Transcript Updates in Stroke - Benton Franklin County Medical Society

Updates in Stroke
Natalie Hendon MD
Virginia Mason Medical Center
Seattle, WA
2/21/2015
Learning Objectives
• Review stroke burden
• Discuss early dual antiplatelet therapy in minor CVA or
TIA
• Use of SSRIs as potential neuromodulators for
improved motor function in stroke patients at 3
months
• Optimal treatment of stroke or TIA due to intracranial
stenosis
• Identify components of aggressive medical
management in secondary stroke prevention
• New directions in emergent treatment of acute
ischemic stroke
Outline
• CHANCE trial
– Early short-term dual antiplatelet therapy
• FLAME trial
– Fluoxetine for motor recovery after ischemic stroke
• Intracranial stenosis – optimal treatment
– SAMMPRIS trial and WASID trial
• Updates in secondary prevention of stroke
– Aggressive medical management
– Statin usage
• Intra-arterial treatment for acute ischemic stroke
– MR CLEAN
– ESCAPE
– EXTEND-IA
Epidemiology and Burden of Stroke
• 800,000 strokes annually in the US
– 600K are new CVA, 200K are recurrent CVA
• Stroke is the leading cause of chronic disability in
the US
• One of the leading causes of death, with 130K140K stroke deaths annually in the US
• Heterogenous disease – primary hemorrhage
(10%), subarachnoid hemorrhage (3%), ischemia
(87%), venous thrombosis, and more
– Varying risk factors
Ischemic Stroke and TIA
• Patients with ischemic stroke and TIA are at high
risk for recurrent events, especially in the first
few days
– Risk of CVA after TIA at 2 days is 3.5-10%
– Risk of CVA after TIA at 90 days is 9-17%
• ABCD2 score to identify patients at higher risk of
stroke
– Patient age, BP, DM, type of symptoms, duration of
symptoms
– High risk scores (>5 points) have 12% risk of recurrent
ischemic event in 1 week
CHANCE
Clopidogrel in High-Risk Patients with Acute
Nondisabling Cereberovascular Events
 Rationale: Stroke is common during the first few weeks
after a TIA or minor ischemic stroke. Dual antiplatelet
therapy may provide additional benefit.
 Methods:
 Randomized, double blind, placebo controlled trial at 114
centers in China
 5170 patients within 24 hrs after onset of high-risk TIA or
minor ischemic stroke
 Randomized to combination therapy with clopidogrel and
aspirin OR to placebo plus aspirin
 Primary outcome was stroke during 90 days
CHANCE: Inclusion Criteria
 Age 40 or older
 Diagnosis of acute minor ischemic CVA
 NIHSS 3 or less at time of randomization
 OR
 Diagnosis of TIA
 Focal brain ischemia with resolution of symptoms
within 24 hrs, plus moderate to high risk of stroke
recurrence (>4 on ABCD)
 Ability to start study drug within 24 hrs after
symptom onset
CHANCE: Exclusion Criteria
 Hemorrhage, vascular malformation, tumor abscess,
other major nonischemic brain disease
 Isolated sensory symptoms
 Isolated visual changes
 Isolated dizziness or vertigo without evidence of acute
infarct on baseline imaging
 Score of >2 on modified Rankin scale prior to event
 NIHSS of 4 or more
 Clear indication for anticoagulation
 Presumed cardioembolic source
 Contraindication to clopidogrel or aspirin
 History of intracranial hemorrhage
 Others, standard tPA exclusion criteria
CHANCE trial
• 41,561 pts screened
• 5170 pts enrolled
• 2548 clopidogrel-ASA
• 2586 to ASA
• Median age 62
• 33.8% were women
• 65.7% with HTN
• 21.1% with DM
• 43% smoking history
• 27.9% with TIA, 72% CVA
• Dual antiplatelet therapy vs aspirin
alone for 21 days, followed by aspirin
OR Plavix
CHANCE: Outcome definitions
• Primary efficacy outcome was new stroke
event (ischemic OR hemorrhagic) at 90 days
• Primary safety outcome was moderate to
severe bleeding event
• Key secondary efficacy outcomes
– New clinical vascular event (CVA, MI, vascular
death due to stroke, MI, CHF, PE, sudden death,
arrhythmia)
CHANCE: Results
 Stroke occurred in 8.2% in the clopidogrel-aspirin
group, and 11.7% in the aspirin group.
