. Wechsler LR. Intravenous thrombolytic therapy for acute ischemic
stroke. N Engl J Med. 2011;364(22):2138-2146. (Systematic review)
22. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early man-
agement of patients with acute ischemic stroke: a guideline for health-
care professionals from the American Heart Association/American
Stroke Association. Stroke. 2013;44(3):870-947. (Guidelines)
23. Tsivgoulis G, Katsanos AH, Mavridis D, et al. Intravenous thromboly-
sis for ischemic stroke patients on dual antiplatelets. Ann Neurol.
2018;84(1):89-97. (Retrospective analysis of prospectively collected
data; 2086 patients)
24. De Silva DA, Manzano JJ, Chang HM, et al. Reconsidering recent myo-
cardial infarction as a contraindication for IV stroke thrombolysis. Neu-
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25. Patel MR, Meine TJ, Lindblad L, et al. Cardiac tamponade in the fibri-
nolytic era: analysis of >100,000 patients with ST-segment elevation
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102,060 patients)
26. Kremen SA, Wu MN, Ovbiagele B. Hemopericardium following in-
travenous thrombolysis for acute ischemic stroke. Cerebrovasc Dis.
2005;20(6):478-479. (Case report)
27. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and
stroke severity on the effects of intravenous thrombolysis with alteplase for
acute ischaemic stroke: a meta-analysis of individual patient data from ran-
domised trials. Lancet. 2014;384(9958):1929-1935. (Meta-analysis; 9 trials,
6756 patients)
28. Meretoja A, Strbian D, Mustanoja S, et al. Reducing in-hospital delay to
20 minutes in stroke thrombolysis. Neurology. 2012;79(4):306-313. (Ret-
rospective analysis of prospectively collected data; 1860 patients)
29. Meretoja A, Weir L, Ugalde M, et al. Helsinki model cut stroke throm-
bolysis delays to 25 minutes in Melbourne in only 4 months. Neurol-
ogy. 2013;81(12):1071-1076. (Retrospective analysis of prospectively
collected data; 48 patients)
30. White-Bateman SR, Schumacher HC, Sacco RL, et al. Consent for intra-
venous thrombolysis in acute stroke: review and future directions. Arch
Neurol. 2007;64(6):785-792. (Systematic review)
31. Larrue V, von Kummer RR, Muller A, et al. Risk factors for severe hemor-
rhagic transformation in ischemic stroke patients treated with recombi-
nant tissue plasminogen activator: a secondary analysis of the European-
Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32(2):438-441.
(Secondary analysis of randomized controlled trial; 450 patients)
32. Paciaroni M, Agnelli G, Corea F, et al. Early hemorrhagic transfor-
mation of brain infarction: rate, predictive factors, and influence on
clinical outcome: results of a prospective multicenter study. Stroke.
2008;39(8):2249-2256. (Prospective multicenter study; 1125 patients)
33. Thomalla G, Sobesky J, Kohrmann M, et al. Two tales: hemorrhagic
transformation but not parenchymal hemorrhage after thrombolysis is
related to severity and duration of ischemia: MRI study of acute stroke
patients treated with intravenous tissue plasminogen activator within 6
hours. Stroke. 2007;38(2):313-318. (Retrospective analysis of prospec-
tively collected data; 152 patients)
34. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability
of a quantitative computed tomography score in predicting out-
come of hyperacute stroke before thrombolytic therapy. ASPECTS
Study Group. Alberta Stroke Programme Early CT Score. Lancet.
2000;355(9216):1670-1674. (Prospective study; 203 patients)
35. Demchuk AM, Hill MD, Barber PA, et al. Importance of early ischemic
computed tomography changes using ASPECTS in NINDS rt-PA Stroke
Study. Stroke. 2005;36(10):2110-2115. (Prospective study; 608 CT scans)
36. Lou M, Safdar A, Mehdiratta M, et al. The HAT score: a simple grad-
ing scale for predicting hemorrhage after thrombolysis. Neurology.
2008;71(18):1417-1423. (Grading scale development)
37. Strbian D, Engelter S, Michel P, et al. Symptomatic intracranial hem-
orrhage after stroke thrombolysis: the SEDAN score. Ann Neurol.
2012;71(5):634-641. (Grading scale development; 974 patients)
38. Mazya M, Egido JA, Ford GA, et al. Predicting the risk of symptomatic
intracerebral hemorrhage in ischemic stroke treated with intravenous
alteplase: safe Implementation of Treatments in Stroke (SITS) symp-
tomatic intracerebral hemorrhage risk score. Stroke. 2012;43(6):1524-
1531. (Prospective study; 31,627 patients)
39. Asuzu D, Nystrom K, Amin H, et al. TURN: a simple predictor of symp-
tomatic intracerebral hemorrhage after IV thrombolysis. Neurocrit
Care. 2015;23(2):166-171. (Retrospective analysis of prospectively
collected data; 1336 patients, validation cohort 983 patients)
40. Strbian D, Michel P, Seiffge DJ, et al. Symptomatic intracranial hem-
orrhage after stroke thrombolysis: comparison of prediction scores.
Stroke. 2014;45(3):752-758. (Retrospective analysis of prospectively
collected data; 3012 patients)
41. Anderson CS, Robinson T, Lindley RI, et al. Low-dose versus standard-
dose intravenous alteplase in acute ischemic stroke. N Engl J Med.
2016;374(24):2313-2323. (Randomized controlled trial; 1607 patients)
42. Goldstein JN, Marrero M, Masrur S, et al. Management of thrombol-
ysis-associated symptomatic intracerebral hemorrhage. Arch Neurol.
2010;67(8):965-969. (Retrospective analysis of prospectively collect-
ed data; 311 patients)
43. French KF, White J, Hoesch RE. Treatment of intracerebral hemorrhage
with tranexamic acid after thrombolysis with tissue plasminogen activa-
tor. Neurocrit Care. 2012;17(1):107-111. (Case report)
44. Yaghi S, Eisenberger A, Willey JZ. Symptomatic intracerebral hemor-
rhage in acute ischemic stroke after thrombolysis with intravenous re-
combinant tissue plasminogen activator: a review of natural history and
treatment. JAMA Neurol. 2014;71(9):1181-1185. (Systematic review)
45. Albers GW, Bates VE, Clark WM, et al. Intravenous tissue-type
plasminogen activator for treatment of acute stroke: the Standard
Treatment with Alteplase to Reverse Stroke (STARS) study. JAMA.
2000;283(9):1145-1150. (Prospective mulitcenter study; 389 patients)
46. Engelter ST, Fluri F, Buitrago-Tellez C, et al. Life-threatening orolingual
angioedema during thrombolysis in acute ischemic stroke. J Neurol.
2005;252(10):1167-1170. (Observational study; 120 patients)
47. Hill MD, Lye T, Moss H, et al. Hemi-orolingual angioedema and ACE in-
hibition after alteplase treatment of stroke. Neurology. 2003;60(9):1525-
1527. (Prospective study; 176 patients)
48. Myslimi F, Caparros F, Dequatre-Ponchelle N, et al. Orolingual an-
gioedema during or after thrombolysis for cerebral ischemia. Stroke.
2016;47(7):1825-1830. (Prospective study; 923 patients)
49. Pahs L, Droege C, Kneale H, et al. A novel approach to the treatment
of orolingual angioedema after tissue plasminogen activator adminis-
tration. Ann Emerg Med. 2016;68(3):345-348. (Case report)
50. Mackey J, Kleindorfer D, Sucharew H, et al. Population-based study
of wake-up strokes. Neurology. 2011;76(19):1662-1667. (Population-
based study; 1854 patients)
51. Fink JN, Kumar S, Horkan C, et al. The stroke patient who woke up:
clinical and radiological features, including diffusion and perfusion
MRI. Stroke. 2002;33(4):988-993. (Prospective study; 364 patients)
52. Michel P, Ntaios G, Reichhart M, et al. Perfusion-CT guided intravenous
thrombolysis in patients with unknown-onset stroke: a randomized,
double-blind, placebo-controlled, pilot feasibility trial. Neuroradiol-
ogy. 2012;54(6):579-588. (Randomized double-blind pilot trial; 12
patients)
53. Michel P, Odier C, Rutgers M, et al. The Acute STroke Registry and
Analysis of Lausanne (ASTRAL): design and baseline analysis of an
ischemic stroke registry including acute multimodal imaging. Stroke.
2010;41(11):2491-2498. (Registry design; 1633 patients)
54. Nogueira RG, Gupta R, Jovin TG, et al. Predictors and clinical rel-
evance of hemorrhagic transformation after endovascular therapy for
anterior circulation large vessel occlusion strokes: a multicenter retro-
spective analysis of 1122 patients. J Neurointerv Surg. 2015;7(1):16-21.
(Retrospective analysis; 1122 patients)
55. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at
6 to 16 hours with selection by perfusion imaging. N Engl J Med.
2018;378(8):708-718. (Multicenter randomized open-label trial with
blinded outcome assessment; 182 patients)
56. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis
for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611-
622. (Randomized controlled trial; 503 patients)
57. Huang X, Cheripelli BK, Lloyd SM, et al. Alteplase versus tenecteplase
for thrombolysis after ischaemic stroke (ATTEST): a phase 2, ran-
domised, open-label, blinded endpoint study. Lancet Neurol.
2015;14(4):368-376. (Randomized open-label blinded endpoint
study; 104 patients)
58. Parsons M, Spratt N, Bivard A, et al. A randomized trial of te-
necteplase versus alteplase for acute ischemic stroke. N Engl J Med.
2012;366(12):1099-1107. (Randomized phase 2 trial; 75 patients)
59. Haley EC, Jr, Thompson JL, Grotta JC, et al. Phase IIB/III trial of te-
necteplase in acute ischemic stroke: results of a prematurely terminat-
ed randomized clinical trial. Stroke. 2010;41(4):707-711. (Randomized
double-blind controlled phase 2B/3 trial; 112 patients)
60. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase
for management of acute ischaemic stroke (NOR-TEST): a phase
3, randomised, open-label, blinded endpoint trial. Lancet Neurol.
2017;16(10):781-788. (Randomized open-label blinded endpoint
61. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus
alteplase before thrombectomy for ischemic stroke. N Engl J Med.
2018;378(17):1573-1582. (Randomized open-label, blinded outcome
62. No authors listed. Randomised controlled trial of streptokinase, as-
pirin, and combination of both in treatment of acute ischaemic
stroke. Multicentre Acute Stroke Trial--Italy (MAST-I) Group. Lancet.
1995;346(8989):1509-1514. (Randomized controlled trial; 662 patients)
63. Multicenter Acute Stroke Trial--Europe Study Group, Hommel M, Cor-
nu C, et al. Thrombolytic therapy with streptokinase in acute ischemic
stroke. N Engl J Med. 1996;335(3):145-150. (Randomized controlled
64. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute
ischemic stroke with relationship to time of administration: Australian
Streptokinase (ASK) Trial Study Group. JAMA. 1996;276(12):961-966.
(Randomized double-blind placebo-controlled trial; 340 patients)
65. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in
patients with acute ischaemic stroke selected by MRI perfusion-
diffusion weighted imaging or perfusion CT (DIAS-2): a prospective,
randomised, double-blind, placebo-controlled study. Lancet Neurol.
2009;8(2):141-150. (Randomized double-blind placebo-controlled
66. Hacke W, Albers G, Al-Rawi Y, et al. The Desmoteplase in Acute Isch-
emic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute
stroke thrombolysis trial with intravenous desmoteplase. Stroke.
phase 2 trial; 104 patients)
67. von Kummer R, Mori E, Truelsen T, et al. Desmoteplase 3 to 9 hours
after major artery occlusion stroke: the DIAS-4 Trial (efficacy and
safety study of desmoteplase to treat acute ischemic stroke). Stroke.
2016;47(12):2880-2887. (Randomized double-blind placebo-con-
trolled phase 3 trial; 270 patients)
68. Albers GW, von Kummer R, Truelsen T, et al. Safety and efficacy of des-
moteplase given 3-9 h after ischaemic stroke in patients with occlusion
or high-grade stenosis in major cerebral arteries (DIAS-3): a double-
blind, randomised, placebo-controlled phase 3 trial. Lancet Neurol.
phase 3 trial; 492 patients)
69. Pancioli AM, Broderick J, Brott T, et al. The combined approach to lysis
utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR
stroke trial. Stroke. 2008;39(12):3268-3276. (Randomized double-blind
dose escalation and safety study; 94 patients)
70. Nacu A, Kvistad CE, Naess H, et al. NOR-SASS (Norwegian So-
nothrombolysis in Acute Stroke Study): randomized controlled con-
trast-enhanced sonothrombolysis in an unselected acute ischemic
stroke population. Stroke. 2017;48(2):335-341. (Randomized double-
blind controlled trial; 183 patients)
CME Questions, Part 1
Take This Test Online!
Current subscribers receive CME credit absolutely free by answering

