Professional Documents
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Stroke AHA Guidelines
Stroke AHA Guidelines
AHA/ASA GUIDELINE
Dawn O. Kleindorfer, MD, FAHA, Chair; Amytis Towfighi, MD, FAHA, Vice Chair; Seemant Chaturvedi, MD, FAHA;
Kevin M. Cockroft, MD, MSc, FAHA; Jose Gutierrez, MD, MPH; Debbie Lombardi-Hill, BS, FAHA; Hooman Kamel, MD;
Walter N. Kernan, MD*; Steven J. Kittner, MD, MPH, FAHA; Enrique C. Leira, MD, MS, FAHA; Olive Lennon, PhD;
James F. Meschia, MD, FAHA; Thanh N. Nguyen, MD, FAHA; Peter M. Pollak, MD; Pasquale Santangeli, MD, PhD;
Anjail Z. Sharrief, MD, MPH, FAHA; Sidney C. Smith Jr, MD, FAHA; Tanya N. Turan, MD, MS, FAHA†; Linda S. Williams, MD, FAHA
Key Words: AHA Scientific Statements ◼ ischemic attack, transient ◼ secondary prevention ◼ stroke
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TOP 10 TAKE-HOME MESSAGES FOR 3. Lifestyle factors, including healthy diet and physi-
cal activity, are important for preventing a second
THE SECONDARY STROKE PREVENTION stroke. Low-salt and Mediterranean diets are rec-
GUIDELINE ommended for stroke risk reduction. Patients with
1. Specific recommendations for prevention strate- stroke are especially at risk for sedentary and
gies often depend on the ischemic stroke/tran- prolonged sitting behaviors, and they should be
sient ischemic attack subtype. Therefore, new in encouraged to perform physical activity in a super-
this guideline is a section describing recommen- vised and safe manner.
dations for the diagnostic workup after ischemic 4. Changing patient behaviors such as diet, exercise,
stroke, to define ischemic stroke etiology (when and medication compliance requires more than just
possible), and to identify targets for treatment simple advice or a brochure from their physician.
in order to reduce the risk of recurrent ischemic Programs that use theoretical models of behavior
stroke. Recommendations are now grouped by change, proven techniques, and multidisciplinary
etiologic subtype. support are needed.
2. Management of vascular risk factors remains 5. Antithrombotic therapy, including antiplatelet or
extremely important in secondary stroke preven- anticoagulant agents, is recommended for nearly
tion, including (but not limited to) diabetes, smok- all patients without contraindications. With very few
ing cessation, lipids, and especially hypertension. exceptions, the combination of antiplatelets and
Intensive medical management, often performed anticoagulation is typically not indicated for sec-
by multidisciplinary teams, is usually best, with ondary stroke prevention. Dual antiplatelet therapy
goals of therapy tailored to the individual patient. is not recommended long term, and short term, dual
*AHA Stroke Council Scientific Statement Oversight Committee on Clinical Practice Guidelines Liaison.
†AAN Representative.
AHA Stroke Council Scientific Statement Oversight Committee Members, see page e000.
© 2021 American Heart Association, Inc.
Stroke is available at www.ahajournals.org/journal/str
antiplatelet therapy is recommended only in very developing cerebrovascular disease. The focus is on
CLINICAL STATEMENTS
specific patients, including those with early arriv- medical practice in the United States, but many aspects
AND GUIDELINES
ing minor stroke and high-risk transient ischemic are relevant to patients throughout the world. Although it
attack or severe symptomatic intracranial stenosis. must be acknowledged that guidelines may be used to
6. Atrial fibrillation remains a common and high- inform regulatory or payer decisions, the core intent is to
risk condition for second ischemic stroke. improve quality of care and to align with patients’ inter-
Anticoagulation is usually recommended if the ests. Guidelines are intended to define practices meeting
patient has no contraindications. Heart rhythm the needs of patients in most, but not all, circumstances
monitoring for occult atrial fibrillation is usu- and should not replace clinical judgment; furthermore,
ally recommended if no other cause of stroke is the recommendations set forth should be considered in
discovered. the context of individual patient values, preferences, and
7. Extracranial carotid artery disease is an impor- associated conditions.
tant and treatable cause of stroke. Patients with The AHA/ASA strive to ensure that guideline writing
severe stenosis ipsilateral to a nondisabling stroke groups contain requisite expertise and are representative
or transient ischemic attack who are candidates of the broader medical community by selecting experts
for intervention should have the stenosis fixed, from a broad array of backgrounds, representing differ-
likely relatively early after their ischemic stroke. ent sexes, races, ethnicities, intellectual perspectives,
The choice between carotid endarterectomy and geographic regions, and scopes of clinical practice and
carotid artery stenting should be driven by specific by inviting organizations and professional societies with
patient comorbidities and features of their vascular related interests and expertise to participate as endors-
anatomy. ers. The AHA/ASA have rigorous policies and methods
8. Patients with severe intracranial stenosis in the for development of guidelines that limit bias and prevent
vascular territory of ischemic stroke or transient improper influence. The complete policy on relationships
ischemic attack should not receive angioplasty and with industry and other entities can be found at https://
stenting as a first-line therapy for preventing recur- professional.heart.org/-/media/phd-files/guidelines-and-
rence. Aggressive medical management of risk statements/policies-devolopment/aha-asa-disclosure-
factors and short-term dual antiplatelet therapy are rwi-policy-5118.pdf?la=en.
preferred. Beginning in 2017, numerous modifications to the
9. Several studies have evaluated secondary stroke guidelines have been implemented to make guidelines
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prevention of patent foramen ovale closure since shorter and to enhance “user friendliness.” Guidelines
the previous guideline in 2014. It is now consid- are written and presented in a modular knowledge chunk
ered reasonable to close patent foramen ovale format, in which each chunk includes a table of recom-
percutaneously in selected patients: those with mendations, a brief synopsis, recommendation-specific
younger age with nonlacunar stroke or no other supportive text, and, when appropriate, flow diagrams or
cause at any age. additional tables. Hyperlinked references are provided for
10. Patients with embolic stroke of uncertain source each modular knowledge chunk to facilitate quick access
should not be treated empirically with anticoagu- and review. Other modifications to the guidelines include
lants or ticagrelor because it was found to be of no the addition of Knowledge Gaps and Future Research
benefit. segments in some sections and a web guideline supple-
ment (Data Supplement) for useful but noncritical tables
and figures.
PREAMBLE Sepideh Amin-Hanjani, MD, FAHA
Since 1990, the American Heart Association (AHA)/ Immediate Past Chair, AHA Stroke Council Scientific
American Stroke Association (ASA)* have translated sci- Statement Oversight Committee
entific evidence into clinical practice guidelines with rec- Joseph P. Broderick, MD, FAHA
ommendations to improve cerebrovascular health. These Chair, AHA Stroke Council Scientific Statement
guidelines, which are based on systematic methods to Oversight Committee
evaluate and classify evidence, provide a foundation for
the delivery of quality cerebrovascular care. The AHA/
ASA sponsor the development and publication of clinical 1. INTRODUCTION
practice guidelines without commercial support, and mem- Each year, ≈795 000 individuals in the United States
bers volunteer their time to the writing and review efforts. experience a stroke, of which 87% (690 000) are isch-
Clinical practice guidelines for stroke provide rec- emic and 185 000 are recurrent.1 Approximately 240 000
ommendations applicable to patients with or at risk of individuals experience a transient ischemic attack (TIA)
each year.2 The risk of recurrent stroke or TIA is high
*The American Stroke Association is a division of the American Heart Association. but can be mitigated with appropriate secondary stroke
prevention. In fact, cohort studies have shown a reduc- selected and published in the present document are
CLINICAL STATEMENTS
tion in recurrent stroke and TIA rates in recent years as representative and not all inclusive.
AND GUIDELINES
secondary stroke prevention strategies have improved.3,4 An independent Evidence Review Committee was
A meta-analysis of randomized controlled trials (RCTs) commissioned to perform a formal systematic review of
of secondary stroke prevention therapies published a critical clinical question (Table 1) related to secondary
from 1960 to 2009 showed a reduction in annual stroke prevention, the results of which were considered
stroke recurrence from 8.7% in the 1960s to 5.0% in by the writing group for incorporation into the present
the 2000s, with the reduction driven largely by improved guideline. Concurrently with this process, writing group
blood pressure (BP) control and use of antiplatelet ther- members evaluated study data relevant to the rest of the
apy.5 The changes may have been influenced by changes guideline. The results of these evidence reviews were
in diagnostic criteria and differing sensitivities of diag- evaluated by the writing group for incorporation into the
nostic tests over the years. present guideline.
The overwhelming majority of strokes can be pre- Each topic area was assigned a primary author and
vented through BP control, a healthy diet, regular physi- a primary, and sometimes secondary, reviewer. Author
cal activity, and smoking cessation. In fact, 5 factors—BP, assignments were based on the areas of expertise of
diet, physical inactivity, smoking, and abdominal obe- the members of the writing group members and their
sity—accounted for 82% and 90% of the population- lack of any relationships with industry related to the sec-
attributable risk (PAR) for ischemic and hemorrhagic tion material. All recommendations were fully reviewed
stroke in the INTERSTROKE study (Global and regional and discussed among the full committee to allow diverse
effects of potentially modifiable risk factors associated perspectives and considerations for this guideline. Rec-
with acute stroke in 32 countries).5a Similarly, the Global ommendations were then voted on to reach consensus.
Burden of Disease Study showed that 90.5% (95% The systematic review has been published in conjunc-
uncertainty interval, 88.5–92.2) of the global burden tion with this guideline and includes its respective data
of stroke was attributable to modifiable risk factors.6 supplements.15
A modeling study showed that targeting multiple risk
factors has additive benefits for secondary prevention;
specifically, aspirin, statin, and antihypertensive medi- 1.2. Organization of the Writing Group
cations, combined with diet modification and exercise, The writing group consisted of neurologists, neurological
can result in an 80% cumulative risk reduction in recur-
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Table 1. Evidence Review Committee Question and less on extensive text and background information;
CLINICAL STATEMENTS
No. Question Section No. with guideline focused updates; and including “chunks”
1 In patients with an ischemic stroke or 5.19 of information after each recommendation.23 Second, the
TIA, what are the benefits and risks of Diagnostic Evaluation and Systems of Care for Second-
DAPT compared to single antiplatelet
therapy within 5 y for prevention of ary Prevention sections are new. The Diagnostic Evalu-
recurrent stroke? ation for Secondary Stroke Prevention section focuses
DAPT indicates dual antiplatelet therapy; and TIA, transient ischemic attack. on the evidence base for laboratory and imaging stud-
ies for guiding secondary stroke prevention decisions.
1.4. Scope of the Guideline Often these tests are completed in the inpatient setting.
The Systems of Care for Secondary Prevention section
The aim of the present guideline is to provide clinicians
contains 3 subsections: (1) Health Systems–Based Inter-
with evidence-based recommendations for the preven-
ventions for Secondary Stroke Prevention, (2) Interven-
tion of future stroke among survivors of ischemic stroke
tions Aimed at Changing Patient Behavior, and (3) Health
or TIA. It should be noted that this guideline does not
Equity. The Health Equity subsection is a refocus of the
cover the following topics, which have been addressed
2014 guideline’s section guiding management of high-
elsewhere:
risk populations. Third, this guideline does not include a
• Acute management decisions (covered in the
separate section on metabolic syndrome because there
“2019 Update to the 2018 Guidelines for the Early
are no unique recommendations for metabolic syndrome
Management of Patients With Acute Ischemic
aside from managing each of the individual components
Stroke”16),
of the syndrome. Fourth, the section on alcohol use was
• Intracerebral hemorrhage (ICH; covered in the
expanded to include the use of other substances. Finally,
“Guidelines for the Management of Spontaneous
several additional conditions were included in the Man-
Intracerebral Hemorrhage”17),
agement by Etiology section: congenital heart disease,
• Primary prevention (covered in the “Guidelines
cardiac tumors, moyamoya disease, migraine, malignancy,
for the Primary Prevention of Stroke” 18 and
vasculitis, other genetic disorders, carotid web, fibromus-
“2019 American College of Cardiology/
cular dysplasia, dolichoectasia, and embolic stroke of
American Heart Association Guideline on
undetermined source (ESUS).
the Primary Prevention of Cardiovascular
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CLINICAL STATEMENTS
Title Organization Publication year
AND GUIDELINES
AHA/ASA guidelines
Guidelines for Carotid Endarterectomy24 AHA/ASA 1998
Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease25 ASA/ACCF/AHA/AANN/ 2011
AANS/ACR/ASNR/CNS/
SAIP/SCAI/SIR/SNIS/
SVM/SVS
Guideline on Lifestyle Management to Reduce Cardiovascular Risk26 AHA/ACC 2013
Guideline for the Management of Overweight and Obesity in Adults27 AHA/ACC/TOS 2013
Guideline for the Management of Patients With Atrial Fibrillation
28
AHA/ACC/HRS 2014
Guidelines for the Management of Spontaneous Intracerebral Hemorrhage17 AHA/ASA 2014
Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack9 AHA/ASA 2014
Guidelines for the Prevention of Stroke in Women 20
AHA/ASA 2014
Guidelines for the Primary Prevention of Stroke18 AHA/ASA 2014
Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults29 ACC/AHA/AAPA/ABC/ 2017
ACPM/AGS/APhA/ASH/
ASPC/NMA/PCNA
Guideline for the Management of Adults With Congenital Heart Disease30 AHA/ACC 2018
Guideline on the Management of Blood Cholesterol31 AHA/ACC/AACVPR/AAPA/ 2018
ABC/ACPM/ADA/AGS/
APhA/ASPC/NLA/PCNA
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 AHA/ASA 2019
Guidelines for the Early Management of Acute Ischemic Stroke16
Guideline on the Primary Prevention of Cardiovascular Disease19 ACC/AHA 2019
Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation32 AHA/ACC/HRS 2019
Guideline for the Management of Patients With Valvular Heart Disease33 ACC/AHA 2020
AHA/ASA statements
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AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; AANN, American Association of Neuroscience Nurses; AANS, American
Association of Neurological Surgeons; AAPA, American Academy of Physician Assistants; ABC, Association of Black Cardiologists; ACC, American College of Cardiol-
ogy; ACCF, American College of Cardiology Foundation; ACPM, American College of Preventive Medicine; ACR, American College of Radiology; ADA, American Diabetes
Association; AGS, American Geriatrics Society; AHA, American Heart Association; ASA, American Stroke Association; APhA, American Pharmacists Association; ASH,
American Society of Hypertension; ASNR, American Society of Neuroradiology; ASPC, American Society for Preventive Cardiology; CNS, Congress of Neurological
Surgeons; HRS, Heart Rhythm Society; NLA, National Lipid Association; NMA, National Medical Association; PCNA, Preventive Cardiovascular Nurses Association;
SAIP, Society of Atherosclerosis Imaging and Prevention; SCAI, Society for Cardiovascular Angiography and Interventions; SIR, Society of Interventional Radiology; SNIS,
Society of NeuroInterventional Surgery; SVM, Society for Vascular Medicine; SVS, Society for Vascular Surgery; and TOS, The Obesity Society.
in any guideline on the prevention of recurrent stroke. provide the best and most complete recommendations
There is often no reason to think that the mechanism of to the clinician about important strategies for secondary
stroke prevention and benefits would be different in pri- stroke prevention. Principles guiding inclusion and extrapo-
mary versus secondary prevention, although not studied lation of the results of these studies were as follows:
within a purely secondary stroke prevention trial. There- 1. The quality of the trial/trials was acceptable.
fore, this writing group occasionally includes recommen- (Ideally, stroke or TIA occurrence or recurrence
dations with evidence based in the primary prevention of was a prespecified end point, with clear protocols
atherosclerotic cardiovascular disease (ASCVD), athero- for assessing stroke end points.)
sclerosis, or combined end points of cardiac disease and 2. From a physiological perspective, the primary pre-
stroke in this guideline. vention strategy used in the study will likely be
To acknowledge that some studies were not performed effective for secondary prevention.
in a purely ischemic stroke population, the LOE was down- 3. Patients with ischemic stroke were included in the
graded. In this way, the writing group agreed that this would population studied when possible.
Abbreviation Meaning/Phrase
ACC American College of Cardiology DiRECT Diabetes Remission Clinical Trial
ACTIVE W Atrial Fibrillation Clopidogrel Trial With Irbesartan for ECST European Carotid Surgery Trial
Prevention of Vascular Events EF ejection fraction
AF atrial fibrillation ENGAGE Global Study to Assess the Safety and Effective-
AHA American Heart Association AF-TIMI 48 ness of Edoxaban (DU-176b) vs Standard Practice
of Dosing With Warfarin in Patients With Atrial
AHI apnea-hypopnea index Fibrillation
ARCH Aortic Arch Related Cerebral Hazard Trial EPA eicosapentaenoic acid
ARISTOTLE Apixaban for Reduction in Stroke and Other Thrombo- EPIC-CVD European Prospective Investigation into Cancer and
embolic Events in Atrial Fibrillation Nutrition-CVD case-cohort study
ASA American Stroke Association ESH-CHL-SHOT European Society of Hypertension and Chinese
ASAP Addressing Sleep Apnea Post Stroke/TIA Hypertension League Stroke in Hypertension Optimal
ASTRO-APS Apixaban for Secondary Prevention of Thromboembo- Treatment Trial
lism Among Patients With Antiphospholipid Syndrome ESPRIT European/Australasian Stroke Prevention in Reversible
ASCVD atherosclerotic cardiovascular disease Ischaemia Trial
BMI body mass index ESPS2 Second European Stroke Prevention Study
BUST-Stroke Breaking Up Sitting Time After Stroke ExStroke Physical Exercise After Acute Ischaemic Stroke
CADISS Cervical Artery Dissection in Stroke Study FASTEST Efficacy and Safety of a TIA/Stroke Electronic Support Tool
CARDIA Coronary Artery Risk Development in Young Adults FMD fibromuscular dysplasia
CAP Continued Access Registry FOURIER Further Cardiovascular Outcomes Research With
PCSK9 Inhibition in Subjects With Elevated Risk
CAPRIE Clopidogrel Versus Aspirin in Patients at Risk of
Ischaemic Events GELIA German Experience With Low Intensity Anticoagulation
CLINICAL STATEMENTS
NASCET North American Symptomatic Carotid Endarterectomy SAPT single antiplatelet therapy
AND GUIDELINES
Trial SAVE Sleep Apnea Cardiovascular Endpoints
NAVIGATE ESUS Rivaroxaban Versus Aspirin in Secondary Prevention SBP systolic blood pressure
of Stroke and Prevention of Systemic Embolism in
Patients With Recent Embolic Stroke of Undetermined SCD sickle cell disease
Source SIT Silent Cerebral Infarct Transfusion multi-center clinical
NIHSS National Institutes of Health Stroke Scale trial
ODYSSEY Evaluation of Cardiovascular Outcomes After an Acute Sleep SMART Sleep for Stroke Management and Recovery Trial
OUTCOMES Coronary Syndrome During Treatment With Alirocumab SMART Second Manifestations of Arterial Disease
OMEMI Omega-3 Fatty Acids in Elderly Patients With Acute SOCRATES Soluble Guanylate Cyclase Stimulator in Heart Failure
Myocardial Infarction Studies
OR odds ratio SPAF Stroke Prevention in Atrial Fibrillation Study
OSA obstructive sleep apnea SPARCL Stroke Prevention by Aggressive Reduction in Choles-
OXVASC Oxford Vascular Study terol Levels
PAST-BP Prevention After Stroke–Blood Pressure STANDFIRM Shared Team Approach Between Nurses and Doctors
for Improved Risk Factor Management for Stroke
PCSK9 proprotein convertase subtilisin/kexin type 9 Patients
PFO patent foramen ovale STOP Stroke Prevention Trial in Sickle Cell Anemia
PODCAST Prevention of Decline in Cognition after Stroke Trial SUCCEED Secondary Stroke Prevention by Uniting Community and
POINT Platelet-Oriented Inhibition in New TIA and Minor Chronic Care Model Teams Early to End Disparities
Ischemic Stroke SUSTAIN Systemic Use of Stroke Averting Interventions
PRAISE Prevent Recurrence of All Inner-City Strokes Through STRENGTH Outcomes Study to Assess Statin Residual Risk
Education Reduction With Epanova in High CV Risk Patients
PREDIMED Prevención con Dieta Mediterránea With Hypertriglyceridemia
PREVAIL Prospective Randomised Evaluation of the Watchman SWiTCH Stroke With Transfusions Changing to Hydroxyurea
LAA Closure Device in Patients With Atrial Fibrillation TARDIS Triple Antiplatelets for Reducing Dependency after
Versus Long Term Warfarin Therapy Ischaemic Stroke
PREVENTION Preventing Recurrent Vascular Events in Patients With T2D type 2 diabetes
Stroke or Transient Ischemic Attack
TCAR transcarotid artery revascularization
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PROTECT AF Watchman Left Atrial Appendage System for Embolic TEE transesophageal echocardiography
Protection in Patients With Atrial Fibrillation THALES Acute Stroke or Transient Ischaemic Attack Treated
PTAS With Ticagrelor and ASA for Prevention of Stroke and
percutaneous transluminal angioplasty and stenting
Death
RCT randomized controlled trial
TIA transient ischemic attack
RE-ALIGN Randomized, Phase II Study to Evaluate the Safety
TOSS Trial of Cilostazol in Symptomatic Intracranial Arterial
and Pharmacokinetics of Oral Dabigatran Etexilate in
Stenosis
Patients After Heart Valve Replacement
TST Treat Stroke to Target
RE-LY Randomized Evaluation of Long-Term Anticoagulant
Therapy TWiTCH TCD With Transfusions Changing to Hydroxyurea
REDUCE-IT Reduction of Cardiovascular Events With Icosapent UKPDS United Kingdom Prospective Diabetes Study
Ethyl–Intervention Trial VAST Vertebral Artery Stenting Trial
REGARDS Reasons for Geographic and Racial Differences in VHD valvular heart disease
Stroke Study
VISP Vitamin Intervention for Stroke Prevention
RESPECT Randomized Evaluation of Recurrent Stroke Compar-
ing PFO Closure to Established Current Standard of VISSIT Vitesse Intracranial Stent Study for Ischemic Stroke
Care Treatment Therapy
RESPECT ESUS Dabigatran Etexilate for Secondary Stroke Preven- VIST Vertebral Artery Ischemic Stenting Trial
tion in Patients With Embolic Stroke of Undetermined VISTA Virtual International Stroke Trials Archive
Source VITATOPS Vitamins to Prevent Stroke
RISE-UP Recovery in Stroke Using PAP VKA vitamin K antagonist
ROCKET AF Rivaroxaban Once Daily Oral Direct Factor Xa Inhibi- VLDL very-low-density lipoprotein
tion Compared With Vitamin K Antagonism for Preven-
tion of Stroke and Embolism Trial in Atrial Fibrillation VZV varicella zoster virus
SAPPHIRE Stenting and Angioplasty With Protection in Patients at WASID Warfarin-Aspirin Symptomatic Intracranial Disease
High Risk for Endarterectomy WEAVE Wingspan Stent System Post Market Surveillance
Table 3. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic
Testing in Patient Care (Updated May 2019)*
CLINICAL STATEMENTS
AND GUIDELINES
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CLINICAL STATEMENTS
AND GUIDELINES
Figure 1. Conceptual representation
of ischemic stroke subtypes.
Percentages are approximate and are
informed by Kolominsky-Rabas et al36 and
Gardener et al.37 Precise percentages will
depend on extent of testing and patient
populations. Ischemic stroke subtype
definitions are informed by the TOAST (Trial
of Org 10172 in Acute Stroke Treatment)
classification scheme38 unless otherwise
indicated. ESUS indicates embolic stroke
of undetermined source.
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assessing and addressing barriers to adherence to medi- 6. In patients with cryptogenic stroke, echocar-
diography with or without contrast is reason-
cations and a healthy lifestyle. If a patient has a recurrent
2a B-R able to evaluate for possible cardiac sources
stroke while on secondary stroke prevention medica- of or transcardiac pathways for cerebral
tions, it is vital to assess whether they were taking the embolism.56,57
medications that they were prescribed and, if possible, 7. In patients with cryptogenic stroke who do
to explore and address factors that contributed to non- not have a contraindication to anticoagula-
tion, long-term rhythm monitoring with mobile
adherence before assuming that the medications were 2a B-R
cardiac outpatient telemetry, implantable loop
ineffective. recorder, or other approach is reasonable to
detect intermittent AF.58–60
8. In patients suspected of having ischemic
2.5. Antithrombotic Dosing stroke, if CT or MRI does not demonstrate
2a B-NR symptomatic cerebral infarct, follow-up CT
Unless stated otherwise in the recommendations herein, or MRI of the brain is reasonable to confirm
the international normalized ratio (INR) goal for warfarin diagnosis.61–65
is 2.0 to 3.0 and the dose of aspirin is 81 to 325 mg. 9. In patients suspected of having had a TIA,
if the initial head imaging (CT or MRI) does
not demonstrate a symptomatic cerebral
2.6. Application Across Populations 2a B-NR
infarct, follow-up MRI is reasonable to
predict risk of early stroke and to support the
Unless otherwise indicated, the recommendations in diagnosis.66–69
this guideline apply across race/ethnicity, sex, and age 10. In patients with cryptogenic stroke, tests
groups. Special considerations to address health equity for inherited or acquired hypercoagulable
are delineated in section 6.3, Health Equity. state, bloodstream or cerebral spinal fluid
infections, infections that can cause central
nervous system (CNS) vasculitis (eg, HIV
and syphilis), drug use (eg, cocaine and
3. DIAGNOSTIC EVALUATION FOR 2a C-LD
amphetamines), and markers of systemic
SECONDARY STROKE PREVENTION inflammation and genetic tests for inherited
diseases associated with stroke are reason-
Recommendations for Diagnostic Evaluation able to perform as clinically indicated to
identify contributors to or relevant risk factors
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COR LOE Recommendations 11. In patients with ischemic stroke or TIA,
noninvasive imaging of the intracranial large
1. In patients suspected of having a stroke or
arteries and imaging of the extracranial
TIA, an ECG is recommended to screen for
2a C-LD vertebrobasilar arterial system with MRA or
1 B-R atrial fibrillation (AF) and atrial flutter and to
CTA can be effective to identify atheroscle-
assess for other concomitant cardiac condi-
rotic disease, dissection, moyamoya, or other
tions.40,41
etiologically relevant vasculopathies.73–75
2. In patients with ischemic stroke or TIA, a diag-
12. In patients with ischemic stroke and a
nostic evaluation is recommended for gaining
treatment plan that includes anticoagulant
insights into the etiology of and planning opti-
1 B-NR therapy, CT or MRI of the brain before
mal strategies for preventing recurrent stroke, 2b B-NR
therapy is started may be considered to
with testing completed or underway within 48
assess for hemorrhagic transformation and
hours of onset of stroke symptoms.42–45
final size of infarction.76
3. In patients with symptomatic anterior
13. In patients with ESUS, transesophageal
circulation cerebral infarction or TIA who are
echocardiography (TEE), cardiac CT,
candidates for revascularization, noninva-
or cardiac MRI might be reasonable to
1 B-NR sive cervical carotid imaging with carotid 2b C-LD
identify possible cardioaortic sources
ultrasonography, CT angiography (CTA), or
of or transcardiac pathways for cerebral
magnetic resonance angiography (MRA) is
embolism.57,77–79
recommended to screen for stenosis.46–50
14. In patients with ischemic stroke or TIA in
4. In patients suspected of having a stroke or
whom patent foramen ovale (PFO) closure
TIA, CT or MRI of the brain is recommended
1 B-NR would be contemplated, TCD (transcranial
to confirm the diagnosis of symptomatic 2b C-LD
Doppler) with embolus detection might
ischemic cerebral vascular disease.51–53
be reasonable to screen for right-to-left
5. In patients with a confirmed diagnosis of shunt.57,80
symptomatic ischemic cerebrovascular
disease, blood tests, including complete
blood count, prothrombin time, partial throm- Synopsis
1 B-NR boplastin time, glucose, HbA1c, creatinine,
and fasting or nonfasting lipid profile, are
Patients presenting with signs and symptoms of acute
recommended to gain insight into risk stroke will undergo an evaluation tailored to ensure that,
factors for stroke and to inform therapeutic when appropriate, they receive reperfusion therapy (Fig-
goals.54,55
ure 2). Imaging recommendations based on acute treatment
CLINICAL STATEMENTS
AND GUIDELINES
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Figure 2. Algorithm for evaluating patients with a clinical diagnosis of stroke for the purposes of optimizing prevention of
recurrent ischemic stroke.
Colors correspond to Class of Recommendation in Table 3. CT indicates computed tomography; CTA, computed tomography angiogram; ECG,
electrocardiogram; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PFO, patent foramen ovale; SOE, source of embolism;
TCD, transcranial Doppler; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography; and US, ultrasound. *Basic laboratory tests
include complete blood count, troponin, prothrombin time, partial thromboplastin time, glucose, hemoglobin A1c, creatinine, and fasting or nonfasting lipid
profile. †When a patient has a transient neurological deficit clinically characteristic of transient ischemic attack, the patient should be evaluated in the
same manner as a patient who has an ischemic stroke with a corresponding cerebral infarct on imaging. ‡TTE, TEE, TCD, cardiac MRI, or cardiac CT.
considerations overlap with, but are not identical to, imaging Confirmation of stroke diagnosis may require follow-up head
recommendations based on secondary stroke prevention imaging because of poor sensitivity of noncontrast CT for
considerations. Recommendations presented in this guide- small or hyperacute infarcts. Some conditions associated
line focus on evaluations done for the purposes of confirming with stroke and with specific therapies are common (eg,
the diagnosis of stroke and characterizing its pathomecha- AF), whereas others are relatively rare (eg, endocarditis).
nism by identifying potential sources of cardioembolism, The variable yield of testing means that treating physicians
thromboembolism from large artery atherosclerosis, dissec- need to exercise judgment on the likelihood that a test will
tion, or other disease processes such as hypercoagulability. alter management in a given clinical situation.
1. An ECG is a simple, noninvasive means of diag- will be given an alternative diagnosis with the help of
AND GUIDELINES
nosing AF in patients with acute stroke. A meta- brain imaging.51 About 13% of patients with stroke
analysis through 2014 found that the proportion or TIA thought to have a nonstroke diagnosis for
of patients diagnosed with poststroke AF in the their neurological symptoms will be given the diag-
emergency department by electrocardiography nosis of stroke with the help of brain imaging.52,53 A
was 7.7% (95% CI, 5.0–10.8).40 An ECG can also prospective, multicenter multinational study showed
detect pertinent comorbidities that may have thera- that, in patients with recent minor focal nonmotor,
peutic implications. About 3% of patients present- nonspeech neurological deficits, diffusion-weighted
ing with acute stroke also have acute myocardial MRI detected acute infarction in 13.5% and that this
infarction (MI).41 finding had prognostic relevance because detection
2. Effective secondary prevention requires timely evalua- of infarction was associated with a >6-fold increase
tion of stroke mechanism, with the intent of identifying in the risk of recurrent stroke at 1 year.85
modifiable risk factors. The risk of recurrent stroke in 5. As reported in this guideline, control of hyperten-
the short term and long term varies by stroke mech- sion (Section 4.2), blood glucose (Section 4.4), and
anism.42–45 The risk of stroke within 90 days after a lipids (Section 4.3) have been proven effective for
first stroke is ≈5%, but the risk can vary greatly from reducing the risk of ischemic stroke; thus, assess-
>10% to <1%, depending in part on mechanism.42 ment of whether the patient is at therapeutic goal
Symptomatic carotid stenosis and AF are important to for these metabolic parameters helps to optimize
diagnose in a timely fashion to allow implementation therapy. Fasting is not routinely required for lipid
of specific treatments with proven efficacy. testing because the lipid profile components under
3. Because patients with symptomatic high-grade fasting and nonfasting conditions differ in non-
cervical carotid stenosis are candidates for revas- clinically significant degrees (the exception being
cularization, it is appropriate to screen for stenosis patients with nonfasting triglycerides of >440
in any patient who may have such stenosis. Initial mg/dL, who should have fasting levels drawn).86
testing for carotid stenosis should be done with a HbA1c determination can detect new cases of
noninvasive test such as CTA, MRA, or ultrasonog- type 2 diabetes (T2D) in ≈11.5% of patients pre-
raphy rather than digital subtraction angiography, senting with acute ischemic stroke and prediabe-
with case series finding a risk of stroke ranging tes in 36.2%.54 Abnormal blood testing can help
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from 0.3% to 3.0%.81–83 Experienced stroke cen- to stratify risk so that physicians can concentrate
ters typically have a risk of stroke attributable efforts of prevention on those at highest risk. In
to digital subtraction angiography of <0.5%. For patients with lacunar infarction, chronic kidney dis-
patients at high risk of carotid artery stenosis who ease is associated with a 50% increase in risk of
can undergo surgery without delay, immediate recurrent stroke.55 Testing prothrombin time and
CTA is the most cost-effective strategy.84 Using activated partial thromboplastin time screens for
consensus interpretation criteria, carotid ultra- diverse clotting and bleeding disorders that are
sonography has a sensitivity of 38.8%, specific- relevant to active management of patients with
ity of 91.6%, and accuracy of 87.1% for ≥70% acute stroke. An isolated prolonged activated par-
stenosis.47 With the use of a 70% cutoff value tial thromboplastin time can be seen with heparin
for carotid stenosis, CTA and digital subtrac- use, lupus anticoagulant, or clotting factor deficien-
tion angiography were in agreement in 78 of 81 cies.87 All of these states or exposures are relevant
vessels (95% CI, 90–99) in a series of patients to long-term management of patients with stroke.
with stroke or TIA.48 Compared with digital sub- Liver failure, malnutrition, malabsorption, myelopro-
traction angiography, a meta-analysis of studies liferative diseases, and disseminated intravascular
performed in 2008 found the overall sensitivity of coagulation can cause acquired factor deficiencies
time-of-flight MRA for the detection of 70% to and would have relevance in managing patients
99% internal carotid artery (ICA) stenoses to be with stroke.88
91.2% with a specificity of 88.3%, whereas the 6. Many diseases with specific indications for specific
sensitivity of contrast-enhanced MRA was 94.6% treatment such as patent foramen ovale (PFO),
with a specificity of 91.9%.49 papillary fibroelastoma, myxoma, endocarditis, and
4. An accurate diagnosis of ischemic stroke or TIA is intracardiac thrombi are diagnosed by echocardiog-
essential for justifying and optimizing stroke preven- raphy.89 Transthoracic echocardiography is preferred
tion. Many patients will have had brain imaging in over TEE for the detection of left ventricular (LV)
the acute setting to exclude stroke mimics and to thrombus, but TEE is superior to transthoracic echo-
include stroke “chameleons” (stroke initially thought cardiogram in detecting left atrial thrombus, aortic
to be an alternative diagnosis). About 15% to 25% atheroma, prosthetic valve abnormalities, native
valve abnormalities, atrial septal abnormalities, and the use of MRI in patients with TIA reported in
CLINICAL STATEMENTS
cardiac tumors.89 A systematic review that included 2014 concluded that MRI was generally not cost-
AND GUIDELINES
65 studies concluded that transthoracic echocar- effective, although there might be utility to MRI
diography in the second harmonic is cost-effective in this population if the imaging is done >1 week
relative to TEE.56 TEE findings will change manage- after onset of symptoms and with a blood-sensitive
ment in ≈1 in 7 patients with ESUS.57 sequence, if the clinical team is considering unusual
7. Randomized trials show that longer heart monitoring causes of symptoms, or if symptoms are related to
in patients with cryptogenic stroke results in higher ipsilateral high-grade stenosis.69 Predictive scores
detection rates for AF. A randomized study of an that incorporate MRI findings (eg, ABCD2-I and
insertable cardiac monitor versus conventional follow- ABCD3-I) are better able to discriminate high risk
up in patients with cryptogenic stroke found that by of early stroke from low risk of early stroke than
6 months AF had been detected in 8.9% of patients predictive scores that do not incorporate MRI find-
in the insertable cardiac monitor group versus 1.4% ings (eg, ABCD2) when MRI is done within 7 days
of patients in the control group (95% CI, 1.9–21.7; of onset of symptoms.67
P<0.001).58 A randomized study of patients ≥55 10. Stroke can be the initial manifestation of a host
years of age who had had a cryptogenic ischemic of systemic conditions that either are treatable by
stroke or TIA within the previous 6 months found themselves or must be identified to avoid misdi-
AF lasting ≥30 seconds in 16.1% in the interven- rected ineffective or harmful therapies. The pretest
tion group monitored with a 30-day event triggered probability of finding a diagnostically meaningful
recorder compared with 3.2% in the control group abnormality for many of these tests will depend
who had standard monitoring, including 24-hour on clinical suspicion informed by demographic
electrocardiography (95% CI, 8.0–17.6; P<0.001).59 variables (eg, age), medical history, physical find-
Repeated Holter electrocardiographic monitoring in ings, and results of basic testing. For example, the
patients ≥60 years of age with recent stroke signifi- yield of testing for a hypercoagulable state is low
cantly increases the likelihood of AF detection over for patients >50 years of age.90 Patients present-
routine monitoring (14% versus 5%; P=0.002).60 ing with stroke will have echocardiographically con-
Improvement in patient outcomes with long-term firmed infectious endocarditis in 1.7% of cases, and
rhythm monitoring has not been established. an initial C-reactive protein of at least 10 mg/L
8. A systematic review in 2012 found no evidence that dramatically increased the likelihood of infectious
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multimodal MRI when used purely for diagnostic endocarditis (odds ratio [OR], 22).70 Use of cocaine
purposes improves outcomes, although there was within the prior 24 hours increases the risk of stroke
limited evidence that it can change management.61 in young adults by >6-fold.71 Toxicology testing for
The use of MRI for in-hospital stroke evaluation cocaine and other drugs of abuse should be done at
grew dramatically from 1999 to 2008, varying widely the time of presentation.91,92 When diagnostic algo-
by state.61 The growth was likely related to wide- rithms were used, monogenic causes of stroke were
spread appreciation of the diagnostic yield of follow- detected in 7% in 1 population-based study.72
up brain imaging with MRI within 1 to 2 days. About 11. Identification of symptomatic intracranial athero-
one-quarter of acute stroke cases with an initially sclerotic disease supports treatment to aggressive
negative head CT will have an MRI with evidence of antiatherosclerotic targets and is often seen as
acute/subacute infarction.62 An emergency depart- an indication for dual antiplatelet therapy (DAPT).
ment series of 252 patients presenting with atypical Both MRA73 and CTA74 have been shown to reli-
stroke symptoms and a negative CT found that 29 ably exclude high-grade intracranial atherosclerotic
patients (11.5%) had acute ischemic stroke on MRI stenosis (ICAS) when digital subtraction catheter
obtained within 24 hours.63 For posterior circulation angiography was used as the reference test. Early
strokes in particular, a follow-up MRI may be appro- identification of symptomatic extracranial vertebro-
priate to confirm a diagnosis even when the initial basilar stenosis identifies patients at high risk of
MRI is negative.64 MRI with diffusion-weighted imag- recurrent stroke.75
ing is also particularly helpful in evaluating patients 12. Hemorrhagic transformation is often seen as a con-
with low-risk TIA and mild neurological symptoms.85 traindication to early (<2 weeks of stroke onset) oral
Confirming the diagnosis of acute ischemic stroke anticoagulation, although no randomized trial has
with brain imaging may help with patient education been done that directly addresses the question. A
and prognostication, which in turn may promote multicenter, prospective international study of con-
adherence to a prescribed prevention regimen.65 secutive patients with acute ischemic stroke and AF
9. About one-third of patients with stroke symptoms that included a second CT 24 to 72 hours after stroke
for <24 hours have a diffusion-weighted imaging– onset found that the presence of hemorrhagic trans-
positive lesion.66 A cost-effectiveness analysis of formation led to an average delay in anticoagulation
of 12 days and that this delay was not associated stroke are being discovered through observational stud-
CLINICAL STATEMENTS
with a significant rise in the rate of recurrent stroke.76 ies, but several knowledge gaps exist relating to the rela-
AND GUIDELINES
Large infarcts, for example, the entire territory of tive importance of testing to identify uncommon or rare
either the middle, anterior, or posterior cerebral artery, conditions associated and potentially causally linked with
had nearly twice the risk of hemorrhagic transforma- recurrent stroke. The less prevalent a comorbid condition
tion as smaller infarcts in this series.76 is among patients with stroke, the more challenging it is
13. TEE, cardiac CT, and cardiac MRI will provide to execute successfully a well-powered clinical trial to
actionable information in a minority of patients with provide high levels of evidence justifying the diagnostic
acute stroke. In a prospective study of 61 patients testing. There are several clinical conditions associated
with ESUS who underwent investigation with TEE with ischemic stroke for which trial evidence would be
(mean age, 44±12 years; 49% men), TEE revealed helpful to guide therapy:
additional findings in 52% (95% CI, 40–65) of the • To better prevent cardioembolism, it would be
study population, and findings changed manage- helpful to have trials that clarify optimal duration
ment (initiation of anticoagulation therapy, admin- of heart rhythm monitoring, determine the clinical
istration of intravenous antibiotic therapy, and PFO significance of brief episodes of AF, and define the
closure) in 10 patients (16% [95% CI, 9–28]).57 In precise role of cardiac CT/MRI and microembolus
a meta-analysis of 3562 patients with acute isch- detection with TCD.
emic stroke, the pooled rate of anticoagulation • In terms of large artery disease, much is known
therapy attributed to abnormal TEE findings was about atherosclerotic stenosis, but far less is known
8.7% (95% CI, 7.3–10.4).57 In a single-center ret- about the importance of detecting microemboli
rospective study of 1458 patients with suspected with TCD or identifying characteristics of unstable
cardioembolic stroke, findings on TEE significantly plaque such as intraplaque hemorrhage.
changed management in 16.7%.77 Smaller series • Further research is also needed to clarify the clinical
have found that the addition of TEE to a standard significance of detecting nonatherosclerotic condi-
stroke workup identified an indication for antico- tions, including carotid dissection, fibromuscular dys-
agulation in 20% to 22.6% of cases.93,94 Cardiac plasia, and carotid webs. Other uncommon causes of
CT has a modest sensitivity (72%) and high speci- stroke such as CNS vasculitis and Susac syndrome
ficity (95%) for detecting potential embolic source suffer from a lack of well-designed clinical trials to
in patients with cryptogenic stroke in whom TEE is guide therapies.