 Hazard ratio 0.68, 95% confidence interval 0.57 to 0.81,
P<0.001
 Composite outcome of vascular events in
clopidogrel-aspirin group 8.4% and 11.9% in
aspirin group
 TIA in 1.5% in clopidogrel-aspirin group and 0.2% in
aspirin group
 Moderate or severe hemorrhage occurred in 7 pts
(0.3%) in clopidogrel-aspirin group and in 8 (0.3%)
in the aspirin group (P=0.73)
CHANCE: Conclusions
• Conclusions: Combination clopidogrel and
aspirin is superior to aspirin alone for reducing
risk of stroke in the first 90 days and does not
increase risk of hemorrhage
– Within 24 hrs of symptom onset
– Dual antiplatelet therapy 21 days followed by
aspirin or Plavix alone
CHANCE: Caveats
• Population at very high risk for recurrent
stroke and at low risk for hemorrhage
• Study conducted entirely in China
– Lower rates of treatment for HTN, DM and HL
– Higher incidence of large artery intracranial
atherosclerosis
– Higher prevalence of genetic polymorphisms that
affect the metabolism of clopidogrel
CHANCE: Take-Home Message
 Dual antiplatelet
therapy for 21
days with onset
within 12 hrs of
TIA or minor
ischemic stroke
reduces chance
of recurrent
ischemia
without change
in bleeding risk
Depression and Stroke
• Mean prevalence of post-stroke depression is
20% among patients receiving care for stroke
• Post-stroke major depression has mean duration
of 9 months
• Significant minority continue to have depression
3 years out
• Several trials have evaluated treatment of
depression post-stroke
• Some trials have suggested improved functional
outcome
FLAME Trial
FLAME
• Rationale: Hemiparesis is common after stroke and
prior small trials suggest that fluoxetine enhances
motor recovery. Study to investigate whether
fluoxetine enhances motor recovery if given soon after
ischemic stroke in pts with motor deficits.
• Methods:
– Double-blind, placebo controlled trial
– 9 stroke centers in France with ischaemic CVA and
hemiparesis
– Fluoxetine 20 mg daily or placebo for 3 months starting 510 days after stroke
– Primary outcome change of motor symptoms between day
0 and 90
FLAME: Background
• Recovery of neurological function is associated with
intracerebral reorganization
• Various interventions after CVA have been shown to
modulate brain plasticity after CVA
– Amphetamines show enhanced recovery in animal models
– BZDs and neuroleptics reduce recovery in these models
– SSRIs have shown acute neuroprotective action on
ischemic brain and promote hippocampal neurogenesis
– Functional MRI studies show that single doses of
fluoxetine and paroxetine overactivate motor cortices
compared with placebo in pts with and without CVA
FLAME: Inclusion Criteria
• Acute ischaemic CVA within prior 5-10 days
that caused hemiparesis/hemiplegia
• 9 stroke units in France
• Age 18-55
• Fugl-Meyer motor scale 55 or less at baseline
FLAME: Exclusion Criteria
• Severe post-stroke disability NIHSS >20
• Substantial premorbid disability
• Pre-existing deficit such as residual motor defict from
prior CVA, comprehension deficits, severe aphasia
• Diagnosis of depression
• On antidepressants, MAOIs, neuroleptics, or BZDs
during month prior to inclusion
• Impending carotid endarterectomy
• Pregnancy
• Major disease processes that would prevent f/u
FLAME
• Primary outcome was
mean change in FMMS
between day 0 and 90
as assessed by
physiotherapist
• Secondary endpoints
were NIHSS, modified
Rankin Scale and
MADRS
FLAME
• 118 patients, 6 lost
• 57 fluoxetine, 56 placebo
• Well balanced baseline,
demographic and stroke
severity characteristics
• Mean age and h/o CVA
higher in fluoxetine group
• FMMS score at day 0
higher in fluoxetine group
• NIHSS, mRS and MADRS
scores similar at day 0
• All patients underwent
physiotherapy
FLAME: Results
• Mean progression
in FMMS total
score from
baseline to day 90
was significantly
higher in
fluoxetine group
than in placebo
group
– Significant for
both upper and
lower limb scores
FLAME: Results
•
•
•
•
•
NIHSS at day 90 did not
differ
Motor component score
significantly higher in
fluoxetine group
Adjusted mean MADRS
change was significantly
lower in fluoxetine group
than placebo
Frequency of depression
significantly higher in
placebo
FMMS change signifiantly