the CME questions for both parts, 1 and 2. The CME questions for Part
2 begin on page 43. This supplement includes 4 AMA PRA Category 1
CreditsTM. To receive your free CME credits for this issue, visit
www.ebmedicine.net/EX0619.
1.1 A 45-year-old man without past medical history presents with

severe aphasia and right-side weakness, onset time unknown.
National Institutes of Health Stroke Scale (NIHSS) score is 18. A
noncontrast head CT shows left middle cerebral artery (MCA) hy-
perdensity. What is the best next step?
a. Administer IV thrombolysis (IVT), since the patient is young.
b. Obtain an electroencephalogram.
c. IVT is contraindicated.
d. Perform CT angiography and CT perfusion, and consider IVT.
1.2 A 58-year-old man with past medical history of atrial fibrillation,

on daily warfarin, presents with left MCA syndrome that started
2 hours ago. Noncontrast head CT is unremarkable. What is the
best next step?
a. If INR ≤ 1.7, administer IV rt-PA.
b. IV rt-PA is contraindicated due to warfarin use.
c. If INR < 2.0, administer IV rt-PA.
d. If pTT is normal, administer IV rt-PA.
1.3 An 85-year-old woman with hypertension and hyperlipidemia

and left temporal hemorrhage in the past, presents with left-side
ataxia and weakness. Noncontrast head CT revealed small-size,
old bilateral strokes, but no acute pathology. What is the best
next step?
a. Obtain MRI of the brain.
b. Administer IV rt-PA 0.9 mg/kg.
c. Administer IV rt-PA 0.6 mg/kg.
d. Obtain CT angiography.
1.4 A 48-year-old woman with a prosthetic mitral valve presents
with fever, acute-onset right MCA syndrome for the last hour, and
cardiac murmur. Stroke code was called. Noncontrast CT head is
unremarkable. What is the best next step?
a. Administer IV rt-PA.
b. Obtain an electroencephalogram.
c. Perform lumbar puncture.
d. Order blood cultures, echocardiogram, and IV antibiotics.
1.5 A 55-year-old woman with known severe hypertension presents

with left MCA stroke within 3 hours from onset. Noncontrast head
CT is unremarkable. Systolic blood pressure (SBP) is 200 mm Hg.
What is the best next step?
a. Lower the SBP < 185 mm Hg and then consider IV rt-PA.
b. Give IV rt-PA right away, as time is brain.
c. Wait for CT angiography results.
d. Lower SBP < 165 mm Hg and then consider IV rt-PA.
Answer Key begins on page 46.
Part 2:
Endovascular Therapy
in Acute Ischemic
Stroke
AUTHORS
Mohsen Nouri, MD
Clinical Fellow of Endovascular Surgical Neuroradiology, Cerebrovascular Center,
Icahn School of Medicine at Mount Sinai, New York, NY
Pramath Kakodkar, MD
School of Medicine, National University of Ireland, Galway, Ireland
Hazem Shoirah, MD
Assistant Professor, Department of Neurosurgery, Icahn School of Medicine at
Mount Sinai, New York, NY
The Evolution of Medical and Endovascular Management of