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drawn from high-risk CVD and coronary heart disease Table 4. Dietary Details of Typical Mediterranean-Type Diets
CLINICAL STATEMENTS
populations, or dietary effects on stroke risk factors, Mediterranean diet (summarized) DASH diet (summarized)
AND GUIDELINES
for example, BP and cholesterol.98 Epidemiological High monounsaturated/saturated Limited saturated fat and cholesterol
diet and nutrition studies identify protective effects fat ratio (use of olive oil as main and emphasized nut consumption
for stroke from regular consumption of fish,99 high cooking ingredient and/or con-
sumption of other traditional foods
consumption of fruit and vegetables100,101 and fiber,102 high in monounsaturated fats such
and following the Mediterranean diet96 and the DASH as tree nuts)
(Dietary Approaches to Stop Hypertension) diet,103 High intake of plant‐based foods, Emphasizes fruit, vegetables, and
reflected in the AHA/American College of Cardiology including fruits, vegetables, and legumes consumption
(ACC) guideline on lifestyle management to reduce legumes
cardiovascular risk.26 PAR for stroke for the lowest High consumption of whole grains Emphasizes whole grains
and cereals
versus the highest tertile of the modified Alternative
Increased consumption of fish
Healthy Eating Index is 18.8% (99% CI, 11.2–29.7).5a
In the United States, the REGARDS cohort study (Rea- Low consumption of meat and Limits red and processed meats
meat products
sons for Geographic and Racial Differences in Stroke Discourages red and processed
Study) identified higher adherence to the Southern diet meats
(high in added fats, fried food, eggs, processed meats, Low to moderate red wine con-
and sugar-sweetened beverages) was associated with sumption
a 39% increased risk of stroke (hazard ratio [HR], 1.39 Moderate consumption of milk and Emphasizes fat-free/low-fat dairy
[95% CI, 1.05–1.84]).105 Sodium and potassium con- dairy products
sumption, unlike many vitamins and minerals in foods, Discourages soda drinks, pastries, Limits sweets, added sugars, salt,
sweets, commercial bakery prod- and sugar-sweetened beverages.
can be adjusted without altering overall dietary pat- ucts, and spread fats
terns.26 Both high potassium consumption106 and low
DASH indicates Dietary Approaches to Stop Hypertension.
salt consumption107 are associated with lower stroke Summarized Mediterranean Diet95,96; summarized DASH diet.103
rates. No evidence supports potassium-based inter-
ventions for CVD reduction26; no dietary interventions a 17% lower likelihood of ischemic stroke in
of increased potassium consumption alone in stroke participants without hypercholesterolemia (95%
survivors were identified. Overnutrition is addressed in CI, 0.72–0.96) and 10% lower likelihood in par-
Section 4.5, Obesity. ticipants with hypercholesterolemia (95% CI,
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0.81–0.99).
Recommendation-Specific Supportive Text 2. A meta-analysis of 13 prospective studies and
1. The interventional arms of the PREDIMED trial >11 000 vascular events (N=177 025 participants;
(Prevención con Dieta Mediterránea), compris- follow-up, 3.5–19 years) identified that higher
ing the Mediterranean diet with either supple- levels of habitual salt intake are associated with
mental extravirgin olive oil or tree nuts (Table 4) greater stroke risk (relative risk [RR], 1.23 [95%
compared with a low-fat diet,95 provide evidence CI, 1.06–1.43]).107 A Japanese population-based
of a reduction in stroke events in individuals study identified that in men the highest compared
with high cardiovascular risk (HR, 0.60 [95% CI, with the lowest tertile of sodium intake recorded
0.45–0.80]), rated moderate-quality evidence.96 was significantly positively associated with death
The primary end point (MI, stroke. or cardiovas- resulting from ischemic stroke (adjusted HR, 3.22
cular death) identified adjusted HRs of 0.72 [95% CI, 1.22–8.53]).109 Meta-analysis in those
(95% CI, 0.54–0.95) for the Mediterranean diet with established CVD identified through long-
with olive oil supplementation and 0.69 (95% CI, term follow-up of participants in 5 salt-reducing
0.53–0.91) with nut supplementation compared trials97 reported a reduction of 1 g/d sodium (2.5
with the control diet. Evidence in secondary pre- g/d salt) is associated with a 20% reduction in
vention is drawn from the Lyon Diet Heart trial further cardiovascular events (RR, 0.80 [95% CI,
of the Mediterranean diet with supplemental 0.66–0.97]). The DASH-sodium trial98 identified
canola compared with a usual post-MI prudent that for a typical US diet in the 1990s (the con-
diet, producing low-quality evidence of reduced trol diet), a reduction in sodium intake from 3.3 to
CVD mortality and total mortality (adjusted HR, 2.4 g/d reduced systolic BP (SBP) by 2.1 mm Hg
0.35 [95% CI, 0.15–0.82] and 0.44 [95% CI, (P<0.001), and further reducing sodium intake
0.21–0.92], respectively) in a coronary heart from 2.4 to 1.5 g/d yielded additional reductions
disease population.96 One study in first stroke of 4.6 mm Hg (P<0.001). The DASH diet was
and matched control cases108 shows each unit associated with a significantly lower SBP at each
(1 of 55) in MedDietScore is associated with sodium level than the control diet.
Recommendations for Physical Activity lifestyle-based programs. These are addressed in Section
AND GUIDELINES
Referenced studies that support recommendations are summarized in 6.2, Interventions Aimed at Changing Patient Behavior.
online Data Supplements 5 and 6.
COR LOE Recommendations Recommendation-Specific Supportive Text
1. In patients with stroke or TIA who are capable of
1. Planned analysis of participants in the medical
physical activity, engaging in at least moderate- management arm (n=227) of the SAMMPRIS trial
intensity aerobic activity for a minimum of 10 min- (Stenting and Aggressive Medical Management
utes 4 times a week or vigorous-intensity aerobic
1 C-LD
activity for a minimum of 20 minutes twice a week
for Preventing Recurrent Stroke in Intracranial
is indicated to lower the risk of recurrent stroke Stenosis)110 at the 3-year follow-up identified 49
and the composite cardiovascular end point of primary end point events (stroke, MI, and vascular
recurrent stroke, MI, or vascular death.110
death), including 32 ischemic strokes. For the com-
2. In patients with stroke or TIA who are able and
willing to increase physical activity, engaging
posite end point at 3 years, participants who were
in an exercise class that includes counseling not in target for physical activity levels, defined as
2a B-R to change physical activity behavior can be a Physician-Based Assessment and Counselling for
beneficial for reducing cardiometabolic risk fac-
tors and increasing leisure time physical activity
Exercise score of ≥4, had a significantly higher odds
participation.111–114 of stroke, MI, and vascular death than those who
3. In patients with deficits after stroke that impair did achieve this target (OR, 5.4 [95% CI, 2.4–12.1]).
their ability to exercise, supervision of an The Physician-Based Assessment and Counselling
exercise program by a health care professional
2a C-EO such as a physical therapist or cardiac reha-
for Exercise score of 4 equates to 10-minute bouts
bilitation professional, in addition to routine of moderate physical activity (sufficient to break a
rehabilitation, can be beneficial for secondary sweat or to noticeably raise heart rate, eg, walking
stroke prevention.
briskly, using an exercise bicycle) up to 4 times a
4. In individuals with stroke or TIA who sit for
week or 20-minute bouts of vigorous activity (eg,
long periods of uninterrupted time during
the day, it may be reasonable to recommend jogging) up to twice a week. For the end point of
2b B-NR breaking up sedentary time with intervals as ischemic stroke, physical activity was the only risk
short as 3 minutes of standing or light exer-
factor associated with lower stroke events; those
cise every 30 minutes for their cardiovascular
health.115 who were out of target for defined physical activ-
ity levels had an OR of 6.7 (95% CI, 2.5–18.1) for
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systematic reviews identified favorable effects for standing every 30 minutes decreased SBP by
CLINICAL STATEMENTS
exercise-based interventions with counseling com- 5.0 mm Hg (95% CI, −7.9 to 2.0) and 4.2 mm Hg
AND GUIDELINES
pared with usual care for reduction in SBP (MD, (95% CI, −7.2 to −1.3), respectively, compared
−5.3 mm Hg [95% CI, −9.0 to −1.6]; I 2=46%; with 8 hours of uninterrupted sitting. No effect by
N=228112; and MD, −5.32 [95% CI, −9.46 to condition for diastolic BP or plasma fibrinogen lev-
−1.18]).113 Exercise interventions initiated within 6 els was observed.115
months of stroke/TIA have a larger effect on SBP 4.1.3. Smoking Cessation
(−8.46 mm Hg [95% CI, −12.18 to −4.75]; I 2=0%)
than those initiated after 6 months (−2.33 mm Hg Recommendations for Smoking Cessation
[95% CI, −3.94 to −0.72]; I 2=0%).130 Referenced studies that support recommendations are summarized in
online Data Supplements 7 and 8.
3. Much of the evidence supporting exercise-based
programs for stroke secondary prevention is based COR LOE Recommendations
on participants with ambulatory stroke or TIA.131–134 1. In patients with stroke or TIA who smoke
tobacco, counseling with or without drug
Many stroke survivors, however, encounter physical 1 A therapy (nicotine replacement, bupropion, or
and environmental barriers to engaging in regular varenicline) is recommended to assist in quit-
physical activity for health. Neurological weakness, ting smoking.139–142
altered perception or balance, or impaired cogni- 2. Patients with stroke or TIA who continue to
smoke tobacco should be advised to stop
tion, for example, may negate their participation in
1 B-NR smoking (and, if unable, to reduce their
conventional exercises programs. Adaptive equip- daily smoking) to lower the risk of recurrent
ment and skilled personnel can help to overcome stroke.143–146
many of these barriers to participation. A systematic 3. In patients with stroke or TIA. avoidance of
review of inclusive studies of exercise-based pro- 1 B-NR
environmental (passive) tobacco smoke is
recommended to reduce risk of recurrent
grams in stroke identified that exercise programs stroke.147–150
are safe and feasible to implement in nonambula-
tory individuals, but to date, no evidence supports Synopsis
their impact on recurrent stroke,135 Promising pilot Cigarette smoking is an independent, potent, and dose-
studies of aerobic exercise programs inclusive of respondent risk factor for first ischemic stroke147,151,152
those with motor disability have shown that with and silent cerebral infarction,153 approximately doubling
adequate pre-exercise screening they are safe and
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[95% CI, 1.27–1.48]), with comparable findings 3. Primary prevention data highlight the risk of
CLINICAL STATEMENTS
in patients with CVD (RR, 1.42 [95% CI, 1.29– exposure to environmental tobacco smoke, also
AND GUIDELINES
1.56]) and interventions initiated in rehabilitation called passive smoking or secondhand smoke,
hospitals (RR 1.71 [95% CI, 1.37–2.14]). Adding on stroke rates in nonsmokers. The most recent
nicotine replacement therapy to the interven- meta-analysis identified that environmental
tion increased cessation rates compared with tobacco smoke exposure compared with no
intensive counseling alone (RR, 1.54 [95% CI, exposure can increase the overall risk of stroke
1.34–1.79]).139 High-quality evidence supports by 45% (OR, 1.45 [95% CI, 1.0–2.11]).147 Other
combined pharmacotherapy (nicotine replace- reports identify comparative rates of an OR of
ment therapy, varenicline, or bupropion) and 1.46 (95% CI, 1.05–2.3), 148 an OR of 1.82 (95%
behavioral interventions compared with usual CI, 1.34–2.49), 149 and an RR of 1.23 (95%
care, brief advice, or less intensive counseling CI, 1.16–1.31). 150 RR estimates were similar
in smoking cessation (RR, 1.83 [95% CI, 1.68– when ever exposure rather than current expo-
1.98]) in health care and community settings.140 sure or total rather than spousal exposure was
Group behavior therapy programs for smoking used, and when dose-response estimates were
cessation are superior to self-help programs pooled, the combined RR for the highest expo-
but are not superior to individual counseling of sure level was 1.56 (95% CI, 1.37–1.79). 150
equal intensity.140 In stroke trials, multibehav- Data from the US National Health and Nutrition
ioral interventions have been associated with a Examination Surveys identified that high expo-
greater likelihood of smoking cessation in the sure to environmental tobacco smoke for stroke
STOP trial (Stroke Prevention Trial in Sickle Cell survivors was associated with an adjusted HR
Anemia; OR, 2.31 [95% CI, 1.99–1.33]) 141 and for all-cause mortality of 1.72 (95% CI, 1.02–
an increase of 17% in cessation rates compared 2.91), with a dose-dependent relationship
with usual care (P=0.001) in the INSPiRE-TMS observed.148 No trials of interventions to reduce
trial (Intensified Secondary Prevention Intending exposure to environmental tobacco smoke as
a Reduction of Recurrent Events in TIA and a stroke secondary prevention strategy were
Minor Stroke Patients).142 identified.
2. Registry-based stroke studies point to an
4.1.4. Substance Use
≈2-fold increase in recurrent stroke rates for
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smokers. The Nanjing Stroke Registry Program Recommendations for Substance Use
Referenced studies that support recommendations are summarized in
(N=3069) reported 9.5% recurrence rates at online Data Supplements 9 and 10.
2.4 years. With nonsmokers as the reference, COR LOE Recommendations
adjusted HRs for stroke recurrence were 1.93
1. Patients with ischemic stroke or TIA who drink
(95% CI, 1.43–2.61) in persistent smokers, >2 alcoholic drinks a day for men or >1 alco-
1.31 (95% CI, 0.99–1.75) in quitters since 1 B-NR holic drink a day for women should be coun-
seled to eliminate or reduce their consumption
stroke, and 1.16 (95% CI, 0.75–1.79) in for-
of alcohol to reduce stroke risk.141,161–163
mer smokers, delineating the effects in smok-
2. In patients with stroke or TIA who use
ers, former smokers and quitters. HRs for stimulants (eg, amphetamines, amphetamine
stroke recurrence ranged from 1.68 (95% CI, derivatives, cocaine, or khat) and in patients
1.14–2.48) in those who smoked 1 to 20 cig- with infective endocarditis (IE) in the context
1 C-EO
of intravenous drug use, it is recommended
arettes daily to 2.72 (95% CI, 1.36–5.43) for that health care providers inform them that
those who smoked >40 cigarettes daily.143 The this behavior is a health risk and counsel them
Cardiovascular Health Study (N=546) similarly to stop.
identifies a substantially increased risk of stroke 3. In patients with stroke or TIA who have a
substance use disorder (drugs or alcohol),
recurrence in elderly smokers at a median 1 C-EO
specialized services are recommended to help
3.2-year follow-up (HR, 2.06 [95% CI, 1.39– manage this dependency.
3.56]).144 A longitudinal study in Han Chinese
individuals with ischemic stroke (N=421) iden- Synopsis
tified an adjusted HR for smokers at 1 year of The PAR for stroke associated with harmful alcohol
2.15 (95% CI, 1.26–3.67). 145 The SMART study consumption (>30 drinks per month or binge drinking
(Second Manifestations of Arterial Disease; >5 drinks per day at least once per month) is 3.8%,
N=4673) identified that smoking cessation (99% CI, 0.9–14.4).5a In addition, binge drinking in
increases life expectancy (average 5 years) and those with known hypertension markedly increases
recurrent major atherosclerotic cardiovascular cardiovascular mortality risk and is cumulative (HR,
events occur 10 years later compared with per- 4.41 [95% CI, 1.38–14.1] for ≥6 drinks; HR, 12.7
sistent smokers. 146 [95% CI, 3.47–46.5] for ≥12 drinks on 1 occasion).164
Alcohol consumption and ischemic stroke have a 2.8–69.0]) and crack cocaine (adjusted OR, 11.2
CLINICAL STATEMENTS
J-shaped relationship, regardless of sex.162,163 Stroke [95% CI, 1.1–118.8]).176 Khat use is associated with
AND GUIDELINES
risk is associated with heavy alcohol consumption (>4 stroke (OR, 2.7 [95% CI, 1.3–5.9).171 Although the
drinks in a day or >14 drinks a week in men; >3 drinks CARDIA study (Coronary Artery Risk Development
a day or >7 drinks a week in women).18,165 The risk of in Young Adults) identified no significant risk for
harmful alcohol consumption in recurrent stroke is not stroke/TIA as a result of cumulative lifetime can-
well defined; >60 g/d (>4 drinks a day) has been asso- nabis use of ≥5 years or recent use,177 increasing
ciated with stroke recurrence at 90 days,161 matching evidence of an association is emerging in younger-
a meta-analysis of an RR of 1.69 (95% CI, 1.34–2.15) onset stroke. Acute ischemic stroke hospitalization
for ischemic stroke at that consumption level.166 The is higher among cannabis users (OR, 1.41 [95%
World Drug Report (2017) relates a 23% increase in CI, 1.31–1.51]),178 and the US Centers for Disease
the number of estimated drug users in 11 years, reach- Control and Prevention179 identified that young
ing 255 million in 2015.167 A sharp increase in US adults (age, 18–44 years) with recent cannabis use
stroke rates attributable to IE was noted to coincide have higher odds of stroke compared with nonus-
with the emergent opioid epidemic.168 Evidence sup- ers (adjusted OR, 1.82 [95% CI, 1.08–3.10]), which
porting an association between drug use and ischemic increases among frequent cannabis users (>10 d/
stroke, notably in stimulants and developing in canna- mo; adjusted OR, 2.45 [95% CI, 1.31–4.60]).
bis use, is emerging18,169–171 and must be addressed in 3. An alcohol or drug use disorder is a chronic relaps-
stroke prevention strategies. ing brain disease characterized by compulsive use,
loss of control over intake, and a negative emo-
Recommendation-Specific Supportive Text
tional state when not using. Therefore, special-
1. Although behavioral interventions, for example,
ized care is required to manage the substance
the STOP (secondary stroke prevention) trial, can
dependency. In alcohol use disorders, established
show decreased alcohol consumption levels,141
screening and counseling strategies such as those
their impact on recurrent stroke is not delineated.
described in the 2004 US Preventive Services
High alcohol intake (>60 g/d), however, has been
Task Force update are recommended. Long-term
identified as an independent risk factor for stroke
treatment strategies, including medication, psy-
recurrence at 90 days in minor stroke/TIA.161 In
chological counseling, and community-based pro-
ischemic stroke, low to moderate alcohol con-
grams, are effective in the management of drug
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• To establish optimal physical activity prescription In 2017, the AHA/ACC hypertension guideline defined
CLINICAL STATEMENTS
(frequency, intensity, time, and type [aerobic, resis- hypertension as BP consistently >130/80 mm Hg.29
AND GUIDELINES
tance, mixed]) for secondary prevention. Potential Yet, for patients with prior stroke or TIA, there is con-
synergistic effects of aerobic exercise combined cern that a possible lower BP threshold may increase the
with resistance-based strengthening exercises in risk of stroke, or a J-curve effect. In the past, post hoc
stroke secondary prevention are unknown. analyses of RCTs, meta-analyses, and population-based
• To further develop stroke registries to address studies of patients with cerebrovascular disease have
knowledge gaps in recurrent stroke, including the shown an inconsistent relationship between achieved
contribution of continued smoking (currently lim- SBP <120 mm Hg and poor outcomes.200–204 New data
ited to Asian and older populations), heavy alcohol from RCTs and large meta-analyses now provide com-
consumption (currently lacking), and substance use pelling evidence that neurologically stable patients with
(currently lacking). cerebrovascular disease also benefit from a BP goal of
• To identify the longer-term cardiovascular conse- <130/80 mm Hg and that BP targets for stroke preven-
quences of newer tobacco products, for example, tion should be more aligned with targets for prevention
electronic nicotine delivery systems (electronic cig- of other cardiovascular conditions. There is insufficient
arettes/vaping), which are not currently known. evidence to recommend a lower limit of BP within the
• To consider the dual use of electronic nicotine normal range for patients with prior stroke. Additional
delivery systems (electronic cigarettes/vaping) with research is needed to determine the optimal timing for
combustible cigarettes in studies relating to the BP reduction after stroke205; therefore, these recommen-
longer-term cardiovascular consequences, includ- dations pertain to outpatient management of neurologi-
ing stroke and recurrent stroke. cally stable patients.
• To examine the association between ischemic
Recommendation-Specific Supportive Text
stroke and recurrent stroke and therapeutic canna-
1. Diuretics, angiotensin-converting enzyme inhibi-
bis use (currently unknown) and recreational can-
tors, and angiotensin receptor blockers have dem-
nabis use (currently limited to young adults only and
onstrated benefit in RCTs or systematic reviews of
using surveillance data).
RCTs.185–188,206 Although calcium channel blockers
are recommended for the treatment of hyperten-
4.2. Hypertension sion, there are limited data on their efficacy for
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targets (pooled RR for recurrent stroke, 0.80 [95% 4.3. Treatment of Hyperlipidemia for Secondary
CLINICAL STATEMENTS
CI, 0.63–1.00]). In addition, the largest meta-analy- Prevention of Stroke
AND GUIDELINES
sis to date including >40 000 patients from 14 RCTs
4.3.1. Treatment and Monitoring of Blood Lipids for
showed a significantly lower rate of recurrent stroke
Secondary Stroke Prevention
in patients with an achieved SBP of <130 mg Hg
Recommendations for Treating and Monitoring Hyperlipidemia
compared with higher SBP groups.194 It should be
Referenced studies that support recommendations are summarized in
noted that for patients with intracranial large artery online Data Supplement 13.
atherosclerosis, a higher BP target may be appropri- COR LOE Recommendations
ate (see Section 5.1.1). Treatment
3. The magnitude of BP lowering appears to be
1. In patients with ischemic stroke with no known
more important for risk reduction than the coronary heart disease, no major cardiac sources
class of antihypertensive agent used.188,189,195,196 1 A of embolism, and LDL cholesterol (LDL-C) >100
mg/dL, atorvastatin 80 mg daily is indicated to
Therefore, individual patient characteristics that
reduce risk of stroke recurrence.208,209
may affect the safety and efficacy of treatment
2. In patients with ischemic stroke or TIA and ath-
(eg, T2D, chronic kidney disease, AF) should be erosclerotic disease (intracranial, carotid, aortic,
taken into account in the selection of antihyper- 1 A
or coronary), lipid-lowering therapy with a statin
tensive agents. and also ezetimibe, if needed, to a goal LDL-C
of <70 mg/dL is recommended to reduce the
4. The recommended threshold BP of >130/80 risk of major cardiovascular events.210
mm Hg for starting antihypertensive medications 3. In patients with ischemic stroke who are
is informed by the baseline BPs of patients with very high risk (defined as stroke plus another
cerebrovascular disease studied in trials of BP major ASCVD or stroke plus multiple high-risk
conditions), are taking maximally tolerated
treatment. Among the 4 RCTs comparing inten- 2a B-NR statin and ezetimibe therapy and still have an
sive and standard BP targets in patients with LDL-C >70 mg/dL, it is reasonable to treat
prior cerebrovascular disease, the RESPECT190, with PCSK9 (proprotein convertase subtili-
sin/kexin type 9) inhibitor therapy to prevent
PAST-BP,191 and PODCAST193 trials included ASCVD events.211–213
patients with baseline SBPs as low as 125 mm Hg. Monitoring
In PAST-BP,191 ≈50% of patients had baseline
4. In patients with stroke or TIA and hyperlip-
SBP <140 mm Hg. Similarly, in the PRoFESS idemia, patients’ adherence to changes in
trial (Prevention Regimen for Effectively Avoiding
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Table 5. Very High Risk of Future ASCVD Events the prior 15 days, documented atherosclerotic
CLINICAL STATEMENTS
Very high risk includes a history of multiple major ASCVD events or 1 major disease (defined as carotid, aortic, intracranial,
AND GUIDELINES
ASCVD event and multiple high-risk conditions: or coronary atherosclerotic disease), and a clear
Major ASCVD events indication for statin therapy. The main exclu-
History of ischemic stroke sion criteria were a cardioembolic stroke/TIA
Recent acute coronary syndrome (within the past 12 mo)
without documented atherosclerotic disease, a
baseline LDL-C <100 mg/dL while not taking a
History of MI (other than recent ACS event listed above)
statin, inability to intensify statin therapy (already
S
ymptomatic peripheral arterial disease (history of claudication with
ankle-brachial index <0.85 or previous revascularization or amputation
on maximum dose), or a history of symptomatic
High-risk conditions
hemorrhagic stroke. Eligible patients were ran-
domly assigned to an LDL-C target of <70 mg/
Age ≥65 y
dL (lower-target group) versus 90 to 110 mg/
Heterozygous familial hypercholesterolemia
dL (higher-target group). LDL-C targets were
H
istory of coronary artery bypass surgery or percutaneous coronary pursued by intensification of statin therapy and
intervention outside of the major ASCVD events
the addition of ezetimibe if needed. During a
Diabetes
median 3.5 years of follow-up, the primary com-
Hypertension posite outcome of major cardiovascular events
C
hronic kidney disease (estimated glomerular filtration rate, 15–59 occurred in 8.5% of those in the lower-target
mL·min−1·1.73 m−2)
group versus 10.9% in the higher-target group
Current smoking (HR, 0.78 [95% CI, 0.61–0.98]).210 In addi-
The information in this table is from the 2018 AHA/ACC Guideline on the tion, a secondary analysis of the IMPROVE-IT
Management of Blood Cholesterol.31 For high-intensity statin therapy, the guide- trial (Improved Reduction of Outcomes: Vytorin
line recommends atorvastatin 80 mg daily or rosuvastatin 20 mg daily. Please
refer to the guideline for contraindications to high-intensity statin therapy and Efficacy International Trial) found a significantly
recommendations for moderate-intensity statin therapy. ACS indicates acute lower risk of ischemic stroke with ezetimibe
coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; and MI, treatment (in addition to simvastatin) among
myocardial infarction.
patients with previous MI.216
The information in this table is from the 2018 AHA/ 3. Very high-risk patients include those with history of
ACC guideline on the management of blood choles- multiple major ASCVD events or 1 major ASCVD
event and multiple high-risk conditions. In these
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target of <70 mg/dL (1.8 mmol/L),210 supporting triglycerides 175–499 mg/dL [2.0–5.6 mmol/L])
CLINICAL STATEMENTS
the use of ezetimibe before PCSK-9 inhibitors in and severe hypertriglyceridemia (fasting triglycerides
AND GUIDELINES
patients with ischemic stroke who are not at their ≥500 mg/dL [≥5.6 mmol/L]). In the former, excess
LDL-C targets. triglycerides are carried in very-low-density lipopro-
4. Goals and clinical efficacy for LDL-C lowering are tein (VLDL). In the latter, most patients have elevated
defined and monitored by percentage LDL-C reduc- VLDL plus chylomicrons. VLDL are atherogenic, simi-
tions relative to baseline levels. Baseline LDL-C is lar to LDL. There are many causes of elevated VLDL,
estimated by pretreatment measurements, chart and it is reasonable to reduce their levels to reduce
reviews, or measurement after drug therapy is inter- the risk of ASCVD. With severe hypertriglyceridemia,
rupted. Without a baseline level, response to therapy elevations of VLDL raise the risk of ASCVD, but as
is difficult to evaluate. Adherence to LDL-lowering triglyceride levels increase, especially above 1000
diets reduces LDL-C levels 10% to >15%.214 mg/dL, increases in chylomicrons impart a risk of
Moderate-intensity statins reduce LDL-C levels acute pancreatitis. In patients with ASCVD receiving
by another 30% to 49%; high-intensity statins, by recommended statin therapy, residual cardiovascu-
≥50%. Adding ezetimibe or bile acid sequestrants lar risk is present. Elevated triglycerides are associ-
to statin therapy reduces LDL-C by an additional ated with such risk. Treatment to reduce triglycerides
15% to 25%. Adding a PCSK9 inhibitor to statin with extended-release niacin and fibrates in addition
plus ezetimibe causes greater reductions. Lifestyle to statin therapy has not improved cardiovascular
changes and statin therapy are commonly introduced outcomes. However, IPE has been shown to reduce
together. The maximum percentage change occurs major adverse cardiovascular events (MACEs; ie, car-
4 to 12 weeks after therapy is started, at which time diovascular death, nonfatal MI, nonfatal stroke, coro-
drug efficacy or initial adherence to therapy can be nary revascularization, or unstable angina), including
evaluated. Periodic remeasurements can confirm ischemic stroke, when added to moderate- or high-
adherence to therapy. Because recommended inten- intensity statin therapy in patients with LDL-C of 41
sities of drug therapies vary in adolescents, young to 100 mg/dL. In this study, patient enrollment crite-
adults, adults 40 to 75 years, those with severe ria included T2D with multiple risk factors for ASCVD
hypercholesterolemia, and those treated for second- (29%) or history of ASCVD (71%).219 Almost 60% of
ary prevention, the recommended LDL-C levels to the entire cohort had T2D.
achieve also vary. Given the modest differences in
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LDL-C levels associated with the postprandial state, Recommendation-Specific Supportive Text
a nonfasting sample is effective to document base- 1.
The REDUCE-IT trial (Reduction of
line lipid levels before initiation of statin therapy. Cardiovascular Events With Icosapent Ethyl–
Insstervention Trial)219 randomized 8179
4.3.2. Treatment of Hypertriglyceridemia patients with ASCVD including history of isch-
Recommendations for Hypertriglyceridemia emic stroke or TIA (70%) or diabetes with
Referenced studies that support recommendations are summarized in
online Data Supplement 13.
other risk factors (30%) to IPE 2 g twice daily
plus statin versus statin alone. Enrollment cri-
COR LOE Recommendations
teria included fasting triglycerides of 135 to
1. In patients with ischemic stroke or TIA, with
fasting triglycerides 135 to 499 mg/dL and
499 mg/dL and LDL-C of 41 to 100 mg/dL
LDL-C of 41 to 100 mg/dL, on moderate- or on statin dose for ≥4 weeks. Follow-up for a
2a B-R
high-intensity statin therapy, with HbA1c median of 4.9 years revealed a 25% reduction
<10%, and with no history of pancreatitis, AF,
or severe heart failure, treatment with icosa-
(17.2% IPE versus 22.0% control; HR, 0.75
pent ethyl (IPE) 2 g twice a day is reasonable [95% CI, 0.68–0.83]; P<0.001) in the pri-
to reduce risk of recurrent stroke.219,220 mary end point of MACEs. Results for nonfa-
2. In patients with severe hypertriglyceridemia tal stroke and TIA were the same for MACEs.
(ie, fasting triglycerides ≥500 mg/dL [≥5.7
No difference occurred in hemorrhagic stroke.
mmol/L]), it is reasonable to identify and
address causes of hypertriglyceridemia and, A small, significant increase in AF occurred in
if triglycerides are persistently elevated or those treated with IPE (5.3% versus 3.9%).
2a B-NR increasing, to further reduce triglycerides in
Because benefits were similar across base-
order to lower the risk of ASCVD events by
implementation of a very low-fat diet, avoidance line triglycerides and unrelated to triglyceride
of refined carbohydrates and alcohol, consump- levels attained, the mechanism by which IPE
tion of omega-3 fatty acids, and, if necessary to
reduces MACEs, including secondary preven-
prevent acute pancreatitis, fibrate therapy.221–223
tion of stroke, is unknown, possibly related
Synopsis to factors other than lowering triglycerides.
The categories of hypertriglyceridemia are mod- The JELIS trial (Japan EPA Lipid Intervention
erate hypertriglyceridemia (fasting or nonfasting Study)220 found a 20% relative reduction of
noic acid (EPA), and low-dose statin. Two stud- Referenced studies that support recommendations are summarized in
online Data Supplements 14 and 15.
ies, the STRENGTH trial (Outcomes Study
to Assess Statin Residual Risk Reduction COR LOE Recommendations
With Epanova in High CV Risk Patients With 1. In patients with an ischemic stroke or TIA
who also have diabetes, the goal for glycemic
Hypertriglyceridemia)224 and the OMEMI trial control should be individualized based on the
(Omega-3 Fatty Acids in Elderly Patients With risk for adverse events, patient characteris-
Acute Myocardial Infarction)225 (underpow- 1 A tics and preferences, and, for most patients,
especially those <65 years of age and without
ered), found no benefit from combined EPA/ life-limiting comorbid illness, achieving a goal
docosahexaenoic acid (DHA) in patients with of HbA1c ≤7% is recommended to reduce
high CVD risk, diabetes, or CVD. Treatment risk for microvascular complications.229,230
with EPA/DHA resulted in lower median blood 2. In patients with an ischemic stroke or TIA who
EPA levels in STRENGTH than those achieved also have diabetes, treatment of diabetes
should include glucose-lowering agents
by treatment with IPE in REDUCE-IT, which 1 B-R with proven cardiovascular benefit to reduce
had a 25% reduction in the primary end point. the risk for future major adverse cardiovas-
Because triglyceride levels were similar, higher cular events (ie, stroke, MI, cardiovascular
death).231–236
EPA levels may account for the results seen in
3. In patients with an ischemic stroke or TIA who
REDUCE-IT. In addition, the differing effects of also have diabetes, multidimensional care (ie,
EPA and DHA on membrane stabilization may lifestyle counseling, medical nutritional therapy,
1 C-EO
contribute to the lack of effect with EPA/DHA diabetes self-management education, support,
and medication) is indicated to achieve glyce-
compared with EPA alone or IPE. mic goals and to improve stroke risk factors.
2. Most patients with triglycerides ≥500 mg/dL (≥5.6
4. In patients with prediabetes and ischemic
mmol/L) have increased VLDL and chylomicrons. stroke or TIA, lifestyle optimization (ie, healthy
Increased chylomicrons occur when triglycerides are 2a B-R diet, regular physical activity, and smoking
cessation) can be beneficial for the preven-
≥500 mg/dL (≥5.6 mmol/L). With increasing triglycer-
tion of progression to diabetes.237,238
ide concentrations, chylomicronemia may intensify and
5. In patients with TIA or ischemic stroke, it is
cause acute pancreatitis. Higher triglycerides levels reasonable to screen for prediabetes/dia-
convey greater risk.222 Patients with triglycerides from
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States. Prediabetes has the same pathophysiology as when the risk and inconvenience of intensive con-
CLINICAL STATEMENTS
T2D but is associated with lower plasma glucose than trol outweigh the potential benefit.
AND GUIDELINES
in T2D. The prevalence of diagnosed diabetes among 2. In response to the development of new classes
US adults is 9%.249 Prediabetes and diabetes are asso- of glucose-lowering medications that also prevent
ciated with increased risk for first ischemic stroke (RR, clinical vascular disease, the American Diabetes
1.5%–3.7% for diabetes).250–254 Prediabetes is pres- Association, the European Association for the
ent in ≈30% of patients with acute ischemic stroke255 Study of Diabetes, and other professional organi-
and is associated with increased risk for recurrence.256 zations have revised their algorithms for the man-
Progression of prediabetes to T2D can be prevented agement of T2D. An evidence-based consensus
by maintaining a healthy weight, exercising, eating a report by the American Diabetes Association and
healthy diet, and taking certain medications.237,238,245 European Association for the Study of Diabetes
T2D is also present in ≈30% of patients with ischemic recommends metformin and comprehensive life-
stroke255 and is associated with increased risk for recur- style optimization as first-line therapy.263 In patients
rence (RR, ≈1.6).209,257 Remission of established T2D with established ASCVD, including ischemic stroke,
can be achieved by weight loss,258–260 although no tri- when prevention of further vascular events is the
als have established that weight loss or diabetes remis- priority, GLP-1 receptor agonist therapy should
sion reduces risk for recurrent stroke. Recent clinical be added to metformin independently of baseline
trials demonstrated that at least 1 drug in each of the HbA1c. When concern for heart failure or chronic
3 classes of glucose-lowering medications can reduce kidney disease predominates, addition of a sodium-
risk for MACEs in patients with T2D and established ath- glucose cotransporter 2 inhibitor to metformin is
erosclerotic vascular disease, including ischemic stroke recommended. These developments in manage-
or high risk: thiazolidinediones, glucagon-like protein 1 ment have implications for the care of patients
(GLP-1) receptor agonist, and sodium-glucose cotrans- with diabetes and ischemic stroke. Clinicians
porter 2 inhibitor. Unlike the data for the thiazolidinedi- should now engage patients in a discussion of the
one pioglitazone and some GLP-1 receptor agonists, new therapies and alternatives. Through shared
the cardiovascular outcome trials of sodium-glucose decision-making, clinicians should help patients
cotransporter 2 inhibitors do not suggest a specific decide if a GLP-1 receptor agonist or a sodium-
effect on stroke but rather on cardiovascular death, MI, glucose cotransporter 2 inhibitor is right for them.
and heart failure.261 Risk for future vascular disease is only one consid-
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glucose tolerance test.255 These patients are at in the placebo, metformin, and intensive coun-
CLINICAL STATEMENTS
risk for progressing to symptomatic disease and seling groups. The rate of progression was 58%
AND GUIDELINES
for developing complications related to their dia- lower (95% CI, 48–66) with intensive counseling
betes, including microvascular and macrovascular and 31% (95% CI, 17–43) lower with metfor-
disease. With the development of drugs that both min compared with standard lifestyle counsel-
control glucose and reduce risk for major adverse ing. Metformin is well tolerated and inexpensive.
cardiovascular events, it has become more impor- Other drugs that have been shown to reduce
tant to identify all patients with diabetes after an progression to diabetes include pioglitazone,245
ischemic stroke so that they can be offered appro- acarbose,246 liraglutide,247 and dapagliflozin.268
priate therapy. Available methods to screen for These are not as well tolerated as metformin.
diabetes include fasting blood sugar, oral glucose Liraglutide is delivered by injection.
tolerance test, and HbA1c. Of these, HbA1c has 8. Approximately 30% of patients with ischemic
advantages in that it is more convenient (ie, it does stroke have prediabetes as defined by HbA1c
not require fasting), has less variability day to day, and other measures of glucose metabolism.255
and is less likely to be perturbed by medications, Most of these patients will have insulin resistance
stress, or illness.265 In general, HbA1c may be more as a contributing cause, but insulin resistance
accurate than other screening tests in the immedi- can occur before prediabetes develops. Thus,
ate postevent period. It is probably the preferred ≈50% of patients without diabetes with ischemic
method of diagnosis for patients hospitalized with stroke have insulin resistance.269,270 Both condi-
an acute stroke. tions have been associated with increased risk for
6. Compared with evidence for a benefit in microvas- first ischemic stroke,252,253,271–275 but no research
cular disease, there is less evidence for a benefit has been designed to test their effect on risk for
of intensive glucose control on macrovascular end recurrent vascular events. One large clinical trial
points such as stroke. No macrovascular benefit has examined the effect of a specific interven-
was demonstrated in the main publications from tion for patients with ischemic stroke and insu-
DCCT, the UKPDS, or 3 other more recent trials lin resistance. The IRIS trial (Insulin Resistance
designed to test intensive control for prevention Intervention After Stroke) examined the effect
of macrovascular disease.239–241 However, a ben- of the insulin-sensitizing agent pioglitazone
efit of intensive control emerged during long-term compared with placebo among patients with-
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follow-up of the DCCT242 and the UKPDS. Two out diabetes who had a recent ischemic stroke
meta-analysis of 5 trials that included the UKPDS and insulin resistance. Patients with heart failure
reported a benefit of intensive control for some were excluded. After a mean of 3.8 years, pio-
cardiovascular outcomes but not for stroke.243,244 glitazone reduced the risk of recurrent stroke or
No trials or meta-analyses have reported the MI by 24% (RR, 0.76 [95% CI, 0.62–0.93]), from
effect of intensive control on patients with a his- 11.8% among placebo recipients to 9.0% among
tory of stroke. Many experts conclude that the pioglitazone recipients. Active treatment, however,
benefit of intensive control on macrovascular dis- was associated with weight gain and increased
ease is likely restricted to younger patients with bone fracture risk. These adverse events have
recent-onset diabetes and without established restrained clinical use of pioglitazone.
vascular disease. In this regard, however, some
professional organizations recommend targeting Knowledge Gaps and Future Research
an HbA1c of 7% to 8% or even 8% to 9% to Having T2D is one of the most prevalent risk factors for
reduce the risk for hypoglycemia in elderly indi- future stroke after an initial acute ischemic stroke or TIA.
viduals with limited life expectancy or significant It is a promising target for secondary prevention because
comorbid illness.266,267 diabetes remission can be achieved in many patients
7. Although lifestyle change is the safest and most through weight management and vascular protection can
efficacious method to prevent progression from be achieved by newer glucose-lowering agents. In addi-
prediabetes to diabetes, several drugs have dem- tion, diabetes is associated with CNS small vessel dis-
onstrated benefit. In the Diabetes Prevention ease and vascular dementia. Potential areas of research
Program trial, patients with impaired glucose include the following:
tolerance were randomized to standard lifestyle • It is plausible that interventions for prediabetes,
recommendations plus metformin 850 mg twice established diabetes, and glucose management
a day, standard lifestyle recommendation plus will reduce risk for neurocognitive outcomes and
placebo, or intensive lifestyle counseling. The subclinical ischemic damage and discrete stroke
primary outcome, progression to diabetes, was events. The IRIS trial demonstrated that 1 glu-
observed in 11.0%, 7.8%, and 4.8% of patients cose-lowering intervention, pioglitazone, prevented
stroke and MI in patients with insulin resistance Weight loss of as little as 5% to 10% produces meaning-
CLINICAL STATEMENTS
without diabetes. The benefit of other interventions ful improvements in vascular risk factors.279 Only 1 trial
AND GUIDELINES
for prediabetes, including GLP-1 receptor agonists, has tested the effect of an intensive lifestyle interven-
dietary improvement, and weight reduction, has not tion for weight loss on the prevention of vascular disease,
been investigated but would logically follow from and it was stopped early for futility.292 Inadequate aver-
the IRIS trial. age weight loss in the active treatment group and statin
• The same interventions could be examined in therapy in the control group might explain the negative
patients with established diabetes. findings. Observational research provides some evidence
• Some early investigations have explored the effec- that weight loss after bariatric surgery may reduce risk
tiveness of poststroke behavioral counseling and for stroke.293,294 Approximately 24% to 30% of patients
physical training, modeled on cardiac rehabilitation, with acute ischemic stroke are obese.295 Paradoxically,
for improving lifestyle after stroke. they have a reduced risk for stroke recurrence,296,297 but
• Because diabetes disproportionately affects Black this is likely attributable to selection bias.298 Weight loss
and Hispanic communities, effective commu- after stroke is expected to improve stroke risk factors,
nity-based research for diabetes prevention and but the effect on future brain health has not yet been
management may yield interventions to reduce dis- directly examined.
parities in stroke risk and recovery.