greater in fluoxetine
group even after
adjusting for depression
FLAME: Caveats
• Small number of patients enrolled (but larger
than prior trials)
• Pts selected for motor deficit and thus do not
represent all CVA deficits
• Treatment stopped at 90 days; long-term
outcome unknown
FLAME: Take-Home
• Fluoxetine 20 mg started in 5-10 days post stroke
with motor deficits resulted in improvement in
motor recovery compared to placebo when
tested with FMMS, but not when tested with
NIHSS
• mRS showed more independent patients in
fluoxetine group than placebo
• Major role of motor function recovery in global
recovery and return to independent activities
Intracranial Stenosis and Stroke
• Intracranial stenosis causes 8-10% of ischemic
strokes in the USA
• Risk of stroke especially high in patients with
recent stroke or TIA and severe arterial
stenosis (70-99%)
• Treatment options have changed over time
due to release of results of major multicenter
randomized stroke prevention trials
WASID Trial:
Comparison of Warfarin and Aspirin for
Symptomatic Intracranial Arterial Stenosis
WASID: Summary
• Warfarin used to be used preferentially instead of aspirin
for treatment of atherosclerotic intracranial arterial
stenosis.
• 569 patients were randomized after found by angiogram to
have 50-99% stenosis of a major intracranial artery to
receive warfarin or aspirin
• Trial stopped early due to safety for patients assigned to
warfarin, with higher rates of death, major hemorrhage,
and MI
• Primary endpoint of ischemic stroke occurred in 22.1% of
aspirin patients and 21.8% of warfarin pts
• Aspirin should be used instead of warfarin in patients with
intracranial arterial stenosis
SAMMPRIS Trial:
Stenting and Aggressive Medical Management for
Preventing Recurrent stroke in Intracranial Stenosis
SAMMPRIS: Rationale
• Designed to assess whether percutaneous
transluminal angioplasty and stenting (PTAS)
with Wingspan stent system plus aggressive
medical treatment is more effective than
aggressive medical treatment alone in high
risk patients
• Patients with recent (<30 days) TIA or nondisabling CVA attributed to angiographically
verified severe intracranial stenosis
SAMMPRIS:
Early results
• Early results of the SAMPRIS trial showed by
30 days 14.7% of patients in the stenting
group and 5.8% of pts in medical group had
died or had a stroke
 Trial stopped early
• Patients continued to be followed to establish
whether early benefit in medical group would
persist over time, or whether they would have
higher incidence of later strokes
SAMMPRIS
• The rate of stroke in the medical management
group was much lower than expected
30 day rate of CVA
or death
1 year rate of CVA,
ICH or death from
vascular causes
other than CVA
WASID
10.7%
25%
SAMMPRIS
5.8%
12.2%
SAMMPRIS:
Aggressive Medical Management
• Aspirin 325 mg daily
• Clopidogrel 75 mg daily for 90 days
• Management of primary risk factors (HTN and elevated
LDL)
– SBP <140 or <130 if comorbid DM
• Drug from each major class of antihypertensives
– LDL <70
• Rosuvastatin
• Management of secondary risk factors (DM, elevated
non-HDL, smoking, obesity, lack of exercise) with help
of lifestyle modification program
SAMMPRIS:
Hyperlipidemia Mangament
SAMMPRIS:
Lifestyle modification program
• Delivered by coach who contacted patients by
telephone every 2 weeks for the first 3
months, then monthly
• Baseline assessment of risk factors
• Formulation of action plan with focus on
exercise, nutrition, weight, tobacco cessation
• Follow up counseling sessions to help acquire
skills, motivation and support to adhere to
plan
SAMMPRIS vs WASID
• Vascular risk factors at trial entry
• Similar rates for hypertension, history of/current
smoking
• SAMMPRIS had higher rates of DM and
hyperlipidemia, higher proportion starting out
already on antithrombotic tx
WASID
SAMMPRIS
HTN
84%
89%
DM
38%
46%
Hyperlipidemia
71%
89.5%
History of/current smoking
65%
64%
Antithrombotic tx
53%
63%
SAMMPRIS Trial:
Stenting and Aggressive Medical Management for
Preventing Recurrent stroke in Intracranial Stenosis
SAMMPRIS Follow Up
• Median follow up of 32 months
• 15% of medical group and 23% of stenting
group had stroke or death
• Occurrence of adverse effects (any stroke,