Acute Ischemic Stroke
The studies that heralded the 1996 United States Food and Drug Adminis-
tration (FDA) approval of recombinant tissue plasminogen activator (rt-PA;
also known as alteplase) as the first medication for the treatment of acute
ischemic stroke set the stage for a new age of hyperacute stroke interven-
tions.1,2 In spite of the impact of intravenous (IV) rt-PA on the treatment of
acute ischemic stroke, some patients do not respond to the drug, par-
ticularly those patients who harbor an embolus lodged in a vessel that is
too large for the medication to lyse. There are studies showing that large-
vessel occlusions may respond to rt-PA in only some patients.1 In addition,
many patients are ineligible for IV rt-PA because treatment requires that
the patient receive the drug within 3 hours from the time of stroke onset
(4.5 hours in selected patients).2 Many patients are excluded from IV rt-PA
due to medical and surgical exclusion criteria.
The first trial of intra-arterial thrombolytic treatment was published in 1998

when the PROACT I study demonstrated the safety and efficacy of intra-
arterial (IA) prourokinase (pro-UK) in the treatment of patients with a large-
vessel occlusion of the middle cerebral artery (MCA).3 In this study, patients
were randomized to treatment with either a continuous infusion of IV hepa-
rin alone or heparin plus treatment with pro-UK, infused intra-arterially via
an endovascularly placed catheter. Patients in the pro-UK arm were found to
have higher recanalization rates compared with the control group, although
in patients treated with pro-UK, there was a non–statistically significant trend
toward a higher rate of intracerebral hemorrhage.
One of the earliest mechanical devices aimed at endovascular lysis of a

cerebrovascular clot was the EKOS MicroLysis® Micro-infusion (EKOS cor-
poration, Bothell, WA), which implemented a combination of mechanical
disruption and ultrasound for clot lysis.4 Another early device, the MERCI®
Retriever (Concentric Medical, CA) is a corkscrew-like device that engages
and retrieves the target clot.5 Penumbra (Penumbra, Inc., Alameda, CA) in-
troduced its first separator aspiration-based systems in 2007, which break
down the clot locally by mechanical disruption, then aspirate the frag-
ments via large-bore catheters.6 Each of these devices has been evaluated
in single-arm studies that have shown modest recanalization rates and
better functional outcomes compared to their nonrandomized matched
patients from the National Institute of Neurological Disorders and Stroke
(NINDS) rt-PA study.4,5,7,8
In 2013, IMS-III, SYNTHESIS, and MR RESCUE, 3 long-anticipated random-

ized controlled trials of endovascular management of stroke, were pub-
lished and demonstrated no additional benefit of endovascular therapy
(EVT) over medical treatment.9-11 In hindsight, there were many factors that
contributed to the failure of these studies to demonstrate a benefit for
EVT in the treatment of large-vessel occlusion. By the time of the conclu-
sion of IMS-III, the majority of the devices used in it were considered obso-
lete by practice standards of the day.
Retrievable stents, also known as stent-retrievers or stentrievers (eg, Soli-

taire [ev3/Covidien, Irvine, CA, USA] and Trevo [Stryker, Kalamazoo, MI,
USA]) and large-bore aspiration catheters (eg, Penumbra aspiration system
[Penumbra, Inc., Alameda, CA]) have demonstrated superiority in achiev-
ing vessel recanalization in head-to-head trials with older devices such as
EKOS and the Penumbra separator.12 Broussalis et al demonstrated that
the rates of successful recanalization in patients treated with stentrievers
was 82% compared with only 62% in patients treated with MERCI retriev-
ers (P = .016).12 A major critique of the IMS-III trial was poor patient selec-
tion, because patients were enrolled on the basis of clinical stroke severity
rather than on direct confirmation of the presence of a large-vessel occlu-
sion using noninvasive computed tomographic (CT) angiography imaging.
The most critical lesson learned from those trials is that clinical benefit is
highly dependent on timely recanalization. In the IMS-I and IMS-II popula-
tions, every 30-minute delay in recanalization was associated with a 10%
decrease in the chance of functional independence (defined as a modified
Rankin scale [mRS] score of ≤ 2).
MDCalc calculator for Modified Rankin Scale for Neurologic Disability:
Current Evidence for Endovascular Thrombectomy

In the last few years, a series of studies have demonstrated the effective-
ness of EVT. The MR CLEAN trial implemented a rigorous screening meth-
odology for patient selection in which only patients demonstrating an oc-
clusion on baseline CT angiography would be candidates for enrollment.13
MR CLEAN enrolled 500 patients and found that 32.6% of patients treated
with EVT were functionally independent at 90 days, compared to only
19.1% of patients treated medically (adjusted odds ratio [OR], 2.16 ; 95%
confidence interval [CI], 1.39-3.38). There were 5 other active trials of EVT
at the time of publication of MR CLEAN, all of which were stopped early,
as the obvious benefit of EVT became clear in each trial. Despite stopping
enrollment early, 4 of 5 trials, SWIFT PRIME,14 REVASCAT,15 EXTEND-IA,16
and ESCAPE,17 still met their primary endpoints, demonstrating over-
whelming benefit; while THERAPY did not meet its endpoint.18 THRACE
was published a year later, and had equally positive results.19 The inclusion
criteria varied slightly between each of the studies but, collectively, they
were able to give a broad base of indications for EVT in acute ischemic
stroke, which will be explored in following sections.
A pooled meta-analysis of 1287 patients from 5 studies of EVT, known

as the HERMES study, demonstrated that, compared to standard medi-
cal therapy, patients treated with EVT were more likely to have a good
neurological outcome at 90 days (adjusted OR, 2.49; 95% CI, 1.76-3.53;
P < .0001).20 This benefit was preserved across different subgroups (ie,
age, time from last known well, ischemic burden, stroke severity, occlusion
location, rt-PA status). The number needed to treat to achieve a reduction
of at least 1 level on the mRS was 2.6. This has shown thrombectomy to
be one of the most effective treatments for stroke ever described in evi-
dence-based literature. The American Heart Association (AHA) was quick
to update its guidelines, issuing a brief update in June 2015 endorsing
EVT for acute ischemic stroke, albeit for narrowly selected patients.21
Following seminal trials of EVT introducing it as the primary modality for

treating large-vessel occlusion, subsequent trials have been geared toward
expanding the indication for intervention to patients who were previously
excluded. For example, the DEFUSE 3 and DAWN trials demonstrated
that, in selected patients with good collateral circulation, thrombectomy
can be performed beyond the standard 6 hours from the time the patient
was last known well: up to 16 hours after in DEFUSE 3, and 24 hours later
in DAWN.22,23 In both of these studies, CT perfusion imaging was used to
delineate the area of salvageable brain tissue at risk, from the irreversibly
infarcted tissue at the core of the stroke. To qualify for enrollment in these
studies of late thrombectomy, patients had to demonstrate a relatively large
volume of potentially viable tissue compared to the ischemic core. Collec-
tively, the 2 studies showed that 47% of patients treated with EVT achieved
functional independence at 90 days compared with only 15% of medically
treated patients.24 In light of such a significant expansion in the time window
for treatment, the AHA updated its guidelines in 2018.25
As more devices are being added to the armamentarium of stroke interven-

tions, such procedures are becoming safer and more effective, while allow-
ing access to previously inaccessible locations of the vasculature. As such,
more safety and feasibility data are being reported in patients who did not
meet enrollment criteria for those seminal randomized controlled trials,
including patients with minor stroke syndromes,26 large ischemic cores,27 or
more distal occlusions.28 These patients could potentially be future candi-
dates for intervention.
Patient Selection
Proper patient selection is key to achieving favorable neurological out-
comes. While the data from the trials of EVT provide guidance for patient
selection, the decision to intervene should be tailored individually to each
patient. The multifactorial criteria of intervention require expertise that is
often available in comprehensive centers of excellence, with input from
multidisciplinary teams of neurologists, radiologists, and neurointerven-
tionists. Communication must be streamlined and efficient, informed by
clinical and radiographic data acquired through a highly efficient, neu-
rotrauma-like algorithm of assessment. The following factors play a role in
such decision-making: (1) age, (2) duration of symptoms, (3) stroke sever-
ity, (4) premorbid functional status, and (5) occlusion location.
Age
The median age of patients treated in the HERMES meta-analysis was 68
years.20 Generally, the studies in the meta-analysis had enrolled patients
between ages 18 and 80 years, with a few of them having no upper limit
on age.13,17 While older patients have worse outcomes, in general, com-
pared with younger patients,29 advanced age should by no means be con-
sidered a contraindication to thrombectomy. In fact, older patients have
a higher treatment benefit,20,30 likely owing to the poor natural history of
large-vessel occlusion in the elderly, which carries a high mortality.31
On the other end of the spectrum, the incidence of large-vessel occlusion