Recommendation-Specific Supportive Text
• Because patients with ischemic stroke or TIA
1. Our recommendation for weight loss in patients
tend to be older and to have established vascu-
with overweight or obesity after stroke is consis-
lar disease, the optimal goal for glycemic control
tent with the 2013 AHA guideline on obesity,27
remains uncertain. In this regard, however, some
the 2014 AHA guideline on primary prevention,18
professional organizations recommend targeting
and other professional guidelines on management
an HbA1c of 7% to 8% or even 8% to 9% to
of obesity.299 Even a modest weight loss of 5% to
reduce the risk for hypoglycemia in elderly indi-
10% is associated with important improvements
viduals with limited life expectancy or significant
in conventional cardiovascular risk factors.279 In
comorbid illness.266,267
particular, weight loss can improve glucose con-
trol in patients with diabetes.277 The DiRECT trial
4.5. Obesity (Diabetes Remission Clinical Trial) compared food
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(OSA), AF, and vascular inflammation. Screening with >90% of cases being OSA rather than central sleep
is necessary to identify adults for referral to apnea.323–326 Limited data suggest that patients with acute
effective weight loss therapy. ischemic stroke and OSA are at increased risk for func-
tional impairment, stroke recurrence, and death, although
Knowledge Gaps and Future Research causation is not established.314,327–329 Limited data from
Treatment of overweight and obesity is a highly prom- small trials show that treatment with CPAP is safe after
ising intervention for primary and secondary preven- stroke, reduces the AHI, improves sleepiness, and may
tion of stroke. The evidence for this includes the high improve neurological function.304–311 Effects on vascular
prevalence of overweight and obesity in the general recurrence are uncertain, although a planned ancillary
population at risk for stroke and with completed stroke, analysis in the SAVE study (Sleep Apnea Cardiovascular
the confirmed association between increased weight Endpoints) revealed that risk for stroke was lower among
and increased risk for stroke, and the favorable effect participants (all had a history of coronary artery disease
of weight reduction on vascular risk factors, including or cerebrovascular disease) who had better adherence to
hypertension. Weight reduction would have additional CPAP therapy (HR, 0.56 [95% CI, 0.32–1.00]).
potential nonvascular benefits for patients at risk for
and with established cerebrovascular disease. What Recommendation-Specific Supportive Text
holds back research on treatment of overweight and 1. Our recommendation to treat patients with OSA
obesity for stroke prevention are the cost and complex- using CPAP is consistent with a guideline from
ity of available treatments. The most effective nonsurgi- the American College of Physicians that recom-
cal approaches require intensive behavioral counseling, mends CPAP as the initial therapy.330 In stud-
possibly with food substitution. Research is ongoing ies of various populations, treatment with CPAP
to understand the biology of obesity and to develop effectively reduced the AHI and improved mea-
more effective and convenient treatments, which may sures of sleepiness, BP control, sleep-related
include pharmacological approaches to appetite sup- quality of life, and physical functioning.302,303 As
pression. Right now, however, trials of counseling and described in the above synopsis, limited data
food substitution could be implemented safely and are from small trials specifically among patients
urgently needed. with stroke show that treatment with CPAP is
safe, reduces the AHI, improves sleepiness, designed clinical trials. Such trials will need to consider
CLINICAL STATEMENTS
and may improve neurological function.304–313 the following:
AND GUIDELINES
Evidence from 1 trial suggests that treat- • The selection of patients who might benefit from
ment may improve mood.314 In a planned ancil- CPAP,
lary analysis in the SAVE trial, which enrolled • Timing of testing and treatment in relation to stroke
patients with either coronary or cerebrovascu- onset,
lar disease, CPAP reduced the risk for stroke • Type of testing (in home or in facility), and
in patients with better CPAP adherence.303 The • Dose/type of CPAP.
American College of Physicians recommends Currently, at least 3 trials are underway that will help in
mandibular advancement devices as an alterna- this regard:
tive for patients who do not tolerate CPAP or 1. Sleep SMART (Sleep for Stroke Management and
who prefer mandibular advancement.330 These Recovery Trial), a randomized trial to determine
devices, however, have not been specifically whether early treatment of OSA with CPAP after
tested in patients with stroke. ischemic stroke or TIA reduces the risk for 2 primary
2. OSA is common among patients with stroke, but outcome measures: recurrent stroke, acute coro-
most cases are undiagnosed.315 The combined nary syndrome, and all-cause mortality 6 months
prevalence of known and unknown moderate to after the event and functional status at 3 months
severe OSA approaches 40%. Arguing against (ClinicalTrials.gov identifier NCT03812653).
evaluating patients for undiagnosed OSA is the 2. The RISE-UP trial (Recovery in Stroke Using PAP)
absence of evidence that treatment improves focused on optimal timing of CPAP initiation after
stroke-related outcomes, including recurrence. stroke (NCT04130503).
Since the last version of this guideline, a trial of 3. ASAP (Addressing Sleep Apnea Post Stroke/TIA),
2717 patients with moderate to severe OSA and which will test a quality improvement initiative in
coronary or cerebrovascular disease failed to show the Veterans Affairs Medical Administration and
a benefit of CPAP on recurrent vascular events.303 include a secondary aim of recurrent vascular dis-
In favor of evaluating stroke patients is the high ease (NCT04322162).
prevalence of undiagnosed OSA, combined with
evidence that treatment improves daytime sleepi-
ness, BP, sleep-related quality of life, and physi- 5. MANAGEMENT BY ETIOLOGY
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Ticagrelor and ASA for Prevention of Stroke and 5. Antithrombotic agents that have been specifically
CLINICAL STATEMENTS
Death; discussed in more detail in Section 5.19, studied in RCTs of patients with ICAS include war-
AND GUIDELINES
Use of Antithrombotic Medications in Secondary farin, aspirin, cilostazol, and the combination of
Stroke Prevention) also inform recommenda- clopidogrel plus aspirin or cilostazol.
tions for short-term treatment with combination 6. Post hoc analyses from WASID (N=567), the med-
ticagrelor and aspirin in patients with atheroscle- ical arm of SAMMPRIS (n=227), and the CICAS
rosis ipsilateral to the ischemic territory, including registry (Chinese Intracranial Atherosclerosis;
ICAS. In this prespecified subgroup analysis,340 N=2426) showed that achievement of a mean
risk of recurrent stroke or death at 30 days SBP <140 mm Hg during follow-up in patients
among patients with ≥30% intracranial stenosis with ICAS was associated with a lower risk of
ipsilateral to the ischemic event was 9.9% in the stroke and vascular events, even in patients with
ticagrelor 90 mg twice a day plus aspirin 100 mg severe stenosis110,337,345,346 or those treated early
once a day group versus 15.2% in the aspirin 100 after stroke.346 Although most patients with ICAS
mg alone group (HR, 0.66 [95% CI, 0.47–0.93]; probably benefit from lower BP, some small stud-
P=0.016). In contrast to the THALES patients ies suggest that patients with documented hemo-
without atherosclerosis, bleeding events among dynamic impairment347 or those treated to SBP
the ipsilateral atherosclerosis subgroup treated <120 mm Hg early after stroke348 may not benefit,
with ticagrelor and aspirin were not significantly and the lower threshold associated with increased
higher than in those taking aspirin alone. Of note, stroke risk is not known. High-intensity statin use
THALES required loading doses of both ticagre- is supported by an RCT in patients with ICAS that
lor and aspirin. Also of note, in this analysis, ICAS showed that high-intensity statins lowered the
was not required to be related to the index isch- rate of cerebrovascular events349 and by general
emic event, so some patients may not have had recommendations (see Section 4.3, Treatment
symptomatic ICAS. Given the lack of comparative of Hyperlipidemia for Secondary Prevention of
data between various dual-antiplatelet regimens Stroke). An optimum target LDL for patients with
in ICAS, the choice of adding ticagrelor or clopido- ICAS has not been determined, but WASID and
grel to aspirin should be based on patient factors SAMMPRIS post hoc analyses show lower LDLs
such as medication adherence (eg, relative cost are associated with lower vascular event rates in
and dose frequency), but the role of genetic stud- patients with ICAS,110,337 and a recent RCT dem-
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ies or platelet function testing remains unclear. onstrated benefit of an LDL target <70 mg/dL
4. Several RCTs have studied the efficacy of cilo- in patients with stroke and atherosclerosis.210
stazol 200 mg/d combined with other antiplate- Moderate physical activity at least 3 to 5 times per
let agents in patients with symptomatic ICAS. The week was the factor most strongly associated with
TOSS-1 and TOSS-2 trials (Trial of Cilostazol in lower risk of recurrent stroke and vascular events
Symptomatic Intracranial Arterial Stenosis) found in a post hoc analysis of SAMMPRIS medically
that cilostazol (200 mg/d) plus aspirin was as treated patients.110
safe as aspirin alone or clopidogrel plus aspirin 7. Two uncontrolled multicenter registries reported
but was no better for stroke prevention in patients outcomes after percutaneous transluminal angio-
with ICAS.341,342 The CATHARSIS trial (Cilostazol- plasty and stenting (PTAS) in patients with ICAS
Aspirin Therapy Against Recurrent Stroke With who have progressive symptoms or failed medical
Intracranial Artery Stenosis) reported that the therapy (ie, had a recurrent stroke or TIA despite
combination of cilostazol and aspirin was superior treatment with antithrombotic medications or risk
to aspirin for the prevention of the combined sec- factor control). The WEAVE prospective registry
ondary end point of all vascular events and new (Wingspan Stent System Post Market Surveillance)
silent brain infarcts (10.7% versus 25%; P=0.04) reported a periprocedural complication rate of
but had no impact on ICAS progression.343 2.6% in 152 patients who met the specific US
Subgroup analysis of the CSPS trial reported Food and Drug Administration Humanitarian
that patients with ICAS who were randomized to Device Exemption criteria for Wingspan stent use,
cilostazol plus either aspirin or clopidogrel (dual but outcomes beyond 72 hours after the procedure
group) had a lower rate of stroke compared with have not been published.350 However, the stroke or
those on aspirin or clopidogrel alone (4% versus death rate was 23.9% in the 46 patients treated off-
9.2%; HR, 0.47 [95% CI, 0.23–0.95]).344 Of note, label, many of whom had not failed medical therapy
these trials were conducted in a primarily Asian or were treated less than a week from symptom
population, the dose of aspirin when used in com- onset.366,367 A retrospective registry of 101 patients
bination with cilostazol did not exceed 150 mg/d, with ICAS receiving stenting or balloon angioplasty,
and many were unblinded. which included both patients who failed medical
therapy and those with progressive stroke symp- Knowledge Gaps and Future Research
CLINICAL STATEMENTS
toms, reported a 90-day ischemic stroke rate of Despite numerous advances in ICAS treatment over the
AND GUIDELINES
6.7% and 90-day mortality of 11.2%.351 Post hoc past several decades, the recurrent stroke risk remains high.
analysis of SAMMPRIS patients who had a prior Further investigation into the following should be prioritized:
stroke or TIA while on antithrombotic therapy • Studying new therapies in well-designed clinical
(n=284) showed that medical therapy was supe- trials, including novel antithrombotic regimens (eg,
rior to PTAS for the prevention of the primary end direct thrombin inhibitors), improved endovascular
point in this subgroup (15% for aggressive medical treatments (eg, submaximal balloon angioplasty),
management versus 24% for PTAS; P=0.043).352 indirect bypass, and ischemic preconditioning.
Given the lack of efficacy data, PTAS is considered • Determining the interaction between hemodynamic
investigational in this population. function or collateral flow and treatments (eg, BP
8. Three RCTs have compared PTAS with medi- management and endovascular therapy).
cal therapy for stroke prevention in patients with • Developing and using surrogate markers of stroke risk
recent stroke or TIA attributable to 70% to 99% (eg, plaque characteristics) or high-risk prognostic fea-
stenosis. The SAMMPRIS trial (N=451) used the tures (eg, diabetes) that may lead to new therapies or
Wingspan stenting system; the VISSIT trial (Vitesse improve patient selection for future therapeutic trials.
Intracranial Stent Study for Ischemic Stroke • Genetic variants that relate to ICAS (eg, ring finger
Therapy; N=112) used the Pharos system; and a protein 213) and whether such variants affect the
single-center RCT in China (N=70) allowed either rate of stroke recurrence or treatment responses.
Wingspan or Coroflex stenting systems. Medical
5.1.2. Extracranial Large Artery Atherosclerosis
therapy was similar in the 3 RCTs and consisted
of risk factor management and combination aspirin 5.1.2.1. Extracranial Carotid Stenosis
and clopidogrel for 90 days and then aspirin alone. Recommendations for Extracranial Carotid Stenosis
All 3 RCTs showed a higher 30-day rate of cere- Referenced studies that support recommendations are summarized in
online Data Supplement 28.
brovascular events or death in the PTAS group than
the medical group and no benefit of PTAS beyond COR LOE Recommendations
the periprocedural period.353–355 Post hoc analyses 1. In patients with a TIA or nondisabling
ischemic stroke within the past 6 months and
of SAMMPRIS baseline characteristics failed to ipsilateral severe (70%–99%) carotid artery
demonstrate any subgroup of patients who ben-
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not vary by degree of stenosis,368 and lack of 4. In patients with recent TIA or ischemic stroke and
ipsilateral moderate (50%–69%) carotid steno-
demonstrated benefit of PTAS in well-designed sis as documented by catheter-based imaging
RCTs performed in a higher-risk population or noninvasive imaging, CEA is recommended
1 B-R
(70%–99% stenosis)336,354,355 do not support the to reduce the risk of future stroke, depending
on patient-specific factors such as age, sex, and
use of PTAS.
comorbidities, if the perioperative morbidity and
10. A large multicenter RCT comparing extracranial- mortality risk is estimated to be <6%.369
intracranial arterial bypass with medical therapy 5. In patients ≥70 years of age with stroke or
in 1377 patients with recent minor stroke or TIA 2a B-R
TIA in whom carotid revascularization is being
included patients with ≥70% intracranial middle considered, it is reasonable to select CEA over
CAS to reduce the periprocedural stroke rate.371
cerebral artery (n=109) or ICA (n=149) stenosis
6. In patients in whom revascularization is
and found higher rates of stroke in patients with planned within 1 week of the index stroke, it
ICAS treated with extracranial-intracranial arterial 2a B-R
is reasonable to choose CEA over CAS to
bypass than in those in the medical group.361 reduce the periprocedural stroke rate.372
CLINICAL STATEMENTS
COR LOE Recommendations
1. A combined analysis by Rothwell et al369 of the
AND GUIDELINES
original CEA trials (NASCET [North American
7. In patients with TIA or nondisabling stroke,
when revascularization is indicated, it is Symptomatic Carotid Endarterectomy Trial], ECST
2a C-LD
reasonable to perform the procedure within [European Carotid Surgery Trial], and VA [Veterans
2 weeks of the index event rather than delay
Affairs Trial 309]) found robust benefit for CEA
surgery to increase the likelihood of stroke-
free outcome.373 in patients with severe (70%–99%) ICA stenosis
8. In patients with symptomatic severe stenosis
(16.0% absolute benefit over 5 years). In these
(≥70%) in whom anatomic or medical condi- studies, patients were typically >40 years of age
tions are present that increase the risk for and of either sex. The NASCET method of stenosis
2a C-LD surgery (such as radiation-induced stenosis
or restenosis after CEA) it is reasonable to
measurement was used in the combined analysis
choose CAS to reduce the periprocedural of the 3 trials. In the original trials (NASCET and
complication rate.374 ECST), angiography was used for stenosis mea-
9. In symptomatic patients at average or surements, but more recent trials (CREST [Carotid
low risk of complications associated with
endovascular intervention, when the ICA
Revascularization Endarterectomy versus Stenting
stenosis is ≥70% by noninvasive imaging or Trial]) and routine clinical practice typically use
>50% by catheter-based imaging and the noninvasive imaging, with angiography used for
anticipated rate of periprocedural stroke or
2b A
death is <6%, CAS may be considered as
cases with discrepant or ambiguous results from
an alternative to CEA for stroke preven- noninvasive tests.
tion, particularly in patients with significant 2. Surgical results and statistical modeling from clini-
cardiovascular comorbidities predispos-
ing to cardiovascular complications with
cal trials such as NASCET and CREST support this
endarterectomy.375 threshold for perioperative outcomes.24
10. In patients with a recent stroke or TIA (past 6 3. On the basis of trials of antiplatelet therapy for
2b B-NR
months), the usefulness of transcarotid artery patients with recent stroke or TIA, antiplatelet
revascularization (TCAR) for prevention of therapy is recommended for patients with symp-
recurrent stroke and TIA is uncertain.376
tomatic carotid stenosis. Similarly, antihyperten-
11. In patients with recent TIA or ischemic
stroke and when the degree of stenosis is
sive therapy and statins are recommended for
3: No patients with symptomatic carotid stenosis. A
A <50%, revascularization with CEA or CAS to
Benefit
reduce the risk of future stroke is not recom- recent trial of 2 different lipid targets for patients
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mended.369
with a recent stroke or TIA found that an LDL tar-
12. In patients with a recent (within 120 get of <70 mg/dL was associated with a reduced
days) TIA or ischemic stroke ipsilateral to
3: No atherosclerotic stenosis or occlusion of the vascular event rate compared with a target of 90
A
Benefit middle cerebral or carotid artery, extracranial- to 110 mg/dL.377a This trial included patients with
intracranial bypass surgery is not recom- symptomatic carotid stenosis. The use of multi-
mended.377
modality medical therapy also has been incorpo-
Synopsis rated into clinical trials.18
Previous randomized clinical trials have compared CEA 4. The analysis by Rothwell et al369 found mild ben-
with best medical therapy in patients with a recent stroke efit in patients with 50% to 69% ICA stenosis
or TIA. A combined analysis of these trials found the (4.6% over 5 years). In the NASCET analysis of
greatest benefit for CEA was in severe (70%–99%) this stenosis range, there was no clear benefit of
ICA stenosis with recent symptoms. Post hoc analysis of CEA seen in women and in patients with retinal
these original trials found a greater benefit of CEA when ischemic events. In the combined analysis of symp-
the surgery was done in patients who were enrolled tomatic CEA trials, the number needed to treat to
within 2 weeks of their last ischemic event. These trials prevent 1 stroke was higher in women compared
were initiated >30 years ago, and current optimal medi- with men (36 versus 9). Life expectancy also
cal therapy was not used in these trials. There is a paucity should be considered when treatment decisions
of data on CEA compared with current optimal medical are made because CEA has delayed benefit.
therapy in patients with symptomatic carotid stenosis. 5. Several variables have been analyzed in relation
CEA also has been compared with CAS. Across several to CEA and CAS outcomes. The Carotid Stenting
trials, CAS was associated with a higher periprocedural Trialists’ Collaboration analyzed outcomes in 4754
stroke rate, but similar results have been seen with CEA patients from 4 clinical trials.371 Within 120 days of
and CAS beyond the immediate periprocedural period. study entry, HRs were calculated according to 5-year
Extracranial-to-intracranial bypass for internal carotid age intervals to compare CAS with CEA. In the group
occlusion has not been demonstrated to reduce the risk 65 to 69 years of age, the HR was 1.61 (95% CI,
of recurrent stroke. 0.90–2.88). In the group 70 to 74 years of age, the
HR comparing CAS to CEA was 2.09 (95% CI, 1.32– (0.5% versus 1.5%).376 TCAR has not been evalu-
CLINICAL STATEMENTS
3.32). This supports the recommendation for consid- ated in randomized trials thus far and has not been
AND GUIDELINES
ering patient age in the selection of the procedure. compared with CEA or intensive medical therapy.
6. In addition, CEA is associated with a reduced 11. The combined analysis by Rothwell et al369 of CEA
complication rate relative to CAS in patients who in patients with recent stroke or TIA found no ben-
undergo the procedure within 1 week of a stroke efit in patients with <50% ICA stenosis.
or TIA. The Carotid Stenosis Trialists’ Collaboration 12. In COSS (Carotid Occlusion Surgery Study), 195
evaluated 4138 patients randomly assigned to subjects with recently symptomatic carotid occlu-
CEA or CAS.372 In patients who received the proce- sion and increased oxygen extraction fraction
dure within 1 week of the last symptomatic event, measured by positron emission tomography were
the stroke/death rate was 8.3% with CAS versus assigned to bypass surgery or medical therapy.377
1.3% with CEA (RR, 6.7; P=0.002). This supports The primary end point was stroke/death within 30
a preference for CEA in patients who undergo days and ipsilateral stroke up to 2 years. The pri-
early revascularization. mary end point occurred in 21.0% of the surgery
7. Post hoc analysis of these trials found a greater ben- group and 22.7% of the medically treated patients
efit of CEA when the surgery was done in patients (P=0.78). This supports the recommendation
who were enrolled within 2 weeks of their last non- against bypass surgery for patients with recently
disabling ischemic event.373 Therefore, if the patient symptomatic carotid occlusion.
is suitable for operation, early CEA is preferred.
5.1.2.2. Extracranial Vertebral Artery Stenosis
8. In the SAPPHIRE trial (Stenting and Angioplasty
With Protection in Patients at High Risk for Recommendations for Extracranial Vertebral Artery Stenosis
Referenced studies that support recommendations are summarized in
Endarterectomy), patients with high anatomic or phys- online Data Supplement 28.
iologic risk for CEA were assigned to CEA or CAS.374 COR LOE Recommendations
The primary end point was stroke, MI, or death within
1. In patients with recently symptomatic extra-
30 days or ipsilateral stroke up to 12 months. Among cranial vertebral artery stenosis, intensive
symptomatic patients, the primary end point occurred 1 A medical therapy (antiplatelet therapy, lipid
lowering, BP control) is recommended to
in 16.8% of patients undergoing CAS and 16.5% of
reduce stroke risk.378
patients undergoing CEA (P=0.95). However, the
2. In patients with ischemic stroke or TIA and
trial was not powered to evaluate only the symptom-
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2. In a combined analysis of 3 trials (VAST, VIST, recurrence rate among patients with aortic plaques ≥4
CLINICAL STATEMENTS
and SAMMPRIS), 244 patients were assigned to mm in thickness, particularly with ulceration or mobile
AND GUIDELINES
either vertebral artery stenting or optimal medical components388 or without plaque calcifications.389 There
therapy.378 The primary end point for this analysis are no strong data from randomized clinical trials or even
was fatal or nonfatal strokes. Two of these trials observational studies that management should be dif-
(VAST, VIST) contributed data for patients with ferent from general secondary prevention recommenda-
extracranial vertebral artery stenosis. During 1036 tions for atherosclerotic stroke.
person-years of follow-up, the HR for stenting
Recommendation-Specific Supportive Text
compared with medical therapy was 0.63 (95% CI,
1. There is evidence that treating patients with ischemic
0.27–1.46). Thus, no clear benefit has been shown
stroke and evidence of atherosclerosis to an LDL tar-
for extracranial vertebral artery stenting.
get of <70 mg/dL is more effective in stroke preven-
3. No randomized trials have been performed for sur-
tion than less intensive lipid management.210 Detailed
gical techniques such as vertebral artery endarter-
guidance for lipid management based on age and very
ectomy or transposition. Case series have been
high-risk status is presented elsewhere in this docu-
reported, but these typically lack a control group with
ment (see Section 4.3, Treatment of Hyperlipidemia
a consistent medical treatment protocol.379 Thus, the
for Secondary Prevention of Stroke). Many patients
utility of these procedures is not well established.
with aortic plaque and ischemic stroke will meet the
Extracranial Large Artery Atherosclerosis criteria for very high-risk status because of concomi-
Knowledge Gaps and Future Research tant atherosclerotic conditions and risk factors. In the
Knowledge gaps within this area include the following: ARCH study (Aortic Arch Related Cerebral Hazard
• Risk-benefit ratio of CEA to modern intensive medi- Trial), the only randomized trial of secondary pre-
cal therapy should be assessed. vention of aortic plaque–associated stroke,380 the
• Previous CEA trials were initiated >30 years ago, event rate was only 20% to 30% of the >12% rate
and clinicians need comparisons of CEA with cur- expected from observational studies.390 This is likely
rently available intensive medical therapy options. attributable to the better risk factor management in
• As a result of the growing elderly population, more the trial compared with historical studies. During the
data are needed on the merits of carotid revascular- trial, mean LDL-C was reduced by ≈40 mg/dL to 83
ization in elderly patients (>80 years of age). to 84 mg/d. It is likely that event rates would be even
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• Additional information is needed on the mecha- lower with current, more intensive recommendations
nisms of sex differences in outcomes for patients for hypertension and cholesterol management.
with symptomatic carotid stenosis. 2. The only randomized trial of this condition, the
• Recent studies have identified that carotid plaques ARCH study,380 compared aspirin and clopidogrel
with <50% stenosis but high-risk features may be with warfarin and was underpowered for the primary
linked to otherwise cryptogenic ischemic strokes. end point. Thus, the comparative benefit of these 2
More information is needed on the frequency and treatments is unknown. However, there were 6 vas-
optimal treatment of these nonstenotic plaques cular deaths (3.4%) in the warfarin arm and none in
with high-risk features. the dual antiplatelet arm (log-rank test, P=0.013),
suggesting no advantage of warfarin over dual anti-
5.1.3. Aortic Arch Atherosclerosis
platelets. It is not known whether DAPT is prefera-
Recommendations for Aortic Arch Atherosclerosis ble to single antiplatelet therapy (SAPT), but recent
Referenced studies that support recommendations are summarized in
online Data Supplement 29. trials381,382,384 have suggested that long-term DAPT
COR LOE Recommendations
generally confers increased bleeding risk without
a corresponding increased antithrombotic benefit.
1. In patients with a stroke or TIA and evidence
of an aortic arch atheroma, intensive lipid There is strong evidence that aspirin is effective
1 B-R management to an LDL cholesterol target in the secondary prevention of noncardioembolic
<70 mg/dL is recommended to prevent recur-
stroke or TIA.383,385 Thus, in the absence of compel-
rent stroke.210
ling evidence for an alternative, more effective anti-
2. In patients with a stroke or TIA and evidence
of an aortic arch atheroma, antiplatelet thrombotic treatment, long-term monotherapy with
1 C-LD
therapy is recommended to prevent recurrent aspirin is recommended. Minor strokes that meet
stroke.380–385 the inclusion criteria for the POINT study (Platelet-
Oriented Inhibition in New TIA and Minor Ischemic
Synopsis
Stroke) also should be treated with short-term
Pathological386 and case-control387 studies using TEE
DAPT with both aspirin and clopidogrel.
have identified complex aortic arch plaque to be inde-
pendently and strongly associated with ischemic stroke. Knowledge Gaps and Future Research
Prospective studies have found an increased stroke Knowledge gaps within this area include the following:
• For patients with a stroke or TIA and evidence of an RCTs have studied medical management of either symp-
CLINICAL STATEMENTS
aortic arch atheroma, the effectiveness of long-term tomatic or asymptomatic moyamoya disease. Although
AND GUIDELINES
DAPT with aspirin and clopidogrel compared with multiple case series and meta-analyses of varying sizes
aspirin monotherapy therapy to prevent recurrent and quality exist, many include both patients with moy-
stroke is unknown. amoya disease and those with moyamoya syndrome, as
• For patients with a stroke or TIA and evidence of well as pediatric and adult patients. Few address second-
an aortic arch atheroma, the effectiveness of anti- ary prevention of ischemic stroke specifically or issues
coagulation with either warfarin or a direct-acting of ethnic/geographic variability in general. Selection
anticoagulant compared with aspirin monotherapy bias and publication bias are significant concerns. The
to prevent recurrent stroke is unknown. resulting low-quality evidence related to the second-
• For patients with a stroke or TIA and evidence of ary prevention of ischemic stroke precludes any strong
an aortic arch atheroma, the effectiveness of com- recommendations.
bination antiplatelet and anticoagulation therapy
compared with aspirin monotherapy to prevent Recommendation-Specific Supportive Text
recurrent stroke is unknown. 1. Within the realm of surgery, there is considerable
• Optimal treatment strategies depending on plaque controversy as to what constitutes the best sur-
morphology and duration of treatment strategies gical option, direct superficial temporal artery to
remain unknown. middle cerebral artery bypass or an indirect bypass
procedure such as encephaloduroarteriosynangio-
5.2. Moyamoya Disease sis or encephalomyosynagiosis. The differences in
surgical technique even within the broad catego-
Recommendations for Moyamoya Disease ries of direct and indirect bypass, the frequent use
Referenced studies that support recommendations are summarized in
online Data Supplement 30.
of combined procedures, and the heterogeneity
of the patient population make it difficult to draw
COR LOE Recommendations
robust conclusions about the superiority of one
1. In patients with moyamoya disease and
a history of ischemic stroke or TIA, surgi-
procedure over another. Again, there are no pro-
cal revascularization with direct or indirect spective RCTs to inform recommendations in this
2a C-LD
extracranial-intracranial bypass can be area. Although several meta-analyses and case
beneficial for the prevention of ischemic stroke
series favor direct over indirect bypass,391–395 all but
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or TIA.391–397
1 of these studies combined both hemorrhagic and
2. In patients with moyamoya disease and a his-
tory of ischemic stroke or TIA, the use of anti- ischemic patients. A propensity score–matched
2b C-LD platelet therapy, typically aspirin monotherapy, analysis on 220 adult patients with ischemic-type
for the prevention of ischemic stroke or TIA
moyamoya disease showed that direct bypass was
may be reasonable.393,394,397–401
superior to indirect bypass for the prevention of
Synopsis recurrent stroke.391 In this series, however, the pri-
Moyamoya disease is an idiopathic rare steno-occlusive mary end point of recurrent stroke was defined as
disease of the arteries of the circle of Willis, typically both ischemic and hemorrhagic events. In contrast,
anterior circulation, with abnormal collateral development another meta-analysis396 and a retrospective mul-
in lenticulostriate arteries, resulting in the characteristic ticenter series397 reported no difference between
angiographic “puff of smoke” appearance. Moyamoya direct and indirect modalities.
disease may be more common in individuals of Asian 2. Although traditionally thought to result from poor
descent, but non-Asian people can be affected.402–404 perfusion, there is some evidence that many
Moyamoya disease has a bimodal distribution, with a instances of ischemia in moyamoya disease actu-
peak in childhood (more ischemic) and adulthood (isch- ally result from thromboembolic phenomenon.406
emic and hemorrhagic), and can be asymptomatic.404 In a propensity score–matched analysis, Onozuka
Although a causal relationship is not well established, et al400 found that prehospital antiplatelet use was
similar vascular changes also may be seen in association significantly associated with good functional sta-
with prior radiation exposure, Down syndrome, sickle cell tus on hospital admission for patients with non-
disease, neurofibromatosis, and atherosclerosis. This sit- hemorrhagic moyamoya disease in Japan. Several
uation is often referred to as moyamoya syndrome. Treat- meta-analyses and case series have compared
ment focuses on preventing progression and reducing antiplatelet therapy with surgical bypass or obser-
the risk of ischemic or hemorrhagic stroke. One prospec- vation alone with mixed results.393,397–399 Although
tive RCT (JAM trial [Japan Adult Moyamoya]) examined some found a benefit or no difference with anti-
the efficacy of surgical revascularization for preventing platelet therapy,394,397,398 others found surgery to
hemorrhagic stroke, but there are no similar prospective be superior.393,399 However, many studies include
RCTs for ischemic stroke prevention.405 No prospective patients with both ischemic and hemorrhagic
moyamoya disease, and conclusions are often in diameter or lacunes in patients often presenting with
CLINICAL STATEMENTS
based on subgroup analyses. Antiplatelet therapy lacunar stroke syndromes.38 Hypertension and diabe-
AND GUIDELINES
may also be of benefit in conjunction with surgi- tes are the most commonly recognized risk factors for
cal revascularization.401 An international survey of small vessel disease.38,412 Although the risk of mortality
perceived experts in the treatment of moyamoya is lower after small vessel stroke compared with other
disease reported that the majority of non-Asian stroke types, the 1-year recurrence risk is estimated at
respondents recommended antiplatelet therapy, 4% per year to 11% per year.412,413 Furthermore, small
in contrast to their Asian counterparts, perhaps vessel disease and lacunar strokes are a leading cause of
reflecting a difference in the typical pattern of dis- vascular dementia and vascular cognitive impairment.414,415
ease seen in the 2 geographic regions.407 Prior investigative studies have assessed the impact of
BP control and antiplatelet therapy on stroke recurrence
Knowledge Gaps and Future Research
after stroke related to small vessel disease.382,408,416,417
Significant knowledge gaps exist in our understand-
These studies support the general guidance for the use
ing of moyamoya disease. No prospective RCT exists
of antiplatelet therapy and BP recommendations refer-
comparing medical management with surgical interven-
enced in relevant sections of this report. More research is
tion for either the primary or secondary prevention of
needed to develop and test disease-specific treatments
ischemic events in patients with moyamoya disease.
for secondary stroke prevention after small vessel stroke.
Similarly, there are no prospective RCTs comparing
We focus here on clinical ischemic stroke related to small
the efficacy of the most common surgical revascular-
vessel disease, not on silent small vessel disease, which
ization procedures used for the prevention of ischemic
was reviewed in a 2017 scientific statement.418
events in this patient population. Numerous obstacles
to the performance of such trials exist, including a lack Recommendation-Specific Supportive Text
of equipoise among many treating neurologists and 1. Cilostazol has been studied as an alternative to
neurosurgeons, particularly for symptomatic patients. aspirin therapy for ischemic stroke related to
Consideration should therefore also be given to com- small vessel disease. In the CSPS trial (Cilostazol
prehensive, adjudicated long-term registries as an for Prevention of Secondary Stroke), cilostazol
alternative means of investigation. Future investigations was compared with placebo in 1095 Japanese
should have the following aims: patients with noncardioembolic ischemic stroke
• To better understand the natural history of moy- (74% small vessel stroke).416 There was a sig-
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amoya disease, including ethnic and geographic nificant reduction in the risk of recurrent stroke
variability. in the cilostazol treatment group and in partici-
• To examine the efficacy of medical management pants with lacunar stroke in the subgroup analy-
options, including antiplatelet therapy and antico- sis. Cilostazol was compared with aspirin for the
agulation, with or without surgical intervention for prevention of ischemic stroke in the CSPS II trial,
ischemic moyamoya disease. which enrolled 2575 Japanese participants, 64%
• To determine the most effective surgical interven- of whom had small vessel stroke as the qualify-
tion for moyamoya disease. ing event.417 Cilostazol was associated with a
• To establish the optimal timing for surgical interven- significantly reduced risk of first occurrence of
tion after an acute clinical event in a patient with ischemic or hemorrhagic stroke in the cilostazol
moyamoya disease. group compared with the aspirin group. There
were significantly fewer hemorrhagic events in
5.3. Ischemic Stroke Caused by Small Vessel the cilostazol group. There was a nonsignificant
Disease reduction in recurrent stroke risk in participants
with small vessel stroke in the subgroup analysis.
Recommendation for Small Vessel Stroke There were more reported side effects, includ-
Referenced studies that support the recommendation are summarized
in online Data Supplement 31.
ing headache, dizziness, palpitations, diarrhea,
tachycardia, and constipation, in the cilostazol
COR LOE Recommendation
group. These findings have not yet been dupli-
1. In patients with ischemic stroke related
to small vessel disease, the usefulness of
cated, and the inclusion of a single ethnic group
2b B-R
cilostazol for secondary stroke prevention is may limit generalizability.
uncertain.382,384,408–410
Knowledge Gaps and Future Research
Synopsis • The role of cilostazol in secondary prevention after
Cerebral small vessel disease represents a common stroke related to small vessel disease.
pathogenetic mechanism for ischemic stroke, accounting • Targeted strategies for secondary prevention after
for 20% to 30% of cases.36 This ischemic stroke sub- small vessel stroke that also reduce the risk of vas-
type is characterized by subcortical infarcts of <15 mm cular dementia.
6. In patients with stroke at high risk of hemor- event rate by 42%.419 Subsequent studies using
rhagic conversion in the setting of AF, it is
2a B-NR reasonable to delay initiation of oral antico-
risk characterization scores have further supported
agulation beyond 14 days to reduce the risk the effectiveness of VKAs in reducing stroke risk
of ICH.428–431 in AF.420–422 Furthermore, in all scoring systems of
7. In patients with TIA in the setting of nonvalvu- stroke risk in AF, prior stroke or TIA alone places a
lar AF, it is reasonable to initiate anticoagu- patient in a risk category in which anticoagulation is
2a C-EO
lation immediately after the index event to
reduce the risk of recurrent stroke. recommended. Four DOACs—apixaban, dabigatran,
8. In patients with stroke or TIA in the setting of
edoxaban, and rivaroxaban—have been studied in 4
nonvalvular AF who have contraindications large randomized trials against VKA with consistent
for lifelong anticoagulation but can tolerate evidence of noninferior reduction in thromboem-
at least 45 days, it may be reasonable to
2b B-R
consider percutaneous closure of the left
bolic risk and reduced bleeding risk.423–426 All trials
atrial appendage with the Watchman device of DOACs specifically excluded patients with val-
to reduce the chance of recurrent stroke and vular AF; however, up to 20% of patients in these
bleeding.432–436
trials had some degree of valvular heart disease
9. In patients with stroke at low risk for hemor-
(VHD). This discrepancy has led to some confu-
rhagic conversion in the setting of AF, it may
2b B-NR be reasonable to initiate anticoagulation 2 to sion in practice, which was clarified in the 2019
14 days after the index event to reduce the AHA/ACC/Heart Rhythm Society guideline on the
risk of recurrent stroke.428,429,437
management of AF.32 DOACs should not be used
10. In patients with AF and stroke or TIA who in patients with moderately severe or greater mitral
have end-stage renal disease or are on
dialysis, it may be reasonable to use warfarin
stenosis or a mechanical heart valve.
2b B-NR
or apixaban (dose adjusted if indicated) for 2. AF is the most common arrhythmia in the adult pop-
anticoagulation to reduce the chance of ulation and can be categorized by the proportion
recurrent stroke.438
of time a given patient spends in AF as paroxys-
Synopsis mal, persistent, or permanent. Even brief subclini-
AF is an important cause of cardioembolic stroke, and cal episodes of AF are associated with increased
the initial clinical presentation of AF is often stroke or risk of stroke.427 Anticoagulation is recommended
TIA. In patients with ischemic stroke or TIA, a diagnosis for patients with stroke or TIA regardless of the
amount of time spent in AF. There is no established of 1121 patients referred for atrial flutter ablation
CLINICAL STATEMENTS
lower limit of embolism risk from time spent in AF; and followed up for 2.1±2.7 years, 31.7% had AF
AND GUIDELINES
furthermore, patients with AF tend to progress to before ablation and 23.2% of patients experienced
greater proportions of time spent in arrhythmia AF after ablation for atrial flutter.446
over time. Moreover, up to 28% of patients are 5. Therapy with VKA has a narrow therapeutic win-
found to have AF with prolonged monitoring after dow. Patients who do not maintain an INR in the
stroke. Patients with a remote history of a discrete therapeutic range are at increased risk for both
AF episode (eg, postoperative or thyrotoxicosis) bleeding and thrombotic events. Time in thera-
represent a group at increased risk for arrhythmia peutic range is an important metric indicating the
recurrence,441–444 but the objective risk of recur- overall time spent by a patient with an INR in the
rence is poorly defined. therapeutic range; time with subtherapeutic INRs
3. All 4 randomized trials of DOACs demonstrated confers greater risk of embolic events, whereas
advantages to stroke risk reduction with the DOAC time spent with supratherapeutic INR confers risk
compared with a VKA with similar or improved of major bleeding. In the ACTIVE W trial (Atrial
stroke rates associated with similar or less bleed- Fibrillation Clopidogrel Trial With Irbesartan for
ing. In the RE-LY trial (Randomized Evaluation of Prevention of Vascular Events), patients random-
Long-Term Anticoagulant Therapy), at 2 years, ized to warfarin who did not maintain >60% time
high-dose dabigatran was associated with lower in therapeutic range did not derive net benefit from
stroke (1.11% versus 1.69%) and similar bleeding anticoagulation therapy.447 A meta-analysis of data
(3.11% versus 3.36%) rates compared with war- from the 4 seminal trials of DOACs confirmed this
farin.423 In ROCKET AF (Rivaroxaban Once Daily finding, observing substantially greater benefit of
Oral Direct Factor Xa Inhibition Compared With DOACs compared with VKAs when the center-
Vitamin K Antagonism for Prevention of Stroke based time in therapeutic range was <66% (31%
and Embolism Trial in Atrial Fibrillation), rivaroxa- versus 7% improvement in major bleeding).445 For
ban was noninferior to warfarin with similar rates patients who have documented suboptimal time in
of stroke or systemic embolism (2.1 vs 2.4 per 100 therapeutic range with VKA in the setting of AF
patient-years) and major bleeding (5.6% versus and prior stroke or TIA, it is recommended to use a
5.4%) in 14 264 patients followed up for 2 years.424 DOAC preferentially.