major hemorrhage) was higher in stenting
group
 Medical management superior to stenting
SAMMPRIS
• Aggressive medical management may help
address vascular risk factors more readily and
may help prevent future strokes
– In patients with intracranial stenosis
– Dual antiplatelet treatment for 30 days post
TIA/CVA
– Following trial’s protocol to lowering BP and LDL
cholesterol
SAMMPRIS: Take Home
• For patients with recently symptomatic severe
(70-99%) intracranial stenosis, aggressive
medical management is superior to stenting
• Aggressive medical management practices can
lower risk of future stroke
Cholesterol Management in Stroke
• Statins have been shown to reduce the risk of
stroke among patients with CAD and those at
increased risk for cardiovascular disease
• Prior studies (meta-analysis 90,000 pts) have
shown that reduction in stroke risk was primarily
related to extent to which LDL was lowered
• SPARCL trial designed to determine whether daily
dose of 80 mg atorvastatin would reduce risk of
stroke in pts with NO known CAD who had had a
CVA or TIA in the previous 6 months
SPARCL:
Baseline
Characteristics
• 2365 pts in atorvastatin
group
• 2366 pts in placebo group
• Entry event was CVA in
about 70% in both, TIA in
about 30% in both.
Hemorrhagic CVA accounted
for 2% in both
• Time since entry about 85
days
• Similar risk factors
• Similar concomitant therapy
for risk factors
• LDL about 133, HDL 50, TG
143-4
SPARCL: Decreased risk of fatal or nonfatal
stroke or TIA with Atorvastatin
SPARCL: Decreased risk of any coronary and
cardiovascular events with Atorvastatin
AHA/ASA Scientific Advisory 2013: Statins
AHA: High/Moderate/Low Intensity
AHA: Secondary Prevention and
Statins
• Women and men with clinical atherosclerotic
cardiovascular disease (ACS, MI, angina, coronary
revascularization, CVA or TIA presumed to be of
atherosclerotic origin, and PVD or revascularization) are
at increased risk of recurrent ASCVD and ASCVD death.
• An extensive body of evidence demonstrates that highintensity statin therapy reduces ASCVD events more
than moderate-intensity statin therapy in individuals
with clinical ASCVD.
• No evidence to support titrating meds to goal LDL, as
clinical trials were mainly fixed dose
AHA Recommendations in Stroke/TIA
• Patients 75 and younger, initiate high intensity
statin therapy
• Patients older than 75, initiate moderate
intensity statin therapy
• Counsel both on healthy lifestyle habits
Recent Advances:
Intra-arterial Treatment for Acute
Ischemic Stroke
MR CLEAN (the Netherlands)
ESCAPE (Canada)
EXTEND-IA (Australia)
Argument for Intra-Arterial Treatment
• IV alteplase within 4.5 hours after onset of symptoms is
the only reperfusion therapy with proven efficacy in
patients with acute ischemic stroke
• Narrow therapeutic window
• Contraindications including surgery, coagulation
abnormalities, h/o ICH
• Less effective at opening proximal occlusions
• >1/3 of acute anterior circulation CVA
• Early recanalization after IV alteplase is seen in only
1/3 of patients with occlusion of the ICA terminus
 poor prognosis
• Among pts with a proximal vessel occlusion in
the anterior circulation, 60-80% die within 90
days after stroke onset, or do not regain
functional independence despite alteplase
treatment.9
• Recent studies have shown superiority of
retrievable stents over the prior generation of
thrombectomy devices.10
Intra-arterial therapy options
• Locally delivered thrombolytic agents with clot
retrieval
• Thrombectomy with mechanical devices
MR CLEAN: Objective
• Is intraarterial treatment plus usual care more
effective than usual care alone
– Patients with proximal arterial occlusion in the
anterior cerebral circulation
– Treatment intraarterially within 6 hours after
symptom onset
MR CLEAN: Design
• Phase 3, multicenter clinical trial, randomized,
open-label treatment, blinded end-point
evaluation
• Patients with acute ischemic stroke and
proximal intracranial anterior ciculation
occlusion on vessel imaging
• Intraarterial thrombolysis, mechanical
treatment, or both plus usual care (which
could include IV altepase)
MR CLEAN: Inclusion Criteria
• 16 centers in the Netherlands
• Age 18-no upper limit