in pediatric patients is exceedingly low, posing diagnostic and treatment
challenges to this vulnerable population. Multiple case series have dem-
onstrated that pediatric patients who are treated with EVT have outcomes
similar to those seen in adults, especially in current practice with newer
technology.32 Rapid diagnosis of stroke and identification of large-vessel
occlusion in this population is an ongoing challenge. Increased vigilance
should be maintained in patients with high-risk premorbid conditions,
such as congenital cardiac disease, hypercoagulable syndromes, and re-
cent trauma with possibility of vascular injury.
Duration of Symptoms
All patients presenting with a large-vessel occlusion and disabling symp-
toms within 6 hours from last known well should be considered for EVT,
though multiple factors can cause delay in presentation beyond the
6-hour window. Up to one-third of patients present with wake-up symp-
toms or the onset of stroke may be unwitnessed. Patients with a known
and witnessed onset of stroke may arrive to the thrombectomy-capable
centers outside of the standard 6-hour window of intervention, especially
if they initially presented to a center that is not thrombectomy-capable.
Such patients should still be triaged and evaluated emergently, with the
additional use of perfusion-based imaging to supplement the routinely
obtained noncontrast head CT and CT angiography, in order to identify
patients with good collateral vessels and a viable penumbra who may still
be candidates for EVT, based on the criteria of the DAWN and DEFUSE-3
trials. (See Figure 1, page 28.)
Stroke Severity
To select patients with strokes severe enough to warrant intervention,
most of the trials that have evaluated EVT have set minimum values for the
NIHSS (National Institutes of Health Stroke Scale) score.13,16 In the
HERMES analysis, only 14% of patients had an NIHSS score < 10.20 With
such a small sample, there was no statistically significant benefit for EVT in
those populations.
MDCalc calculator for NIH Stroke Scale/Score (NIHSS):

www.mdcalc.com/nih-stroke-scale-score-nihss
Treatment of patients with an NIHSS score ≥ 6 is recommended. Also, if pa-

tients present with lower NIHSS score but disabling symptoms (eg, aphasia),
they should also be also considered for EVT. Some patients who present
with large-vessel occlusion and a minor stroke syndrome will have a good
outcome, but up to 25% will progress to have early neurological deteriora-
tion that requires emergent rescue therapy.33,34 Early neurological deteriora-
tion is often the result of failure of the previously robust collateral vessels to
sustain the vascular demands of the ischemic penumbra. The outcome of
rescue EVT is worse than outcome of patients treated pre-emptively.35 More
data are necessary to assess patients and identify those at highest risk for
early neurological deterioration.
Figure 1. Application of CT Perfusion in Management

of a Patient With Acute Stroke
www.ebmedicine.net
A 65-year-old woman with no past medical history presented with wake-up symptoms of aphasia
and right hemiplegia; NIHSS score, 16. CT perfusion performed 17 hours from last known
well revealed a large penumbra, evidenced by the prolonged mean transit time and relatively
preserved cerebral blood volume (A). Angiographic run demonstrated lack of flow in the cervical
ICA, owing to the presence of a downstream occlusion in the ICA terminus (B). Stentriever
thrombectomy was performed, achieving TICI-2B recanalization (C). The retrieved clot is shown in
panel D. Diffusion-weighted imaging sequence of her follow-up MRI revealed minimal ischemic
injury (E). 24 hours after her procedure, her NIHSS score was 6.
Abbreviations: CT, computed tomography; ICA, internal carotid artery; MRI, magnetic resonance
imaging; NIHSS, National Institutes of Health Stroke Scale; TICI, thrombolysis in cerebral
infarction.
Premorbid Functional Status
The Rankin scale was introduced in 1957 as a means of assessing disability
caused by stroke.36 Its modification in 1988 aimed to stratify levels of disability
according to dependence of patients on others for accomplishing daily activi-
ties.37 The modified Rankin Scale (mRS) starts at 0 (no stroke symptoms at all)
and goes to 6 (patient death). The goal of most hyperacute stroke interventions
is to restore the patient’s ability to maintain independence (reflected in an mRS
score of ≤ 2). To achieve that, most trials required that the patient’s premorbid
condition be functionally independent. As a result, most trials have excluded
patients who are not independent at baseline, and the current AHA recom-
mendations concur. In practice, many patients who do not meet the criterion
of premorbid functional independence still have a sufficient quality of life that
would be impacted severely by the disability caused by their new stroke, justify-
ing an attempt at EVT. The decision to treat patients whose mRS score is > 2
should be tailored, based on the patient’s values, quality of life, and the cause
and prognosis of their premorbid disability.
Occlusion Location
Occlusions of the intracranial internal carotid artery (ICA), the M1 and M2
segments of the middle cerebral artery (MCA), have been shown to have
the best benefit from EVT, based on data from the HERMES meta-analysis.
Current advances in technology have provided interventionists with cathe-
ters that are able to reach farther into the vasculature, allowing for interven-
tions on occlusions in the more distal M3/M4- or A3/A4-level branches. (See
Figure 2.) While randomized controlled trials evaluating this indication are
still lacking, several case series suggest their safety and feasibility.28
Figure 2. Distal Anterior Cerebral Artery Thrombectomy
www.ebmedicine.net
Acute stroke patient with right internal carotid artery terminus occlusion (A). After recanalization
of the terminal internal carotid artery, occlusion of the anterior cerebral artery A3-A4 segments
junction is seen (B). Aspiration thrombectomy through a 3Max™ aspiration catheter (Penumbra,
Inc., Alameda, CA) resulted in thrombolysis in cerebral infarction (TICI)-2B final recanalization (C).
Occlusions of the vertebrobasilar system, including the basilar artery,
were generally excluded in trials, given the extremely poor natural his-
tory of those lesions if left untreated. Those occlusions will still be treated
by most interventionists if the vascular territory of the affected vessel is
expected to be viable and the patient is sufficiently symptomatic. A Euro-
pean randomized controlled trial evaluating patients with vertebrobasilar
occlusion is actively enrolling patients.38
Tandem Occlusion
Tandem occlusion occurs when there are simultaneous occlusions in both the
cervical portion of the ICA as well as an intracranial arterial occlusion, com-
monly the terminal ICA or proximal MCA. Patients with tandem lesions have
a poorer prognosis compared to patients with a single lesion.39 Acute carotid
revascularization still carries a high risk of complication and hemorrhagic
transformation of the ischemic core. The hemorrhagic risk is possibly exac-
erbated by the use of systemic thrombolysis with rt-PA and the subsequent
use of intraprocedural IV antithrombotic agents (such as glycoprotein IIb/IIIa
inhibitors) needed during acute stent placement.40 Abciximab carries a higher
risk of hemorrhagic complications compared to eptifibatide, although both
still carry substantial risk. The use of newer adenosine diphosphate (ADP)-
inhibiting IV agents, such as cangrelor, has been found in the cardiac literature
to have a significantly lower risk of hemorrhagic complications and is likely to
play a role in neurovascular settings.41
In patients with tandem occlusion, it is reasonable to consider performing