The ARISTOTLE trial (Apixaban for Reduction 6. Patients with stroke or TIA in the setting of AF are
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in Stroke and Other Thromboembolic Events at increased risk of recurrent ischemic stroke and
in Atrial Fibrillation) of 18 201 patients demon- at risk for ICH. Recurrent ischemic stroke risk is
strated that apixaban was superior to warfarin at 0.5% per day to 1.3% per day in the first 14 days,
1.8 years with fewer strokes or systemic embo- whereas the rate of symptomatic hemorrhagic
lisms (1.27% versus 1.60%) and less bleeding transformation after stroke ranges substantially,
(2.13% versus 3.09%).425 The ENGAGE AF-TIMI depending on the use of thrombolytics, with rates
48 trial (Global Study to Assess the Safety and of 6% to 21% and 1% to 7% in the thrombolytic
Effectiveness of Edoxaban [DU-176b] vs Standard and placebo arms, respectively, across multiple tri-
Practice of Dosing With Warfarin in Patients With als of thrombolytic therapy.428,448 Anticoagulation
Atrial Fibrillation) showed similar rates of stroke or reduces the risk of recurrent ischemic stroke but
systemic embolism with less bleeding in 21 105 increases the risk of cerebral hemorrhage dur-
patients comparing 2 doses of edoxaban with war- ing the acute poststroke phase.429,449 Patients
farin.426 A meta-analysis combining the data from with larger cerebral infarcts are at greater risk for
all 4 trials found an overall 19% reduction in stroke hemorrhagic transformation and worse bleeding
or systemic embolism driven by a 51% reduction in with early initiation of anticoagulation430; thus, it is
hemorrhagic stroke and a 10% overall reduction in reasonable to delay initiation of oral anticoagula-
mortality.445 The improved safety profile of DOACs tion for 14 days after stroke onset in that setting.
in the context of noninferior thromboembolic risk Although there is no uniformly accepted definition
leads to the recommendation to consider prefer- of a large cerebral infarction, accepted defini-
ential use of a DOAC over a VKA. tions have included National Institutes of Health
4. Compared with AF, atrial flutter is a more organized Stroke Scale (NIHSS) score >15450 and lesions
macro-reentrant arrhythmia often involving the tri- involving complete arterial territory or >1 arterial
cuspid isthmus. Atrial flutter is less common than territory.431 Moreover, patients with early signs of
AF overall; however, patients with atrial flutter are hemorrhage on neuroimaging are at highest risk
at increased risk for developing AF, and the risk of further intracerebral bleeding and should delay
of stroke associated with atrial flutter is similar to initiation of oral anticoagulation to allow healing of
that associated with AF.28 In a single-center series the blood–brain barrier.451
7. Patients who have a TIA rather than stroke in the stroke can be significant, the daily risk of embolism
CLINICAL STATEMENTS
setting of AF are at relatively low risk for intra- from AF is generally small. For example, a patient
AND GUIDELINES
cranial hemorrhage but remain at increased risk with a 6% risk of stroke over 1 year would have a
for recurrent stroke. The balance of bleeding risk daily risk of 0.016% and a risk of 0.23% over 14
versus benefit of stroke risk reduction from oral days. Nevertheless, an analysis of the VISTA cohort
anticoagulation favors earlier initiation in the set- study (Virtual International Stroke Trials Archive) of
ting of TIA when no cerebral infarction is present. 1644 patients found fewer recurrent strokes with
The relative safety of earlier anticoagulation in initiation of VKA 2 to 3 days after stroke compared
TIA is in contrast to the recommended delay with with >3 days without increased risk of symptom-
stroke (particularly large stroke), in which cerebral atic ICH.437 In patients with larger cerebral infarcts,
infarction can disrupt the blood–brain barrier and evidence of hemorrhage on neuroimaging, NIHSS
increases the risk of hemorrhage with initiation of score >9, or other features that place them at
anticoagulation. increased risk of hemorrhagic conversion after
8. In patients with stroke in the setting of nonvalvular acute stroke, the balance of risk and benefit favors
AF, the left atrial appendage is the location of identi- waiting for healing and reduced bleeding risk.429
fied thrombus 90% of the time.432 This observation 10. Patients with renal failure on dialysis are at
gave rise to the concept of left atrial appendage increased risk for both bleeding and thrombotic
closure to reduce the risk of stroke from AF. The events. All DOAC medications are renally cleared,
Watchman device is a plug-style device placed in increasing the risk for drug accumulation, supra-
the ostium of the left atrial appendage to occlude therapeutic drug levels, and bleeding events in
it and prevent thromboembolism. It was studied in patients with renal failure. Although overall data
the randomized PROTECT AF trial (Watchman Left are limited in this population, a large retrospective
Atrial Appendage System for Embolic Protection study matched 2351 patients with AF on dialysis
in Patients With Atrial Fibrillation) and PREVAIL who took apixaban against 23 172 taking warfarin
trial (Prospective Randomised Evaluation of the and found a 28% lower rate of bleeding events in
Watchman LAA Closure Device in Patients With those taking apixaban.438 This finding supports the
Atrial Fibrillation Versus Long Term Warfarin use of apixaban as an alternative choice for antico-
Therapy), as well as the nonrandomized CAP agulation in patients with AF on dialysis.
(Continued Access Registry), demonstrating non-
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significant numerically greater thrombotic risk Knowledge Gaps and Future Research
with the device but lower bleeding risk and over- Optimal management strategies to reduce the risk of
all net benefit.433–436 The Watchman device is the recurrent stroke in patients with AF have improved sub-
only currently available device with US Food and stantially with support from large trial data; however,
Drug Administration approval for left atrial append- knowledge gaps remain, including:
age closure. Other devices to close the left atrial • The minimal duration of AF that engenders signifi-
appendage are under investigation. Current prac- cant stroke risk and benefit of oral anticoagulation
tice based on clinical trial design involves short- beyond the bleeding risk remains unknown. Multiple
term (1.5 months) use of oral anticoagulation after studies reflecting the increased use of monitoring
Watchman device placement to reduce the risk of technologies are ongoing.
device-related thrombus followed by 4.5 months of • The safety of discontinuing oral anticoagulation
DAPT. In patients at high bleeding risk from oral after surgical appendage closure remains uncertain.
anticoagulation, left atrial appendage closure can Small series of surgical technologies have demon-
reduce the long-term risk of bleeding with an isch- strated technical success, but the relevance to clini-
emic stroke risk comparable to that of anticoagula- cal need for oral anticoagulation remains unknown.
tion with VKA. • Multiple transcatheter approaches to left atrial
9. Cerebral infarction weakens the blood–brain bar- appendage closure are under investigation and will
rier, increasing the risk of spontaneous hemor- provide additional options for stroke risk reduction
rhage after acute ischemic stroke, yet patients with while minimizing risk of bleeding with long-term
stroke or TIA in the setting of AF are at increased anticoagulation.
risk of recurrent stroke.428 Anticoagulation reduces • For patients who have had AF followed by success-
the risk of recurrent embolism but increases the ful ablation, the need for continued anticoagulation
risk of cerebral hemorrhage during the acute post- is uncertain and continues to be studied.
stroke phase.449 The optimal timing of initiating • Patients with limited postoperative AF are at
oral anticoagulation should be individualized for increased risk of recurrence; however, further
each patient’s risk of hemorrhage versus recurrent research is needed to identify which patients would
embolism. Although the annualized risk of recurrent benefit from long-term anticoagulation.
• The safety of oral anticoagulation in the setting of Recommendations for Valvular Disease Continued
CLINICAL STATEMENTS
cerebral amyloid angiopathy and in the presence of COR LOE Recommendations
AND GUIDELINES
microhemorrhages remains unclear and merits fur-
8. In patients with ischemic stroke or TIA and
ther study. IE, early valve surgery (during initial hospital-
• The efficacy of left atrial appendage closure com- ization before completion of a full therapeutic
2b B-NR course of antibiotics) may be considered in
pared with DOACs is unknown.
patients with an indication for surgery who
• The DOAC efficacy in morbidly obese patients is have no evidence of intracranial hemorrhage
unknown. or extensive neurological damage.466,467
9. In patients with IE and major ischemic
5.4.2. Valvular Disease stroke, delaying valve surgery for at least 4
Recommendations for Valvular Disease weeks may be considered for patients with
2b B-NR
Referenced studies that support recommendations are summarized in IE and major ischemic stroke or intracranial
online Data Supplements 33 and 34. hemorrhage if the patient is hemodynamically
stable.460,468
COR LOE Recommendations
10. In patients with ischemic stroke or TIA and
1. In patients with ischemic stroke or TIA and 3: Harm B-R mechanical heart valves, treatment with
valvular AF (moderate to severe mitral steno- dabigatran causes harm.*457
1 B-R sis or any mechanical heart valve), warfarin is
recommended to reduce the risk of recurrent *A similar recommendation in another guideline is worded slightly differently;
stroke or TIA.452–457 however, the process used to reach consensus was the same in both cases.
2. In patients with a mechanical mitral valve and
a history of ischemic stroke or TIA before valve Synopsis
1 C-LD
replacement, aspirin (75–100 mg/d) is recom- In patients with VHD (except moderate to severe mitral
mended in addition to warfarin with an INR
target of 3.0 (range, 2.5–3.5) to reduce the risk
stenosis or a mechanical heart valve), ischemic stroke
of thrombosis and recurrent stroke or TIA.458,459 or TIA, and AF, DOACs (dabigatran, rivaroxaban, apixa-
3. In patients with ischemic stroke or TIA and ban, and edoxaban) are recommended over warfarin
native aortic or nonrheumatic mitral valve therapy.452–457 In patients with valvular AF (ie, moderate
disease (eg, mitral annular calcification or
to severe mitral stenosis or a mechanical heart valve),
1 C-EO mitral valve prolapse) who do not have AF or
another indication for anticoagulation, anti- warfarin is recommended.32,458,464,469–472 Antiplatelet
platelet therapy is recommended to reduce therapy continues to be recommended over warfarin in
the risk of recurrent stroke or TIA.
patients with VHD other than rheumatic mitral disease
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4. In patients with a bioprosthetic aortic or and ischemic stroke or TIA.9 For patients with prosthetic
mitral valve, a history of ischemic stroke
or TIA before valve replacement, and no
heart valves, the choice of type of antithrombotic therapy
other indication for anticoagulation therapy after ischemic stroke or TIA is influenced by the type of
1 C-EO beyond 3 to 6 months from the valve valve (bioprosthetic versus mechanical), the timing of
placement, long-term therapy with aspirin
is recommended in preference to long-term
the embolic event, prior documented compliance to anti-
anticoagulation to reduce the risk of recur- thrombotic therapy, and assessment of the function of
rent stroke or TIA. the prosthetic valve.9,33 Indications and timing for surgical
5. In patients with ischemic stroke or TIA and interventions in patients with IE and stroke or TIA depend
IE who present with recurrent emboli and
on multiple factors, including recurrent events while on
persistent vegetations despite appropri-
ate antibiotic therapy, early surgery (during antibiotic therapy, size of the vegetation, and presence of
2a B-NR
initial hospitalization before completion of associated intracranial hemorrhage.33,460,464–467 Figure 3
a full therapeutic course of antibiotics) is
summarizes the recommended antithrombotic regimen
reasonable to reduce the risk of recurrent
embolism if there is no evidence of intracra- in patients with history of ischemic stroke or TIA and dif-
nial hemorrhage or extensive neurological ferent VHD conditions.
damage.460–465
6. In patients with history of ischemic stroke Recommendation-Specific Supportive Text
or TIA and a mechanical aortic valve, anti- 1. AF is highly prevalent in patients with VHD and
coagulation with higher-intensity warfarin to
represents one of the most important risk fac-
2a C-EO achieve an INR of 3.0 (range, 2.5–3.5) or the
addition of aspirin (75–100 mg/d) can be tors for ischemic stroke and TIA. In patients with
beneficial to reduce the risk of thromboem- prior ischemic stroke or TIA and associated AF,
bolic events.
the distinction between valvular and nonvalvular
7. In patients with ischemic stroke or TIA and AF is crucial because it has important implications
native left-sided valve endocarditis who exhibit
mobile vegetations >10 mm in length, early
in the selection of the optimal oral anticoagula-
surgery (during initial hospitalization before tion regimen.452–457 Valvular AF refers to AF in the
2b B-NR completion of a full therapeutic course of anti- context of moderate to severe mitral stenosis or
biotics) may be considered to reduce the risk
of recurrent embolism if there is no evidence of in the presence of any mechanical heart valve.32 It
intracranial hemorrhage or extensive neurologi- is important to highlight that the term nonvalvular
cal damage.460–465 AF does not imply the absence of VHD but only
Figure 3. Recommended antithrombotic regimen in patients with history of ischemic stroke or transient ischemic attack (TIA)
and different valvular heart disease conditions.
Colors correspond to Class of Recommendation in Table 3. Abx indicates antibiotics; AF, atrial fibrillation; AV, aortic valve; AVD, aortic valve
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disease; DOAC, direct oral anticoagulant; MAC, mitral annular calcification; MS, mitral stenosis; MV, mitral valve; MVD, mitral valve disease; MVP,
mitral valve prolapse; and VHD, valvular heart disease. *Definition of valvular AF. †Includes MAC and MVP. ‡Rheumatic and nonrheumatic AVD.
§Increase the target international normalized ratio by 0.5, depending on bleeding risk.
the absence of moderate to severe mitral stenosis a higher target INR range (2.5–4.5).458 Although
or mechanical heart valves (ie, AF in the setting routine addition of aspirin to warfarin therapy
of bioprosthetic valves, mild mitral stenosis, and in patients with mechanical valves is not recom-
any native aortic, pulmonary, or tricuspid valve dis- mended, patients with a history of ischemic stroke
ease is still considered nonvalvular).32 According to or TIA before the mechanical valve surgery repre-
the results of subgroup analyses of RCTs testing sent a group with an inherently higher thrombo-
DOACs to prevent thromboembolic complications embolic risk in whom the protection from recurrent
in patients with AF and meta-analyses of random- thromboembolic events associated with the com-
ized trials,452–457 in patients with VHD except mod- bination of aspirin and warfarin therapy may out-
erate to severe mitral stenosis or a mechanical weigh the competing bleeding risk.459
heart valve, ischemic stroke or TIA, and AF, DOACs 3. In the absence of AF, observational studies have
(apixaban, dabigatran, edoxaban, and rivaroxaban) reported conflicting results with regard to the asso-
are recommended over warfarin therapy. ciation between nonrheumatic mitral valve disease
2. In patients with mechanical mitral valve replacement, or native aortic disease and increased risk of throm-
anticoagulation with warfarin is recommended with boembolic complications.474–479 An early case-con-
an INR target of 3.0 (range, 2.5–3.5).33,473 The inci- trol study reported that mitral valve prolapse was
dence of thromboembolism is higher in patients associated with an increased risk for ischemic
with mechanical prostheses in the mitral compared stroke.474 More recent studies have not confirmed
with the aortic position, and the rate of thrombo- an association.475–477,480 Observational studies
embolism is lower in patients with a higher INR have consistently shown that the risk for stroke
goal. In the GELIA study (German Experience With in people with mitral valve prolapse is low (<1%
Low Intensity Anticoagulation) of patients with a annually).481–483 At least 4 population-based cohort
mechanical mitral prosthesis, a lower INR (2.0– studies have evaluated the association between
3.5) was associated with lower survival rates than mitral annular calcification and stroke.478,479,484,485
The cumulative evidence does not support a causal for ischemic stroke or TIA include vegetation
CLINICAL STATEMENTS
association between mitral annular calcification size and mobility, infection with Staphylococcus
AND GUIDELINES
and increased risk of thromboembolism. Similarly, aureus, and involvement of the mitral valve.460
there is no conclusive evidence supporting a causal Timely and appropriate institution of antibiotic
association between native aortic valve disease therapy is the first-line therapy for patients with
and increased risk of stroke or TIA.478,479 Additional IE and embolic stroke or TIA. ACC/AHA guid-
distinct valvular lesions such as Libman-Sacks ance on the management of patients with IE
endocarditis,486 age-related calcifications,487 or has been published in separate guidelines.33,463
bicuspid aortic valves487 have been associated with In patients with IE and recurrent embolic stroke
increased risk of thromboembolism, although no or TIA despite antibiotic therapy, an early consid-
properly designed trial has addressed the optimal eration for surgery (during the index hospitaliza-
therapeutic strategy to prevent ischemic stroke or tion and before completion of a full therapeutic
TIA in these specific conditions. Therefore, no spe- course of antibiotics) is reasonable if there is no
cific management recommendations can be made evidence of intracranial hemorrhage or extensive
for these conditions. neurological damage.464,465
4. In patients undergoing bioprosthetic mitral or aor- 7. Vegetation size represents an important risk fac-
tic valve replacement surgery, oral anticoagulation tor for systemic embolization in patients with
with warfarin to achieve a target INR of 2.5 (range, IE.460,465 In a multicenter prospective study includ-
2.0–3.0) is reasonable for at least 3 months and ing 384 consecutive patients with IE who under-
for as long as 6 months after surgery in patients went TEE, embolic complications occurred in 131
at low risk of bleeding.33 This recommendation is cases (34.1%). Of these, 28 patients (7.3%) had
based on the results of observational studies that an embolic event after the institution of adequate
have reported an increased risk of ischemic stroke antibiotic therapy. Vegetation length was larger in
early after surgery.488–490 After 3 to 6 months after patients with new embolic events (after initiation of
surgery, long-term therapy with only aspirin 75 to antibiotic therapy) than in those without (median,
100 mg daily is recommended.473,491–493 Patients 15.5 mm versus 9 mm, respectively; P<0.001). A
with a history of ischemic stroke or TIA (before vegetation length threshold of 10 mm was iden-
the bioprosthetic valve surgery) who are already tified as having the highest predictive value for
receiving antiplatelet therapy and have no indica- embolic events while on adequate antibiotic ther-
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tion for anticoagulation therapy should continue to apy.465 In a small randomized trial including 76
be managed with antiplatelet therapy alone after patients with left-sided IE, severe mitral valve or
the bioprosthetic valve insertion. aortic disease, and large vegetations (>10 mm),
5. In patients with mechanical prosthetic heart valves, early surgery (within 48 hours of randomization)
effective antithrombotic therapy requires continu- was associated with a significant reduction of the
ous effective warfarin anticoagulation with an INR composite end point of in-hospital death or embolic
in the target range.33 ACC/AHA guidance on the events (HR, 0.10 [95% CI, 0.01–0.82]) compared
selection of the most appropriate antithrombotic with conventional treatment.464
regimen in patients with mechanical heart valves 8. Decisions on the optimal timing of surgical inter-
has been published in separate guidelines.33 vention in patients with IE after an acute stroke
Anticoagulation with warfarin to achieve an INR of should balance the benefits associated with sur-
2.5 is typically recommended for patients with a gical correction of the IE lesion with the risk of
mechanical bileaflet or current-generation single- worsening of the neurological insult attributable to
tilting-disk aortic valve replacement and no risk ICH (typically caused by hemorrhagic conversion
factors for thromboembolism.458,469,472,473 However, of ischemic lesions, mycotic aneurysms, or septic
patients with an aortic mechanical prosthesis who necrotic arteritis), hypotension, and further intraop-
have a history of ischemic stroke or TIA are at erative embolization.33 In patients with IE who have
higher risk of thromboembolic complications, and had an acute stroke without extensive neurologi-
it is recommended to maintain the INR at a higher cal damage and no intracranial hemorrhage, data
target of 3.0 (range, 2.5–3.5) or to add aspirin 75 suggest that early surgery (with no delay) may be
to 100 mg daily.9,33,473,494,495 associated with better outcomes.33,466,467 An early
6. Neurological complications are the most frequent Japanese retrospective study including 181 of
and severe extracardiac complications of IE, with 244 patients with cerebral complications reported
an estimated incidence of up to 20% to 40% and a correlation between the time delay to surgery and
a significant impact on mortality.460–462 Ischemic mortality.466 More recently, a prospective cohort
cerebrovascular events represent the most com- study evaluated the relationship between the tim-
mon neurological complication of IE. Risk factors ing of surgery after a stroke and in-hospital and
1-year mortality rates.467 A total of 198 patients • In patients with IE, small observational series sug-
CLINICAL STATEMENTS
with IE who underwent valve replacement surgery gest a role for routine neurovascular imaging studies
AND GUIDELINES
after a stroke were analyzed. Of these, 58 patients (CT or MRA) to screen for mycotic aneurysms, which
(29.3%) underwent early surgical treatment and can potentially influence the treatment plan.498,499
140 (70.7%) had late surgical treatment. After Further larger studies are needed to determine
adjustment for other risk factors, early surgery was whether routine neurovascular imaging to screen
not associated with increased in-hospital or 1-year for mycotic aneurysms in IE improves outcomes.
mortality rates.467 • Patients with transcatheter aortic valve replacement
9. Hemorrhagic complications of IE are multifactorial and transcatheter mitral valve replacement represent
and can result from hemorrhagic conversions of a growing population.500,501 Antiplatelet therapy is the
ischemic lesions, rupture of mycotic aneurysms, or standard antithrombotic regimen after transcatheter
septic necrotic arteritis.460,468 Patients with hemor- aortic valve replacement,33 whereas a combination
rhagic stroke and IE have high surgical risk for at of oral anticoagulation and antiplatelet therapy has
least 4 weeks after the event. One observational been used with transcatheter mitral valve replace-
study showed a substantial difference in mortality ment, although with scant supporting evidence.501
rates when patients who underwent surgery within At the present time, DOACs are not routinely used
4 weeks of a hemorrhagic stroke were compared in transcatheter aortic valve replacement,502,503 and
with those whose surgery was delayed until after additional studies are needed to further evaluate the
4 weeks (75% versus 40%, respectively). Notably, potential benefit of DOACs therapy to prevent isch-
the rate of new hemorrhagic events after surgery emic stroke or TIA in this population. Furthermore,
was 50% in patients who underwent surgery within the optimal antithrombotic regimen for patients with
the first 2 weeks, 33% in patients who underwent a transcatheter aortic valve replacement who have a
surgery in the third week, and 20% in patients who TIA or ischemic stroke despite adequate antiplatelet
underwent surgery at least 21 days after the neu- therapy is still undefined.
rological event.460
5.4.3. LV Thrombus
10. A phase II randomized trial comparing dabigatran
and warfarin in patients with mechanical heart Recommendations for LV Thrombus
Referenced studies that support recommendations are summarized in
valves (RE-ALIGN [Randomized, Phase II Study to online Data Supplement 35.
Evaluate the Safety and Pharmacokinetics of Oral
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mended oral anticoagulant in these patients. 3. In patients with stroke or TIA and new LV
thrombus (<3 months), the safety of antico-
2b C-LD
Knowledge Gaps and Future Research agulation with a direct oral anticoagulant to
reduce risk of recurrent stroke is uncertain.509
• Rheumatic mitral valve disease often results in left
4. In patients with stroke or TIA in the setting
atrial structural changes and adverse remodeling,
of acute anterior MI with reduced ejection
which predisposes to thromboembolic complica- fraction (EF; <50%) but no evidence of LV
2b C-EO
tions also when in sinus rhythm, a condition that thrombus, empirical anticoagulation for at least
3 months might be considered to reduce the
has been defined as atrial cardiomyopathy.496,497
risk of recurrent cardioembolic stroke.
In patients with ischemic stroke or TIA who have
rheumatic mitral valve disease without AF and no Synopsis
other likely cause for their symptoms (eg, carotid Decreased contractility in the LV, particularly at the LV
stenosis), the role of oral anticoagulation has not apex, creates the possibility of blood pooling and subse-
been adequately investigated. quent coagulation and thrombus formation. Thrombus in
• Patients with a bioprosthetic aortic or mitral valve the LV is then at risk of systemic embolization. Although
are typically managed with antiplatelet therapy. If LV thrombus can form anytime blood stasis occurs,
an ischemic stroke or TIA occurs in these patients patients with acute MI, who have had acute vessel clo-
despite adequate antiplatelet, the benefit of switch- sure with associated loss of myocardial contractility, are at
ing to oral anticoagulation with warfarin or a DOAC risk of forming LV thrombus. Patients with anterior MI and
is unknown and warrants further investigation. reduced EF are a subgroup shown to be at particular risk
for LV thrombus formation. The associated risk of stroke thrombus or the LV thrombus was a marker of a
CLINICAL STATEMENTS
or systemic embolism in the presence of LV thrombus is higher-risk population.
AND GUIDELINES
reduced by use of systemic anticoagulation. Over time, 2. Both administration of microbubble contrast with
thrombus in the LV matures and becomes incorporated transthoracic echocardiography and cardiac MRI
into the wall of the akinetic segment, and the risk of have been shown to be superior to echocardiog-
embolism is reduced. The exact time for each thrombus raphy without contrast for the detection of LV
to mature to this point is unknown, but the risk of sys- thrombus. Both modalities also increase the defi-
temic embolism or stroke is reduced after 3 months. In nition of MI size where larger areas of infarction
the context of secondary stroke prevention, detection of increase the risk of thrombus formation. In a study
LV thrombus is an important determinant of stroke type of 210 patients with cardiac MRI and echocar-
and appropriate therapy. Standard transthoracic echocar- diography after ST-segment elevation MI, cardiac
diography is relatively insensitive for the detection of LV MRI detected LV thrombus in 12.3% of patients,
thrombus. Both contrast echocardiography with the use and echocardiography detected LV thrombus
of a microbubble contrast agent and cardiac MRI are in 6.2%.505 Another single-center study of 201
superior imaging modalities for detecting LV thrombus patients with ST-segment elevation MI also noted
compared with standard transthoracic echocardiography. lower rates of LV thrombus detection using echo-
cardiography (35%) and contrast echocardiogra-
Recommendation-Specific Supportive Text phy (64%) compared with cardiac MRI.511 Overall,
1. Patients with stroke or TIA in the context of LV detection of LV thrombus is increased by admin-
thrombus should be anticoagulated until the istration of microbubble contrast, and cardiac
thrombus has matured and the risk of further MRI has the highest demonstrated sensitivity.512
embolism has waned, ≈3 months. The bulk of evi- Tailoring imaging strategy on the basis of patient
dence has used VKA for oral anticoagulation with risk may optimize diagnostic yield.
a goal INR of 2.0 to 3.0. A large cohort study of 3. In a pooled meta-analysis of studies of mural throm-
2160 patients from 1979 to 1998 noted that the bus after anterior MI, use of oral anticoagulation
risk of stroke after MI was dramatically higher in with VKA reduced the risk of stroke by 86% and
the first month after infarct and remained elevated resulted in resolution of LV thrombus in 68%.506
for years afterward.510 In the percutaneous coro- Anticoagulation with DOACs has been shown to be
nary angiography era, a multicenter study of 753 as effective as VKA for the prevention of stroke in
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patients with ST-segment elevation MI identified LV AF and for the treatment of deep vein thrombosis
thrombus in 3.5% and 7.1% of patients after ante- and pulmonary embolism with a lower risk of bleed-
rior ST-segment elevation MI using cardiac MRI, ing and with greater convenience, driving interest in
although mural thrombus has been noted in as use for LV thrombus. A single-center retrospective
many as 26% of those studied in other series.504,505 study of anticoagulation with a DOAC in 52 patients
In a meta-analysis of 8 studies encompassing for the treatment of LV thrombus found resolution of
856 patients, Vaitkus and Barnathan506 noted an the thrombus in 86% of patients on follow-up echo-
increased risk of stroke or systemic embolism in cardiography, but the study was too small to address
the presence of LV thrombus demonstrated on embolic event rates.509 A larger retrospective analy-
echocardiogram with an OR of 5.45. Moreover, sis of 514 patients with identified LV thrombi from 3
the risk of embolism was substantially reduced in centers and a median follow-up of 351 days com-
the presence of oral anticoagulation with a VKA pared 300 patients who received warfarin with 185
with an OR of 0.14. A smaller single-center ret- patients treated with DOAC and noted a higher rate
rospective study of 33 patients with LV thrombus of stroke or systemic embolism in the DOAC group
on cardiac MRI compared with 66 matched con- (HR, 2.71 versus warfarin), although this difference
trols observed a short-term risk of stroke of 9.1%; was noted beyond the currently recommended
another study of LV thrombus noted stroke or duration of therapy for LV thrombi.513
systemic embolism in 7.7% of patients with docu- 4. Patients with reduced LV systolic function (LV EF
mented thrombus.505,507 Finally, a larger, more het- <50%) in the setting of acute anterior MI are at
erogeneous single-center study of 155 patients the greatest risk of developing LV thrombus.514
with LV thrombus found on cardiac MRI compared The observed rate of LV thrombus in anterior MI
with 400 matched patients over 3.3 years found was 24% in 1 series by cardiac MRI.505 The risk
an annualized rate of stroke or systemic embolism of stroke among patients with defined LV throm-
of 3.7% versus 0.8% in those without LV throm- bus has been reported to be as high as 9% to
bus, suggesting that an increased risk of embo- 11%.507,515 Therefore, for patients who have stroke
lism may persist.508 It is unclear whether events in or TIA in the context of anterior MI with reduced
the cohort with LV thrombus were caused by the EF (ie, the cardiac population at the highest risk for
cal anticoagulation even in the absence of demon- Compared with the general population without cardio-
AND GUIDELINES
CLINICAL STATEMENTS
AND GUIDELINES
Figure 4. Anticoagulant therapy
for patients with cardiomyopathy,
ischemic stroke, or transient ischemic
attack (TIA) in sinus rhythm.
Colors correspond to Class of
Recommendation in Table 3. LV indicates
left ventricle; and LVAD, left ventricular
assist device.
2. Thromboembolic complications represent a major ranging from asymptomatic state to severe heart
therapeutic challenge in the LVAD population and failure, ventricular arrhythmias, and thromboembolic
can occur at any point after LVAD implantation, events.197,533,535 The risk of thromboembolism in LV
including the immediate postoperative period and noncompaction cardiomyopathy has been evaluated
the long-term follow-up.516–519 The pathophysiology in several case series, which have reported an up
associated with ischemic stroke in the LVAD popula- to 24% risk of cerebral embolism at follow-up.534,549
tion is complex, and the postulated underlying mech- This increased risk has been theorized to result
anisms are different for early versus late strokes. In from blood stasis within the prominent LV trabecula-
the immediate postoperative period, several surgical tions and intertrabecular recesses.533–535 Given the
factors have been reported to possibly increase the shared pathophysiological basis with LV endocavi-
risk. These factors include duration of cardiopul- tary thrombus, we make this recommendation.
monary bypass and the need for other associated 4. There are 5 randomized trials evaluating the
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surgeries (eg, coronary artery bypass surgery, valve effects of antithrombotic therapy on clinical out-
surgery).517,520 Pump thrombosis, reduced pump comes, including strokes, in patients with heart
speeds, venous thromboembolism, uncontrolled failure and reduced LV EF in sinus rhythm.524–528
hypertension, and systemic infections have been The WARCEF trial (Warfarin vs. Aspirin in Reduced
associated with late strokes.518,519,521,522 A subopti- Cardiac Ejection Fraction) documented no ben-
mal anticoagulation regimen, which includes either efit of warfarin therapy compared with acetyl-
supratherapeutic or subtherapeutic INR and no aspi- salicylic acid at a mean follow-up of 3.5 years for
rin use, has also been associated with increased risk the primary outcome (death, ischemic stroke, or
of ischemic strokes. The use of DAPT compared with intracranial hemorrhage),526 although patients on
acetylsalicylic acid alone in addition to warfarin does warfarin had reduced incidence of stroke, par-
not appear to affect the rates of ischemic stroke.523 ticularly patients with an EF ≥15%,550 The more
Therefore, at the present time, the combination of recent COMMANDER HF trial (A Study to Assess
warfarin and aspirin is the preferred regimen in pre- the Effectiveness and Safety of Rivaroxaban in
venting recurrent ischemic stroke. Reducing the Risk of Death, Myocardial Infarction
3. LV noncompaction is a rare primary cardiomyopa- or Stroke in Participants With Heart Failure and
thy possibly caused by an arrest of normal embryo- Coronary Artery Disease Following an Episode of
genesis of the endocardium and mesocardium that Decompensated Heart Failure) randomized a total
leads to the formation of prominent trabeculations of 5022 patients with chronic heart failure, an EF
and deep intertrabecular recesses within the LV wall of ≤40%, coronary artery disease, and elevated
communicating with the cavity. The inferior and lat- plasma natriuretic peptides to rivaroxaban 2.5 mg
eral walls of the LV from the midcavity to the apex are twice daily or placebo.528 After a median follow-up
most commonly involved by this process.547 Among of 21.1 months, the primary end point (death, MI, or
cohorts of patients with cardiac disease, the esti- stroke) occurred in 25.0% of patients assigned to
mated prevalence of LV noncompaction varies from rivaroxaban versus 26.2% of those receiving pla-
0.9% by echocardiographic criteria to 9.8% with car- cebo. Patients with history of ischemic stroke and
diac magnetic resonance criteria.548 LV noncompac- TIA were underrepresented in these trials, and the
tion has a broad spectrum of clinical manifestations, main end point always included death, which dwarfs
the ischemic stroke outcomes. Therefore, the Recommendations for PFO (Continued)
CLINICAL STATEMENTS
types of cardiomyopathy (eg, LV noncompaction) coagulant treatment, and 2 of these558,560 showed a non-
requires further investigation. significant trend toward benefit of device closure. Two
• Data from isolated case reports and small case series subsequent trials554,556 compared device closure with
suggest that DOACs or low-molecular-weight hepa- antiplatelet treatment alone, and each trial showed a
rin may be beneficial in these clinical scenarios, but significant benefit of PFO closure. An additional positive
larger-scale multicenter observational data will be trial553 did not restrict medical treatment to antiplatelets
necessary to clarify whether DOACs or low-molecu- but did limit eligibility to patients with high-risk anatomic
lar-weight heparin can be used safely and effectively PFO features, including larger shunt size and atrial sep-
in these patients.551 tal aneurysm. A meta-analysis of all trials561 found that
• The role of empirical oral anticoagulation in patients the number needed to treat with device closure to pre-
with cardiomyopathy, reduced EF, and a history of vent 1 recurrent stroke was 131 during 1 person-year
stroke/TIA should also be investigated further in of follow-up or 13 during 10 person-years of follow-
future studies because these patients were largely up, which may be clinically important in this generally
underrepresented in RCTs of prophylactic oral anti- young population. Analysis of administrative claims data
coagulation in patients with cardiomyopathies and showed a 4.9% rate of serious periprocedural complica-
reduced EF. tion, including AF, in patients ≤60 years of age.562 RCT
data of PFO closure in patients >60 years of age are
5.4.5. Patent Foramen Ovale extremely limited,553 and the rate of serious periproce-
Recommendations for PFO dural complications in this older age group is signifi-
Referenced studies that support recommendations are summarized in cantly higher (10.9%).562
online Data Supplements 38 and 39.
COR LOE Recommendations Recommendation-Specific Supportive Text
1. In patients with a nonlacunar ischemic stroke 1. Recommendations for secondary stroke preven-
of undetermined cause and a PFO, recom- tion in a patient with a PFO should be based on
mendations for PFO closure versus medical joint input from a neurologist with expertise in vas-
1 C-EO management should be made jointly by the
patient, a cardiologist, and a neurologist, cular neurology and a cardiologist with expertise
taking into account the probability of a causal in PFO closure (Figure 5).563,564 Although 1 small
role for the PFO. trial with 120 patients did include some patients
CLINICAL STATEMENTS
AND GUIDELINES
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Figure 5. Patent foramen ovale (PFO) and ischemic stroke management guide.
Colors correspond to Class of Recommendation in Table 3. CT indicates computed tomography; DVT, deep vein thrombosis; LP, lumbar puncture;
MRI, magnetic resonance imaging; MRV, magnetic resonance venography; RoPE, Risk of Paradoxical Embolism; and TIA, transient ischemic attack.
>60 years of age, this should not be construed as to nonlacunar stroke of undetermined source, or
randomized clinical trial evidence of benefit in this ESUS. Furthermore, clinical judgement is required
age group; therefore, this procedure should rarely because many strokes in the ESUS category may
be performed in older patients and only in very not have a definite cause but other lower-compet-
unusual clinical circumstances. It is essential that ing-risk conditions such as a proximal large artery
a thorough evaluation has been completed and disease with 40% stenosis.565 Analysis of observa-
that there is no alternative cause of the stroke. All tional data566 indicates that younger patients with-
studies553–556 that showed benefit from PFO clo- out other vascular risk factors are more likely to
sure excluded lacunar strokes. Thus, the require- have PFOs that are related to their stroke. Similarly,
ment that the stroke be cryptogenic is equivalent the anatomic characteristics of the PFO need to
be considered in decision-making (see text under anticoagulation was not a prespecified analysis in
CLINICAL STATEMENTS
Recommendations 2 and 3). the CLOSE trial (Patent Foramen Ovale Closure
AND GUIDELINES
2. Two recent trials553,554 in which the comparator or Anticoagulants Versus Antiplatelet Therapy to
was antiplatelet therapy and long-term follow-up Prevent Stroke Recurrence),563 but a post hoc
from an earlier trial555 in which the comparator underpowered analysis of recurrent stroke found
was antiplatelet or anticoagulation therapy found no events in the device closure group and 3
a benefit of device closure. There is evidence that events in the warfarin group, which was not a sta-
patients with high-risk anatomic features, including tistically significant difference.561 Similarly, if long-
larger shunt size (defined variably), particularly an term warfarin treatment is planned, the additional
atrial septal aneurysm, are more likely to benefit benefit of closure with a transcatheter device
from device closure.563 The individual patient–level for preventing recurrent stroke is unknown. An
meta-analysis of the first 3 trials552 found slightly important consideration is that short-term trials in
greater benefit among patients with these char- younger adults do not capture the long-term risk
acteristics, but the differences did not approach of warfarin or the long-term safety of indwelling
statistical significance. In contrast, the RESPECT PFO closure devices.
trial555 showed significant interactions between
Knowledge Gaps and Future Research
treatment and both larger shunt size (>20 micro-
Future research is needed within this area:
bubbles) and atrial septal aneurysm, with benefit
• Trials of closure versus medical management in
shown only when either was present. A pooled
patients ≥60 years of age with ESUS.569
individual patient data analysis from medically
• Further trials and individual-level meta-analysis of
treated patients from 2 observational studies and
all randomized trial data in patients with ESUS <60
2 clinical trials found that atrial septal aneurysm,
years of age addressing the benefit of PFO closure
but not shunt size, was independently associ-
compared with aspirin in patients with a PFO with-
ated with recurrent stroke.557 A meta-analysis of
out high-risk anatomic features.
PFO closure trials found benefit for closure only
• Further trials and individual-level meta-analysis of all
for patients with high-risk anatomic features.561
randomized trial data addressing the benefit of PFO
However, this finding may have resulted from con-
closure compared with long-term anticoagulation.
founding because trials that showed benefit had a
• Individual-level meta-analysis of all randomized tri-
higher proportion of high-risk features and limited
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CLINICAL STATEMENTS
Patients with congenital heart disease represent a group with complex congenital heart disease had the
AND GUIDELINES
at higher risk of ischemic stroke and systemic throm- highest risk (8.9% [95% CI, 6.0–11.5]). The mech-
boembolism,574–576 particularly in the presence of cya- anisms underlying such an increased risk of stroke
notic or other complex anatomic lesions.574–577 In these are different and multifactorial and are related to
patients, it is reasonable to start oral anticoagulant ther- the high prevalence of atrial arrhythmias, risk for
apy with a VKA (warfarin) for the secondary prevention paradoxical embolization (eg, cyanotic congeni-
of stroke or TIA of presumed cardioembolic origin after tal heart disease), atrial mechanical dysfunction
careful individual assessment of the competing bleed- resulting from the presence of scar, and associ-
ing risks associated with oral anticoagulation. Fontan ated hyperviscosity/hypercoagulability caused by
repair is associated with high risk of atrial arrhythmias, chronic hypoxemia. In patients with cyanotic and
intracardiac thrombosis related to atrial scarring, and other complex congenital heart disease and isch-
right-to-left shunting from Fontan fenestration.578–580 emic stroke or TIA of presumed cardioembolic
Patients with Fontan palliation and known or suspected origin, treatment with warfarin is reasonable in the
thrombus, ischemic stroke or TIA, or prior atrial arrhyth- absence of contraindications to oral anticoagula-
mia should be treated with warfarin in the absence of tion (eg, increased risk of bleeding).
contraindications.30
Knowledge Gaps and Future Research
Recommendation-Specific Supportive Text • A subset of patients with Fontan palliative surgery
1. The Fontan circulation is a palliative approach to have a fenestration between the Fontan path-
complex single-ventricle physiology and is associ- way and the pulmonary venous atrium to provide
ated with complex hemodynamics related to an a controlled right-to-left shunt to augment ven-
obligatory chronic elevation in central venous pres- tricular preload and to partially offload systemic
sure and reduced cardiac output.30 Consideration venous (Fontan) hypertension. Right-to-left shunt
for antithrombotic therapy in Fontan patients from a fenestration can be a potential source of
should take into account the high prevalence of thromboembolism and stroke.584 Catheter closure
thrombus formation and potentially catastrophic of Fontan fenestration along with anticoagulation
impact of pulmonary or systemic thromboembo- has been performed in some patients with a patent
lism. The physiology associated with the Fontan fenestration presenting with stroke,585 although
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circulation may lead to stroke/TIA via different more data are needed to determine whether this
mechanisms. The associated ventricular dysfunc- approach is of real incremental benefit to prevent
tion and abnormal ventricular morphology, the ischemic stroke or TIA compared with oral antico-
progressive atrial scarring from the Fontan sur- agulation therapy alone.
gery, and the elevated intra-atrial pressures may • DOACs have been demonstrated to be noninferior
trigger atrial arrhythmias, increasing the risk of or superior to dose-adjusted warfarin therapy to
thromboembolic events.581 The role of DOACs in prevent thromboembolism and bleeding in patients
patients with Fontan is less defined, and thus far, with nonvalvular AF, and they have rapidly become
the published evidence is limited to small obser- the standard of care for these patients. Important
vational series.582,583 Given the lack of conclusive advantages of DOAC therapy compared with war-
evidence on the safety of DOACs in the presence farin include a more predictable pharmacokinetic
of the hepatic dysfunction and altered coagula- profile requiring no monitoring, fewer interactions
tion in patients who underwent Fontan palliation, with other drugs, and a rapid onset/offset of action.
warfarin should be considered the preferred oral Thus far, data on the efficacy and safety of DOACs
anticoagulant regimen. to prevent recurrent thromboembolism in patients
2. Complex congenital heart disease is associated with congenital heart disease and history of isch-
with an increased risk of stroke in adults.574–576 emic stroke or TIA are limited to small observational
Mandalenakis et al575 conducted a large pro- series. Larger-scale multicenter observational data
spective registry in Sweden and documented an will be necessary to achieve adequate statistical
almost 11-fold increase in the risk of ischemic power and to clarify whether DOACs can be used
stroke in patients with congenital heart disease safely in patients with congenital heart disease.
compared with control subjects matched by age, Multicenter registries such as that for non-VKA
with the highest risk among patients with complex anticoagulants for thromboembolic prevention585a
lesions. In a retrospective large database includ- are currently ongoing and will provide important and
ing >29 000 adult (age >18 years) patients with needed data on the safety and efficacy of DOACs
congenital heart disease, Lanz et al574 reported an for thromboembolic prevention in patients with con-
overall risk of ischemic stroke of 6.1% in women genital heart disease.
Referenced studies that support the recommendation are summarized sion to reduce the risk of recurrent stroke.
in online Data Supplement 42.