• Acute ischemic stroke of proximal anterior
circulation confirmed on vessel imaging (CTA
or MRA or DSA)
• NIHSS 2 or higher
• Patients with additional extracranial ICA
occlusion or dissection left to judgment of
treating physician
MR CLEAN
• 502 patients
• Similar age (mid-60s), gender
distribution, NIHSS, associated
risk factors, blood pressure,
prestroke modified Rankin
score
• Similar time from stroke onset
to start of IV alteplase (85-87
minutes)
• Similar distribution of clot
• Higher extracranial ICA
occlusion in intervention
group
• Time from stroke onset to
randomization about 200
minutes
• Time from stroke onset to
groin puncture 260 minutes
MR CLEAN: Intervention
• Arterial catheterization with a microcatheter to the
level of occlusion and delivery of a thromboylitic agent,
mechanical thrombectomy, or both
• Use of alteplase or urokinase
– Restricted total dosage if IV-alteplase was given
• Mechanical treatment: thrombus retraction, aspiration,
wire disruption, use of retrievable stent
• Devices approved by FDA or CE and approved by
steering committee
• 1+ members of each intervention team had to have
completed at least 5 full procedures with a particular
device
MR CLEAN: Outcome
• Primary outcome – score on modified Rankin scale at 90
days
• Secondary outcomes included:
– NIHSS at 24 hrs and at 5-7 days or discharge if sooner
– ADLs as measured with Barthel index
– Health related quality of life with EuroQol Group 5-Dimension
Self-Report Questionaire at 90 days
• Imaging outcomes: arterial recanalization mesausred with
CTA or MRA at 24 hrs, final infarct volume on noncontrast
head CT at 5-7 days
• Safety outcomes: hemorrhagic complications, progression
of ischemia, new ischemic CVA in new vascular territory,
death
MR CLEAN: Results
• Intraarterial therapy with or without mechanical
thrombectomy performed in 196 of the 233 patients in
the intervention group (84.1%
– General anesthesia used in 37.8%
– Second revascularization procedure (acute cervical carotid
stenting) in 12.9%
• Mechanical treatment in 195 of the 233 pts (83.7%)
– Retrievable stents in 190 patients (81.5%)
– Other devices used in 5 pts (2.1%)
• Intraarterial thrombolytic agents used as monotherapy
in 1 of the 233 pts (0.4%)
• No intervention in 37 pts (15.9%
• No significant between-group
difference in serious adverse
effects in 90-day follow up
period
• 13/233 pts (5.6% in
intervention group had clinical
signs of a NEW ischemic CVA in
a different vascular territory
within 90 days, and only 1/267
(0.4%) in the control group did
• No significant difference in
mortality at 7, 30, 90 days of
follow up
• Procedure related
complications included
embolization into new vascular
territories outside the target
downstream in 20/233 (8.6%),
procedure related dissection in
4 (1.7%) and vessel
perforations in 2 (0.9%)
MR CLEAN – Conclusions and
Discussion
• Patients with acute ischemic stroke caused by
a proximal intracranial arterial occlusion of the
anterior circulation have BENEFIT with respect
to FUNCTIONAL RECOVERY when intraarterial
treatment is given within 6 hrs of onset
 Clinically significant increase in functional
independence in daily life by 3 months,
without increase in mortality
MR CLEAN and prior IA trials
• Prior trials have not shown a benefit to IA
treatment
– Timing: Interventional Management of Stroke (IMS) III
trial gave IV alteplase plus IA treatment with
randomization 40 minutes after start of IV alteplase
(about 120 minutes after IV alteplase
• This may have led to inclusion of more pts with favorable
response to IV alteplase than MR CLEAN
– Proximal occlusion vs more distal: IMS III and
SYNTHESIS Expansion trial did not require
radiographically proven intracranial occlusion
• Presence of proximal arterial occlusion uncertain in 47% of
the study population
MR CLEAN Caveats
• 9% of pts in the intervention group had embolizationn
into new vascular territories
• 13% underwent simultaneous second revascularization
procedure (acute cervical carotid stent)
– Unclear how this impacts results
• Low proportion of pts in control group had mRS of 0-2
in 90 day f/u
– Broad inclusion with older pts and contraindications to IV
alteplase? Poorer prognosis at baseline?