a thrombectomy, deferring the carotid revascularization, especially in pa-
tients with large ischemic cores on their presurgical evaluation. However,
when the ischemic core is known to be small, acute carotid revasculariza-
tion is often performed concomitantly, using the same endovascular setup
used for intracranial thrombectomy.
Two different approaches for treatment have been described. In the prox-
imal-to-distal approach, when necessary, the cervical lesion is treated first
by stenting, followed by poststenting balloon angioplasty.42 The advan-
tage to this approach is the ease of subsequent access to the intracra-
nial vasculature. In the distal-to-proximal approach, the cervical lesion is
crossed, but not treated, and thrombectomy of the large-vessel occlusion
is performed;43 the cervical lesion is then treated upon successful recanali-
zation. The advantage to this approach is a more rapid restoration of flow
in the ischemic penumbra.
Imaging
Computed Tomography
All patients should be evaluated preprocedure for their ischemic burden, with
head and neck CT scan and CT angiogram. (See Figure 3.) In anterior circula-
tion syndromes and occlusions, MRI is rarely needed, if ever. The burden of
ischemic core is assessed with the Alberta Stroke Program early CT score (AS-
PECTS). This score ranges from 0-10, in which higher values suggest smaller
core. Higher ASPECTS correlate with better outcomes after recanalization,
and patients with low ASPECTS have a higher risk of hemorrhagic transforma-
tion.44 Generally, an ASPECTS of ≥ 5 is considered “treatable.” The role of
EVT for patients with ASPECTS < 5 is not yet clear, as the HERMES meta-anal-
ysis did not show a statistically significant benefit for those patients.
MDCalc calculator for Alberta Program Early CT Score (ASPECTS):

Figure 3. Evaluation of Ischemic Changes on Brain CT Scan
www.ebmedicine.net
Ten components of the Alberta Stroke Program early CT score (ASPECTS) at ganglionic (A) and
supraganglionic (B) levels. While score 10 represents a normal CT scan, 1 point is deducted for
ischemic evidence, such as loss of gray-white matter differentiation, edema, or sulcal effacement
in each component. BG: basal ganglia; C: caudate nucleus; I: insula ribbon; IC: internal capsule;
M1: frontal cortex; M2: temporal cortex lateral to insula; M3: posterior temporal cortex; M4-M6:
anterior, middle, and posterior cortex at supraganglionic level.
Computed Tomographic Angiography
Baseline noninvasive angiographic assessment with CT angiography of the
head and neck have now become an integral part of hyperacute stroke tri-
age to allow for rapid identification of large-vessel occlusion. All patients
who present to the emergency department with consideration of an acute
ischemic stroke should undergo CT angiography of the head and neck in
addition to noncontrast head imaging. EVT planning depends on the cervi-
cal vasculature anatomy. For example, the presence of stenosis or occlusion
of the cervical ICA may necessitate planning for carotid revascularization,
which utilizes different devices. The presence of severe tortuosity may also
change the choice of catheters a provider would use for vascular access.
Computed Tomographic Perfusion

CT perfusion scans provide us with different maps that include information
on blood flow, timing, and blood volume in brain tissue. After analyzing
these data, the volume and location of already infarcted tissue and areas in
danger (ie, the penumbra) can be identified and mapped, which can help
with selecting patients for EVT. The primary objective of EVT is to salvage
ischemic tissue in the penumbra of the stroke that has not yet infarcted. The
region of established infarction is usually defined by the hypodense area
on noncontrast CT or the region of reduced cerebral flow and volume on
the perfusion scan. The mismatch between the area of infarction and the
penumbra is defined as reduced blood flow but normal or increased blood
volume. Perfusion imaging allows for a direct comparison between the isch-
emic core and the penumbra through complex estimations that are based
on cerebral blood flow (CBF), cerebral blood volume (CBV), the mean transit
time (MTT), and the time to peak (TTP). The profile of alteration in those val-
ues differs between tissues that are fully infarcted and the penumbra. CBF
is reduced in infarcted and penumbral regions, while CBV stays about the
same level or even increased in penumbral area, and reduces only in infarc-
tions. Comparison of CBF and CBV maps help with estimation of penumbra
versus infarction core. MTT and TTP are universally increased in ischemic
tissues, either infarcted or penumbral. Those specific profiles can be used to
calculate the estimated volume of infarction and numerically compare it with
the volume of the penumbra. (See Figure 4, page 33.)
Software that implements artificial intelligence and complex algorithms,

such as RAPID (iSchemaView, Menlo Park, CA), are able to make those
calculations and expeditiously provide physicians with the numeric values
that can help guide further treatment. Perfusion imaging was heavily relied
on in the DAWN and DEFUSE 3 trials that evaluated an extended time
window for EVT. CT perfusion continues to play a strong role in patient
selection among those presenting with stroke 6 to 24 hours after symptom
onset, but this role may come under further investigation in the future, as
providers become more experienced with assessing the penumbra based
on a clinical-radiographic mismatch.
Magnetic Resonance Imaging

The role of MRI in hyperacute stroke triage is very limited, since it takes more
time than CT imaging. In the current model of stroke triage, even a few min-
utes of additional imaging time may have a longstanding impact on outcome
and recovery. CT imaging provides sufficient data to guide hyperacute man-
agement and was the primary modality of assessment in all of the endovas-
cular thrombectomy trials. Occasionally, MRI may be necessary to assess
ischemic burden in vertebrobasilar occlusions, given the poor capacity of CT
imaging to assess the contents of the posterior fossa, particularly the brain
stem. In such situations, hyperacute MRI protocols that prioritize diffusion-
weighted imaging and gradient echo sequences should be pursued.
Figure 4. CT Perfusion Modalities and Their Interpretation in Acute Stroke
www.ebmedicine.net
CT perfusion images. Processed image by Olea Sphere® software shows a mismatch between
penumbra (yellow) and infarction core (red) (A). Cerebral blood flow is severely reduced in a region
compatible with stroke core (B). Time to peak is increased in the whole ischemic region as a
sensitive indicator (C) while cerebral blood volume is reduced in the core and mildly increased in
regions compatible with penumbra (D).
rt-PA Status
The practice of assessing the effect of rt-PA before making a decision
for thrombectomy, which was evaluated in the IMS-III trial, has been
abandoned entirely. Any time spent anticipating the outcome of rt-PA is
time for ongoing ischemic injury. Additionally, EVT could be extended
to patients who are ineligible for rt-PA. Furthermore, given the low rates
of recanalization of large-vessel occlusion with rt-PA, there is ongoing
debate regarding optimal prearrival systems of care organization. There
is a general direction towards bypassing hospitals that are not thrombec-
tomy capable for patients who have a likelihood of large-vessel occlu-
sion, based on field assessment tools.
Technique
Vascular Access
The cerebrovascular space could essentially be reached via any arterial
access. Transfemoral approach is the conventional access, as it provides
a relatively simple approach to the aortic arch and all the great vessels.
When transfemoral access is hindered by aortofemoral disease or when
the origin of the target vessel off the arch is challenging, other ap-
proaches could be attempted. Trans-radial or trans-brachial approaches
may be particularly helpful for access of the vertebral artery in cases of
vertebrobasilar occlusions. (See Figure 5, page 35.) Trans-carotid ap-
proaches can overcome any number of proximal anatomical or patho-
logical vascular obstacles with no safety concerns.
Catheter System Setup