Knowledge Gaps and Future Research
COR LOE Recommendation
Cardiac tumors are rare, and systematic research has
1. In patients with stroke or TIA found to have
a left-sided cardiac tumor, resection of the been limited to case series, leaving gaps in our under-
2a C-LD
tumor can be beneficial to reduce the risk of standing and opportunities for future research.
recurrent stroke.586–588 • Most cardiac tumors are found incidentally, car-
rying the threat of stroke or recurrent stroke, and
Synopsis open heart surgery is the only established treat-
Primary cardiac tumors are uncommon, occurring in ment option. Better understanding of the risk
0.02% of people according to a large autopsy series, modification from antiplatelet or anticoagulation
and the most common primary cardiac tumors are in particular tumor subtypes or morphologies may
myxoma and fibroelastoma.589 Patients with cardiac provide alternative therapeutic options for patients.
tumors are at increased risk for stroke with an over- Specifically, pooled experiences including national
all rate of embolism of 25% in the largest single- and multi-institutional data sets may allow a better
center study.590 The mechanism of stroke in patients understanding of tumor subtypes, fractionation by
with left-sided cardiac tumors is embolic and can be morphology, and natural history.
either embolization of thrombus that has formed on • As technology advances, minimally invasive and
the tumor or embolization of the tumor or piece of the percutaneous treatment strategies should be inves-
tumor.591 This finding is the basis for recommending tigated. Similarly, advances in imaging technology
antiplatelet or anticoagulation to conservatively man- will allow greater delineation of tumor subtypes and
aged patients. There are no prospective randomized morphologies. The prognostic implications of these
trials of management of patients diagnosed with car- findings should be investigated.
diac tumors after stroke or TIA; however, surgical exci-
sion of papillary fibroelastoma has been associated
with decreased risk of stroke compared with control 5.7. Dissection
subjects in 1 single-center study.592 For patients with Recommendations for Dissection
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metastatic disease to the heart or with right-sided Referenced studies that support recommendations are summarized in
online Data Supplements 43 and 44.
tumors, paradoxical embolism of tumor or venous
thrombus through a PFO could occur. COR LOE Recommendations
1. In patients with ischemic stroke or TIA after
an extracranial carotid or vertebral arterial dis-
Recommendation-Specific Supportive Text 1 C-EO section, treatment with antithrombotic therapy
1. Retrospective studies have shown increased risk for at least 3 months is indicated to prevent
of stroke with left-sided cardiac myxoma and papil- recurrent stroke or TIA.
lary fibroelastoma.586 Atrial myxomas can occur in 2. In patients with ischemic stroke or TIA who
any cardiac chamber but are noted most frequently are <3 months after an extracranial carotid or
2a B-R vertebral arterial dissection, it is reasonable to
in the left atrium adherent to the interatrial septum. use either aspirin or warfarin to prevent recur-
Broad morphological variation of atrial myxomas rent stroke or TIA.593,594
has been described, and more villous tumors are 3. In patients with stroke or TIA and extracranial
felt to have greater embolic and thromboembolic carotid or vertebral artery dissection who
2b C-LD have recurrent events despite antithrombotic
potential. Papillary fibroelastomas are fibrinous therapy, endovascular therapy may be consid-
mobile tumors occurring most frequently adher- ered to prevent recurrent stroke or TIA.595,596
ent to a cardiac valve with nearly equal distribu-
tion across the cardiac valves.587 In a single-center Synopsis
study of 323 patients after excision of a cardiac Extracranial carotid or vertebral dissections can be the
tumor, the OR of embolism associated with left result of trauma or spontaneous. It is a relatively uncom-
atrial tumors was 1.95 and higher (4.17) with aortic mon mechanism of ischemic stroke that is relevant mostly
valve tumors.586 In another series of 725 patients to younger individuals.597 The most common mechanism
with papillary fibroelastoma, tumor mobility and aor- of stroke with extracranial dissection is artery-to-artery
tic valve location were independent predictors of embolism598 from an intraluminal thrombus, which is the
embolism.588 Less common tumors and metastatic rationale for using antithrombotic agents to decrease
lesions in the heart have been anecdotally associ- the rate of ischemic stroke.599 Although most dissections
ated with stroke; however, there is not enough evi- heal spontaneously, a subset of patients will undergo
dence to make a consistent recommendation for disease progression and arterial complications such as
those circumstances. For patients with stroke or pseudoaneurysm formation.597
CLINICAL STATEMENTS
1. The recommendation of using antithrombotic agents
AND GUIDELINES
is based on expert opinion. Although arterial dissec- 5.8.1. Hematologic Traits
tion is a hemorrhagic process within the arterial wall, Recommendation for Hematologic Traits
the most common mechanism for stroke is artery- Referenced studies that support the recommendation are summarized
to-artery embolism598 from an intraluminal throm- in online Data Supplement 45.
bus. This is the rationale for using antithrombotic COR LOE Recommendation
agents to decrease the rate of ischemic stroke.599 1. In patients with ischemic stroke or TIA of
unknown source despite thorough diagnostic
2. CADISS (Cervical Artery Dissection in Stroke
evaluation and no other thrombotic history
Study) was an open-label trial that randomized 250 who are found to have prothrombin 20210A
patients with extracranial dissection within 7 days 2a C-LD mutation, activated protein C resistance,
elevated factor VIII levels, or deficiencies of
from symptom onset to receive either antiplatelets
protein C, protein S, or antithrombin III, anti-
or anticoagulants in the following 3 months.593 The platelet therapy is reasonable to reduce the
specific agents and treatment regimens were left risk of recurrent stroke or TIA.600–606
to the treating physician. Stroke or death occurred
Synopsis
in 3 patients (2%) assigned to antiplatelets versus
Hypercoagulable states refer to heterogeneous hema-
1 patient (1%) in the anticoagulation group (OR,
tologic traits that predispose to venous or arterial
0.335 [95% CI, 0.006–4.233]; P=0.63).593 At the
thrombosis, which then may increase the risk of stroke,
1-year follow-up, there was no difference in the
particularly in younger populations. Hypercoagula-
primary end point of stroke or death between the
ble states may increase the risk of stroke via various
2 groups: 3.2% in the antiplatelet group versus
mechanisms. Hypercoagulable disorders may predis-
1.6% in the anticoagulant group (OR, 0.56 [95%
pose to arterial or venous thrombosis. Among people
CI, 0.10–3.21]; P=0.51).594 This trial supports that
with venous thrombosis, stroke may be caused by
there is equipoise between antiplatelets and anti-
paradoxical emboli via right-to-left arterial shunt, either
coagulants in the first 3 months after a cervical
pulmonary or cardiac (often via a PFO). Hypercoagu-
artery dissection.
lable states that cause arterial thrombosis may cause
3. Endovascular procedures are used to reconstruct
stroke via distant thrombosis (eg, intracardiac) with
cervical arterial dissections refractory to medical
embolization or via in situ thrombosis of the brain or
treatment and to treat complications such as pseu-
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the absence of a diagnosis that would change antibody indicated a treatment interaction with
CLINICAL STATEMENTS
the default treatment for ischemic stroke, it is warfarin or aspirin for secondary stroke preven-
AND GUIDELINES
uncertain whether testing for these hematologic tion. Participants had to be 30 to 85 years of age,
traits is of benefit in the context of secondary to be deemed safe for warfarin therapy, to have
stroke prevention. If in certain clinical scenarios experienced an ischemic stroke within 30 days,
(eg, paradoxical emboli caused by venous throm- and to have had a modified Rankin Scale score
bosis or recurrent venous thrombosis) testing for of ≤3. Investigators found no differential stroke
thrombophilic states is considered, testing for risk reduction in people with a 1-time positive
protein C, protein S, or antithrombin levels should antiphospholipid antibody with warfarin (RR, 0.99
be deferred or repeated at least 4 to 6 weeks (or [95% CI, 0.75–1.13]) or aspirin (RR, 0.94 [95%
up to 6 months for factor VIII609) after the acute CI, 0.70–1.28]; treatment-by-antiphospholipid
stroke given that these protein levels may be interaction, P=0.91) compared with those without
altered during the acute stroke phase.607,608,610,611 a positive antibody.612 Therefore, aspirin is more
preferable than warfarin because of the lower
5.8.2. Antiphospholipid Syndrome
risk of bleeding with aspirin. The prevalence of
Recommendations for Antiphospholipid Syndrome antiphospholipid syndrome in the stroke popula-
Referenced studies that support recommendations are summarized in
online Data Supplement 46. tion varies, but younger populations are most com-
COR LOE Recommendations
monly affected.620 Approximately 13% of patients
with antiphospholipid syndrome have stroke as
1. In patients with ischemic stroke or TIA who
have an isolated antiphospholipid antibody the initial clinical manifestation of the disease.621
1 B-NR
but do not fulfill the criteria for antiphospho- In patients with cryptogenic stroke and a history
lipid syndrome, antiplatelet therapy alone is
of thrombosis or rheumatological disease, it would
recommended to reduce the risk of recurrent
stroke.612 seem reasonable to consider testing for antiphos-
2. In patients with ischemic stroke or TIA with pholipid antibodies.622,623 In older populations with
confirmed antiphospholipid syndrome treated increasing frequency of vascular risk factors, there
with warfarin, it is reasonable to choose a is no evidence supporting the systematic testing
2a B-R
target INR between 2 and 3 over a target INR
>3 to effectively balance the risk of excessive
for antiphospholipid antibodies.
bleeding against the risk of thrombosis.613–615 2. Although no trials of antithrombotic intervention
have been performed exclusively in stroke patients,
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4. The role of DOACs in antiphospholipid syndrome • There is a knowledge gap with respect to the role
CLINICAL STATEMENTS
treatment is the focus of multiple ongoing and of dual antiplatelets in antiphospholipid syndrome,
AND GUIDELINES
recently completed studies. In an open-label, with reports suggesting a possible role to reduce
noninferiority RCT of patient with established the risk of stroke alone or in addition to antico-
antiphospholipid syndrome and triple-positive agulation. The absence of definitive data prevents
antiphospholipid antibodies, rivaroxaban was asso- us from providing a stronger recommendation at
ciated with higher risk of thrombotic events.616 A this point.
similar result in favor of VKA over rivaroxaban was
reported in an open-label RCT of patients with
5.9. Hyperhomocysteinemia
antiphospholipid syndrome. In this study, ≈60%
had triple-positive antiphospholipid antibodies, but Recommendation for Hyperhomocysteinemia
there was no statistical interaction suggestive of a Referenced studies that support the recommendation are summarized
in online Data Supplements 46 and 47.
differential effect among those with antiphospho-
COR LOE Recommendation
lipid syndrome and 1 or 2 antiphospholipid anti-
bodies.617 Observational data also suggest a high 1. In patients with ischemic stroke or TIA with
hyperhomocysteinemia, supplementation
risk of recurrent thrombosis among patients with 3: No
B-R with folate, vitamin B6, and vitamin B12 is
Benefit
antiphospholipid syndrome who receive DOACs.618 not effective for preventing subsequent
Until other ongoing trials such as ASTRO-APS stroke.625,626
migraine frequency in patients with migraine and prior molecular-weight heparin agents are commonly used
ischemic stroke. The use of oral contraceptive agents empirically when a hypercoagulable state is suspected,
with exogenous estrogen among women with migraine, but the benefit is unclear,654 particularly in this patient
especially when combined with active smoking, has population with a high tendency for hemorrhage.651 A
been associated with an increased risk of stroke in specific situation in these patients that has been more
numerous studies, although the quality of such studies adequately studied is the best anticoagulation regimen
is low.644 On the basis of these data, avoiding oral con- for the prevention of cardioembolism from AF,651 which
traceptive agents with exogenous estrogen in women is extrapolated from subgroup analysis of the large ran-
with migraine with aura and prior ischemic stroke may domized clinical trials of anticoagulation. (We also refer
perhaps be appropriate. the reader to Section 5.13.3, Neoplastic Vasculitis.)
Knowledge Gaps and Future Research Recommendation-Specific Supportive Text
Observational studies provide conflicting evidence 1. A subgroup analysis in the ROCKET AF trial
about the association between triptan therapy and comparing rivaroxaban and warfarin in patients
stroke risk, and these studies excluded patients with with AF and history of cancer showed similar
prior ischemic stroke.645 There are theoretical risks of rates of stroke and systemic embolism 0.52
cerebral vasoconstriction and ischemia with the use (95% CI, 0.22–1.21) and nonmajor bleeding
of calcitonin gene–related peptide receptor antago- events 1.09 (95% CI, 0.82–1.44).647 Similarly,
nists,646 but clinical evidence to quantify such risks is the efficacy (1.09 [95% CI, 0.53–2.26]) and
lacking. Therefore, no recommendations can be made safety (0.76 [95% CI, 0.45–1.29]) of apixaban
for the use of triptans and calcitonin gene–related were comparable to those of warfarin in patients
peptide receptors in patients with migraine and prior with AF and history of cancer in the ARISTOTLE
ischemic stroke. Future studies will be required to trial.648 This was supported by claims data analy-
better understand the safety of triptans and calcito- sis looking at bleeding events of rivaroxaban
nin gene–related peptide receptor antagonists in this (1.09 [95% CI, 0.79–1.50]), dabigatran (0.96
population. [95% CI, 0.72–1.27]), and apixaban (0.37 [95%
CI, 0.17–0.79]) compared with warfarin.649 A lit- patient to both ischemic stroke and intracranial hemor-
CLINICAL STATEMENTS
erature search of 31 660 patients in 5 trials in rhage. There are no randomized trials for antithrombot-
AND GUIDELINES
patients with AF and cancer DOACs showed a ics for secondary stroke prevention in SCD. Caution is
trend for more efficacy and better safety com- advised when considering antithrombotics for second-
pared with warfarin.650 ary stroke prevention in patients with SCD because the
stroke mechanism is less certain and patients with SCD
Knowledge Gaps and Future Research
are also at higher risk for hemorrhagic stroke. If there is
• Patients who had a stroke attributable to hyper-
evidence for other stroke mechanisms in a patient with
coagulability from cancer may be at a particularly
SCD (ie, atherosclerosis), then it would be reasonable
high risk of bleeding with anticoagulation. In these
to administer antithrombotics as supported elsewhere in
patients, the benefit of anticoagulants for second-
this guideline.
ary stroke prevention is not well established, and
further research is needed. Recommendation-Specific Supportive Text
• The particular need of anticoagulation to prevent 1. The recommendations for treatment of patients
stroke in different type of cancers is not known and with SCD are based on stroke primary prevention
should be a matter of further research. studies in a pediatric population and a secondary
• In patients who had a stroke attributable to hyper- stroke prevention study in a population of pediat-
coagulability from cancer who are anticoagulated, ric patients with SCD with silent cerebral infarc-
there is a paucity of data on the best treatment regi- tions (SIT [Silent Cerebral Infarct Transfusion]
men for these patients. multi-center clinical trial).671 The STOP trial was a
• Although low-molecular-weight heparin is often randomized, placebo-controlled trial that showed
used in patients with cancer and stroke to prevent that a long-term prophylactic transfusion strategy
thromboembolic complications, the potential ben- was effective for the primary prevention of stroke
efit on stroke prevention is unknown. in children with SCD and high TCD velocities.655
Blood transfusion was used because it was dem-
5.12. Sickle Cell Disease onstrated effective in reducing recurrent clinical
ischemic stroke and progression of arterial steno-
Recommendations for Sickle Cell Disease
Referenced studies that support recommendations are summarized in
sis in a series of children with SCD.656 This was
online Data Supplement 49. associated with a reduction in the rate of recurrent
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to transfusion or hydroxyurea. Noninferiority was dependent. In cohorts of younger patients (eg, age <45
CLINICAL STATEMENTS
shown: 3 TIAs in each group and no new MRI years), vasculitis may account for 0% to 20% of stroke
AND GUIDELINES
stroke in either group. Hematopoietic cell trans- cases, depending on the depth of workup.705 In older
plantation can be curative for SCD662 but is usu- population, the proportion of strokes caused by vas-
ally undertaken in children refractory to other culitis is smaller because of the increasing burden of
treatment; it results in survival without SCD in aging-related risk factors. Vasculitis may cause stroke
80% to 90% of patients. Clinical and subclini- by directly causing brain arterial inflammation, which
cal infarctions have been reported to be arrested subsequently results in endothelial damage and pro-
by this procedure.663 Surgical bypass has been motes thrombosis.706 Alternatively, extracranial vascu-
reported with improved outcomes in patients with litis may cause stroke by promoting artery-to-artery
SCD with moyamoya, but no randomized data are embolism, flow obstruction attributable to endothelial
available.664,665 Given the lack of experience with thickening, or aneurysmatic wall damage.707 The over-
antithrombotics, antihypertensive agents, and all approach to treat vasculitis causing stroke is with
statins for secondary stroke prevention in SCD, immunosuppressants and antiplatelets, but the choice
specific recommendations cannot be stated out- of immunosuppressant and regimens is specific to the
side of general treatment recommendations. type of vasculitis.
Knowledge Gaps and Future Research Recommendation-Specific Supportive Text
Most studies for primary or secondary stroke preven- 1. Giant cell arteritis is a rare vasculitis (incidence
tion in SCD were conducted in the pediatric popu- rate, 9–16 per 100 000 per year in individuals
lation. Therefore, there is a gap in understanding ≥50 years of age) that can cause stroke in ≈7%
whether transfusion or hydroxyurea recommendations of confirmed cases.672–674 Patients with symptoms
in the pediatric population hold true in the adult patient of giant cell arteritis should be treated urgently,
with SCD with symptomatic or asymptomatic stroke, and high-dose steroids should be initiated quickly
elevated TCD velocities, or vessel imaging notable for within the first 24 hours after symptoms onset
vasculopathy. to reduce the risk of permanent blindness and
to increase the chance of visual recovery.675–678
5.13. Vasculitis Practitioners should keep a high index of clini-
cal suspicion to consider giant cell arteritis in the
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CLINICAL STATEMENTS
methotrexate,687 azathioprine,688 or leflunamide.689 Infectious diseases may cause stroke through vari-
AND GUIDELINES
There are no data to support 1 agent over the ous mechanisms. Direct infection of cerebral arteries
other in terms of efficacy in stroke risk reduction by VZV may cause inflammation, endothelial activation,
among patients with Takayasu arteritis. In adults and thrombosis.724 Infectious cardiomyopathies may
with ischemic stroke or TIA and diagnosis of giant cause stroke by increasing the risk of cardioembolic
cell arteritis or Takayasu arteritis, a slow taper of stroke, as in the case of Chagas disease.725–728 Infection
oral steroids to a target of ≤5 mg/d after 1 year is with HIV may cause stroke by multiple mechanisms,
reasonable in light of reports of exacerbation after including increased risk of cerebral infection or oppor-
rapid steroid withdrawal.690,709 tunistic neoplasias, as well as accelerated atheroscle-
3. Primary CNS angiitis or vasculitis is a rare cause rosis in the setting of certain antiretroviral agents.729,730
of stroke (2.4 cases per 1 million patient-years),691 Basilar meningitis caused by Mycobacterium tubercu-
and it affects predominantly younger populations losis, Treponema pallidum, or Cryptococcus may cause
(mean age at presentation, 45 years) and is slightly stroke by contiguous spreading of the inflammation in
more prevalent in men.692 In cases with confirmed the cerebrospinal fluid to the brain arteries at the base
primary CNS angiitis, administration of high-dose of the skull.731–734
steroids is supported by observational data.693,694 In
most cases, slow tapering of steroids followed by Recommendation-Specific Supportive Text
the addition of a steroid-sparing agent seems pre- 1. Stroke associated with CNS infection should be
ferred over long-term monotherapy with steroids considered a life-threatening emergency and should
because of a higher rate of relapse and poorer be triaged accordingly. The risk of stroke recurrence
outcomes with steroid monotherapy.694,695 Some depends on the underlying infection, and the treat-
commonly used maintenance steroid-sparing ment should be target as indicated. It may be help-
agents include cyclophosphamide,693,694,696 aza- ful to consult with an infectious disease expert as
thioprine,692–694 mycofenolate mofetil,692,693 meth- needed. VZV vasculitis may present with large and
otrexate,692 or rituximab.696 There are no robust small artery strokes in the context of arterial luminal
data related to efficacy between these agents. irregularities, beading, or stenosis.710,711 Patients in
Therefore, we recommend an interdisciplinary fol- whom VZV vasculitis is suspected should undergo
low-up for patient with primary CNS angiitis and a lumbar puncture for anti-VZV immunoglobulin G,
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that the choice of steroid-sparing agent be made immunoglobulin M, and polymerase chain reaction.
considering the profile of each agent and associ- Anti-VZV immunoglobulin G has the highest sen-
ated comorbidities. sitivity of the 3 tests. A negative VZV polymerase
4. Infliximab should not be used to treat patients with chain reaction does not rule out VZV vasculitis.712,713
stroke and giant cell arteritis. This recommendation If suspicion of VZV vasculitis is high, it may be rea-
is based on a phase II clinical trial that random- sonable to treat empirically while awaiting the results
ized patients with giant cell arteritis to infliximab (5 of confirmatory tests. Acyclovir is the drug of choice
mg/kg body weight) versus placebo after steroid- for the treatment of VZV infection.714 Among patients
induced remission. During follow-up, patients who with stroke and diagnosed neurosyphilis, intense
received infliximab had a higher risk of disease treatment with penicillin G is mandated.735 In some
activity at 12 weeks (eg, lower chances of remis- instances, there may be coexisting comorbidities that
sion) than those who received placebo.697 may also predispose to stroke such as large artery
atherosclerosis or AF. In such cases, treating neuro-
5.13.2. Infectious Vasculitis syphilis is still indicated in addition to the confounding
Recommendations for Infectious Vasculitis competing risk of stroke. Testing for HIV is indicated
Referenced studies that support recommendations are summarized in in patients with stroke and diagnosis of neurosyphilis.
online Data Supplement 51.
This recommendation is supported by a relatively high
COR LOE Recommendations coexistence (5%–16%) of both sexually transmitted
1. In patients with ischemic stroke or TIA and diseases.715,716
infectious vasculitis such as varicella zoster
virus (VZV) cerebral vasculitis, neurosyphilis,
2. Secondary stroke prevention among patients
1 B-NR with HIV vasculopathy is focused on daily anti-
or bacterial meningitis, treating the underlying
infectious etiology is indicated to reduce the platelets and treatment aimed at restoring the
risk of stroke.710–716
CD4 counts and immune system. There are
2. In patients with ischemic stroke or TIA in the no randomized data to support these claims.
context of HIV vasculopathy, daily aspirin plus
2a C-LD HIV viral control with combined antiretroviral Restoring the immune system as captured by
therapy is reasonable to reduce the risk of the CD4 count is indicated in all patients with
recurrent stroke.717–723 HIV regardless of whether they have stroke.717
The presence of stroke may be seen as an even • Steroids are often used to treat autoimmune vascu-
CLINICAL STATEMENTS
greater indication to treat the most devastating litis. This may be problematic in people with coexist-
AND GUIDELINES
consequences of HIV infection and associated ing vascular risk such as hypertension and diabetes.
immunosuppression. Observational data support Further research is needed on the safety profile of
this approach in patients with HIV vasculopa- long-term steroids and steroid-sparing agents in
thy.718–721 Some authors have noted a possible stroke populations. Similarly, the timing of steroid
link between the initiation of combined antiret- initiation and poststeroid biopsy yield should be fur-
roviral therapy and stroke risk, suggesting an ther delineated.
immune reconstitution-like syndrome in these • In adults with ischemic stroke or TIA and symptoms
cases.722,723 It is uncertain whether steroids may of giant cell arteritis, the benefit of an initial high-
play a role in stroke risk reduction in this clinical dose intravenous pulse of steroids versus oral ste-
setting. roids in stroke prevention is uncertain.
• For the treatment of VZV vasculitis, the role of ste-
5.13.3. Neoplastic Vasculitis
roids as adjunctive therapy to acyclovir is not well
Synopsis established.
Neoplastic vasculitis refers to inflammation of the brain • Chronic inflammation is often found in people liv-
arteries resulting from direct invasion of neoplastic ing with well-controlled HIV infection. It is uncer-
cells, as opposed to paraneoplastic vasculitis in which tain whether, in addition to comprehensive vascular
the inflammation of the brain arteries is not attributable risk factor control, there may be a role for additional
to direct tumor invasion or compression. Conditions in immunomodulation in this population.
this category are rare and include lymphomatoid granu-
lomatosis and angiotropic or intravascular lymphoma
(also known as angioendotheliomatosis)736 among 5.14. Other Genetic Disorders
other even less common disorders.737,738 Treating the Recommendations for Other Genetic Disorders
Referenced studies that support recommendations are summarized in
underlying malignancy also reduces the risk of recur- online Data Supplements 51 and 52.
rent stroke. The relatively rare occurrence of neoplastic
COR LOE Recommendations
vasculitis is a challenge for the systematic study of the
1. In patients with ischemic stroke or TIA
disease. Even less homogeneous information exists on and cystathionine β-synthase deficiency,
what strategy may be the most effective to reduce the
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CLINICAL STATEMENTS
1. An ecological study of a newborn screening pro- Recommendations for Carotid Web
AND GUIDELINES
gram in Ireland supports the effectiveness of Referenced studies that support recommendations are summarized in
interventions to drive free homocysteine to ≤11 online Data Supplement 53.
mmol/L to prevent thromboembolic events.739 A COR LOE Recommendations
study of treatment of severe hyperhomocysteine 1. In patients with carotid web in the distribu-
performed in Australia, the Netherlands, and Ireland tion of ischemic stroke and TIA, without other
1 B-NR attributable causes of stroke, antiplatelet
on patients who had cystathionine β-synthase defi- therapy is recommended to prevent recurrent
ciency (mean age, 27.8 years; range, 2.5–70 years) ischemic stroke or TIA.748,749
supported a dramatic reduction of risk of vascu- 2. In patients with carotid web in the distribution
lar events relative to a historical cohort study (RR, of ischemic stroke refractory to medical man-
agement, with no other attributable cause of
0.091 [95% CI, 0.043–0.190]; P<0.001).740 2b C-LD
stroke despite comprehensive workup, carotid
2. A systematic review of RCTs of agalsidase alfa stenting or CEA may be considered to prevent
or beta in patients with Anderson-Fabry disease recurrent ischemic stroke.748–750
found that the enzyme replacement therapy
improved pain-related quality of life but that their Synopsis
effects on morbidity or mortality required further Carotid web is a thin, circumferential shelf-like filling
study.741 defect that arises from the posterior wall of the ICA bulb
visualized on CTA or carotid angiography. Pathologi-
Knowledge Gaps and Future Research cally, carotid web is a variant of fibromuscular dysplasia
• Specific treatments are needed for several single- and can be classified as focal or multifocal. Platelet
gene disorders associated with high risk of stroke, deposition can occur in the corrugations of carotid
including mitochondrial myopathy, encephalopa- web, forming a nidus for potential blood flow stagna-
thy, lactic acidosis, stroke-like episodes, cerebral tion and thromboembolism. Carotid web is a known
autosomal dominant arteriopathy with subcorti- cause of ischemic stroke in young patients <65 years
cal infarcts and leukoencephalopathy, cerebral of age; it is detected in up to 9.5% of patients <65
autosomal recessive arteriopathy with subcorti- years of age with anterior circulation stroke of unknown
cal infarcts and leukoencephalopathy, cathep- cause.751
sin-A–related arteriopathy with strokes and
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5.16. Fibromuscular Dysplasia not routinely prescribed for isolated FMD in the
CLINICAL STATEMENTS
Referenced studies that support recommendations are summarized in 2. Dissection is a common manifestation associated
online Data Supplement 54. with FMD, present in 11% to 15% of patients
COR LOE Recommendations with spontaneous carotid or vertebral artery dis-
1. In patients with fibromuscular dysplasia section.757,758 In the US FMD registry, ischemic
(FMD) and a history of ischemic stroke or TIA stroke was present in 19% of patients presenting
without other attributable causes, antiplatelet
1 C-LD
therapy, BP control, and lifestyle modification
with cervical artery dissections.759 The CADISS
are recommended for the prevention of future study demonstrated equivalent efficacy for recur-
ischemic events.752,753 rent stroke risk in patients with spontaneous,
2. In patients with a history of ischemic stroke symptomatic cervical carotid dissection random-
or TIA attributable to dissection, with FMD,
ized to antiplatelet versus anticoagulant for 3
2a C-EO and no evidence of intraluminal thrombus, it is
reasonable to administer antiplatelet therapy months (3% versus 1%; P=0.66) (see Section
for the prevention of future ischemic events. 5.7, Dissection).
3. In patients with cervical carotid artery FMD 3. This recommendation has been adapted from a
and recurrent ischemic stroke without other prior guideline by Brott et al25 on carotid angio-
attributable causes despite optimal medical
2b C-LD
management, carotid angioplasty with or plasty with or without stenting in symptomatic
without stenting may be reasonable to prevent patients with patients to COR 2b. There are no
ischemic stroke.754 comparative data evaluating medical manage-
ment versus angioplasty or stenting for patients
Synopsis with FMD and recurrent ischemic stroke. A
FMD is a nonatherosclerotic segmental disease of case series of 7 patients with symptomatic
small or medium-sized arteries that can result in arte- FMD revealed no complications with balloon
rial stenosis, occlusion, intraluminal thrombus, aneu- angioplasty.754
rysm, or dissection.752 It can involve the extracranial
carotid, vertebral. and renal arteries. On a histological Knowledge Gaps and Future Research
level, FMD affects the musculature or media layer of The optimal medical or interventional management
the vessel wall, leading to medial fibroplasia and the of symptomatic FMD is unknown. Future prospective
appearance of a “string of beads” on angiography research evaluating the natural history of symptom-
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imaging. Multiple fibrous webs can serve as a nidus atic FMD on medical management compared with
for platelet deposition755 or obstruct flow, resulting in interventional management would be of interest and
thromboembolic TIA or ischemic stroke. Women are evolve to multicenter randomized trials comparing
more commonly affected than men. The frequency of medical management (ie, antiplatelet versus anti-
neurological events in the US FMD registry was noted: coagulant, then best medical therapy versus carotid
13.4% had TIA; 5% had experienced amaurosis fugax; angioplasty or carotid stenting) if enough patients can
12% had experienced cervical artery dissection; and be identified.
9.8% had had a stroke.756
5.17. Dolichoectasia
Recommendation-Specific Supportive Text Recommendation for Dolichoectasia
1. High BP is common in patients with FMD, from Referenced studies that support the recommendation are summarized
either essential hypertension or renovascular in online Data Supplement 55.
hypertension related to FMD.752 The optimal COR LOE Recommendation
BP target for patients with FMD is unknown. 1. In patients with vertebrobasilar dolichoectasia
In the US FMD registry, most patients were on and a history of ischemic stroke or TIA without
2a C-LD other attributable causes, the use of antiplatelet
antihypertensive medicine.753 Smoking cessa- or anticoagulant therapy is reasonable for the
tion should be encouraged for all patients with prevention of recurrent ischemic events.760–764
FMD who smoke because of its health benefits
in the general population. The recommenda- Synopsis
tion of using antiplatelet therapy for secondary Vertebrobasilar dolichoectasia is characterized by the
stroke prevention is based on current practice fusiform dilatation and elongation and tortuosity of the
and expert opinion.752,753,755 In the US FMD regis- vertebral and basilar arteries. Vertebrobasilar dolicho-
try, 73% of patients were prescribed antiplatelet ectasia is associated with traditional ischemic stroke
therapy; aspirin was the most common agent.753 risk factors such as increasing age, hypertension, and
There are no placebo-controlled randomized tri- male sex. However, its relationship to atherosclerotic
als of patients with symptomatic or asymptomatic disease is less clear.765–767 Although many patients may
FMD comparing aspirin with placebo. Statins are be asymptomatic, others may present with a variety of
clinical syndromes, including cranial nerve or brainstem • Development of an agreed-on definition for ver-
CLINICAL STATEMENTS
compression, obstructive hydrocephalus, subarachnoid tebrobasilar dolichoectasia that is distinguishable
AND GUIDELINES
hemorrhage, and ischemia.760,764,768 Ischemic events from the definition of a fusiform aneurysm.
may be related to thromboembolic phenomenon but • Accumulation of more robust natural history data
may also result from the disruption of small perforat- with detailed clinical outcomes.
ing vessels.764,769 Asymptomatic patients have the most • Clarification of the type, dosing regimens, and
favorable prognosis,764 whereas those presenting with efficacy of antiplatelet therapy versus anticoagu-
compressive symptoms or demonstrating progressive lation for primary and secondary ischemic stroke
enlargement have a worse prognosis.760,768,770 The rate prevention.
of recurrent ischemic stroke may be quite high,761,771,772 • Improved understanding of the role of reconstruc-
with 1 study reporting a rate of 19% at just under 2 tive procedures, whether endovascular or open
years.761 Increasing basilar artery diameter, diffuse surgical, in the management of patients with verte-
intracranial dolichoectasia, and associated ischemic brobasilar dolichoectasia.
heart disease increased the risk of recurrent events.761
Many patients with vertebrobasilar dolichoectasia are
treated medically with antithrombotic medication, but 5.18. Embolic Stroke of Undetermined Source
high-quality evidence on the management strategies Recommendations for ESUS
Referenced studies that support recommendations are summarized in
for patients with vertebrobasilar dolichoectasia, par- online Data Supplement 56.
ticularly in the setting of a prior ischemic stroke or COR LOE Recommendations
TIA, is lacking. Several case series describe endovas-
1. In patients with ESUS, treatment with direct
cular techniques773–775 and various surgical interven- 3: No
B-R oral anticoagulants is not recommended to
Benefit
tions114,775–778; however, there is little evidence that reduce risk of secondary stroke.779,780
such treatments reduce the risk of additional ischemic 2. In patients with ESUS, treatment with ticagre-
3: No
events in patients who present with an ischemic stroke Benefit
B-NR lor is not recommended to reduce the risk of
secondary stroke.781
or TIA. The literature on dolichoectasia of the anterior
circulation in patients with prior ischemic stroke or
Synopsis
TIA is even more sparse; therefore, this topic is not
ESUS is an evolving stroke subtype commonly defined
addressed in this guideline.
as a nonlacunar cryptogenic ischemic stroke. Lack of a
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new ischemic events (silent strokes) as clinical trial Recommendations for Antithrombotic Medications
CLINICAL STATEMENTS
• The use of different strategies for long-term arrhyth- 6. For patients with noncardioembolic ischemic
stroke or TIA, the continuous use of DAPT
mia detection and their impact on ESUS diagnosis 3: Harm ASR (aspirin plus clopidogrel) for >90 days or the
criteria. use of triple antiplatelet therapy is associated
• The use of additional cardiac markers of atrial with excess risk of hemorrhage.381,382,801
pathology, including atrial size, and their impact on SR indicates systematic review.
ESUS diagnosis criteria, secondary stroke risk, and *The subgroup of patients with noncardioembolic stroke who meet clinical cri-
teria for DAPT have a more specific recommendation for antiplatelet therapy as
response to anticoagulation. described in Recommendation 3.
Synopsis
5.19. Use of Antithrombotic Medications in Patients with stroke/TIA not attributable to other
Secondary Stroke Prevention stroke causes related to specific antithrombotic rec-
As described in prior sections of this guideline, recom- ommendations (eg, AF, intracranial stenosis) should
mendations for secondary stroke prevention have been receive antithrombotic therapy for the prevention of
constructed on the basis of the best evidence among recurrent stroke. If patients with mild stroke or high-
patients with a specific cause of their initial ischemic risk TIA are evaluated early after the onset of their
stroke. For patients with noncardioembolic ischemic stroke, starting short-term DAPT followed by long-term
stroke who do not have a specific identified cause, ques- SAPT is preferred compared with SAPT according to
tions about optimal antithrombotic medication use for the reduction of risk of early recurrent stroke.384,410
secondary prevention may thus arise. In general, when Beyond 90 days after stroke, DAPT is associated with
those specific antithrombotic recommendations vary increased risk of bleeding and no benefit in long-term
slightly from the general recommendations that follow in reduction of recurrent stroke risk.381,382 For patients
this section, the most specific recommendation should not treated until later after their stroke event, use of
be prioritized. any SAPT is indicated to reduce long-term recurrent
CLINICAL STATEMENTS
AND GUIDELINES
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Figure 6. Antiplatelet therapy for noncardioembolic stroke and transient ischemic attack (TIA).
Note: Algorithm does not apply to patients who receive acute thrombolysis. Note: Please see Section 5.1.1 for recommendations related to severe
symptomatic intracranial large vessel stenosis. Early ischemic stroke (IS), <24 hours from onset; high-risk TIA, ABCD2 score ≥4; low-risk TIA,
ABCD2 score <4; dual antiplatelet, acetylsalicylic acid (ASA)+clopidogrel. Colors correspond to Class of Recommendation in Table 3. NIHSS
indicates National Institutes of Health Stroke Scale. Data from Brown et al,15 Pan et al,409 and Wang et al.410
stroke risk. Although the optimal time to switch from (17.8% warfarin versus 16% acetylsalicylic acid;
DAPT to SAPT to maximize benefit and reduce risk HR, 1.13 [95% CI, 0.92–1.38]). Similarly, a sub-
is not entirely clear, benefit in stroke reduction with sequent meta-analysis of 8 other trials of VKA
DAPT may be maximized as early as the first 21 days among 5762 patients with TIA or nondisabling
after the event.802 This treatment approach is summa- noncardioembolic stroke found no benefit in sec-
rized in Figure 6, with consideration of clinical event ondary stroke prevention with the use of oral anti-
criteria, DAPT versus SAPT, and length of therapy. Tri- coagulation of various intensities compared with
ple therapy with aspirin, clopidogrel, and dipyridamole antiplatelet agents (medium-intensity anticoagula-
and use of anticoagulation in this population are not tion: RR, 0.80 [95% CI, 0.56–1.14]; high-intensity
recommended on the basis of increased bleeding risk anticoagulation: RR, 1.02 [95% CI, 0.49–2.13]);
and no benefit in stroke reduction.790,801 both medium-intensity anticoagulation and high-
intensity anticoagulation were associated with a
Recommendation-Specific Supportive Text significantly increased risk of bleeding.789
1. The WARSS study randomized 2206 patients with 2. A series of single antiplatelet trials conducted in
stroke not attributable to cardioembolism or high- patients with noncardioembolic stroke did not
grade carotid stenosis to adjusted-dose warfarin use clinical eligibility criteria in the same man-
(INR, 1.4–2.8) versus aspirin 325 mg.790 The pri- ner as the more recent DAPT trials. Thus, some
mary end point of 2-year recurrent ischemic stroke patients in the general noncardioembolic stroke
or death was no different between the 2 groups pathogenesis group may qualify for the more
specific recommendation for early DAPT. For those increase in bleeding risk with DAPT, this was offset
CLINICAL STATEMENTS
who do not meet DAPT clinical criteria, SAPT is by the stroke prevention benefit if limited to short-
AND GUIDELINES
However, similar studies have not been performed 5. No randomized trials have focused on the ques-
for secondary stroke prevention. tion of changing long-term antiplatelet therapy for
3. Recommendations for the short-term (21–90 the prevention of recurrent stroke. A meta-analysis
days) use of DAPT with aspirin and clopidogrel suggested that, among the 4 studies that exam-
are informed by 2 major RCTs,384,410 4 meta-anal- ined stroke outcomes, there was a reduced risk of
yses,802,804–806 and a systematic review by an AHA recurrent stroke (HR, 0.70 [95% CI, 0.54–0.92])
Evidence Review Committee.15 Both the CHANCE among patients who switched from 1 antiplatelet
and POINT trials compared DAPT with SAPT with agent to another or to DAPT.800 However, both
aspirin initiated early after onset (<24 and <12 of the RCTs that specifically examined recur-
hours, respectively) of minor stroke (NIHSS score rent stroke used DAPT rather than switching
≤3) or high-risk TIA (ABCD2 score ≥4) but varied antiplatelets. In a subgroup analysis of the SPS3
in duration of DAPT treatment (21 and 90 days, trial, there was no benefit from the addition of
respectively). DAPT dosing was also slightly differ- clopidogrel to aspirin among patients with isch-
ent in the 2 trials: POINT used a 600-mg clopido- emic stroke who were already taking aspirin (risk
grel load (then 75 mg daily) and an aspirin regimen of recurrent stroke, 3.1% versus 3.3%; HR, 0.91
of 50 to 325 mg daily, whereas CHANCE used a [95% CI, 0.61–1.37]).798 In a subgroup of patients
300-mg clopidogrel load (then 75 mg daily) and already on aspirin in the CHANCE trial, there was
an aspirin load of 75 to 300 mg followed by 75 a reduction in recurrent stroke among patients with
mg daily. Both trials demonstrated a reduction in clopidogrel added to aspirin versus aspirin alone
recurrent ischemic stroke at 90 days. Further anal- (12.3%–9.0%; HR, 0.66 [95% CI, 0.47–0.92]).410
yses of POINT revealed that the benefit of DAPT A prospective registry study found that maintaining
was seen primarily in the first 21 days.365 Meta- aspirin therapy was associated with higher recur-
analyses that included other DAPT trials also have rent stroke rates (8.0%) compared with switching
shown a reduction in recurrent stroke from DAPT to another antiplatelet (6.9%) or adding another
compared with aspirin monotherapy, but the ben- antiplatelet (6.6%).799
efit is limited if not started early (<7 days) after the 6. Long-term use of DAPT with aspirin and clopi-
index event. Although most studies showed some dogrel has been shown in 2 secondary stroke
prevention RCTs381,382 to have no benefit over • Effectiveness and potential harm of DAPT among
CLINICAL STATEMENTS
SAPT for recurrent stroke prevention and to specific subgroups of patients according to stroke
AND GUIDELINES
have a significantly increased risk of ICH and characteristics, laboratory or genetic tests, or other
major bleeding. The exact duration of DAPT at factors.
which the risk of hemorrhage begins to outweigh • Effectiveness/selection of a given antiplatelet agent
the benefit of stroke prevention is unknown, but over another in specific subgroups of patients with
meta-analyses report as early as 21,802 30,805 or noncardioembolic stroke.
90 days.806 Older patients804 and those with more • Benefit of switching antiplatelet agent for patients
severe stroke806 appear to be at higher risk of ICH already taking 1 antiplatelet medication at the time
with DAPT. Triple antiplatelet therapy with aspirin, of stroke.
clopidogrel, and dipyridamole was compared with • Effectiveness of DOACs compared with or in com-
standard antiplatelet therapy in the TARDIS trial bination with antiplatelet therapy for secondary
(Triple Antiplatelets for Reducing Dependency stroke prevention among patients with noncardio-
after Ischaemic Stroke), which found no difference embolic ischemic stroke.
in stroke outcomes and a significantly increased
risk of bleeding with triple antiplatelet therapy.801
There may be other non–stroke-related indica-
6. SYSTEMS OF CARE FOR SECONDARY
tions for DAPT beyond 90 days after stroke (eg, PREVENTION
recent drug-eluting cardiac stent placement), but 6.1. Health Systems–Based Interventions for
these indications should be clarified to ensure that
Secondary Stroke Prevention
DAPT is not continued indefinitely beyond the
clinically recommended time frame. Recommendations for Health Systems–Based Interventions
Referenced studies that support recommendations are summarized in
Knowledge Gaps and Future Research online Data Supplements 60–62.