• Pts not blinded to intervention
– May have influenced their opinions about
health/functionality
ESCAPE
• Included: Patients with proximal intracranial occlusion
in the anterior circulation up to 12 hours after
symptom onset. Selected based on imaging with
ASPECTS score
• Excluded: Large infarct core or poor collateral
circulation on imaging.
• Randomly assigned participants to receive standard
care or standard care plus endovascular treatment with
use of available thrombectomy devices.
• Primary outcome: score on modified Rankin scale at 90
days.
• Trial stopped early because of efficacy.
Assessment at
90 days
ESCAPE: Conclusions
• Pts with acute ischemic CVA with small infarct
core on imaging, proximal intracranial occlusion
in the anterior circulation, and moderate to good
intracranial collateral circulation, rapid
endovascular treatment improved clinical
outcome and reduced mortality.
– Rapid reperfusion associated with better clinical
outcome than slower reperfusion
– Shorter interval times in this trial with median time
from CT to first reperfusion of 84 minutes
EXTEND-IA
• Purpose: Prior trials of endovascular therapy
for ischemic CVA have produced variable
results. Study performed to test whether
more advanced imaging selection, recently
developed devices, and earlier intervention
improve outcomes.
EXTEND-IA: Methods
• Pts with ischemic CVA, occlusion of ICA or MCA,
evidence of small ischemic core, who were receiving
IV-alteplase <4.5 hrs after onset of ischemic CVA
• Assigned to undergo endovascular thrombectomy with
the Solitare Flow Restoration stent retriever, or to
continue IV-alteplase alone
• Primary outcomes: Reperfusion at 24 hrs and early
neurological improvement (>8 point reduction on
NIHSS or score of 0 or 1 at day 3.
• Secondary outcomes included functional score on mRS
at 90 days.
EXTEND-IA: Results
• Stopped early due to efficacy after 70 pts had
undergone randomization.
• Percentage of ischemic territory that underwent
reperfusion was higher in endovascular therapy
at 24 hrs (median 100% vs 37%) and improved
functional outcome at 90 days (71% achieving
functional independence vs 40%)
• No significant differences in rates of death or
symptomatic intracerebral hemorrhage.
EXTEND-IA: Conclusions
• In pts with ischemic CVA and proximal
cerebral artery occlusion and salvagable tissue
on CT perfusion imaging, early thrombectomy
with Solitare FR stent retriever as compared
with alteplase alone, improved reperfusion,
early neuro recovery and functional outcome.
• Limitations: small number of patients limiting
subgroup analyses
Conclusions
•
•
•
•
Stroke is a common disorder with significant disability and mortality
Dual antiplatelet therapy for 21 days, with treatment onset within 12 hrs of TIA or
minor ischemic stroke, reduces chance of recurrent ischemia without change in
bleeding risk
Fluoxetine and potentially other SSRIs may improve motor function in CVA pts at 3
months, potentially through neuromodulation (animal models)
For treatment of symptomatic intracranial stenosis:
– Early studies showed aspirin is superior to warfarin
– SAMMPRIS trial showed dual antiplatelet therapy for 3 months and aggressive medical
treatment was superior to angioplasty and stenting
•
SAMMPRIS trial also suggested that aggressive medical management alone led to a
greater reduction in stroke risk factors than expected and can lower risk of future
stroke
–
–
–
–
•
Dual antiplatelet therapy 90 days
High intensity statin therapy in pts 75 and younger
Aggressive BP management and LDL management (q30 day assessments)
Aggressive lifestyle modification with significant improvement seen at 4 months
For patients with large artery intracranial occlusion in the anterior circulation,
endovascular treatment within 6-12 hrs after stroke symptom onset is superior to
alteplase alone without increased risk of hemorrhage or death
THANK YOU
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