One of the key factors of successful interventions is the stability of the en-
dovascular devices in their target vasculature. Larger catheters with thicker
walls offer significant support within the vessels. However, this comes at
the expense of navigability, because such large catheters (also known
as guide or support catheters) cannot be navigated into distal vessels
and are often left in the cervical vasculature. On the other hand, smaller
catheters with slimmer walls are much easier to navigate into more distal
vascular branches, but will have a risk of instability and prolapse in more
proximal, larger vessels. To achieve the balance of stability and navigabili-
ty, a system of 2 (biaxial), 3 (triaxial) or even 4 (quadraxial) catheters can be
implemented by telescoping smaller, more navigable catheters through
sequentially larger, more supportive catheters. Most stroke interventions
will be performed via a triaxial system, although some providers prefer us-
ing biaxial or quadraxial systems. The location of the occlusion, the size of
the target vessel, and the degree of tortuosity will often dictate the device
setup of each case. (See Figure 6, page 36.)
Figure 5. Trans-Radial Approach for Acute Thrombectomy
www.ebmedicine.net
A 61-year-old man with multiple comorbidities was found unresponsive. Head CT angiography
revealed a basilar occlusion. CT angiography of the chest revealed a type B aortic dissection
extending from the origin of the left subclavian artery to the aortic bifurcation (A). A right
trans-radial approach was pursued via a 6-French sheath (B). Baseline angiographic run of the
right vertebral artery revealed a mid-to-distal basilar occlusion (C). A single-pass aspiration
thrombectomy through a Penumbra 041 reperfusion catheter resulted in TICI-2C recanalization (D).
Figure 6. Challenging Arterial Anatomy for Thrombectomy
in a Patient With Acute Stroke
www.ebmedicine.net
A tortuous anatomy of the aortic arch and cervical vessels (A and B) in a patient with right
middle cerebral artery occlusion (C). Blue, red, and yellow arrows refer to the guiding catheter,
intermediate catheter, and microcatheter, respectively. Black arrow points to a buddy wire inside
the microcatheter to increase distal stability and support to help with advancing the guiding
catheter. Final recanalization TICI-2B was achieved (D).
Balloon Guide Catheters

Balloon guide catheters (BGC) are guide catheters used for support of the
stroke intervention platform. In addition, they have an inflatable balloon
near the tip that is intended to be inflated during clot manipulation and
retrieval, to create arrest of anterograde flow. This is often is coupled with
aspiration to result in true reversal of flow. While there is evidence that this
technique may result in decreased risk of distal emboli,45 there is no conclu-
sive evidence for the superiority of BGCs over regular guide catheters. The
stiffness of the BGC and its preparation time may limit its widespread use.
Thrombectomy Devices
Perhaps one of the most important advances in thrombectomy technology
is the thrombectomy device itself. Two main modalities of thrombectomy
are currently practiced widely. One involves the advancement of a retriev-
able nitinol stent, often called a stentriever, through a microcatheter that
has been used to traverse the clot. The microcatheter would then be with-
drawn to unsheathe and deploy the stentrievers, engaging the clot for 3 to
5 minutes before being retrieved into a more proximal catheter of a larger
caliber (ie, an intermediate or a guide catheter). The second technique in-
volves bringing a large-bore catheter to the face of the clot and attempt-
ing aspiration of the clot en bloc. Aspiration can be used as the primary
modality of thrombectomy, in which case it is dubbed ADAPT (a direct
aspiration first-pass technique), or can be an adjuvant for a stentriever
thrombectomy to increase the chances of a successful recanalization and
reduce the risk of embolization of any clot fragmentation debris. Head-to-
head trials between the 2 techniques have demonstrated that both tech-
niques are equally effective at vessel recanalization, with no difference in
long-term functional outcome of treated patients.46,47
Future Directions and Systems of Care

EVT has caused a paradigm shift in the field of hyperacute stroke manage-
ment. Systems of care have been reshaped by the ongoing evidence re-
garding the safety and effectiveness of this treatment and the expanding
population of eligible patients. New designations at the state level have
been created to reflect the capacity of stroke centers to perform thrombec-
tomy and care for patients with large-vessel occlusion after the procedure.
Field triage tools aimed at identifying large-vessel occlusion are being
implemented in large emergency medical services (EMS) networks. These
examination tools are meant to help EMS providers identify patients at
highest risk of harboring a large-vessel occlusion amenable to EVT, with the
idea that such patients may benefit from bypassing stroke centers capable
of administering only rt-PA and proceeding directly to EVT-capable hospi-
tals. States are changing legislation to enable EMS providers to take pa-
tients with suspected large-vessel occlusion to properly designated—rather
than the closest—centers. In-hospital assessment protocols are prioritizing
large-vessel occlusion identification and following models of trauma care
in patient assessment. Rapid advancements in technology are bringing
forth new devices, techniques, and platforms of treatment that are making
previously impossible outcomes a daily reality. Expanding the indication of
thrombectomy to previously excluded patients is ongoing and will continue
to allow more patients to benefit from this treatment.
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Evidence-based medicine requires a critical appraisal of the literature
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and blinded trial should carry more weight than a case report.
To help the reader judge the strength of each reference, pertinent infor-
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spective; 139 patients)
46. Gory B, Lapergue B, Blanc R, et al. Contact aspiration versus stent
retriever in patients with acute ischemic stroke with M2 occlusion in the
ASTER randomized trial (contact aspiration versus stent retriever for
successful revascularization). Stroke. 2018;49(2):461-464. (Prospective
randomized controlled trial; 79 patients)
47. Turk AS, Siddiqui AH, Mocco J. A comparison of direct aspiration ver-
sus stent retriever as a first approach (‘COMPASS’): protocol. J Neuro-
interv Surg. 2018;10(10):953-957. (Literature review)
CME Questions, Part 2
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www.ebmedicine.net/EX0619.
2.1 A 65-year-old man with history of diabetes and hypertension pres-

ents to a community hospital with aphasia and right-sided hemiple-
gia, for a total NIHSS score of 12. CT scan did not reveal bleeding
or major ischemic changes, and the patient received IV rt-PA. CT
angiography performed immediately after IV rt-PA was started
showed a left MCA-M2 occlusion, with good collateral arteries. The
patient is transferred to your hospital for possible endovascular
intervention. Upon arrival, 3 hours have passed since the patient
was last seen normal, and his clinical examination has improved to
NIHSS 3, for mild dysarthria and right upper extremity drift. What
would be the most appropriate next step for this patient?
a. Perform emergent thrombectomy for a large-vessel occlusion and
high chance of clinical deterioration
b. Repeat CT angiography to evaluate the status of the occlusion
c. Load the patient with aspirin or clopidogrel and admit to ICU for
neuromonitoring
d. Control systolic blood pressure (SBP) to < 120 mm Hg to prevent
bleeding and deterioration
2.2 A 94-year-old woman with history of lung cancer, diabetes, and dyslip-
idemia was found unresponsive by her daughter at 7:00 am. She was
at her baseline mental status when her daughter spoke to her yes-
terday evening 6:00 pm. Her baseline mRS was 2 and she was using
a cane for chronic arthritis. Her current examination revealed NIHSS
score of 23. Brain CT scan shows ischemia in the territory of the left
MCA with ASPECTS 7, and CT angiography shows left M1 occlusion
with good distal collaterals. Which of the following factors is NOT
important in your decision-making for intervention in this patient?
a. NIHSS score
b. Duration of symptoms
c. Baseline functional status
d. Advanced age
e. Prognosis of the underlying cancer
2.3 For the patient presented in question 2, a decision was made to
obtain brain CT perfusion scan. Which of the following statements
about this study is CORRECT?
a. Increased mean transit time is highly specific for penumbra (vs
infarction core)
b. Increased cerebral blood volume may indicate the penumbra zone
c. Time to peak is not sensitive for detecting penumbra
d. Due to autoregulatory mechanisms and compensations in the first
few hours after stroke, CT perfusion is not useful beyond 6 hours
from the onset of symptoms
2.4 73-year-old man with history of diabetes and atrial fibrillation who
stopped taking his warfarin 2 weeks ago, developed a witnessed
right-sided hemiplegia and aphasia 1 hour prior to presentation.
His baseline mRS was 0, and his NIHSS score at presentation was
23. CT scan showed no evidence of ischemia and rt-PA was given
before performing CT angiography, which showed a left MCA-M1
occlusion with good collaterals. Right after CT angiography, he
showed some improvement in his physical examination (NIHSS
score 16). Which of the following is the most appropriate next
step?
a. Observe the patient in the neuro ICU, considering improvement in
symptoms following rt-PA injection
b. Perform mechanical thrombectomy, considering severity of the
symptoms
c. Perform orthostatic challenge test, to evaluate the efficacy of
collaterals
d. Perform CT perfusion to evaluate stroke core and penumbra and
their mismatch
2.5 A 72-year-old woman with history of hypertension presents to the
ED with witnessed acute-onset left-sided hemiplegia and dysar-
thria (NIHSS score at presentation, 14). Her baseline mRS was
2 from a prior stroke 3 years ago. She had 2 episodes of similar
symptoms in recent months and was diagnosed with right cervi-
cal ICA plaque with 90% stenosis, but refused any surgical or
interventional treatment and was noncompliant for antiplatelet
medications. Her CT angiogram revealed complete occlusion of
the right cervical ICA with reconstitution of the intracranial ICA
through the anterior communicating artery (from the left ICA).
Right ACA is filling with contrast, but there is a cutoff at dis-
tal right MCA M1 segment. CT scan did not show hemorrhagic
changes, and ASPECTS was 9. The patient received rt-PA. Consid-
ering tandem lesions in this patient, which of the following state-
ments is INCORRECT?
a. There is strong evidence in favor of proximal recanalization as the
first intervention in tandem lesions.
b. Distal-to-proximal recanalization approach results in more-rapid
restoration of flow in the ischemic tissues.
c. Proximal-to-distal recanalization approach facilitates access to the
intracranial vasculature
d. Patients with tandem lesions have a poorer prognosis compared
with patients with a single lesion.
Answer Key begins on page 46.
Answer Key, Part 1: Current Advances in Thrombolysis
1.1 Answer: C. IV thrombolysis is contraindicated in case of unknown
clear onset or last usual state. Some studies support administration of IVT
in case of perfusion/ischemia mismatch; however, no large randomized
controlled trials have been conducted, and it is not considered standard
of care. Seizures cannot be ruled out; however, the hyperdense MCA in
noncontrast head CT implies MCA occlusion. The patient could eventually
be a candidate for mechanical thrombectomy if perfusion/ischemia mis-
match in CT perfusion is present.
1.2 Answer: A. In patients who are taking warfarin, IVT is considered safe
only if INR ≤ 1.7.
1.3 Answer: D. History of intracerebral hemorrhage is a contraindication