To date, most DAPT trials have used aspirin and clopi- COR LOE Recommendations
dogrel in combination for 21 to 90 days, but whether 1. In patients with ischemic stroke or TIA,
the duration of treatment should be 21 days, 90 days, voluntary hospital-based or outpatient-focused
quality monitoring and improvement programs
or some other amount of time is not fully established. 1 C-EO are recommended to improve short-term and
Similarly, whether other combinations of medications are long-term adherence to nationally accepted,
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equally or more beneficial is not known. The risk of DAPT evidence-based guidelines for secondary
stroke prevention.
among patients with stroke who may be more likely to
2. In patients with ischemic stroke or TIA, a mul-
experience hemorrhagic transformation of the ischemic
tidisciplinary outpatient team-based approach
stroke or other bleeding complication such as those with (ie, care provision with active medication adjust-
2a B-R
large stroke or microhemorrhages remains uncertain. ment from advanced practice providers, nurses,
or pharmacists) can be effective to control BP,
Pharmacological responsiveness to antiplatelet ther-
lipids, and other vascular risk factors.810–817
apy has been studied most extensively in patients with
3. In patients presenting to their primary care
acute CVD, but the utility of such tests for guiding adjust- provider as the first contact after TIA or minor
ment of antiplatelet medications for long-term prevention stroke, it is reasonable to use a decision sup-
remains unclear. Relatively few head-to-head compari- port tool that improves diagnostic accuracy,
stratifies patients in risk categories to support
sons of antiplatelet medications have been evaluated for 2a B-R
appropriate triage, and prompts the initiation
the prevention of recurrent stroke, and in the existing of medications and counseling for lifestyle
trials, the benefit of 1 medication over another is small. modification for secondary stroke prevention
to reduce the 90-day risk of recurrent stroke
Despite the common practice of changing antiplate- or TIA.818
let medications in patients already taking 1 medication
at the time of stroke, there is relatively little evidence Synopsis
from RCTs to support the benefit of this practice. Finally, Optimal treatment recommendations exist for many stroke
although DOACs may be beneficial in vascular event risk factors. However, treatment targets are often unmet
reduction in patients with stable CVD (COMPASS after ischemic stroke and TIA, thereby increasing the risk
[Cardiovascular Outcomes for People Using Antico- of recurrent events.819–825 Health system approaches to
agulation Strategies]),809 whether they have any role acute stroke management have transformed care delivery
in secondary stroke prevention for patients with recent and have led to improved access to stroke treatment and
noncardioembolic stroke remains an unanswered improved stroke outcomes.826–828 Similar approaches to
question. In summary, further research is needed in the poststroke care and secondary prevention hold promise
following areas: for improving risk factor control after stroke.829 Risk factor
• Optimal combination of medications, timing of initia- control is affected by patient, provider, and system-level
tion, and duration of DAPT. factors. We define health systems-based interventions
for secondary stroke prevention as those that influence data. In Ontario, Canada, Stroke Prevention Clinics
CLINICAL STATEMENTS
vascular risk factor treatment and control by influencing evolved as an interdisciplinary approach to stroke
AND GUIDELINES
provider or patient behaviors. These are often multicom- assessment, prevention, and risk factor manage-
ponent interventions that fit into categories defined by ment.832 Patients are referred to these clinics from
Wensing et al829 and referenced in a Cochrane review their primary doctors after TIA or after emergency
of interventions for secondary stroke prevention.830 Cat- department visit for TIA or stroke. Care in these
egories include interventions that involve revision of pro- clinics has been associated with increased use of
fessional roles, collaboration between multidisciplinary evidence-based strategies for stroke prevention and
teams, integrated care services, knowledge management decreased risk of mortality at 1 year compared with
systems, and quality management systems. We review patients who are not referred to such clinics.816 In
best available data here but consider that the generaliz- the COMPASS pragmatic trial (United States), there
ability of findings may be affected by the study setting, was no benefit of a stroke transitional care model
patient access to care after an acute stroke, and other on secondary behavioral outcomes for risk factor
patient demographic characteristics. control; however, implementation of the model into
real-world practice was a major barrier. Additional
Recommendation-Specific Supportive Text
ongoing and recently completed randomized trials
1. Adherence to evidence-based guidelines for
are evaluating the impact of team-based interven-
secondary stroke prevention is affect by health
tions on risk factor control and secondary preven-
system–level, hospital-level, provider-level, and
tion after ischemic stroke and TIA.833–838
patient- and community-specific factors. Regular
3. In the FASTEST study (Efficacy and Safety of a
hospital and outpatient-based programs for adher-
Transient Ischaemic Attack [TIA] Electronic Support
ence and risk factor monitoring provide the oppor-
Tool) conducted in New Zealand, use of an elec-
tunity to identify areas of need and to optimize
tronic decision support tool for TIA and stroke man-
strategies to improve care quality, improve risk fac-
agement by general practitioners was compared
tor control, and ultimately reduce the risk of recur-
with usual care for patients presenting to their gen-
rent stroke and TIA. The Get With The Guidelines
eral practitioner as first care contact after stroke or
registry is an example of an inpatient registry used
TIA.818 The tool was designed to improve diagnostic
for quality monitoring and improvement.831
accuracy, to support appropriate triage, and to guide
2. Interventions that include a multidisciplinary team–
providers in appropriate medication and nonphar-
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CLINICAL STATEMENTS
trol and secondary stroke prevention are needed. Hypertension, smoking, T2D, physical activity, diet, psy-
AND GUIDELINES
• Additional studies are needed to evaluate the chosocial factors, abdominal obesity, alcohol, cardiac
impact of decision support tools on risk factor con- causes, and apolipoproteins account for 91.5% of the
trol and secondary stroke prevention after stroke PAR for ischemic stroke, similar across world regions,
hospitalization. sexes, and ages.5a,846 One in 3 US citizens has at least
• The impact of telemedicine on acute stroke care 1 of these risk factors,847 which can be modulated by
is well established.839 Although telemedicine offers health behaviors, indicating a focus for stroke second-
many potential benefits over in-person care, patients ary prevention and self-care.848 Changing entrenched
with stroke may face multiple barriers to engaging behavior is difficult, and sustaining change over time is
in telemedicine, including cognitive impairment and challenging. Several systematic reviews examine lifestyle
physical disability. Research is needed to evaluate interventions after stroke; optimal approaches to reduce
the impact of telemedicine on poststroke risk factor recurrent stroke remain unknown.112,840,841,849 Guidance
control and secondary stroke prevention. on changing behaviors associated with chronic disease
• Once proven effective, interventions must be imple- at an individual level is available850; however, a Delphi
mented across hospital and health systems in order consensus identified that interventions to self-manage
to achieve desired outcomes. Research that exam- lifestyle risk factors after stroke need to be contextual-
ines the implementation of interventions across ized to the capacities, needs, and personal priorities of
health systems is needed. the individual and their families.851 Lifestyle change after
stroke is more attainable when the lifestyle counseling
is interactive, the advantages of behavior change are
6.2. Interventions Aimed at Changing Patient perceived as beneficial, and the counselor has sufficient
Behavior resources (eg, availability of healthcare professionals’
Recommendations for Behavior Change Interventions time; appropriate counseling materials; knowledge and
Referenced studies that support recommendations are summarized in skills), highlighting a training need for healthcare staff to
online Data Supplements 63 and 64. ensure good-quality counseling and patients’ adherence
COR LOE Recommendations to healthier behavior.852
1. In patients with ischemic stroke or TIA,
behavior change interventions targeting Recommendation-Specific Supportive Text
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1 B-R stroke literacy, lifestyle factors, and medica- 1. Longer-term follow-up in behavioral interventions
tion adherence are recommended to reduce
after stroke addressing recurrent events is lack-
cardiovascular events.131,134,840
ing.111,112,840 However, meta-analysis (from 4 iden-
2. In patients with ischemic stroke or TIA, teaching
self-management skills or using behavior change tified studies; N=4053; I 2=0) demonstrates that
2a B-R
theory (eg, motivational interviewing) can be ben- multimodal interventions addressing active educa-
eficial in improving medication adherence.840–843 tion about risk factors, medications, and medication
3. In patients with stroke or TIA, combined compliance and interventions to modify ≥1 lifestyle
exercise-based and behavior change interven-
tions are probably indicated in preference to
risk factors decrease the odds of recurrent cardiac
2a B-R events (OR, 0.38 [95% CI, 0.16–0.88]), although
behavior interventions alone, exercise interven-
tions alone, or usual care to reduce physiologi- no significant difference in the odds of recurrent
cal stroke risk factors such as SBP.111–113,829
TIA/stroke was reported in this review.840 Two
4. In patients with TIA or nondisabling stroke, small multimodal RCTs show promise for reducing
engagement in targeted secondary prevention
programs (eg, cardiac rehabilitation programs cardiovascular end points. However, the small trial
2a B-R
or exercise and lifestyle counseling programs) numbers dictate that results must be interpreted
can be beneficial to reduce risk factors and with caution pending larger, more definitive trials.
recurrent ischemic events.133,134
A 24-week Japanese RCT (N=70)134 compris-
5. For patients with disabling stroke who are
discharged from acute services, engaging in
ing exercise, salt restriction, and nutrition advice
targeted secondary prevention programs (eg, an compared with usual care terminated at a median
2a B-NR adapted cardiac rehabilitation program or struc- follow-up of 2.9 years when the prespecified effi-
tured exercise including aerobic activity and
healthy lifestyle counseling) can be beneficial to
cacy point for the intervention was reached for the
reduce vascular risk factors and mortality.111,844 primary end point (composite stroke death, cardiac
6. In patients with stroke or TIA, provision of health death, and hospitalization for stroke recurrence,
information or advice about stroke prevention is MI, angina pectoris, or peripheral artery disease;
essential; however, information or advice alone,
3: No (adjusted HR, 0.194 [95% CI, 0.121–0.737]).
B-R in the absence of a behavioral intervention, is
Benefit
not an effective means to change modifiable, Long-term effects (3.5 years) of an exercise and
lifestyle-related risk factors in order to reduce education program, compared with usual care in
future ischemic events.129,829,845
TIA or minor stroke patients (N=60), found that
within the intervention group, recurrent stroke, interventions alone (MD, −2.51 [95% CI, −4.72
CLINICAL STATEMENTS
minor stroke, or TIA events were reduced com- to −0.30]).113 A review of educational/behavioral
AND GUIDELINES
pared with the usual care group (RR, 0.23 [95% interventions (excluding exercise) showed no
CI, 0.07–0.72]; number needed to treat, 3) and a effect on SBP.829
reduction in mortality associated with the inter- 4. Cardiac rehabilitation reduces cardiovascular
vention (RR, 0.11 [95% CI, 0.01–1.98]; number mortality in coronary heart disease.854 Emerging
needed to treat, 8).131 evidence supports its broad application in TIA/
2. Adhering to pharmacological secondary preven- nondisabling stroke populations. One small RCT
tion strategies is an important self-care behavior (N=22) demonstrated superiority to usual care in
in stroke secondary prevention. However, nonad- risk profiles, perceived physical functioning, and
herence to medication regimens is reported in up mental health when patients with TIA/nondis-
to 40% of individuals with stroke.853 Multimodal abling stroke access existing programs.133 A cohort
interventions have been shown in a meta-analysis study (N=80) of participants with TIA attending a
to improve compliance with antithrombotic medi- 6-month cardiac rehabilitation program demon-
cations (OR, 1.45 [95% CI, 1.21–1.75]; I 2=0%; strated a significant (26%) increase in the lowest
N=2792) and statins (OR, 2.53 [95% CI, 2.15– mortality risk category of the Duke treadmill score
2.97]; I 2=0%; N=2636).840 Self-management and significant improvements in fitness, total cho-
interventions have similarly shown a moder- lesterol/high density lipoprotein ratios, waist cir-
ate effect size in adherence to prescribed sec- cumference, and BMI.132 Two RCTs demonstrated
ondary prevention medications after stroke promising longer-term reductions in cardiovascular
(standardized MD, 0.31 [95% CI, 0.07–0.56]; events. A mixed exercise program combined with
I 2=0%; N=802).841 In the MIST phase III RCT education and lifestyle counseling (N=60) dem-
(Motivational Interviewing in Stroke; N=386), onstrated reduced recurrent stroke or TIA events
improving adherence to secondary stroke preven- in the intervention group compared with the usual
tion strategies through motivational interviewing care control group (RR, 0.23 [95% CI, 0.07–0.72])
demonstrated positive effects on self-reported and a reduction in mortality (RR, 0.11 [95% CI,
medication adherence 9 months after stroke (RR, 0.01–1.98]) at 3.5 years.131 A tailored intervention
4.295 [95% CI, 1.56–11.84]; P=0.0049) but no of exercise, salt restriction, and nutrition advice for
associated reduction in recurrent stroke (RR, 0.67 24 weeks compared with usual care (N=70) was
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[95% CI, 0.19–2.33]).842 Assistive technology may also associated with a reduction in the primary
play an emerging role. The SMS4Stroke (Short composite endpoint of cardiovascular outcome
Messaging Service for Stroke) trial (N=200) (HR, 0.194 [95% CI, 0.121–0.737]) at 2.9 years.134
showed an adjusted MD of 0.54 (95% CI, 0.22– 5. The Cochrane nonpharmacological interventions
0.85) in the Morisky Medication Adherence Scale (based on cardiac rehabilitation) review for pre-
score after 2 months of receiving short messaging venting vascular events after stroke/TIA855 identi-
service reminders for each dose of medication.843 fied 1 pilot RCT of cardiac rehabilitation compared
3. Systematic reviews of lifestyle interventions com- with usual stroke care (N=48), demonstrating
pared with usual care after stroke identify favor- promising and statistically significant gains in
able effects on reducing BP.111,112 A mean SBP vascular risk profiles and cardiovascular fitness.
reduction of −3.6 mm Hg (95% CI, −5.6 to −1.6; A systematic review of lifestyle interventions in
I 2=33%, N=650) has been noted.112 Subgroup stroke identified this study and 2 others broadly
analysis identified nonsignificant effects for behav- matching cardiac rehabilitation in their format and
ior interventions alone, significant effects for concluded that, although meta-analysis was not
cardiovascular exercise interventions (MD, −3.9 possible, all studies were associated with signifi-
mm Hg [95% CI, −6.5 to −1.3]; I 2=19; N=70), and cant improvements in health profiles and manage-
larger effects for combined exercise and lifestyle ment of risk,111 with this approach endorsed in the
interventions (MD, −5.3 mm Hg [95% CI, −9.0 to AHA/ASA physical activity and exercise recom-
−1.6]; I 2=46%; N=228). A systematic review of mendations for stroke survivors.34 A recent pro-
exercise-based interventions on cardiovascular risk spective cohort study with a matched subgroup
factors after stroke113 reported similar reductions comparison (N=609) evaluated a Stroke Recovery
in SBP in addition to other physiological outcomes Programme with 3 components: physician visits,
(fasting insulin and glucose and high-density outpatient therapy, and modified cardiac rehabilita-
lipoprotein cholesterol). Mean SBP reductions in tion consisting of group therapy of 4 to 5 patients
exercise interventions with or without other inter- with stroke directed by a specially trained physical
ventions (MD, −5.32 [95% CI, −9.46 to −1.18]) therapist and physical therapy assistant compared
were greater than those observed with exercise with usual rehabilitation. Nonrandomized subgroup
analysis comparing Stroke Recovery Programme • A clearly identified behavior change theory as a
CLINICAL STATEMENTS
participants (n=76) and matched pairs of nonpar- basis for intervention
AND GUIDELINES
ticipants (n=66), in addition to functional gains, • A documented time point after stroke for targeted
identified an age-adjusted HR of 0.11 (SE, 1.07 intervention delivery
[95% CI, 0.01–0.90]; P=0.039) for the effect of • A detailed intervention description that identifies
participant group, suggesting that nonparticipants the frequency and duration of the intervention, the
had a 9 times higher hazard of mortality.844 personnel required to deliver the intervention, the
6. Although acknowledging that educating patients intervention setting (eg, subacute care, commu-
with stroke or TIA about their condition and the nity care, mixed), and the skill level and training in
causes of their stroke is an important aspect of stroke behavioral counseling of the interventionist
care, evidence does not support its role in modifying • Data collection that permits disaggregation by
health risk behaviors. The Cochrane review of inter- sex and other relevant characteristics to identify
ventions for improving modifiable risk factor control responders/nonresponders to intervention.
in the secondary prevention of stroke identified that
patient education alone does not lead to improve-
6.3. Health Equity
ments in modifiable risk factor control or the pre-
vention of recurrent cardiovascular events.829 The Recommendations for Health Equity
recent STANDFIRM trial (Shared Team Approach Referenced studies that support recommendations are summarized in
online Data Supplement 65.
Between Nurses and Doctors for Improved Risk
COR LOE Recommendations
Factor Management for Stroke Patients; N=563)
of specialist review and nurse education found no 1. In patients with stroke or TIA, evaluating and
addressing social determinants of health (eg,
effect on attainment of cardiometabolic targets for literacy level, language proficiency, medica-
secondary prevention.845 Similarly, the ExStroke 1 C-EO tion affordability, food insecurity, housing,
trial (N=314 ambulatory participants with stroke) and transportation barriers) when managing
stroke risk factors is recommended to reduce
identified that repeated encouragement with verbal healthcare disparities.
instruction on being physically active over a 2-year 2. In patients with stroke or TIA, monitoring the
period after stroke was not an effective means of achievement of nationally accepted, evidence-
1 C-EO
increasing physical activity participation.129 based performance measures is recommended
to allow inequities to be identified and addressed.
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care and increasing the consistency of care have been language, encourage questions, apply teach-back
CLINICAL STATEMENTS
shown to reduce race/ethnic inequities in care,874 special methods, address language differences, are culturally
AND GUIDELINES
approaches may be required to actively reduce recur- competent, and incorporate graphics in their teach-
rent stroke risk in populations at risk for inequities and to ing promote a culture sensitive to health literacy.880
address the underlying structural determinants of ineq- 4. Several RCTs have tested secondary stroke pre-
uities. Several RCTs have tested secondary stroke pre- vention interventions in predominantly Black,
vention interventions in predominantly Black, Hispanic, Hispanic, and/or low-socioeconomic-status pop-
and low-socioeconomic-status populations.815,856–859 The ulations.815,856–859 In all trials, primary outcomes
optimal approaches for reducing recurrent stroke risk in improved in the intervention and control groups
high-risk populations are unclear; however, key strate- without significant differences between the 2 arms.
gies include evaluating and addressing social determi- A few of the trials showed improvement in second-
nants of health, implementing evidence-based protocols, ary outcomes or subpopulations. The SUSTAIN trial
monitoring adherence to evidence-based guidelines on (Systemic Use of Stroke Averting Interventions) of a
a population level, enhancing health and stroke literacy culturally tailored Chronic Care Model–based inter-
and self-management skills, and using the Agency for vention (incorporating advance practice provider
Healthcare Research and Quality Universal Precautions delivery of evidence-based care, protocols, real-
Toolkit of Health Literacy. time decision support, self-management support,
and education) in a multiracial/multiethnic popula-
Recommendation-Specific Supportive Text
tion in a safety-net setting showed better LDL con-
1. Socioeconomic inequalities are strong predictors of
trol (secondary outcome) in the intervention arm;
cardiovascular risk.873 Interventions should be tailored
intervention participants were more likely to lower
to patients’ socioeconomic and educational status, as
LDL <100 md/dL compared with control subjects
well as cultural, work, and home environments.19,875
(OR, 2.0 [95% CI, 1.1–3.5]).815 In the PRAISE
Examples of upstream social determinants of health
trial (Prevent Recurrence of All Inner-City Strokes
that affect treatment adherence and ASCVD health
Through Education) of peer-led community-based
outcomes include comorbid mental illness, lack of
poststroke self-management workshops in the
health literacy, exposure to adversity (eg, home/com-
inner city, the primary composite outcome of BP,
munity violence, trauma exposures, safety concerns),
LDL, and antithrombotic use at 6 months was not
financial strain, inadequate housing conditions, lack of
different in the intervention and control arms, but a
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vulnerable populations at risk for inequities. Specific AHA/ASA Stroke Guidelines Staff
CLINICAL STATEMENTS
gaps and areas for future research include the following:
Prashant Nedungadi, PhD, Director, Stroke Guidelines,
AND GUIDELINES
• A more thorough understanding of which populations
Office of Science, Medicine and Health
have inequities in risk factor control after stroke.
Melanie Stephens-Lyman, MS, Guideline Advisor, Stroke,
• A more nuanced understanding of the drivers of
Office of Science, Medicine and Health
inequities in risk factor control after stroke, including
Anne Leonard, MPH, RN, FAHA, CCRC, Senior Science and
social determinants of health and structural racism.
Medicine Advisor, Office of Science, Medicine and Health
• Strategies for improving risk factor control among
Katherine Sheehan, PhD, Evidence Review Committee
groups at risk for inequities.
Staff Lead, Science and Medicine Advisor, Office of
• Strategies for addressing social determinants of
Science, Medicine and Health
health among stroke survivors.
PRESIDENT AND STAFF stroke and transient ischemic attack: a guideline from the American Heart As-
sociation/American Stroke Association. Stroke. 2021;52:e•••–e•••. doi: 10.1161/
STR.0000000000000375
American Heart Association/American Stroke The expert peer review of AHA-commissioned documents (eg, scientific
Association statements, clinical practice guidelines, systematic reviews) is conducted by
the AHA Office of Science Operations. For more on AHA statements and
Mitchell S. V. Elkind, MD, MS, FAAN, FAHA, President guidelines development, visit https://professional.heart.org/statements. Se-
Nancy Brown, Chief Executive Officer lect the “Guidelines & Statements” drop-down menu, then click “Publication
Development.”
Mariell Jessup, MD, FAHA, Chief Science and Medical Officer Permissions: Multiple copies, modification, alteration, enhancement, and/or
Radhika Rajgopal Singh, PhD, Senior Vice President, distribution of this document are not permitted without the express permission of
Office of Science and Medicine the American Heart Association. Instructions for obtaining permission are located
at https://www.heart.org/permissions. A link to the “Copyright Permissions Re-
Jody Hundley, Production and Operations Manager, Sci- quest Form” appears in the second paragraph (https://www.heart.org/en/about-
entific Publications, Office of Science Operations us/statements-and-policies/copyright-request-form).
Disclosures
CLINICAL STATEMENTS
Appendix 1. Writing Group Relationships With Industry and Other Entities (Relevant): 2021 Guideline for the Prevention of
AND GUIDELINES
Writing Speakers’
group Other research bureau/ Expert Ownership Consultant/
member Employment Research grant support honoraria witness interest advisory board Other
Dawn O. University of NIH (epidemiology of stroke)† None None None None None None
Kleindorfer Michigan
Amytis University NIH/NINDS (secondary stroke None None None None None None
Towfighi of Southern prevention trial)†
California
Seemant School of Medi- Boehringer-Ingelheim (grant support)* None None None None None NINDS
Chaturvedi cine, University (executive
of Maryland committee
CREST 2)*
Kevin M. Penn State Medtronic (PI for multi-institution Intersocietal None None Actuated Medtronic†; None
Cockroft Hershey Medical study)†; Nico Corp (PI for multi-institu- Accreditation Medical* Minnetronix*
(AANS/CNS Center tion study)† Commission
WG Represen- (Board of
tative) Directors)*
Jose Columbia NIH (PI in research grant)† None None Hanna, None None None
Gutierrez University Campbell &
Medical Powell, LLP*;
Center Heidell, Pittoni,
Murphy & Bach,
LLP*; Aaronson
Rappaport*;
Johnson, Graffe,
Keay, Moniz &
Wick*; Luca
Law, PLLC*
Hooman Weill Cornell BMS (BMS provides in-kind study drug None None None None None None
Kamel Medical College [apixaban/aspirin/placebo] for ARCADIA
trial, of which he is co-PI)†; Boehringer
Ingelheim (Endpoint Adjudication
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(Continued )
Appendix 1. Continued
CLINICAL STATEMENTS
Writing Speakers’ Consultant/
AND GUIDELINES
group Other research bureau/ Expert Ownership advisory
member Employment Research grant support honoraria witness interest board Other
Enrique C. University of NIH/NINDS salary support through U24 None None None None None None
Leira Iowa, and R21 grant mechanisms)†; Keystone
Hospitals Heart (performed local neurological
and Clinics assessments as a local co-PI in a
cardiology trial)*; Edwards Lifesciences
(performed local neurological assess-
ments as a local co-PI in a cardiology
trial)*; Bayer AG and Jansen LLC (was
the local PI for the NAVIGATE-ESUS
trial)*; ZZ Biotech (consulting in the
RHAPSODY acute trial proposal that
will be submitted to NIH)*; NIH-Fred
Hutchinson Research Center (adjudicate
stroke events for the WHI NIH Study)*
Olive Lennon University EU MSCA (research exchange pro- None None None Cft Recruit- None None
College Dublin, gramme grant)*; UCD (seed funding ment Ltd
School of Public dissemination grant)* registration
Health, Phys- No. 642571*;
iotherapy and Cft Recruit-
Sports Science, ment Ltd
Health Sciences registration
Centre (Ireland) No. 642571
(immedi-
ate family
members)†
Debbie Self-employed Vanderbilt University Medical Center None None None Lombardi None Lombardi Hill
Lombardi-Hill (consultant to a PCORI-funded Com- Hill Consult- Consulting
(patient parative Effectiveness Trial for Stroke ing Group, Group, LLP
representative) Post-Acute Care)* LLP†; Stroke (owner/
Challenges, principal)†;
LLC* Stroke Chal-
lenges, LLC
(cofounder/
co-owner)*
Downloaded from http://ahajournals.org by on June 12, 2021
James F. Mayo Clinic NINDS (Crest-2 Trial; he is one of None None None None None None
Meschia 3 co-PIs for this trial that compares
revascularization with and without
intensive medical management. The
trial is funded by NINDS. His support
is funding for salary substitution to
devote ≈30% of his effort to the trial)†
Thanh N. Boston Medical Medtronic (PI Clear Study)* None None None None None None
Nguyen Center
Peter M. Pollak Mayo Clinic None None None None None None None
Pasquale Hospital of the None None Abbott None None Abbott Medi- None
Santangeli University of Medical*; cal*; Baylis
Pennsylvania Biosense Medical*;
Webster*; Biosense
Biotronik*; Webster*
Medtronic*
Anjail Z. University of None Omron (donation None None None None None
Sharrief Texas Medical of blood pressure
School at machines for
Houston clinical care
and research)*
Sidney C. University of None None None None None None None
Smith Jr North Carolina
Tanya N. Turan Medical Univer- Sanofi-Regeneron (alirocumab is None None None None Boehringer None
(AAN WG sity of South donated to the CREST2, for Ingelheim*;
Representa- Carolina which she is the director of Gore*;
tive) medical management)† Pfizer†
Linda S. Wil- Roudebush VA VHA (VA HSR&D PI)† None None None None None None
liams Medical Center
This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure
Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5 000 or more
during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5 000 or more of
the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.
Appendix 2. Peer Reviewer Relationships With Industry and Other Entities (Comprehensive): 2021 Guideline for the Preven-
tion of Stroke in Patients With Stroke and Transient Ischemic Attack
CLINICAL STATEMENTS
AND GUIDELINES
Other Speakers’
Peer Research research bureau/ Ownership Consultant/advisory
reviewer Employment grant support honoraria Expert witness interest board Other
Mary Massaschusetts None None None None None None None
Amatangelo General
Hugo Boston University American Alzheimer’s None None None None None
Aparicio School of Medicine Academy Association
of Neurol- Research
ogy Career grant†
Development
Award†
Negar University of Miami None None None None None None None
Asdaghi
Devin University of Michi- NIH† None Grand Rounds None None None AHA*
Brown gan Honorarium–
The Ohio State
University*
Askiel Medical College of NINDS†; None Abbott Pharma* None None None None
Bruno Georgia at Augusta Georgia
University Rehabilitation
Foundation†
Cheryl Wake Forest Baptist None None None None Care Directions, ZZ Biotech, Clinical None
Bushnell Health LLC* Advisory Committee
for RHAPSODY II
trial*
Dominique Monash University Amgen (paid to None None None None None Med-
Cadilhac Institution)† tronic
(donation
paid
to Institu-
tion)*
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Clay University of Texas None None Novartis* None None None None
Cauthen
Tiffany University of Penn- None None None None None None None
Chen sylvania
Ephraim Penn State Health None None None None None None None
Church
John Cole University of Mary- NIH/NINDS None None None None None None
land R01*
Gioacchino Boston University None None None National Medical None None None
Curiale Neurology Associ- Consultants PC*
ates
Mary None None None None None None None None
Cushman
Alexandra McGoven Medical NIH† None None None None None None
Czap School, University of
Texas
Colin University of Iowa None None None None None None None
Derdeyn
Marco R. Columbia University NIH/NINDS† None None None None None None
Di Tullio
Kenneth Vanderbilt University PCORI: C3FIT None None Expert witness Stroke Link None None
Gaines Medical Center National PI†; for medical Health†
USDA malpractice*
Distance
Learning and
Telemedicine
Grant†
(Continued )
Appendix 2. Continued
CLINICAL STATEMENTS
Other Speakers’
AND GUIDELINES
Peer Research research bureau/ Ownership Consultant/advisory
reviewer Employment grant support honoraria Expert witness interest board Other
Philip B. Michigan State Local Site None None None None None Bayer*;
Gorelick PI for C3FIT Novartis*
recurrent stroke
prevention
trial funded by
PCORI†
Virginia University of Alabama NIH† None None None None None None
Howard at Birmingham
Judy Johns Hopkins None None None Weber Gal- Longeviti* None None
Huang University lagher*
Silvio Yale School of None None None None None Boehringer Ingelheim*; None
Inzuccchi Medicine AstraZeneca†; Novo
Nordisk†; Merck*
Ashutosh Barrow Brain and None None None None None None None
Jadhav Spine Institute
Salomeh University of Califor- None None None None None None None
Keyhani nia, San Francisco
Anthony University of Califor- SanBio† None None Consultant* None None None
Kim nia San Francisco
Christopher University of Virginia Regeneron† None None None None None None
Kramer
Sandeep Beth Israel Deacon- NIH/NINDS† None None None None None None
Kumar ess Medical Center;
Harvard Medical
School
Lester Y. Tufts Medical NIH† None None None None None None
Leung Center
Helmi Oregon Health & None None None None None BMS*; Axiomatic– Modest*
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Appendix 2. Continued
CLINICAL STATEMENTS
Other Speakers’
AND GUIDELINES
Stern University
Jeffrey Augusta University None None None None None None None
Switzer
Stavropoula Thomas Jefferson None None None None None None None
Tjoumakaris University
Stanley Mount Sinai Hospital None None None None None None None
Tuhrim
David Barrow Neurological None None Boehringer None None None None
Wang Institute Ingelheim*
Babu University of Texas None None Stryker Neuro- None None Medtronic; Microven- Peter
Welch Southwestern Medi- vascular* tion*; Stryker Neuro- Lazic*
cal Center vascular*
Deborah J. Massachusetts NIDDK† None None None None None Novo
Wexler Hospital and Harvard Nordisk*
Medical School
Daniel Woo University of NIH† None None None None None None
Cincinnati
Bradford American Academy NIH† None None None None None None
Worrall of Neurology
Henry Klar Yale School of None None None None None None None
Yaggi Medicine
Richard Tulane University None None None None None None None
Zweifler
This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques-
tionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $5 000 or more during any
12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $5 000 or more of
the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition.
*Modest.
†Significant.
REFERENCES ischemic attack (published online ahead of print May 24, 2021). Stroke. doi:
10.1161/STR.0000000000000377
CLINICAL STATEMENTS
1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, 16. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC,
AND GUIDELINES
Chamberlain AM, Chang AR, Cheng S, Delling FN, et al; on behalf of the Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, et al. Guidelines
American Heart Association Council on Epidemiology and Prevention Sta- for the early management of patients with acute ischemic stroke: 2019
tistics Committee and Stroke Statistics Subcommittee. Heart disease and update to the 2018 guidelines for the early management of acute isch-
stroke statistics–2020 update: a report from the American Heart Association. emic stroke: a guideline for healthcare professionals from the American
Circulation. 2020;141:e139–e596. doi: 10.1161/CIR.0000000000000757 Heart Association/American Stroke Association [published correction
2. Kleindorfer D, Panagos P, Pancioli A, Khoury J, Kissela B, Woo D, appears in Stroke. 2019;50:e441]. Stroke. 2019;50:e344–e418. doi:
Schneider A, Alwell K, Jauch E, Miller R, et al. Incidence and short-term 10.1161/STR.0000000000000211
prognosis of transient ischemic attack in a population-based study. Stroke. 17. Hemphill JC 3rd, Greenberg SM, Anderson CS, Becker K, Bendok BR,
2005;36:720–723. doi: 10.1161/01.STR.0000158917.59233.b7 Cushman M, Fung GL, Goldstein JN, Macdonald RL, Mitchell PH, et al;
3. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after on behalf of the American Heart Association Stroke Council; Council on
emergency department diagnosis of TIA. JAMA. 2000;284:2901–2906. Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guide-
doi: 10.1001/jama.284.22.2901 lines for the management of spontaneous intracerebral hemorrhage:
4. Amarenco P; Steering Committee Investigators of the TIAregistry.org. Risk a guideline for healthcare professionals from the American Heart Asso-
of stroke after transient ischemic attack or minor stroke. N Engl J Med. ciation/American Stroke Association. Stroke. 2015;46:2032–2060. doi:
2016;375:387. doi: 10.1056/NEJMc1606657 10.1161/STR.0000000000000069
5. Hong KS, Yegiaian S, Lee M, Lee J, Saver JL. Declining stroke and vascular 18. Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi
event recurrence rates in secondary prevention trials over the past 50 years S, Creager MA, Eckel RH, Elkind MS, Fornage M, et al; on behalf of the
and consequences for current trial design. Circulation. 2011;123:2111– American Heart Association Stroke Council; Council on Cardiovascular
2119. doi: 10.1161/CIRCULATIONAHA.109.934786 and Stroke Nursing; Council on Clinical Cardiology; Council on Functional
5a. O’Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan Genomics and Translational Biology; Council on Hypertension. Guidelines
S, Islam S, Pais P, McQueen MJ, et al; INTERSTROKE Investigators. Risk for the primary prevention of stroke: a statement for healthcare profession-
factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries als from the American Heart Association/American Stroke Association.
(the INTERSTROKE study): a case-control study. Lancet. 2010;376:112– Stroke. 2014;45:3754–3832. doi: 10.1161/STR.0000000000000046
123. doi: 10.1016/S0140-6736(10)60834-3 19. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn
6. Feigin VL, Roth GA, Naghavi M, Parmar P, Krishnamurthi R, Chugh S, Mensah EJ, Himmelfarb CD, Khera A, Lloyd-Jones D, McEvoy JW, et al. 2019
GA, Norrving B, Shiue I, Ng M, et al; Global Burden of Diseases, Injuries and ACC/AHA guideline on the primary prevention of cardiovascular disease:
Risk Factors Study 2013 and Stroke Experts Writing Group. Global burden a report of the American College of Cardiology/American Heart Asso-
of stroke and risk factors in 188 countries, during 1990-2013: a system- ciation Task Force on Clinical Practice Guidelines [published corrections
atic analysis for the Global Burden of Disease Study 2013. Lancet Neurol. appear in Circulation. 2019;140:e649–e650, Circulation. 2020;141:e60,
2016;15:913–924. doi: 10.1016/S1474-4422(16)30073-4 and Circulation. 2020;141:e774]. Circulation. 2019;140:e596–e646. doi:
7. Hackam DG, Spence JD. Combining multiple approaches for the secondary 10.1161/CIR.0000000000000678
prevention of vascular events after stroke: a quantitative modeling study. 20. Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL,
Stroke. 2007;38:1881–1885. doi: 10.1161/STROKEAHA.106.475525 Howard VJ, Lichtman JH, Lisabeth LD, Piña IL, et al; on behalf of the Ameri-
8. Coutts SB, Wein TH, Lindsay MP, Buck B, Cote R, Ellis P, Foley N, Hill MD, can Heart Association Stroke Council; Council on Cardiovascular and Stroke
Jaspers S, Jin AY, et al; Heart and Stroke Foundation Canada Canadian Nursing; Council on Clinical Cardiology; Council on Epidemiology and Pre-
Downloaded from http://ahajournals.org by on June 12, 2021
Stroke Best Practices Advisory Committee. Canadian Stroke Best Prac- vention; Council for High Blood Pressure Research. Guidelines for the pre-
tice Recommendations: secondary prevention of stroke guidelines, update vention of stroke in women: a statement for healthcare professionals from the
2014. Int J Stroke. 2015;10:282–291. doi: 10.1111/ijs.12439 American Heart Association/American Stroke Association [published cor-
9. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz rections appear in Stroke. 2014;45:e214 and Stroke. 2014;45:e95]. Stroke.
MD, Fang MC, Fisher M, Furie KL, Heck DV, et al; on behalf of the American 2014;45:1545–1588. doi: 10.1161/01.str.0000442009.06663.48
Heart Association Stroke Council, Council on Cardiovascular and Stroke 21. Biller J, Sacco RL, Albuquerque FC, Demaerschalk BM, Fayad P, Long PH,
Nursing, Council on Clinical Cardiology, and Council on Peripheral Vascular Noorollah LD, Panagos PD, Schievink WI, Schwartz NE, et al; on behalf
Disease. Guidelines for the prevention of stroke in patients with stroke and of the American Heart Association Stroke Council. Cervical arterial dissec-
transient ischemic attack: a guideline for healthcare professionals from the tions and association with cervical manipulative therapy: a statement for
American Heart Association/American Stroke Association [published cor- healthcare professionals from the American Heart Association/American
rection appears in Stroke. 2015;46:e54]. Stroke. 2014;45:2160–2236. doi: Stroke Association [published correction appears in Stroke. 2016;47:e261].
10.1161/STR.0000000000000024 Stroke. 2014;45:3155–3174. doi: 10.1161/STR.0000000000000016
10. Razmara A, Ovbiagele B, Markovic D, Towfighi A. Patterns and predictors 22. Saposnik G, Barinagarrementeria F, Brown RD Jr, Bushnell CD, Cucchiara
of blood pressure treatment, control, and outcomes among stroke survi- B, Cushman M, deVeber G, Ferro JM, Tsai FY; on behalf of the American
vors in the United States. J Stroke Cerebrovasc Dis. 2016;25:857–865. doi: Heart Association Stroke Council and the Council on Epidemiology and
10.1016/j.jstrokecerebrovasdis.2015.12.027 Prevention. Diagnosis and management of cerebral venous thrombosis:
11. Lin MP, Ovbiagele B, Markovic D, Towfighi A. “Life’s Simple 7” and long- a statement for healthcare professionals from the American Heart Asso-
term mortality after stroke. J Am Heart Assoc. 2015;4:e001470. doi: ciation/American Stroke Association. Stroke. 2011;42:1158–1192. doi:
10.1161/JAHA.114.001470. 10.1161/STR.0b013e31820a8364
12. Heuschmann PU, Kircher J, Nowe T, Dittrich R, Reiner Z, Cifkova R, Malojcic 23. Levine GN, O’Gara PT, Beckman JA, Al-Khatib SM, Birtcher KK, Cigarroa JE,
B, Mayer O, Bruthans J, Wloch-Kopec D, et al. Control of main risk factors de Las Fuentes L, Deswal A, Fleisher LA, Gentile F, et al. Recent innovations,
after ischaemic stroke across Europe: data from the stroke-specific module modifications, and evolution of ACC/AHA clinical practice guidelines: an
of the EUROASPIRE III survey. Eur J Prev Cardiol. 2015;22:1354–1362. update for our constituencies: a report of the American College of Cardiol-
doi: 10.1177/2047487314546825 ogy/American Heart Association Task Force on Clinical Practice Guidelines.
13. Lin AM, Lin MP, Markovic D, Ovbiagele B, Sanossian N, Towfighi A. Less Circulation. 2019;139:e879–e886. doi: 10.1161/CIR.0000000000000651
than ideal: trends in cardiovascular health among US stroke survivors. 24. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey
Stroke. 2019;50:5–12. doi: 10.1161/STROKEAHA.118.022644 RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, et al. Guidelines for
14. Bravata DM, Daggy J, Brosch J, Sico JJ, Baye F, Myers LJ, Roumie CL, carotid endarterectomy: a statement for healthcare professionals from a
Cheng E, Coffing J, Arling G. Comparison of risk factor control in the year special writing group of the Stroke Council, American Heart Association.
after discharge for ischemic stroke versus acute myocardial infarction. Stroke. 1998;29:554–562. doi: 10.1161/01.str.29.2.554
Stroke. 2018;49:296–303. doi: 10.1161/STROKEAHA.117.017142 25. Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, Cates
15. Brown DL, Levine DA, Albright K, Kapral MK, Leung LY, Reeves MJ, Sico CU, Creager MA, Fowler SB, Friday G, et al. 2011 ASA/ACCF/AHA/
J, Strong B, Whiteley WN; on behalf of the American Heart Association AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS
Stroke Council. Benefits and risks of dual versus single antiplatelet ther- guideline on the management of patients with extracranial carotid and ver-
apy for secondary stroke prevention: a systematic review for the 2021 tebral artery disease: a report of the American College of Cardiology Foun-
guideline for the prevention of stroke in patients with stroke and transient dation/American Heart Association Task Force on Practice Guidelines, and
the American Stroke Association, American Association of Neuroscience 34a. Hayes SN, Kim ESH, Saw J, Adlam D, Arslanian-Engoren C, Economy
Nurses, American Association of Neurological Surgeons, American College KE, Ganesh SK, Gulati R, Lindsay ME, Mieres JH, et al; on behalf
CLINICAL STATEMENTS
of Radiology, American Society of Neuroradiology, Congress of Neurologi- of the American Heart Association Council on Peripheral Vascular
AND GUIDELINES
cal Surgeons, Society of Atherosclerosis Imaging and Prevention, Society Disease; Council on Clinical Cardiology; Council on Cardiovascular
for Cardiovascular Angiography and Interventions, Society of Interventional and Stroke Nursing; Council on Functional Genomics and Translational
Radiology, Society of NeuroInterventional Surgery, Society for Vascular Biology; and Stroke Council. Spontaneous coronary artery dissec-
Medicine, and Society for Vascular Surgery [published corrections appear tion: current state of the science: a scientific statement from the
in Circulation. 2011;124:e146 and Circulation. 2012;126:e26]. Circulation. American Heart Association. Circulation. 2018;137:e523–e557. doi:
2011;124:e54–e130. doi: 10.1161/CIR.0b013e31820d8c98 10.1161/CIR.0000000000000564
26. Eckel RH, Jakicic JM, Ard JD, de Jesus JM, Houston Miller N, Hubbard VS, Lee 35. Gorelick PB, Furie KL, Iadecola C, Smith EE, Waddy SP, Lloyd-Jones DM,
IM, Lichtenstein AH, Loria CM, Millen BE, et al. 2013 AHA/ACC guideline on Bae HJ, Bauman MA, Dichgans M, Duncan PW, et al; on behalf of the
lifestyle management to reduce cardiovascular risk: a report of the American American Heart Association/American Stroke Association. Defining opti-
College of Cardiology/American Heart Association Task Force on Practice mal brain health in adults: a presidential advisory from the American Heart
Guidelines [published corrections appear in Circulation. 2014;129(suppl Association/American Stroke Association. Stroke. 2017;48:e284–e303.
2):S100–S101 and Circulation. 2015;131:e326]. Circulation. 2014; doi: 10.1161/STR.0000000000000148
129(suppl 2):S76–S99. doi: 10.1161/01.cir.0000437740.48606.d1 36. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann
27. Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, Hu PU. Epidemiology of ischemic stroke subtypes according to TOAST cri-
FB, Hubbard VS, Jakicic JM, Kushner RF, et al. 2013 AHA/ACC/TOS guide- teria: incidence, recurrence, and long-term survival in ischemic stroke
line for the management of overweight and obesity in adults: a report of the subtypes: a population-based study. Stroke. 2001;32:2735–2740. doi:
American College of Cardiology/American Heart Association Task Force on 10.1161/hs1201.100209
Practice Guidelines and The Obesity Society [published correction appears in 37. Gardener H, Sacco RL, Rundek T, Battistella V, Cheung YK, Elkind
Circulation. 2014;129(suppl 2):S139–S140e33]. Circulation. 2014;129(suppl MSV. Race and ethnic disparities in stroke incidence in the Northern
2):S102–S138. doi: 10.1161/01.cir.0000437739.71477.ee Manhattan Study. Stroke. 2020;51:1064–1069. doi: 10.1161/
28. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, STROKEAHA.119.028806
Conti JB, Ellinor PT, Ezekowitz MD, Field ME, et al. 2014 AHA/ACC/HRS 38. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL,
guideline for the management of patients with atrial fibrillation: a report of Marsh EE 3rd. Classification of subtype of acute ischemic stroke: definitions
the American College of Cardiology/American Heart Association Task Force for use in a multicenter clinical trial: TOAST: Trial of Org 10172 in Acute
on practice guidelines and the Heart Rhythm Society [published correction Stroke Treatment. Stroke. 1993;24:35–41. doi: 10.1161/01.str.24.1.35
appears in Circulation. 2019;140:e285]. Circulation. 2014;130:e199–e267. 39. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell
doi: 10.1161/CIR.0000000000000041 MJ, Sacco RL, Connolly SJ; Cryptogenic Stroke/ESUS International
29. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Working Group. Embolic strokes of undetermined source: the case
Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, for a new clinical construct. Lancet Neurol. 2014;13:429–438. doi:
et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/ 10.1016/S1474-4422(13)70310-7
NMA/PCNA guideline for the prevention, detection, evaluation, and man- 40. Sposato LA, Cipriano LE, Saposnik G, Ruíz Vargas E, Riccio PM, Hachinski
agement of high blood pressure in adults: executive summary: a report V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack:
of the American College of Cardiology/American Heart Association Task a systematic review and meta-analysis. Lancet Neurol. 2015;14:377–387.
Force on Clinical Practice Guidelines. Circulation. 2018;138:e426–e483. doi: 10.1016/S1474-4422(15)70027-X
doi: 10.1161/CIR.0000000000000597 41. Micheli S, Agnelli G, Caso V, Alberti A, Palmerini F, Venti M, Paciaroni M.
Downloaded from http://ahajournals.org by on June 12, 2021
30. Stout KK, Daniels CJ, Aboulhosn JA, Bozkurt B, Broberg CS, Colman JM, Acute myocardial infarction and heart failure in acute stroke patients: fre-
Crumb SR, Dearani JA, Fuller S, Gurvitz M, et al. 2018 AHA/ACC guide- quency and influence on clinical outcome. J Neurol. 2012;259:106–110.
line for the management of adults with congenital heart disease: a report doi: 10.1007/s00415-011-6136-4
of the American College of Cardiology/American Heart Association Task 42. Arsava EM, Kim GM, Oliveira-Filho J, Gungor L, Noh HJ, Lordelo MdJ,
Force on Clinical Practice Guidelines [published correction appears in Cir- Avery R, Maier IL, Ay H. Prediction of early recurrence after acute
culation. 2019;139:e833–e834]. Circulation. 2019;139:e698–e800. doi: ischemic stroke. JAMA Neurol. 2016;73:396–401. doi: 10.1001/
10.1161/CIR.0000000000000603 jamaneurol.2015.4949
31. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, 43. Moroney JT, Bagiella E, Paik MC, Sacco RL, Desmond DW. Risk factors
Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, et al. 2018 AHA/ for early recurrence after ischemic stroke: the role of stroke syndrome and
ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/ subtype. Stroke. 1998;29:2118–2124. doi: 10.1161/01.str.29.10.2118
PCNA guideline on the management of blood cholesterol: a report of the 44. Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers
American College of Cardiology/American Heart Association Task Force DO. Ischemic stroke subtypes: a population-based study of functional
on Clinical Practice Guidelines [published correction appears in Circula- outcome, survival, and recurrence. Stroke. 2000;31:1062–1068. doi:
tion. 2019;139:e1182–e1186]. Circulation. 2019;139:e1082–e1143. doi: 10.1161/01.str.31.5.1062
10.1161/CIR.0000000000000625 45. Sacco RL, Foulkes MA, Mohr JP, Wolf PA, Hier DB, Price TR. Determinants
32. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, of early recurrence of cerebral infarction: the Stroke Data Bank. Stroke.
Ellinor PT, Ezekowitz MD, Field ME, Furie KL, et al. 2019 AHA/ACC/HRS 1989;20:983–989. doi: 10.1161/01.str.20.8.983
focused update of the 2014 AHA/ACC/HRS guideline for the management 46. Willinsky RA, Taylor SM, TerBrugge K, Farb RI, Tomlinson G, Montanera W.
of patients with atrial fibrillation: a report of the American College of Cardiol- Neurologic complications of cerebral angiography: prospective analysis of
ogy/American Heart Association Task Force on Clinical Practice Guidelines 2,899 procedures and review of the literature. Radiology. 2003;227:522–
and the Heart Rhythm Society in collaboration with the Society of Thoracic 528. doi: 10.1148/radiol.2272012071
Surgeons [published correction appears in Circulation. 2019;140:e285]. Cir- 47. Kim AH, Augustin G, Shevitz A, Kim H, Trivonovich MR, Powell AR, Kumins
culation. 2019;140:e125–e151. doi: 10.1161/CIR.0000000000000665 N, Tarr R, Kashyap VS. Carotid Consensus Panel duplex criteria can replace
33. Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP 3rd, Gentile F, modified University of Washington criteria without affecting accuracy. Vasc
Jneid H, Krieger EV, Mack M, McLeod C, et al. 2020 ACC/AHA guideline for the Med. 2018;23:126–133. doi: 10.1177/1358863X17751655
management of patients with valvular heart disease: a report of the American 48. Josephson SA, Bryant SO, Mak HK, Johnston SC, Dillon WP, Smith WS.
College of Cardiology/American Heart Association Joint Committee on Clinical Evaluation of carotid stenosis using CT angiography in the initial evalua-
Practice Guidelines [published correction appears in Circulation. 2021;143:e229]. tion of stroke and TIA. Neurology. 2004;63:457–460. doi: 10.1212/01.
Circulation. 2021;143:e72–e227. doi: 10.1161/CIR.0000000000000923 wnl.0000135154.53953.2c
34. Billinger SA, Arena R, Bernhardt J, Eng JJ, Franklin BA, Johnson CM, 49. Debrey SM, Yu H, Lynch JK, Lövblad KO, Wright VL, Janket SJ, Baird
MacKay-Lyons M, Macko RF, Mead GE, Roth EJ, et al; on behalf of the Ameri- AE. Diagnostic accuracy of magnetic resonance angiography for inter-
can Heart Association Stroke Council; Council on Cardiovascular and Stroke nal carotid artery disease: a systematic review and meta-analysis. Stroke.
Nursing; Council on Lifestyle and Cardiometabolic Health; Council on Epide- 2008;39:2237–2248. doi: 10.1161/STROKEAHA.107.509877
miology and Prevention; Council on Clinical Cardiology. Physical activity and 50. U-King-Im JM, Hollingworth W, Trivedi RA, Cross JJ, Higgins NJ, Graves
exercise recommendations for stroke survivors: a statement for healthcare MJ, Gutnikov S, Kirkpatrick PJ, Warburton EA, Antoun NM, et al. Cost-
professionals from the American Heart Association/American Stroke Associa- effectiveness of diagnostic strategies prior to carotid endarterectomy. Ann
tion. Stroke. 2014;45:2532–2553. doi: 10.1161/STR.0000000000000022 Neurol. 2005;58:506–515. doi: 10.1002/ana.20591
51. Kvistad CE, Novotny V, Næss H, Hagberg G, Ihle-Hansen H, Waje- cost-effectiveness of magnetic resonance, including diffusion-weighted
Andreassen U, Thomassen L, Logallo N. Safety and predictors of stroke imaging, in patients with transient ischaemic attack and minor stroke: a
CLINICAL STATEMENTS
mimics in The Norwegian Tenecteplase Stroke Trial (NOR-TEST). Int J systematic review, meta-analysis and economic evaluation. Health Technol
AND GUIDELINES
Stroke. 2019;14:508–516. doi: 10.1177/1747493018790015 Assess. 2014;18:1–368, v. doi: 10.3310/hta18270
52. Madsen TE, Khoury J, Cadena R, Adeoye O, Alwell KA, Moomaw CJ, 70. Hobohm C, Hagendorff A, Schulz S, Fritzsch D, Budig S, Stöbe S, Michalski
McDonough E, Flaherty ML, Ferioli S, Woo D, et al. Potentially missed D. Clinical presentation and multi-parametric screening surrogates of isch-
diagnosis of ischemic stroke in the emergency department in the emic stroke patients suffering from infective endocarditis. Cerebrovasc Dis.
Greater Cincinnati/Northern Kentucky Stroke Study. Acad Emerg Med. 2016;41:60–67. doi: 10.1159/000442005
2016;23:1128–1135. doi: 10.1111/acem.13029 71. Cheng YC, Ryan KA, Qadwai SA, Shah J, Sparks MJ, Wozniak MA,
53. Newman-Toker DE, Moy E, Valente E, Coffey R, Hines AL. Missed diagno- Stern BJ, Phipps MS, Cronin CA, Magder LS, et al. Cocaine use and
sis of stroke in the emergency department: a cross-sectional analysis of risk of ischemic stroke in young adults. Stroke. 2016;47:918–922. doi:
a large population-based sample. Diagnosis (Berl). 2014;1:155–166. doi: 10.1161/STROKEAHA.115.011417
10.1515/dx-2013-0038 72. Bersano A, Markus HS, Quaglini S, Arbustini E, Lanfranconi S, Micieli G,
54. Roquer J, Rodríguez-Campello A, Cuadrado-Godia E, Giralt-Steinhauer E, Boncoraglio GB, Taroni F, Gellera C, Baratta S, et al; Lombardia GENS
Jiménez-Conde J, Soriano C, Ois A. The role of HbA1c determination in Group. Clinical pregenetic screening for stroke monogenic diseases:
detecting unknown glucose disturbances in ischemic stroke. PLoS One. results from Lombardia GENS Registry. Stroke. 2016;47:1702–1709. doi:
2014;9:e109960. doi: 10.1371/journal.pone.0109960 10.1161/STROKEAHA.115.012281
55. Agarwal A, Cheung AK, Ma J, Cho M, Li M. Effect of baseline kidney func- 73. Feldmann E, Wilterdink JL, Kosinski A, Lynn M, Chimowitz MI, Sarafin
tion on the risk of recurrent stroke and on effects of intensive blood pres- J, Smith HH, Nichols F, Rogg J, Cloft HJ, et al; Stroke Outcomes and
sure control in patients with previous lacunar stroke: a post hoc analysis of Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial Investi-
the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes). J Am gators. The Stroke Outcomes and Neuroimaging of Intracranial Ath-
Heart Assoc. 2019;8:e013098. doi: 10.1161/JAHA.119.013098 erosclerosis (SONIA) trial. Neurology. 2007;68:2099–2106. doi:
56. Holmes M, Rathbone J, Littlewood C, Rawdin A, Stevenson M, Stevens J, 10.1212/01.wnl.0000261488.05906.c1
Archer R, Evans P, Wang J. Routine echocardiography in the management 74. Liebeskind DS, Kosinski AS, Saver JL, Feldmann E; SONIA Investigators.
of stroke and transient ischaemic attack: a systematic review and economic Computed tomography angiography in the Stroke Outcomes and Neu-
evaluation. Health Technol Assess. 2014;18:1–176. doi: 10.3310/hta18160 roimaging of Intracranial Atherosclerosis (SONIA) Study. Interv Neurol.
57. Katsanos AH, Bhole R, Frogoudaki A, Giannopoulos S, Goyal N, Vrettou AR, 2014;2:153–159. doi: 10.1159/000360952
Ikonomidis I, Paraskevaidis I, Pappas K, Parissis J, et al. The value of trans- 75. Gulli G, Marquardt L, Rothwell PM, Markus HS. Stroke risk after posterior
esophageal echocardiography for embolic strokes of undetermined source. circulation stroke/transient ischemic attack and its relationship to site of
Neurology. 2016;87:988–995. doi: 10.1212/WNL.0000000000003063 vertebrobasilar stenosis: pooled data analysis from prospective studies.
58. Sanna T, Diener HC, Passman RS, Di Lazzaro V, Bernstein RA, Morillo Stroke. 2013;44:598–604. doi: 10.1161/STROKEAHA.112.669929
CA, Rymer MM, Thijs V, Rogers T, Beckers F, et al; CRYSTAL AF Investi- 76. Paciaroni M, Bandini F, Agnelli G, Tsivgoulis G, Yaghi S, Furie KL, Tadi P,
gators. Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med. Becattini C, Zedde M, Abdul-Rahim AH, et al. Hemorrhagic transforma-
2014;370:2478–2486. doi: 10.1056/NEJMoa1313600 tion in patients with acute ischemic stroke and atrial fibrillation: time to
59. Gladstone DJ, Spring M, Dorian P, Panzov V, Thorpe KE, Hall J, Vaid H, initiation of oral anticoagulant therapy and outcomes. J Am Heart Assoc.
O’Donnell M, Laupacis A, Côté R, et al; EMBRACE Investigators and Coor- 2018;7:e010133. doi: 10.1161/JAHA.118.010133
dinators. Atrial fibrillation in patients with cryptogenic stroke. N Engl J Med. 77. Khariton Y, House JA, Comer L, Coggins TR, Magalski A, Skolnick DG,
2014;370:2467–2477. doi: 10.1056/NEJMoa1311376 Good TH, Main ML. Impact of transesophageal echocardiography on man-
Downloaded from http://ahajournals.org by on June 12, 2021
60. Wachter R, Gröschel K, Gelbrich G, Hamann GF, Kermer P, Liman J, agement in patients with suspected cardioembolic stroke. Am J Cardiol.
Seegers J, Wasser K, Schulte A, Jürries F, et al; Find-AF(randomised) 2014;114:1912–1916. doi: 10.1016/j.amjcard.2014.09.035
Investigators and Coordinators. Holter-electrocardiogram-monitoring 78. Boussel L, Cakmak S, Wintermark M, Nighoghossian N, Loffroy R, Coulon
in patients with acute ischaemic stroke (Find-AFRANDOMISED): an open- P, Derex L, Cho TH, Douek PC. Ischemic stroke: etiologic work-up with
label randomised controlled trial. Lancet Neurol. 2017;16:282–290. doi: multidetector CT of heart and extra- and intracranial arteries. Radiology.
10.1016/S1474-4422(17)30002-9 2011;258:206–212. doi: 10.1148/radiol.10100804
61. Burke JF, Gelb DJ, Quint DJ, Morgenstern LB, Kerber KA. The impact of 79. Liberman AL, Kalani RE, Aw-Zoretic J, Sondag M, Daruwalla VJ, Mitter
MRI on stroke management and outcomes: a systematic review. J Eval Clin SS, Bernstein R, Collins JD, Prabhakaran S. Cardiac magnetic resonance
Pract. 2013;19:987–993. doi: 10.1111/jep.12011 imaging has limited additional yield in cryptogenic stroke evaluation after
62. Gargan ML, Kok HK, Kearney J, Collins R, Coughlan T, O’Neill D, Ryan transesophageal echocardiography. Int J Stroke. 2017;12:946–952. doi:
D, Torreggiani W, Doody O. Added value of stroke protocol MRI following 10.1177/1747493017706242
negative initial CT in the acute stroke setting. Ir Med J. 2015;108:302–304. 80. Mazzucco S, Li L, Binney L, Rothwell PM; Oxford Vascular Study Pheno-
63. Hammoud K, Lanfranchi M, Li SX, Mehan WA. What is the diagnostic value of head typed Cohort. Prevalence of patent foramen ovale in cryptogenic transient
MRI after negative head CT in ED patients presenting with symptoms atypical ischaemic attack and non-disabling stroke at older ages: a population-based
of stroke? Emerg Radiol. 2016;23:339–344. doi: 10.1007/s10140-016-1408-z study, systematic review, and meta-analysis. Lancet Neurol. 2018;17:609–
64. Morita S, Suzuki M, Iizuka K. False-negative diffusion-weighted MRI in 617. doi: 10.1016/S1474-4422(18)30167-4
acute cerebellar stroke. Auris Nasus Larynx. 2011;38:577–582. doi: 81. Choudhri O, Schoen M, Mantha A, Feroze A, Ali R, Lawton MT, Do HM.
10.1016/j.anl.2011.01.017 Increased risk for complications following diagnostic cerebral angiography in
65. Nadeau SE, Dobkin B, Wu SS, Pei Q, Duncan PW; LEAPS Investigative older patients: trends from the Nationwide Inpatient Sample (1999-2009).
Team. The effects of stroke type, locus, and extent on long-term outcome J Clin Neurosci. 2016;32:109–114. doi: 10.1016/j.jocn.2016.04.007
of gait rehabilitation: the LEAPS experience. Neurorehabil Neural Repair. 82. Fifi JT, Meyers PM, Lavine SD, Cox V, Silverberg L, Mangla S, Pile-Spellman J. Com-
2016;30:615–625. doi: 10.1177/1545968315613851 plications of modern diagnostic cerebral angiography in an academic medical
66. Brazzelli M, Chappell FM, Miranda H, Shuler K, Dennis M, Sandercock PA, center. J Vasc Interv Radiol. 2009;20:442–447. doi: 10.1016/j.jvir.2009.01.012
Muir K, Wardlaw JM. Diffusion-weighted imaging and diagnosis of transient 83. Kaufmann TJ, Huston J 3rd, Mandrekar JN, Schleck CD, Thielen KR,
ischemic attack. Ann Neurol. 2014;75:67–76. doi: 10.1002/ana.24026 Kallmes DF. Complications of diagnostic cerebral angiography: evalua-
67. Kelly PJ, Albers GW, Chatzikonstantinou A, De Marchis GM, Ferrari J, tion of 19,826 consecutive patients. Radiology. 2007;243:812–819. doi:
George P, Katan M, Knoflach M, Kim JS, Li L, et al. Validation and com- 10.1148/radiol.2433060536
parison of imaging-based scores for prediction of early stroke risk after 84. Tholen AT, de Monyé C, Genders TS, Buskens E, Dippel DW, van der Lugt
transient ischaemic attack: a pooled analysis of individual-patient data A, Hunink MG. Suspected carotid artery stenosis: cost-effectiveness of CT
from cohort studies. Lancet Neurol. 2016;15:1238–1247. doi: 10.1016/ angiography in work-up of patients with recent TIA or minor ischemic stroke.
S1474-4422(16)30236-8 Radiology. 2010;256:585–597. doi: 10.1148/radiol.10091157
68. Mlynash M, Olivot JM, Tong DC, Lansberg MG, Eyngorn I, Kemp S, 85. Coutts SB, Moreau F, Asdaghi N, Boulanger JM, Camden MC, Campbell
Moseley ME, Albers GW. Yield of combined perfusion and diffusion BCV, Demchuk AM, Field TS, Goyal M, Krause M, et al; Diagnosis of
MR imaging in hemispheric TIA. Neurology. 2009;72:1127–1133. doi: Uncertain-Origin Benign Transient Neurological Symptoms (DOUBT) Study
10.1212/01.wnl.0000340983.00152.69 Group. Rate and prognosis of brain ischemia in patients with lower-risk tran-
69. Wardlaw J, Brazzelli M, Miranda H, Chappell F, McNamee P, Scotland G, sient or persistent minor neurologic events. JAMA Neurol. 2019;76:1439–
Quayyum Z, Martin D, Shuler K, Sandercock P, et al. An assessment of the 1445. doi: 10.1001/jamaneurol.2019.3063
86. Nordestgaard BG, Langsted A, Mora S, Kolovou G, Baum H, Bruckert E, cardiometabolic outcomes: an umbrella review of systematic reviews and
Watts GF, Sypniewska G, Wiklund O, Borén J, et al; European Atherosclerosis meta-analyses. Nutrients. 2019;11:338. doi: 10.3390/nu11020338
CLINICAL STATEMENTS
Society (EAS) and the European Federation of Clinical Chemistry and 104. Deleted in proof.
AND GUIDELINES
Laboratory Medicine (EFLM) Joint Consensus Initiative. Fasting is not 105. Judd SE, Gutiérrez OM, Newby PK, Howard G, Howard VJ, Locher JL,
routinely required for determination of a lipid profile: clinical and labora- Kissela BM, Shikany JM. Dietary patterns are associated with incident
tory implications including flagging at desirable concentration cutpoints: a stroke and contribute to excess risk of stroke in Black Americans. Stroke.
joint consensus statement from the European Atherosclerosis Society and 2013;44:3305–3311. doi: 10.1161/STROKEAHA.113.002636
European Federation of Clinical Chemistry and Laboratory Medicine. Clin 106. Vinceti M, Filippini T, Crippa A, de Sesmaisons A, Wise LA, Orsini N. Meta-
Chem. 2016;62:930–946. doi: 10.1373/clinchem.2016.258897 analysis of potassium intake and the risk of stroke. J Am Heart Assoc.
87. Rasmussen KL, Philips M, Tripodi A, Goetze JP. Unexpected, isolated acti- 2016;5:e004210. doi: 10.1161/JAHA.116.004210
vated partial thromboplastin time prolongation: a practical mini-review. Eur 107. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke,
J Haematol. 2020;104:519–525. doi: 10.1111/ejh.13394 and cardiovascular disease: meta-analysis of prospective studies. BMJ.
88. Kamal AH, Tefferi A, Pruthi RK. How to interpret and pursue an abnormal 2009;339:b4567. doi: 10.1136/bmj.b4567
prothrombin time, activated partial thromboplastin time, and bleeding time 108. Kastorini CM, Milionis HJ, Kantas D, Bika E, Nikolaou V, Vemmos KN,
in adults. Mayo Clin Proc. 2007;82:864–873. doi: 10.4065/82.7.864 Goudevenos JA, Panagiotakos DB. Adherence to the Mediterranean
89. Saric M, Armour AC, Arnaout MS, Chaudhry FA, Grimm RA, Kronzon I, diet in relation to ischemic stroke nonfatal events in nonhypercholes-
Landeck BF, Maganti K, Michelena HI, Tolstrup K. Guidelines for the use of terolemic and hypercholesterolemic participants: results of a case/
echocardiography in the evaluation of a cardiac source of embolism. J Am case-control study. Angiology. 2012;63:509–515. doi: 10.1177/
Soc Echocardiogr. 2016;29:1–42. doi: 10.1016/j.echo.2015.09.011 0003319711427392
90. Bushnell C, Siddiqi Z, Morgenlander JC, Goldstein LB. Use of specialized 109. Nagata C, Takatsuka N, Shimizu N, Shimizu H. Sodium intake and risk of
coagulation testing in the evaluation of patients with acute ischemic stroke. death from stroke in Japanese men and women. Stroke. 2004;35:1543–
Neurology. 2001;56:624–627. doi: 10.1212/wnl.56.5.624 1547. doi: 10.1161/01.STR.0000130425.50441.b0
91. Lappin JM, Darke S, Farrell M. Stroke and methamphetamine use in young 110. Turan TN, Nizam A, Lynn MJ, Egan BM, Le NA, Lopes-Virella MF, Hermayer
adults: a review. J Neurol Neurosurg Psychiatry. 2017;88:1079–1091. doi: KL, Harrell J, Derdeyn CP, Fiorella D, et al. Relationship between risk
10.1136/jnnp-2017-316071 factor control and vascular events in the SAMMPRIS trial. Neurology.
92. Levine SR, Brust JC, Futrell N, Ho KL, Blake D, Millikan CH, Brass LM, 2017;88:379–385. doi: 10.1212/WNL.0000000000003534
Fayad P, Schultz LR, Selwa JF. Cerebrovascular complications of the use of 111. Lennon O, Galvin R, Smith K, Doody C, Blake C. Lifestyle interventions
the “crack” form of alkaloidal cocaine. N Engl J Med. 1990;323:699–704. for secondary disease prevention in stroke and transient ischaemic at-
doi: 10.1056/NEJM199009133231102 tack: a systematic review. Eur J Prev Cardiol. 2014;21:1026–1039. doi:
93. de Bruijn SF, Agema WR, Lammers GJ, van der Wall EE, Wolterbeek R, 10.1177/2047487313481756
Holman ER, Bollen EL, Bax JJ. Transesophageal echocardiography is su- 112. Deijle IA, Van Schaik SM, Van Wegen EE, Weinstein HC, Kwakkel G,
perior to transthoracic echocardiography in management of patients of any Van den Berg-Vos RM. Lifestyle interventions to prevent cardiovascu-
age with transient ischemic attack or stroke. Stroke. 2006;37:2531–2534. lar events after stroke and transient ischemic attack: systematic re-
doi: 10.1161/01.STR.0000241064.46659.69 view and meta-analysis. Stroke. 2017;48:174–179. doi: 10.1161/
94. Harloff A, Handke M, Reinhard M, Geibel A, Hetzel A. Therapeutic strate- STROKEAHA.116.013794
gies after examination by transesophageal echocardiography in 503 pa- 113. D’Isabella NT, Shkredova DA, Richardson JA, Tang A. Effects of exercise
tients with ischemic stroke. Stroke. 2006;37:859–864. doi: 10.1161/01. on cardiovascular risk factors following stroke or transient ischemic attack:
STR.0000202592.87021.b7 a systematic review and meta-analysis. Clin Rehabil. 2017;31:1561–1572.
Downloaded from http://ahajournals.org by on June 12, 2021
95. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, doi: 10.1177/0269215517709051
Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, et al; PREDIMED 114. Wang L, Cai L, Qian H, Oh JS, Tanikawa R, Shi X. Repositioning tech-
Study Investigators. Primary prevention of cardiovascular disease with a nique for the decompression of symptomatic dolichoectatic verte-
Mediterranean diet supplemented with extra-virgin olive oil or nuts. N Engl brobasilar pathology: a comprehensive review of sling characteristics
J Med. 2018;378:e34. doi: 10.1056/NEJMoa1800389 and surgical experience. World Neurosurg. 2019;122:620–631. doi:
96. Rees K, Takeda A, Martin N, Ellis L, Wijesekara D, Vepa A, Das A, Hartley 10.1016/j.wneu.2018.11.200
L, Stranges S. Mediterranean-style diet for the primary and second- 115. English C, Janssen H, Crowfoot G, Bourne J, Callister R, Dunn A,
ary prevention of cardiovascular disease. Cochrane Database Syst Rev. Oldmeadow C, Ong LK, Palazzi K, Patterson A, et al. Frequent, short bouts
2019;3:CD009825. doi: 10.1002/14651858.CD009825.pub3 of light-intensity exercises while standing decreases systolic blood pres-
97. He FJ, Tan M, Ma Y, MacGregor GA. Salt reduction to prevent hyperten- sure: Breaking Up Sitting Time After Stroke (BUST-Stroke) trial. Int J
sion and cardiovascular disease: JACC state-of-the-art review. J Am Coll Stroke. 2018;13:932–940. doi: 10.1177/1747493018798535
Cardiol. 2020;75:632–647. doi: 10.1016/j.jacc.2019.11.055 116. Warburton DER, Bredin SSD. Health benefits of physical activity: a system-
98. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, atic review of current systematic reviews. Curr Opin Cardiol. 2017;32:541–
Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, et al; DASH- 556. doi: 10.1097/HCO.0000000000000437
Sodium Collaborative Research Group. Effects on blood pressure of re- 117. Kyu HH, Bachman VF, Alexander LT, Mumford JE, Afshin A, Estep K,
duced dietary sodium and the Dietary Approaches to Stop Hypertension Veerman JL, Delwiche K, Iannarone ML, Moyer ML, et al. Physical activ-
(DASH) diet: DASH-Sodium Collaborative Research Group. N Engl J Med. ity and risk of breast cancer, colon cancer, diabetes, ischemic heart dis-
2001;344:3–10. doi: 10.1056/NEJM200101043440101 ease, and ischemic stroke events: systematic review and dose-response
99. Zhao W, Tang H, Yang X, Luo X, Wang X, Shao C, He J. fish consump- meta-analysis for the Global Burden of Disease Study 2013. BMJ.
tion and stroke risk: a meta-analysis of prospective cohort stud- 2016;354:i3857. doi: 10.1136/bmj.i3857
ies. J Stroke Cerebrovasc Dis. 2019;28:604–611. doi: 10.1016/j. 118. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a
jstrokecerebrovasdis.2018.10.036 meta-analysis. Stroke. 2003;34:2475–2481. doi: 10.1161/01.STR.
100. Aune D, Giovannucci E, Boffetta P, Fadnes LT, Keum N, Norat T, Greenwood 0000091843.02517.9D
DC, Riboli E, Vatten LJ, Tonstad S. Fruit and vegetable intake and the risk 119. Paixão C, Dias CM, Jorge R, Carraça EV, Yannakoulia M, de Zwaan M, Soini
of cardiovascular disease, total cancer and all-cause mortality: a system- S, Hill JO, Teixeira PJ, Santos I. Successful weight loss maintenance: a sys-
atic review and dose-response meta-analysis of prospective studies. Int J tematic review of weight control registries. Obes Rev. 2020;21:e13003.
Epidemiol. 2017;46:1029–1056. doi: 10.1093/ije/dyw319 doi: 10.1111/obr.13003
101. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and 120. Sherman DL. Exercise and endothelial function. Coron Artery Dis.
stroke: meta-analysis of cohort studies. Lancet. 2006;367:320–326. doi: 2000;11:117–122. doi: 10.1097/00019501-200003000-00005
10.1016/S0140-6736(06)68069-0 121. Ernst E. Regular exercise reduces fibrinogen levels: a review of longitudinal
102. Tong TYN, Appleby PN, Key TJ, Dahm CC, Overvad K, Olsen A, Tjønneland studies. Br J Sports Med. 1993;27:175–176. doi: 10.1136/bjsm.27.3.175
A, Katzke V, Kühn T, Boeing H, et al. The associations of major foods and 122. Wosornu D, Allardyce W, Ballantyne D, Tansey P. Influence of power and
fibre with risks of ischaemic and haemorrhagic stroke: a prospective study aerobic exercise training on haemostatic factors after coronary artery sur-
of 418 329 participants in the EPIC cohort across nine European coun- gery. Br Heart J. 1992;68:181–186. doi: 10.1136/hrt.68.8.181
tries. Eur Heart J. 2020;41:2632–2640. doi: 10.1093/eurheartj/ehaa007 123. Reinholdsson M, Palstam A, Sunnerhagen KS. Prestroke physical activ-
103. Chiavaroli L, Viguiliouk E, Nishi SK, Blanco Mejia S, Rahelić D, Kahleová H, ity could influence acute stroke severity (part of PAPSIGOT). Neurology.
Salas-Salvadó J, Kendall CW, Sievenpiper JL. DASH dietary pattern and 2018;91:e1461–e1467. doi: 10.1212/WNL.0000000000006354
124. Biswas A, Oh PI, Faulkner GE, Bajaj RR, Silver MA, Mitchell MS, Alter DA. 141. Evans-Hudnall GL, Stanley MA, Clark AN, Bush AL, Resnicow K, Liu Y, Kass
Sedentary time and its association with risk for disease incidence, mortality, JS, Sander AM. Improving secondary stroke self-care among underserved
CLINICAL STATEMENTS
and hospitalization in adults: a systematic review and meta-analysis. Ann ethnic minority individuals: a randomized clinical trial of a pilot intervention.
AND GUIDELINES
Intern Med. 2015;162:123–132. doi: 10.7326/M14-1651 J Behav Med. 2014;37:196–204. doi: 10.1007/s10865-012-9469-2
125. Ekelund U, Steene-Johannessen J, Brown WJ, Fagerland MW, Owen N, 142. Ahmadi M, Laumeier I, Ihl T, Steinicke M, Ferse C, Endres M, Grau A,
Powell KE, Bauman A, Lee IM; Lancet Physical Activity Series 2 Executive Hastrup S, Poppert H, Palm F, et al. A support programme for secondary
Committe; Lancet Sedentary Behaviour Working Group. Does physical prevention in patients with transient ischaemic attack and minor stroke
activity attenuate, or even eliminate, the detrimental association of sit- (INSPiRE-TMS): an open-label, randomised controlled trial. Lancet Neurol.
ting time with mortality? A harmonised meta-analysis of data from more 2020;19:49–60. doi: 10.1016/S1474-4422(19)30369-2
than 1 million men and women. Lancet. 2016;388:1302–1310. doi: 143. Chen J, Li S, Zheng K, Wang H, Xie Y, Xu P, Dai Z, Gu M, Xia Y, Zhao M,
10.1016/S0140-6736(16)30370-1 et al. Impact of smoking status on stroke recurrence. J Am Heart Assoc.
126. Bernhardt J, Dewey H, Thrift A, Donnan G. Inactive and alone: physi- 2019;8:e011696. doi: 10.1161/JAHA.118.011696
cal activity within the first 14 days of acute stroke unit care. Stroke. 144. Kaplan RC, Tirschwell DL, Longstreth WT Jr, Manolio TA, Heckbert SR,
2004;35:1005–1009. doi: 10.1161/01.STR.0000120727.40792.40 Lefkowitz D, El-Saed A, Psaty BM. Vascular events, mortality, and pre-
127. Fini NA, Holland AE, Keating J, Simek J, Bernhardt J. How physically active ventive therapy following ischemic stroke in the elderly. Neurology.
are people following stroke? Systematic review and quantitative synthesis. 2005;65:835–842. doi: 10.1212/01.wnl.0000176058.09848.bb
Phys Ther. 2017;97:707–717. doi: 10.1093/ptj/pzx038 145. Huang ZX, Lin XL, Lu HK, Liang XY, Fan LJ, Liu XT. Lifestyles correlate with
128. Saunders DH, Sanderson M, Hayes S, Johnson L, Kramer S, Carter stroke recurrence in Chinese inpatients with first-ever acute ischemic stroke.
DD, Jarvis H, Brazzelli M, Mead GE. Physical fitness training for stroke J Neurol. 2019;266:1194–1202. doi: 10.1007/s00415-019-09249-5
patients. Cochrane Database Syst Rev. 2020;3:CD003316. doi: 146. van den Berg MJ, van der Graaf Y, Deckers JW, de Kanter W, Algra A,
10.1002/14651858.CD003316.pub7 Kappelle LJ, de Borst GJ, Cramer MM, Visseren FLJ; SMART Study
129. Boysen G, Krarup LH, Zeng X, Oskedra A, Kõrv J, Andersen G, Gluud Group. Smoking cessation and risk of recurrent cardiovascular events
C, Pedersen A, Lindahl M, Hansen L, et al; ExStroke Pilot Trial Group. and mortality after a first manifestation of arterial disease. Am Heart J.
ExStroke Pilot Trial of the effect of repeated instructions to improve physi- 2019;213:112–122. doi: 10.1016/j.ahj.2019.03.019
cal activity after ischaemic stroke: a multinational randomised controlled 147. Pan B, Jin X, Jun L, Qiu S, Zheng Q, Pan M. The relationship between smok-
clinical trial. BMJ. 2009;339:b2810. doi: 10.1136/bmj.b2810 ing and stroke: a meta-analysis. Medicine (Baltimore). 2019;98:e14872.
129a. Lynch EA, Jones TM, Simpson DB, Fini NA, Kuys SS, Borschmann doi: 10.1097/MD.0000000000014872
K, Kramer S, Johnson L, Callisaya ML, Mahendran N, et al; ACTIOnS 148. Lin MP, Ovbiagele B, Markovic D, Towfighi A. Association of second-
Collaboration. Activity monitors for increasing physical activity in adult hand smoke with stroke outcomes. Stroke. 2016;47:2828–2835. doi:
stroke survivors. Cochrane Database Syst Rev. 2018;7:CD012543. doi: 10.1161/STROKEAHA.116.014099
10.1002/14651858.CD012543.pub2 149. Bonita R, Duncan J, Truelsen T, Jackson RT, Beaglehole R. Passive smok-
130. Wang C, Redgrave J, Shafizadeh M, Majid A, Kilner K, Ali AN. Aerobic ing as well as active smoking increases the risk of acute stroke. Tob
exercise interventions reduce blood pressure in patients after stroke or Control. 1999;8:156–160. doi: 10.1136/tc.8.2.156
transient ischaemic attack: a systematic review and meta-analysis. Br J 150. Lee PN, Thornton AJ, Forey BA, Hamling JS. Environmental tobacco
Sports Med. 2019;53:1515–1525. doi: 10.1136/bjsports-2017-098903 smoke exposure and risk of stroke in never smokers: an updated review
131. Faulkner J, Stoner L, Lanford J, Jolliffe E, Mitchelmore A, Lambrick with meta-analysis. J Stroke Cerebrovasc Dis. 2017;26:204–216. doi:
D. Long-term effect of participation in an early exercise and education 10.1016/j.jstrokecerebrovasdis.2016.09.011
program on clinical outcomes and cost implications, in patients with TIA 151. Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking
Downloaded from http://ahajournals.org by on June 12, 2021
and minor, non-disabling stroke. Transl Stroke Res. 2017;8:220–227. doi: and stroke. BMJ. 1989;298:789–794. doi: 10.1136/bmj.298.6676.789
10.1007/s12975-016-0510-6 152. Wolf PA, D’Agostino RB, Kannel WB, Bonita R, Belanger AJ. Cigarette
132. Prior PL, Hachinski V, Unsworth K, Chan R, Mytka S, O’Callaghan C, smoking as a risk factor for stroke: the Framingham study. JAMA.
Suskin N. Comprehensive cardiac rehabilitation for secondary prevention 1988;259:1025–1029.
after transient ischemic attack or mild stroke, I: feasibility and risk factors. 153. Howard G, Wagenknecht LE, Cai J, Cooper L, Kraut MA, Toole JF. Cigarette
Stroke. 2011;42:3207–3213. doi: 10.1161/STROKEAHA.111.620187 smoking and other risk factors for silent cerebral infarction in the general
133. Kirk H, Kersten P, Crawford P, Keens A, Ashburn A, Conway J. The car- population. Stroke. 1998;29:913–917. doi: 10.1161/01.str.29.5.913
diac model of rehabilitation for reducing cardiovascular risk factors post 154. Deleted in proof.
transient ischaemic attack and stroke: a randomized controlled trial. Clin 155. Lee PN, Forey BA. Environmental tobacco smoke exposure and risk of
Rehabil. 2014;28:339–349. doi: 10.1177/0269215513502211 stroke in nonsmokers: a review with meta-analysis. J Stroke Cerebrovasc
134. Kono Y, Yamada S, Yamaguchi J, Hagiwara Y, Iritani N, Ishida S, Araki A, Dis. 2006;15:190–201. doi: 10.1016/j.jstrokecerebrovasdis.2006.05.002
Hasegawa Y, Sakakibara H, Koike Y. Secondary prevention of new vascular 156. Ives SP, Heuschmann PU, Wolfe CD, Redfern J. Patterns of smok-
events with lifestyle intervention in patients with noncardioembolic mild ing cessation in the first 3 years after stroke: the South London
ischemic stroke: a single-center randomized controlled trial. Cerebrovasc Stroke Register. Eur J Cardiovasc Prev Rehabil. 2008;15:329–335. doi:
Dis. 2013;36:88–97. doi: 10.1159/000352052 10.1097/HJR.0b013e3282f37a58
135. Lloyd M, Skelton DA, Mead GE, Williams B, van Wijck F. Physical fitness 157. Edjoc RK, Reid RD, Sharma M, Fang J; Registry of the Canadian Stroke
interventions for nonambulatory stroke survivors: a mixed-methods sys- Network. The prognostic effect of cigarette smoking on stroke severity,
tematic review and meta-analysis. Brain Behav. 2018;8:e01000. doi: disability, length of stay in hospital, and mortality in a cohort with cere-
10.1002/brb3.1000 brovascular disease. J Stroke Cerebrovasc Dis. 2013;22:e446–e454. doi:
136. Biasin L, Sage MD, Brunton K, Fraser J, Howe JA, Bayley M, Brooks D, 10.1016/j.jstrokecerebrovasdis.2013.05.001
McIlroy WE, Mansfield A, Inness EL. Integrating aerobic training within sub- 158. Kammersgaard LP, Olsen TS. Cardiovascular risk factors and 5-year mor-
acute stroke rehabilitation: a feasibility study. Phys Ther. 2014;94:1796– tality in the Copenhagen Stroke Study. Cerebrovasc Dis. 2006;21:187–
1806. doi: 10.2522/ptj.20130404 193. doi: 10.1159/000090531
137. Lennon O, Carey A, Gaffney N, Stephenson J, Blake C. A pilot randomized 159. Myint PK, Welch AA, Bingham SA, Luben RN, Wareham NJ, Day NE, Khaw
controlled trial to evaluate the benefit of the cardiac rehabilitation paradigm KT. Smoking predicts long-term mortality in stroke: the European Prospective
for the non-acute ischaemic stroke population. Clin Rehabil. 2008;22:125– Investigation into Cancer (EPIC)-Norfolk prospective population study.
133. doi: 10.1177/0269215507081580 Prev Med. 2006;42:128–131. doi: 10.1016/j.ypmed.2005.11.014
138. English C, Healy GN, Coates A, Lewis L, Olds T, Bernhardt J. Sitting and 160. Lancaster T, Stead LF. Individual behavioural counselling for smok-
activity time in people with stroke. Phys Ther. 2016;96:193–201. doi: ing cessation. Cochrane Database Syst Rev. 2017;3:CD001292. doi:
10.2522/ptj.20140522 10.1002/14651858.CD001292.pub3
139. Rigotti NA, Clair C, Munafò MR, Stead LF. Interventions for smok- 161. Ois A, Gomis M, Rodríguez-Campello A, Cuadrado-Godia E, Jiménez-Conde
ing cessation in hospitalised patients. Cochrane Database Syst Rev. J, Pont-Sunyer C, Cuccurella G, Roquer J. Factors associated with a high
2012;5:CD001837. doi: 10.1002/14651858.CD001837.pub3 risk of recurrence in patients with transient ischemic attack or minor stroke.