for IVT administration. In this case, CT angiography should be obtained
and mechanical thrombectomy in case of vessel occlusion considered.
1.4 Answer: D. Clinical suspicion of endocarditis is a contraindication for

IVT. Lumbar puncture should be obtained in case of suspicion of central
nervous system infection. Nonetheless, endocarditis management and
workup should not be delayed.
1.5 Answer: A. Before IV rt-PA administration, SBP should be well con-

trolled < 185 mm Hg to decrease the risk of hemorrhagic transformation.
In case of higher levels, an IV antihypertensive should be administered to
reach the SBP goal before administrating rt-PA.
Answer Key, Part 2: Endovascular Therapy in Acute Ischemic

Stroke
2.1 Answer: B. In the absence of disabling symptoms (eg, severe apha-

sia), a low NIHSS score does not warrant intervention (A). Also, consider-
ing remarkable improvement of the patient after rt-PA, there is a chance
of recanalization, and performing angiography without further nonin-
vasive evaluation imposes unnecessary procedural risk for the patient.
Repeating CT angiography can direct management of this patient (B).
First, recanalization in repeat CT angiography obviates the need for
intervention at the present time. On the other hand, knowing the status
of recanalization can help with targeting blood pressure goals. Persistent
occlusion requires a high-normal to slightly hypertensive pressure (SBP
yet < 180 for rt-PA precautions) to help with collateral vessels feeding
the penumbra. In the case of confirmed recanalization, SBP is often more
tightly controlled, to reduce the chance of reperfusion hemorrhage. A
patient treated with rt-PA should not receive antiplatelet medications for
24 hours to reduce the chance of bleeding (C). (Some situations, such as
emergent intracranial or extracranial stenting may be considered excep-
tions.) As noted, blood pressure control without knowing the status of
collaterals and occlusion may result in deterioration of the patient.
2.2 Answer: D. Age is not considered a limitation for intervention, as far

as it has not resulted in functional limitation (C and D). Any underlying
disease that limits life expectancy to less than 6 months can be considered
against mechanical thrombectomy (E). Recent studies (eg, DAWN) have
showed benefit for mechanical thrombectomy in selected patients up to
24 hours from the last known normal status (B). The benefit of thrombec-
tomy is not established in patients with low NIHSS score (A).
2.3 Answer: B. Increased MTT could be seen in areas of both hypoperfusion

(penumbra) and infarction (core) (A). An increase in cerebral blood volume
is sometimes seen in the penumbra, a phenomenon called luxury perfu-
sion, and is related to compensatory vasodilatation of arteries in the region
of ischemia as an adaptive mechanism to preserve blood flow (B). It can also
be increased after reperfusion (in the setting of recanalization) and its results
should be interpreted in the context of post-rt-PA CT angiography results.
TTP in the range of 3 to 5 seconds is sensitive in detecting penumbra (C).
CT perfusion plays an important role in patient selection when presenting
with acute stroke, up to 24 hours from their last known well time (D). There
are many reports of using CT perfusion for patient selection well beyond 24
hours. Chronic infarctions may not be well-evaluated on CT perfusion.
2.4 Answer: B. In a patient with moderate to severe stroke symptoms

and a large-vessel occlusion, immediate thrombectomy should be consid-
ered and, in this case, performed (B). Observation after rt-PA for signs of
improvement is no longer recommended, as it subjects patients to ongo-
ing ischemic injury (A). Any further ancillary tests such as an orthostatic
challenge or CT perfusion in a patient who otherwise meets the standard
criteria for intervention would impose unnecessary delays (C & D).
2.5 Answer: A. In patients with tandem cervical and intracranial lesions, 2

approaches exist. Anterograde treatment of the cervical (proximal) lesion
first provides easier access for the subsequent treatment of the intracranial
(distal) occlusion (C). When crossing the proximal lesion without treatment
is feasible, treatment of the intracranial (distal) occlusion first would restore
intracranial circulation to the occluded vessel via the collaterals of the circle
of Willis faster (B). There are no studies that compare the 2 techniques, thus
no evidence that one is superior to the other (A). Patients with tandem oc-
clusions have worse prognosis and less favorable procedural outcomes (D).
List of Selected Abbreviations
ADAPT A direct aspiration first-pass technique (thrombectomy)
AHA American Heart Association
aPTT Activated prothrombin time
ASPECTS Alberta Stroke Program early CT score
BGC Balloon guide catheter
CBC Complete blood cell (count)
CBF Cerebral blood flow
CBV Cerebral blood volume
CMB Cerebral microbleed
CI Confidence interval
CT Computed tomography
CTA Computed tomographic angiography
DBP Diastolic blood pressure
END Early neurological deterioration
EVT Endovascular therapy
FDA United States Food and Drug Administration
HI Hemorrhagic infarct
ICA Internal carotid artery
IV Intravenous
IVT Intravenous thrombolysis
MCA Middle cerebral artery
MERCI Retriever Mechanical Embolus Removal in Cerebral Ischemia
MRI Magnetic resonance imaging
mRS Modified Rankin Scale
MTT Mean transit time
NIHSS National Institutes of Health Stroke Scale
NINDS National Institute of Neurological Disorders and Stroke
OR Odds ratio
PH Parenchymal hemorrhage
Pro-UK Prourokinase
rt-PA Recombinant tissue plasminogen activator
SBP Systolic blood pressure
TICI Thrombolysis in cerebral infarction
TTP Time to peak
Clinical Trial Abbreviations

(Clinical Trial Registry Number, https://ClinicalTrials.gov)
ASTER Contact Aspiration vs Stent Retriever for Successful Revas-
cularization (NCT03290885)
BASICS Basilar Artery International Cooperation Study
(NCT01717755)
DAWN Clinical Mismatch in the Triage of Wake-Up and Late Pre-
senting Strokes Undergoing Neurointervention with Trevo
(NCT02142283)
DEFUSE 3 Endovascular Therapy Following Imaging Evaluation for
Ischemic Stroke 3 (NCT02586415)
ECASS European Cooperative Acute Stroke Study (NCT00153036)
ESCAPE Endovascular Treatment for Small Core and Anterior Circu-
lation Proximal Occlusion With Emphasis on Minimizing CT
to Recanalization Times (NCT01778335)
EXTEND Extending the Time for Thrombolysis in Emergency Neuro-
logical Deficits (NCT00887328, NCT01580839)
EXTEND-IA Tenecteplase Versus Alteplase Before Endovascular Thera-
py for Ischemic Stroke (NCT02388061)
HERMES Highly Effective Reperfusion Evaluated in Multiple Endo-
vascular Stroke Trials
IMS-III Interventional Management of Stroke (NCT00359424)
IST-3 Third International Stroke Trial (http://www.isrctn.com/IS-
RCTN25765518)
MR CLEAN Multicenter Randomized Clinical Trial of Endovascular
Treatment for Acute Ischemic Stroke in the Netherlands
MR RESCUE Mechanical Retrieval and Recanalization of Stroke Clots Us-
ing Embolectomy (NCT00389467)
PROACT Prolyse in Acute Cerebral Thromboembolism
REVASCAT Endovascular Revascularization With Solitaire Device Versus
Best Medical Therapy in Anterior Circulation Stroke Within
8 Hours (NCT01692379)
SITS-MOST Safe Implementation of Thrombolysis in Stroke-Monitoring
Study (NCT02229812)
SWIFT PRIME Solitaire™ With the Intention For Thrombectomy as PRI-
Mary Endovascular Treatment (NCT01657461)
SYNTHESIS Local Versus Systemic Thrombolysis for Acute Ischemic
Stroke (NCT00540527)
THERAPY The Randomized, Concurrent Controlled Trial to Assess the
Penumbra System’s Safety and Effectiveness in the Treat-
ment of Acute Stroke (NCT01429350)
THRACE Mechanical Thrombectomy After Intravenous Alteplase
Versus Alteplase Alone After Stroke (NCT01062698)
Current Advances in Emergency Department
Care of Acute Ischemic Stroke
Part 1: Intravenous Thrombolysis
Part 2: Endovascular Therapy
June 2019
CME Information
Date of Original Release: June 15, 2019. Date of most recent review:
May 15, 2019. Termination date: June 15, 2022.
Accreditation: EB Medicine is accredited by the Accreditation Council
for Continuing Medical Education (ACCME) to provide continuing
medical education for physicians. This activity has been planned and
implemented in accordance with the accreditation requirements and
policies of the ACCME.
Credit Designation: EB Medicine designates this enduring material for a
maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim
only the credit commensurate with the extent of their participation in the
activity.
Specialty CME: Included as part of the 4 credits, this CME activity is eligible
for 4 Stroke CME credits and 2 Pharmacology CME credits, subject to your
state and institutional requirements. Note: the CME tests for both Parts 1
and 2 must be completed before CME credit will be awarded.
Needs Assessment: The need for this educational activity was
determined by a survey of medical staff, including the editorial board of
this publication; review of morbidity and mortality data from the CDC,
AHA, NCHS, and ACEP; and evaluation of prior activities for emergency
physicians.
Target Audience: This enduring material is designed for emergency
medicine physicians, physician assistants, nurse practitioners, and
residents.
Goals: Upon completion of this activity, you should be able to: (1)
demonstrate medical decision-making based on the strongest clinical
evidence; (2) cost-effectively diagnose and treat the most critical
presentations; and (3) describe the most common medicolegal pitfalls
for each topic covered.
CME Objectives: Upon completion of this activity, you should be able to:
(1) utilize the inclusion and exclusion criteria for initiation of intravenous
thrombolysis, (2) manage complications of intravenous thrombolysis
based on the current guidelines and evidence, (3) develop strategies
for managing wake-up stroke, (4) apply patient selection criteria
for initiating endovascular therapy; (5) choose appropriate imaging
modalities to guide treatment with endovascular therapy; and (6) utilize
devices and equipment for endovascular therapy.
Discussion of Investigational Information: As part of the activity, faculty
may be presenting investigational information about pharmaceutical
products that is outside Food and Drug Administration–approved
labeling. Information presented as part of this activity is intended solely
as continuing medical education and is not intended to promote off-
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Faculty Disclosure: It is the policy of EB Medicine to ensure objectivity,
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compliance with all ACCME accreditation requirements and policies,
all faculty for this CME activity were asked to complete a full disclosure
statement. The information received is as follows: Dr. Tsetsou, Dr.
Nouri, Dr. Khadokar, Dr. Shoirah, Dr. Cadena, Dr. Lay, and their related
parties report no relevant financial interest or other relationship with
the manufacturer(s) of any commercial product(s) discussed in this
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Commercial Support: This supplement to Emergency Medicine Practice
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EXTRA!

JUNE 2019 :: STROKE

Current Advances in Emergency

Part 2: Endovascular Therapy

Prior to beginning this activity, see "CME Information" on page 50.

Part 1 CME Questions..................................................................................... 21

Part 2: Endovascular Therapy in Acute Ischemic Stroke.............................. 23

Part 2 CME Questions..................................................................................... 43

Abbreviations of Clinical Trials....................................................................... 48

Alteplase (recombinant tissue plasminogen activator [rt-PA]) was the first

In 2008, the ECASS III study13 showed a statistically significant benefit in

Inclusion and Exclusion of Intravenous Thrombolysis:

Hematologic Disorders and Previous Antithrombotic Treatment

For patients who have received a therapeutic dose of low-molecular-weight

Table 2. American Heart Association Definitions of

MDCalc calculator for NIH Stroke Scale/Score (NIHSS):

Myocardial Infarction and Other Cardiological Disorders

In the absence of any evidence-based data, AHA recommends IVT at the

Intravenous Thrombolysis in Clinical Practice

MDCalc calculator for Modified Rankin Scale for Neurologic Disability:

After the stroke code is activated, it is recommended to discuss the ben-

If the patient develops new headache, vomiting, acute hypertension, or a

Intravenous Thrombolysis Complications

Clinical Implications of Hemorrhagic Transformation

MDCalc calculator for Alberta Program Early CT Score (ASPECTS):

If symptomatic hemorrhagic transformation occurs within 24 hours after

HI 1: small petechial hemorrhage (punctuate hyperdensities, red arrow)

Table 3. Management of Orolingual Angioedema

• Maintain airway; initiate endotracheal intubation, if necessary

Michel et al published a pilot CT perfusion-guided trial in 2012 that empha-

Despite these promising results pointing to the possibility of extending

New Thrombolysis Agents and Techniques

There is no proven benefit to using any other fibrinolytic agent (such as

Take This Test Online!

Current subscribers receive CME credit absolutely free by answering

1.1 A 45-year-old man without past medical history presents with

1.2 A 58-year-old man with past medical history of atrial fibrillation,

1.3 An 85-year-old woman with hypertension and hyperlipidemia

1.5 A 55-year-old woman with known severe hypertension presents

Answer Key begins on page 46.

The Evolution of Medical and Endovascular Management of

The first trial of intra-arterial thrombolytic treatment was published in 1998

One of the earliest mechanical devices aimed at endovascular lysis of a

In 2013, IMS-III, SYNTHESIS, and MR RESCUE, 3 long-anticipated random-

Retrievable stents, also known as stent-retrievers or stentrievers (eg, Soli-

Current Evidence for Endovascular Thrombectomy

A pooled meta-analysis of 1287 patients from 5 studies of EVT, known

Following seminal trials of EVT introducing it as the primary modality for

As more devices are being added to the armamentarium of stroke interven-

On the other end of the spectrum, the incidence of large-vessel occlusion

MDCalc calculator for NIH Stroke Scale/Score (NIHSS):

Treatment of patients with an NIHSS score ≥ 6 is recommended. Also, if pa-

Figure 1. Application of CT Perfusion in Management

Figure 2. Distal Anterior Cerebral Artery Thrombectomy

In patients with tandem occlusion, it is reasonable to consider performing

MDCalc calculator for Alberta Program Early CT Score (ASPECTS):

Figure 3. Evaluation of Ischemic Changes on Brain CT Scan

Computed Tomographic Perfusion

Software that implements artificial intelligence and complex algorithms,

Magnetic Resonance Imaging

Figure 4. CT Perfusion Modalities and Their Interpretation in Acute Stroke

Catheter System Setup

Balloon Guide Catheters

Future Directions and Systems of Care