140. Stead LF, Koilpillai P, Fanshawe TR, Lancaster T. Combined pharmacothera- Stroke. 2008;39:1717–1721. doi: 10.1161/STROKEAHA.107.505438
py and behavioural interventions for smoking cessation. Cochrane Database 162. Ricci C, Wood A, Muller D, Gunter MJ, Agudo A, Boeing H, van der Schouw
Syst Rev. 2016;3:CD008286. doi: 10.1002/14651858.CD008286.pub3 YT, Warnakula S, Saieva C, Spijkerman A, et al. Alcohol intake in relation
to non-fatal and fatal coronary heart disease and stroke: EPIC-CVD case- 184. Doehner W, Schenkel J, Anker SD, Springer J, Audebert HJ. Overweight
cohort study. BMJ. 2018;361:k934. doi: 10.1136/bmj.k934 and obesity are associated with improved survival, functional outcome,
CLINICAL STATEMENTS
163. Patra J, Taylor B, Irving H, Roerecke M, Baliunas D, Mohapatra S, Rehm J. and stroke recurrence after acute stroke or transient ischaemic attack:
AND GUIDELINES
Alcohol consumption and the risk of morbidity and mortality for different observations from the TEMPiS trial. Eur Heart J. 2013;34:268–277. doi:
stroke types–a systematic review and meta-analysis. BMC Public Health. 10.1093/eurheartj/ehs340
2010;10:258. doi: 10.1186/1471-2458-10-258 185. Zonneveld TP, Richard E, Vergouwen MD, Nederkoorn PJ, de Haan R, Roos
164. Sull JW, Yi SW, Nam CM, Choi K, Ohrr H. Binge drinking and hy- YB, Kruyt ND. Blood pressure-lowering treatment for preventing recur-
pertension on cardiovascular disease mortality in Korean men and rent stroke, major vascular events, and dementia in patients with a his-
women: a Kangwha cohort study. Stroke. 2010;41:2157–2162. doi: tory of stroke or transient ischaemic attack. Cochrane Database Syst Rev.
10.1161/STROKEAHA.110.586347 2018;7:CD007858. doi: 10.1002/14651858.CD007858.pub2
165. National Institute on Alcohol Abuse and Alcoholism. 2010. Accessed December 186. PROGRESS Collaborative Group. Randomised trial of perindopril-based
1, 2019. https://www.niaaa.nih.gov/strategic-plan/introduction#ob-0 blood-pressure lowering regimen among 6105 individuals with previous
166. Reynolds K, Lewis B, Nolen JD, Kinney GL, Sathya B, He J, Lewis stroke or transient ischaemic attack. Lancet. 2001;358:1033–1041. doi:
BL. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 10.1016/S0140-6736(01)06178-5
2003;289:579–588. doi: 10.1001/jama.289.5.579 187. Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger
167. United Nations Office on Drugs and Crime (UNODC). World Drug Report J, Zidek W, Dominiak P, Diener HC; MOSES Study Group. Morbidity
2017: Booklet 2: Global Overview of Drug Demand and Supply. Accessed and mortality after stroke, eprosartan compared with nitrendipine
December 1, 2019. https://www.unodc.org/wdr2017/en/drug-demand- for secondary prevention: principal results of a prospective random-
and-supply.html ized controlled study (MOSES). Stroke. 2005;36:1218–1226. doi:
168. Salehi Omran S, Chatterjee A, Chen ML, Lerario MP, Merkler AE, Kamel H. 10.1161/01.STR.0000166048.35740.a9
National trends in hospitalizations for stroke associated with infective en- 188. Rashid P, Leonardi-Bee J, Bath P. Blood pressure reduction and secondary
docarditis and opioid use between 1993 and 2015. Stroke. 2019;50:577– prevention of stroke and other vascular events: a systematic review. Stroke.
582. doi: 10.1161/STROKEAHA.118.024436 2003;34:2741–2748. doi: 10.1161/01.STR.0000092488.40085.15
169. Indave BI, Sordo L, Bravo MJ, Sarasa-Renedo A, Fernández-Balbuena S, 189. Liu L, Wang Z, Gong L, Zhang Y, Thijs L, Staessen JA, Wang J. Blood pres-
De la Fuente L, Sonego M, Barrio G. Risk of stroke in prescription and sure reduction for the secondary prevention of stroke: a Chinese trial and a
other amphetamine-type stimulants use: a systematic review. Drug Alcohol systematic review of the literature. Hypertens Res. 2009;32:1032–1040.
Rev. 2018;37:56–69. doi: 10.1111/dar.12559 doi: 10.1038/hr.2009.139
170. Sordo L, Indave BI, Barrio G, Degenhardt L, de la Fuente L, Bravo MJ. 190. Kitagawa K, Yamamoto Y, Arima H, Maeda T, Sunami N, Kanzawa T,
Cocaine use and risk of stroke: a systematic review. Drug Alcohol Depend. Eguchi K, Kamiyama K, Minematsu K, Ueda S, et al; Recurrent Stroke
2014;142:1–13. doi: 10.1016/j.drugalcdep.2014.06.041 Prevention Clinical Outcome Study Group. Effect of standard vs inten-
171. Ali WM, Zubaid M, Al-Motarreb A, Singh R, Al-Shereiqi SZ, Shehab A, sive blood pressure control on the risk of recurrent stroke: a randomized
Rashed W, Al-Sagheer NQ, Saleh AH, Al Suwaidi J. Association of khat clinical trial and meta-analysis. JAMA Neurol. 2019;76:1309–1318. doi:
chewing with increased risk of stroke and death in patients presenting 10.1001/jamaneurol.2019.2167
with acute coronary syndrome. Mayo Clin Proc. 2010;85:974–980. doi: 191. Mant J, McManus RJ, Roalfe A, Fletcher K, Taylor CJ, Martin U, Virdee
10.4065/mcp.2010.0398 S, Greenfield S, Hobbs FD. Different systolic blood pressure targets for
172. Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, people with history of stroke or transient ischaemic attack: PAST-BP
Cheetham TC, Quinn VP, Dublin S, Boudreau DM, et al. ADHD medications (Prevention After Stroke–Blood Pressure) randomised controlled trial.
and risk of serious cardiovascular events in young and middle-aged adults. BMJ. 2016;352:i708. doi: 10.1136/bmj.i708
Downloaded from http://ahajournals.org by on June 12, 2021
JAMA. 2011;306:2673–2683. doi: 10.1001/jama.2011.1830 192. SPS3 Study Group; Benavente OR, Coffey CS, Conwit R, Hart RG,
173. Holick CN, Turnbull BR, Jones ME, Chaudhry S, Bangs ME, Seeger JD. McClure LA, Pearce LA, Pergola PE, Szychowski JM. Blood-pressure tar-
Atomoxetine and cerebrovascular outcomes in adults. J Clin Psychopharmacol. gets in patients with recent lacunar stroke: the SPS3 randomised trial.
2009;29:453–460. doi: 10.1097/JCP.0b013e3181b2b828 Lancet. 2013;382:507–515. doi: 10.1016/S0140-6736(13)60852-1
174. Huang MC, Yang SY, Lin SK, Chen KY, Chen YY, Kuo CJ, Hung YN. Risk 193. Bath PM, Scutt P, Blackburn DJ, Ankolekar S, Krishnan K, Ballard C, Burns
of cardiovascular diseases and stroke events in methamphetamine users: A, Mant J, Passmore P, Pocock S, et al; PODCAST Trial Investigators.
a 10-year follow-up study. J Clin Psychiatry. 2016;77:1396–1403. doi: Intensive versus guideline blood pressure and lipid lowering in patients
10.4088/JCP.15m09872 with previous stroke: main results from the pilot ‘Prevention of Decline in
175. Westover AN, McBride S, Haley RW. Stroke in young adults who abuse am- Cognition after Stroke Trial’ (PODCAST) randomised controlled trial. PLoS
phetamines or cocaine: a population-based study of hospitalized patients. One. 2017;12:e0164608. doi: 10.1371/journal.pone.0164608
Arch Gen Psychiatry. 2007;64:495–502. doi: 10.1001/archpsyc.64.4.495 194. Katsanos AH, Filippatou A, Manios E, Deftereos S, Parissis J, Frogoudaki
176. Petitti DB, Sidney S, Quesenberry C, Bernstein A. Stroke and cocaine or A, Vrettou AR, Ikonomidis I, Pikilidou M, Kargiotis O, et al. Blood pres-
amphetamine use. Epidemiology. 1998;9:596–600. sure reduction and secondary stroke prevention: a systematic review
177. Reis JP, Auer R, Bancks MP, Goff DC Jr, Lewis CE, Pletcher MJ, Rana JS, and metaregression analysis of randomized clinical trials. Hypertension.
Shikany JM, Sidney S. Cumulative lifetime marijuana use and incident car- 2017;69:171–179. doi: 10.1161/HYPERTENSIONAHA.116.08485
diovascular disease in middle age: the Coronary Artery Risk Development 195. Lakhan SE, Sapko MT. Blood pressure lowering treatment for preventing
in Young Adults (CARDIA) Study. Am J Public Health. 2017;107:601–606. stroke recurrence: a systematic review and meta-analysis. Int Arch Med.
doi: 10.2105/AJPH.2017.303654 2009;2:30. doi: 10.1186/1755-7682-2-30
178. Desai R, Singh S, Patel K, Goyal H, Shah M, Mansuri Z, Patel S, Mahuwala 196. Wang WT, You LK, Chiang CE, Sung SH, Chuang SY, Cheng HM, Chen CH.
ZK, Goldstein LB , Qureshi AI. Stroke in young cannabis users (18–49 Comparative effectiveness of blood pressure-lowering drugs in patients
years): National trends in hospitalizations and outcomes. Int J Stroke. who have already suffered from stroke: traditional and bayesian network
2020;15:535–539. doi: 10.1177/1747493019895651 meta-analysis of randomized trials. Medicine (Baltimore). 2016;95:e3302.
179. Parekh T, Pemmasani S, Desai R. Marijuana use among young adults doi: 10.1097/MD.0000000000003302
(18-44 years of age) and risk of stroke: a Behavioral Risk Factor 197. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch
Surveillance System Survey analysis. Stroke. 2020;51:308–310. doi: Y, Martin RH, Albers GW, Bath P, et al; PRoFESS Study Group. Telmisartan
10.1161/STROKEAHA.119.027828 to prevent recurrent stroke and cardiovascular events. N Engl J Med.
180. Camí J, Farré M. Drug addiction. N Engl J Med. 2003;349:975–986. doi: 2008;359:1225–1237. doi: 10.1056/NEJMoa0804593
10.1056/NEJMra023160 198. Clark D 3rd, Colantonio LD, Min YI, Hall ME, Zhao H, Mentz RJ, Shimbo D,
181. Herbeck DM, Hser YI, Teruya C. Empirically supported substance abuse treat- Ogedegbe G, Howard G, Levitan EB, et al. Population-attributable risk for
ment approaches: a survey of treatment providers’ perspectives and prac- cardiovascular disease associated with hypertension in Black adults. JAMA
tices. Addict Behav. 2008;33:699–712. doi: 10.1016/j.addbeh.2007.12.003 cardiology. 2019;4:1194–1202. doi: 10.1001/jamacardio.2019.3773
182. World Health Organization. Guidelines for the Psychosocially Assisted 199. Willey JZ, Moon YP, Kahn E, Rodriguez CJ, Rundek T, Cheung K, Sacco RL,
Pharmacological Treatment of Opioid Dependence. World Health Organization; Elkind MS. Population attributable risks of hypertension and diabetes for
2009. cardiovascular disease and stroke in the Northern Manhattan Study. J Am
183. Edjoc RK, Reid RD, Sharma M. The effectiveness of smoking cessation in- Heart Assoc. 2014;3:e001106. doi: 10.1161/JAHA.114.001106
terventions in smokers with cerebrovascular disease: a systematic review. 200. Arima H, Chalmers J, Woodward M, Anderson C, Rodgers A, Davis S,
BMJ Open. 2012;2:e002022. doi: 10.1136/bmjopen-2012-002022 Macmahon S, Neal B; PROGRESS Collaborative Group. Lower target
blood pressures are safe and effective for the prevention of recurrent 217. Cannon CP, Khan I, Klimchak AC, Reynolds MR, Sanchez RJ, Sasiela WJ.
stroke: the PROGRESS trial. J Hypertens. 2006;24:1201–1208. doi: Simulation of lipid-lowering therapy intensification in a population with ath-
CLINICAL STATEMENTS
10.1097/01.hjh.0000226212.34055.86 erosclerotic cardiovascular disease. JAMA Cardiol. 2017;2:959–966. doi:
AND GUIDELINES
201. Ovbiagele B, Diener HC, Yusuf S, Martin RH, Cotton D, Vinisko R, 10.1001/jamacardio.2017.2289
Donnan GA, Bath PM; PROFESS Investigators. Level of systolic blood 218. Virani SS, Akeroyd JM, Nambi V, Heidenreich PA, Morris PB, Nasir K,
pressure within the normal range and risk of recurrent stroke. JAMA. Michos ED, Bittner VA, Petersen LA, Ballantyne CM. Estimation of eligibil-
2011;306:2137–2144. doi: 10.1001/jama.2011.1650 ity for proprotein convertase subtilisin/kexin type 9 inhibitors and associ-
202. Ovbiagele B. Low-normal systolic blood pressure and second- ated costs based on the FOURIER Trial (Further Cardiovascular Outcomes
ary stroke risk. J Stroke Cerebrovasc Dis. 2013;22:633–638. doi: Research With PCSK9 Inhibition in Subjects With Elevated Risk): insights
10.1016/j.jstrokecerebrovasdis.2011.12.003 from the Department of Veterans Affairs. Circulation. 2017;135:2572–
203. Lin MP, Ovbiagele B, Markovic D, Towfighi A. Systolic blood pressure and 2574. doi: 10.1161/CIRCULATIONAHA.117.028503
mortality after stroke: too low, no go? Stroke. 2015;46:1307–1313. doi: 219. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle
10.1161/STROKEAHA.115.008821 RT Jr, Juliano RA, Jiao L, Granowitz C, et al; REDUCE-IT Investigators.
204. Kim J, Gall SL, Nelson MR, Sharman JE, Thrift AG. Lower systolic blood Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
pressure is associated with poorer survival in long-term survivors of stroke. J N Engl J Med. 2019;380:11–22. doi: 10.1056/NEJMoa1812792
Hypertens. 2014;32:904–911. doi: 10.1097/HJH.0000000000000098 220. Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y,
205. Sandset EC, Bath PM, Boysen G, Jatuzis D, Kõrv J, Lüders S, Murray GD, Matsuzawa Y, Sasaki J, Oikawa S, Hishida H, et al; JELIS Investigators,
Richter PS, Roine RO, Terént A, et al; SCAST Study Group. The angioten- Japan. Reduction in the recurrence of stroke by eicosapentaenoic acid
sin-receptor blocker candesartan for treatment of acute stroke (SCAST): a for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke.
randomised, placebo-controlled, double-blind trial. Lancet. 2011;377:741– 2008;39:2052–2058. doi: 10.1161/STROKEAHA.107.509455
750. doi: 10.1016/S0140-6736(11)60104-9 221. Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, Braeckman
206. PATS Collaborating Group. Post-stroke antihypertensive treatment study: a RA, Soni PN. Eicosapentaenoic acid ethyl ester (AMR101) therapy
preliminary result. Chinese Med J. 1995;108:710–717. in patients with very high triglyceride levels (from the Multi-center, plA-
207. Zanchetti A, Liu L, Mancia G, Parati G, Grassi G, Stramba-Badiale M, cebo-controlled, Randomized, double-blINd, 12-week study with an open-
Silani V, Bilo G, Corrao G, Zambon A, et al. Blood pressure and LDL- label Extension [MARINE] trial). Am J Cardiol. 2011;108:682–690. doi:
cholesterol targets for prevention of recurrent strokes and cognitive 10.1016/j.amjcard.2011.04.015
decline in the hypertensive patient: design of the European Society of 222. Christian JB, Arondekar B, Buysman EK, Johnson SL, Seeger JD, Jacobson
Hypertension-Chinese Hypertension League Stroke in Hypertension TA. Clinical and economic benefits observed when follow-up triglyceride
Optimal Treatment randomized trial. J Hypertens. 2014;32:1888–1897. levels are less than 500 mg/dL in patients with severe hypertriglyceride-
doi: 10.1097/HJH.0000000000000254 mia. J Clin Lipidol. 2012;6:450–461. doi: 10.1016/j.jacl.2012.08.007
208. Amarenco P, Bogousslavsky J, Callahan A 3rd, Goldstein LB, Hennerici M, 223. Rhodes KS, Weintraub M, Marchlewicz EH, Rubenfire M, Brook RD.
Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, et al; Stroke Medical nutrition therapy is the essential cornerstone for effective treat-
Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) ment of “refractory” severe hypertriglyceridemia regardless of pharmaceu-
Investigators. High-dose atorvastatin after stroke or transient ischemic at- tical treatment: evidence from a lipid management program. J Clin Lipidol.
tack. N Engl J Med. 2006;355:549–559. doi: 10.1056/NEJMoa061894 2015;9:559–567. doi: 10.1016/j.jacl.2015.03.012
209. Callahan A, Amarenco P, Goldstein LB, Sillesen H, Messig M, Samsa GP, 224. Nicholls SJ, Lincoff AM, Garcia M, Bash D, Ballantyne CM, Barter PJ,
Altafullah I, Ledbetter LY, MacLeod MJ, Scott R, et al; SPARCL Investigators. Davidson MH, Kastelein JJP, Koenig W, McGuire DK, et al. Effect of high-
Risk of stroke and cardiovascular events after ischemic stroke or transient dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events
Downloaded from http://ahajournals.org by on June 12, 2021
ischemic attack in patients with type 2 diabetes or metabolic syndrome: in patients at high cardiovascular risk: the STRENGTH randomized clinical
secondary analysis of the Stroke Prevention by Aggressive Reduction in trial. JAMA. 2020;324:2268–2280. doi: 10.1001/jama.2020.22258
Cholesterol Levels (SPARCL) trial. Arch Neurol. 2011;68:1245–1251. doi: 225. Kalstad AA, Myhre PL, Laake K, Tveit SH, Schmidt EB, Smith P, Nilsen
10.1001/archneurol.2011.146 DWT, Tveit A, Fagerland MW, Solheim S, et al; OMEMI Investigators. Effects
210. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, Cabrejo L, of n-3 fatty acid supplements in elderly patients after myocardial infarc-
Cha JK, Ducrocq G, Giroud M, et al; Treat Stroke to Target Investigators. A tion: a randomized, controlled trial. Circulation. 2021;143:528–539. doi:
comparison of two LDL cholesterol targets after ischemic stroke. N Engl J 10.1161/CIRCULATIONAHA.120.052209
Med. 2020;382:9. doi: 10.1056/NEJMoa1910355 226. Brunzell JD, Schrott HG. The interaction of familial and secondary causes
211. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, of hypertriglyceridemia: role in pancreatitis. Trans Assoc Am Physicians.
Darius H, Lewis BS, Ophuis TO, Jukema JW, et al; IMPROVE-IT Investigators. 1973;86:245–254.
Ezetimibe added to statin therapy after acute coronary syndromes. N Engl 227. Wiggins BS, Saseen JJ, Page RL 2nd, Reed BN, Sneed K, Kostis
J Med. 2015;372:2387–2397. doi: 10.1056/NEJMoa1410489 JB, Lanfear D, Virani S, Morris PB; on behalf of the American Heart
212. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy Association Clinical Pharmacology Committee of the Council on Clinical
SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al; FOURIER Steering Cardiology; Council on Hypertension; Council on Quality of Care
Committee and Investigators. Evolocumab and clinical outcomes in pa- and Outcomes Research; and Council on Functional Genomics and
tients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722. Translational Biology. Recommendations for management of clinically
doi: 10.1056/NEJMoa1615664 significant drug-drug interactions with statins and select agents used
213. Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg in patients with cardiovascular disease: a scientific statement from the
JM, Goodman SG, Hanotin C, Harrington RA, et al; ODYSSEY OUTCOMES American Heart Association. Circulation. 2016;134:e468–e495. doi:
Committees and Investigators. Alirocumab and cardiovascular outcomes 10.1161/CIR.0000000000000456
after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107. doi: 228. Basar R, Uzum AK, Canbaz B, Dogansen SC, Kalayoglu-Besisik S,
10.1056/NEJMoa1801174 Altay-Dadin S, Aral F, Ozbey NC. Therapeutic apheresis for severe hypertri-
214. Chiavaroli L, Nishi SK, Khan TA, Braunstein CR, Glenn AJ, Mejia SB, glyceridemia in pregnancy. Arch Gynecol Obstet. 2013;287:839–843. doi:
Rahelić D, Kahleová H, Salas-Salvadó J, Jenkins DJA, et al. Portfolio di- 10.1007/s00404-013-2786-z
etary pattern and cardiovascular disease: a systematic review and meta- 229. Diabetes Control and Complications Trial Research Group. The effect of
analysis of controlled trials. Prog Cardiovasc Dis. 2018;61:43–53. doi: intensive treatment of diabetes on the development and progression of
10.1016/j.pcad.2018.05.004 long-term complications in insulin dependent diabetes mellitus. N Engl J
215. Benner JS, Tierce JC, Ballantyne CM, Prasad C, Bullano MF, Willey VJ, Med. 1993;329:977–986.
Erbey J, Sugano DS. Follow-up lipid tests and physician visits are asso- 230. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose
ciated with improved adherence to statin therapy. Pharmacoeconomics. control with sulphonylureas or insulin compared with conventional treat-
2004;22(suppl 3):13–23. doi: 10.2165/00019053-200422003-00003 ment and risk of complications in patients with type 2 diabetes (UKPDS
216. Bohula EA, Wiviott SD, Giugliano RP, Blazing MA, Park JG, Murphy SA, 33). Lancet. 1998;352:837–853.
White JA, Mach F, Van de Werf F, Dalby AJ, et al. Prevention of stroke 231. Gerstein HC, Calhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P,
with the addition of ezetimibe to statin therapy in patients with acute Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, et al. Dulaglutide and
coronary syndrome in IMPROVE-IT (Improved Reduction of Outcomes: cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind,
Vytorin Efficacy International Trial). Circulation. 2017;136:2440–2450. doi: randomized, placebo-controlled trial. Lancet. 2019;394:121–130. doi:
10.1161/CIRCULATIONAHA.117.029095 10.1016/S0140-6736(19)31149-3
232. Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger prediabetes: a randomised, double-blind trial. Lancet. 2017;389:1399–
CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, 1409. doi: 10.1016/S0140-6736(17)30069-7
CLINICAL STATEMENTS
et al; Harmony Outcomes Committees and Investigators. Albiglutide 248. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M,
AND GUIDELINES
and cardiovascular outcomes in patients with type 2 diabetes and Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, et al; IRIS Trial Investigators.
cardiovascular disease (Harmony Outcomes): a double-blind, ran- Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J
domised placebo-controlled trial. Lancet. 2018;392:1519–1529. doi: Med. 2016;374:1321–1331. doi: 10.1056/NEJMoa1506930
10.1016/S0140-6736(18)32261-X 249. Bullard KM, Cowie CC, Lessem SE, Saydah SH, Menke A, Geiss LS,
233. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay Orchard TJ, Rolka DB, Imperatore G. Prevalence of diagnosed diabetes
I, Rosenstock J, Seufert J, Warren ML, et al; SUSTAIN-6 Investigators. in adults by diabetes type–United States 2016. Morb Mortal Wkly Rep.
Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. 2018;67:359–361. doi: 10.15585/mmwr.mm6712a2
N Engl J Med. 2016;375:1834–1844. doi: 10.1056/NEJMoa1607141 250. Almdal T, Scharling H, Jensen JS, Vestergaard H. The independent ef-
234. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck fect of type 2 diabetes mellitus on ischemic heart disease, stroke, and
MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al; LEADER Steering death: a population-based study of 13,000 men and women with
Committee; LEADER Trial Investigators. Liraglutide and cardiovascular 20 years of follow-up. Arch Intern Med. 2004;164:1422–1426. doi:
outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322. doi: 10.1001/archinte.164.13.1422
10.1056/NEJMoa1603827 251. Banerjee C, Moon YP, Paik MC, Rundek T, Mora-McLaughlin C, Vieira
235. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw JR, Sacco RL, Elkind MS. Duration of diabetes and risk of ischemic
W, Law G, Desai M, Matthews D; CANVAS Program Collaborative Group. stroke: the Northern Manhattan Study. Stroke. 2012;43:1212–1217. doi:
Canagliflozin and cardiovascular and renal events in type 2 diabetes. N 10.1161/STROKEAHA.111.641381
Engl J Med. 2017;377:2099. doi: 10.1056/NEJMc1712572 252. Mitsios JP, Ekinci EI, Mitsios GP, Churilov L, Thijs V. Relationship between
236. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, glycated hemoglobin and stroke risk: a systematic review and meta-analy-
Mattheus M, Devins T, Johansen OE, Woerle HJ, et al; EMPA-REG sis. J Am Heart Assoc. 2018;7:e007858. doi: 10.1161/JAHA.117.00785
OUTCOME Investigators. Empagliflozin, cardiovascular outcomes and 253. Folsom AR, Rasmussen ML, Chambless LE, Howard G, Cooper LS, Schmidt
mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: MI, Heiss G. Prospective associations of fasting insulin, body fat distribu-
10.1056/NEJMoa1504720 tion, and diabetes with risk of ischemic stroke: the Atherosclerosis Risk in
237. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Communities (ARIC) study investigators. Diabetes Care. 1999;22:1077–
Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta A, 1083. doi: 10.2337/diacare.22.7.1077
Rastas M, et al; Finnish Diabetes Prevention Study Group. Prevention 254. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J,
of type 2 diabetes mellitus by changes in lifestyle among subjects with Coresh J, Brancati FL. Glycated hemoglobin, diabetes, and cardiovas-
impaired glucose tolerance. N Engl J Med. 2001;344:1343–1350. doi: cular risk in nondiabetic adults. N Engl J Med. 2010;362:800–811. doi:
10.1056/NEJM200105033441801 10.1056/NEJMoa0908359
238. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin 255. Kernan WN, Viscoli CM, Inzucchi SE, Brass LM, Bravata DM, Shulman GI,
JM, Walker EA, Nathan DM; Diabetes Prevention Program Research McVeety JC. Prevalence of abnormal glucose tolerance following a tran-
Group. Reduction in the incidence of type 2 diabetes with lifestyle in- sient ischemic attack or ischemic stroke. Arch Intern Med. 2005;165:227–
tervention or metformin. N Engl J Med. 2002;346:393–403. doi: 233. doi: 10.1001/archinte.165.2.227
10.1056/NEJMoa012512 256. Pan Y, Chen W, Wang Y. Prediabetes and outcome of ischemic stroke
239. ADVANCE Collaborative Group. Intensive blood glucose control and or transient ischemic attack: a systematic review and meta-analy-
vascular outcomes in patients with type 2 diabetes. N Engl J Med. sis. J Stroke Cerebrovasc Dis. 2019;28:683–692. doi: 10.1016/j.
Downloaded from http://ahajournals.org by on June 12, 2021
265. American Diabetes Association. 2: Classification and diagnosis of diabe- 282. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends
tes: standards of medical care in diabetes–2020. Diabetes Care. 2020;43 in obesity among adults in the United States, 2005 to 2014. JAMA.
CLINICAL STATEMENTS
(suppl 1):S14–S31. doi: 10.2337/dc20-S002 2016;315:2284–2291. doi: 10.1001/jama.2016.6458
AND GUIDELINES
266. American Geriatrics Society Expert Panel on Care of Older Adults With 283. Ward ZJ, Bleich SN, Cradock AL, Barrett JL, Giles CM, Flax C, Long
Diabetes Mellitus, Moreno G, Mangione CM, Kimbro L, Vaisberg E. MW, Gortmaker SL. Projected U.S. state-level prevalence of adult obe-
Guidelines abstracted from the American Geriatrics Society guidelines for sity and severe obesity. N Engl J Med. 2019;381:2440–2450. doi:
improving the care of older adults with diabetes mellitus: 2013 update. J 10.1056/NEJMsa1909301
Am Geriatr Soc. 2013;61:2020–2026. doi: 10.1111/jgs.12514 284. Suk SH, Sacco RL, Boden-Albala B, Cheun JF, Pittman JG, Elkind MS,
267. Qaseem A, Wilt TJ, Kansagara D, Horwitch C, Barry MJ, Forciea MA; Paik MC; Northern Manhattan Stroke Study. Abdominal obesity and
Clinical Guidelines Committee of the American College of Physicians. risk of ischemic stroke: the Northern Manhattan Stroke Study. Stroke.
Hemoglobin A1c targets for glycemic control with pharmacologic therapy 2003;34:1586–1592. doi: 10.1161/01.STR.0000075294.98582.2F
for nonpregnant adults with type 2 diabetes mellitus: a guidance state- 285. Ni Mhurchu C, Rodgers A, Pan WH, Gu DF, Woodward M; Asia Pacific
ment update from the American College of Physicians. Ann Intern Med. Cohort Studies Collaboration. Body mass index and cardiovascular disease
2018;168:569–576. doi: 10.7326/M17-0939 in the Asia-Pacific region: an overview of 33 cohorts involving 310,000
268. Inzucchi SE, Docherty K, Kober L, Kosiborod MN, Martinez F. Effect of participants. Int J Epidemiol. 2004;33:751–758. doi: 10.1093/ije/dyh163
dapagliflozin on the incidence of diabetes: a prespecified exploratory anal- 286. Bazzano LA, Gu D, Whelton MR, Wu X, Chen CS, Duan X, Chen J, Chen JC,
ysis from DAPA-HF. Paper presented at: American Diabetes Association He J. Body mass index and risk of stroke among Chinese men and women.
80th Scientific Sessions; 2020; virtual. Ann Neurol. 2010;67:11–20. doi: 10.1002/ana.21950
269. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Shulman GI, 287. Hu G, Tuomilehto J, Silventoinen K, Sarti C, Männistö S, Jousilahti P. Body
McVeety JC, Horwitz RI. Impaired insulin sensitivity among nondiabetic mass index, waist circumference, and waist-hip ratio on the risk of total
patients with a recent TIA or ischemic stroke. Neurology. 2003;60:1447– and type-specific stroke. Arch Intern Med. 2007;167:1420–1427. doi:
1451. doi: 10.1212/01.wnl.0000063318.66140.a3 10.1001/archinte.167.13.1420
270. Hishinuma A, Majima M, Kurabayashi H. Insulin resistance in pa- 288. Kurth T, Gaziano JM, Berger K, Kase CS, Rexrode KM, Cook NR, Buring
tients with stroke is related to visceral fat obesity and adipocyto- JE, Manson JE. Body mass index and the risk of stroke in men. Arch Intern
kines. J Stroke Cerebrovasc Dis. 2008;17:175–180. doi: 10.1016/j. Med. 2002;162:2557–2562. doi: 10.1001/archinte.162.22.2557
jstrokecerebrovasdis.2008.01.004 289. Kurth T, Gaziano JM, Rexrode KM, Kase CS, Cook NR, Manson JE,
271. Rundek T, Gardener H, Xu Q, Goldberg RB, Wright CB, Boden-Albala B, Disla Buring JE. Prospective study of body mass index and risk of stroke in
N, Paik MC, Elkind MS, Sacco RL. Insulin resistance and risk of ischemic apparently healthy women. Circulation. 2005;111:1992–1998. doi:
stroke among nondiabetic individuals from the Northern Manhattan Study. 10.1161/01.CIR.0000161822.83163.B6
Arch Neurol. 2010;67:1195–1200. doi: 10.1001/archneurol.2010.235 290. Kroll ME, Green J, Beral V, Sudlow CL, Brown A, Kirichek O, Price A, Yang
272. Thacker EL, Psaty BM, McKnight B, Heckbert SR, Longstreth WT Jr, TO, Reeves GK; Million Women Study Collaborators. Adiposity and ischemic
Mukamal KJ, Meigs JB, de Boer IH, Boyko EJ, Carnethon MR, et al. and hemorrhagic stroke: prospective study in women and meta-analysis.
Fasting and post-glucose load measures of insulin resistance and risk Neurology. 2016;87:1473–1481. doi: 10.1212/WNL.0000000000003171
of ischemic stroke in older adults. Stroke. 2011;42:3347–3351. doi: 291. Global Burden of Metabolic Risk Factors for Chronic Diseases
10.1161/STROKEAHA.111.620773 Collaboration (BMI Mediated Effects), Lu Y, Hajifathalian K, Ezzati
273. Hyvärinen M, Tuomilehto J, Mähönen M, Stehouwer CD, Pyörälä K, M, Woodward M, Rimm EB, Danaei G. Metabolic mediators of the effects
Zethelius B, Qiao Q; DECODE Study Group. Hyperglycemia and inci- of body-mass index, overweight, and obesity on coronary heart disease
dence of ischemic and hemorrhagic stroke: comparison between fast- and stroke: a pooled analysis of 97 prospective cohorts with 1·8 million
Downloaded from http://ahajournals.org by on June 12, 2021
ing and 2-hour glucose criteria. Stroke. 2009;40:1633–1637. doi: participants. Lancet. 2014;383:970–983.
10.1161/STROKEAHA.108.539650 292. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray
274. Lee M, Saver JL, Hong KS, Song S, Chang KH, Ovbiagele B. Effect of pre- GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, et al.
diabetes on future risk of stroke: meta-analysis. BMJ. 2012;344:e3564. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
doi: 10.1136/bmj.e3564 N Engl J Med. 2013;369:145–154. doi: 10.1056/NEJMoa1212914
275. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose 293. Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H,
intolerance and 22-year stroke incidence: the Honolulu Heart Program. Ahlin S, Anveden Å, Bengtsson C, Bergmark G, et al. Bariatric surgery
Stroke. 1994;25:951–957. doi: 10.1161/01.str.25.5.951 and long-term cardiovascular events. JAMA. 2012;307:56–65. doi:
276. Ikramuddin S, Korner J, Lee WJ, Connett JE, Inabnet WB, Billington CJ, 10.1001/jama.2011.1914
Thomas AJ, Leslie DB, Chong K, Jeffery RW, et al. Roux-en-Y gas- 294. Fisher DP, Johnson E, Haneuse S, Arterburn D, Coleman KJ, O’Connor
tric bypass vs intensive medical management for the control of type PJ, O’Brien R, Bogart A, Theis MK, Anau J, et al. Association between
2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery bariatric surgery and macrovascular disease outcomes in patients with
Study randomized clinical trial. JAMA. 2013;309:2240–2249. doi: type 2 diabetes and severe obesity. JAMA. 2018;320:1570–1582. doi:
10.1001/jama.2013.5835 10.1001/jama.2018.14619
277. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. 295. Kernan WN, Inzucchi SE, Sawan C, Macko RF, Furie KL. Obesity: a stub-
Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and bornly obvious target for stroke prevention. Stroke. 2013;44:278–286. doi:
hyperglycemia by moderate weight reduction in patients with type 2 diabe- 10.1161/STROKEAHA.111.639922
tes. Diabetes. 2005;54:603–608. doi: 10.2337/diabetes.54.3.603 296. Huang K, Liu F, Han X, Huang C, Huang J, Gu D, Yang X. Association
278. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, of BMI with total mortality and recurrent stroke among stroke patients: a
Thomas S, Abood B, Nissen SE, Bhatt DL. Bariatric surgery versus in- meta-analysis of cohort studies. Atherosclerosis. 2016;253:94–101. doi:
tensive medical therapy in obese patients with diabetes. N Engl J Med. 10.1016/j.atherosclerosis.2016.08.042
2012;366:1567–1576. doi: 10.1056/NEJMoa1200225 297. Aparicio HJ, Himali JJ, Beiser AS, Davis-Plourde KL, Vasan RS, Kase
279. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, Hill CS, Wolf PA, Seshadri S. Overweight, obesity, and survival after stroke in
JO, Brancati FL, Peters A, Wagenknecht L; Look AHEAD Research Group. the Framingham Heart Study. J Am Heart Assoc. 2017;6:e004721. doi:
Benefits of modest weight loss in improving cardiovascular risk factors 10.1161/JAHA.116.00472
in overweight and obese individuals with type 2 diabetes. Diabetes Care. 298. Lajous M, Banack HR, Kaufman JS, Hernan MA. Should patients with
2011;34:1481–1486. doi: 10.2337/dc10-2415 chronic disease be told to gain weight? The obesity paradox and selection
280. Jebb SA, Ahern AL, Olson AD, Aston LM, Holzapfel C, Stoll J, bias. Am J Med. 2015;128:334–336. doi: 10.1016/j.amjmed.2014.10.043
Amann-Gassner U, Simpson AE, Fuller NR, Pearson S, et al. Primary care 299. Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM,
referral to a commercial provider for weight loss treatment versus standard Nadolsky K, Pessah-Pollack R, Plodkowski R; Reviewers of the AACE/
care: a randomised controlled trial. Lancet. 2011;378:1485–1492. doi: ACE Obesity Clinical Practice Guidelines. American Association of Clinical
10.1016/S0140-6736(11)61344-5 Endocrinologists and American College of Endocrinology comprehensive
281. LeBlanc ES, Patnode CD, Webber EM, Redmond N, Rushkin M, O’Connor clinical practice guidelines for medical care of patients with obesity. Endocr
EA. Behavioral and pharmacotherapy weight loss interventions to prevent Pract. 2016;22(suppl 3):1–203. doi: 10.4158/EP161365.GL
obesity-related morbidity and mortality in adults: updated evidence report 300. US Preventive Services Task Force, Curry SJ, Krist AH, Owens DK, Barry
and systematic review for the US Preventive Services Task Force. JAMA. MJ, Caughey AB, Davidson KW, Doubeni CA, Epling JW Jr, Grossman
2018;320:1172–1191. doi: 10.1001/jama.2018.7777 DC, Kemper AR, et al. Behavioral weight loss interventions to prevent
obesity-related morbidity and mortality in adults: US Preventive Services 318. Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased
Task Force recommendation statement. JAMA. 2018;320:1163–1171. prevalence of sleep-disordered breathing in adults. Am J Epidemiol.
CLINICAL STATEMENTS
301. Moyer VA; U.S. Preventive Services Task Force. Screening for and man- 319. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V.
agement of obesity in adults: U.S. Preventive Services Task Force rec- Obstructive sleep apnea as a risk factor for stroke and death. N Engl J
ommendation statement. Ann Intern Med. 2012;157:373–378. doi: Med. 2005;353:2034–2041. doi: 10.1056/NEJMoa043104
10.7326/0003-4819-157-5-201209040-00475 320. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ,
302. Jonas DE, Amick HR, Feltner C, Weber RP, Arvanitis M, Stine A, Lux L, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered
Harris RP. Screening for obstructive sleep apnea in adults: evidence report breathing and cardiovascular disease: cross-sectional results of the Sleep
and systematic review for the US Preventive Services Task Force. JAMA. Heart Health Study. Am J Respir Crit Care Med. 2001;163:19–25. doi:
2017;317:415–433. doi: 10.1001/jama.2016.19635 10.1164/ajrccm.163.1.2001008
303. McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen 321. Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick
R, Drager LF, Liu Z, et al; SAVE Investigators and Coordinators. CPAP for HE, Diener-West M, Sanders MH, Wolf PA, Geraghty EM, et al.
prevention of cardiovascular events in obstructive sleep apnea. N Engl J Obstructive sleep apnea-hypopnea and incident stroke: the Sleep Heart
Med. 2016;375:919–931. doi: 10.1056/NEJMoa1606599 Health Study. Am J Respir Crit Care Med. 2010;182:269–277. doi:
304. Tsivgoulis G, Alexandrov AV, Katsanos AH, Barlinn K, Mikulik R, Lambadiari 10.1164/rccm.200911-1746OC
V, Bonakis A, Alexandrov AW. Noninvasive ventilatory correction in patients 322. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the associa-
with acute ischemic stroke: a systematic review and meta-analysis. Stroke. tion between sleep-disordered breathing and hypertension. N Engl J Med.
2017;48:2285–2288. doi: 10.1161/STROKEAHA.117.017661 2000;342:1378–1384. doi: 10.1056/NEJM200005113421901
305. Parra O, Sanchez-Armengol A, Bonnin M, Arboix A, Campos-Rodriguez F, 323. Johnson KG, Johnson DC. Frequency of sleep apnea in stroke and TIA
Perez-Ronchel J, Duran-Cantolla J, de la Torre G, Gonzalez Marcos JR, patients: a meta-analysis. J Clin Sleep Med. 2010;6:131–137.
de la Pena M, et al. Early treatment of obstructive apnoea and stroke out- 324. Mohsenin V. Obstructive sleep apnea: a new preventive and therapeutic
come: a randomized controlled trial. Eur Respir J. 2011;37:1128–1136. target for stroke: a new kid on the block. Am J Med. 2015;128:811–816.
doi: 10.1183/09031936.00034410 doi: 10.1016/j.amjmed.2015.01.037
306. Bravata DM, Sico J, Vaz Fragoso CA, Miech EJ, Matthias MS, Lampert R, 325. Seiler A, Camilo M, Korostovtseva L, Haynes AG, Brill AK, Horvath T,
Williams LS, Concato J, Ivan CS, Fleck JD, et al. Diagnosing and treating Egger M, Bassetti CL. Prevalence of sleep-disordered breathing after
sleep apnea in patients with acute cerebrovascular disease. J Am Heart stroke and TIA: a meta-analysis. Neurology. 2019;92:e648–e654. doi:
Assoc. 2018;7:e008841. doi: 10.1161/JAHA.118.008841 10.1212/WNL.0000000000006904
307. Gupta A, Shukla G, Afsar M, Poornima S, Pandey RM, Goyal V, Srivastava A, 326. Parra O, Arboix A, Bechich S, García-Eroles L, Montserrat JM, López JA,
Vibha D, Behari M. Role of positive airway pressure therapy for obstructive Ballester E, Guerra JM, Sopeña JJ. Time course of sleep-related breathing
sleep apnea in patients with stroke: a randomized controlled trial. J Clin disorders in first-ever stroke or transient ischemic attack. Am J Respir Crit
Sleep Med. 2018;14:511–521. doi: 10.5664/jcsm.7034 Care Med. 2000;161(pt 1):375–380. doi: 10.1164/ajrccm.161.2.9903139
308. Minnerup J, Ritter MA, Wersching H, Kemmling A, Okegwo A, Schmidt 327. Sahlin C, Sandberg O, Gustafson Y, Bucht G, Carlberg B, Stenlund H,
A, Schilling M, Ringelstein EB, Schäbitz WR, Young P, et al. Continuous Franklin KA. Obstructive sleep apnea is a risk factor for death in patients
positive airway pressure ventilation for acute ischemic stroke: a with stroke: a 10-year follow-up. Arch Intern Med. 2008;168:297–301.
randomized feasibility study. Stroke. 2012;43:1137–1139. doi: doi: 10.1001/archinternmed.2007.70
10.1161/STROKEAHA.111.637611 328. Birkbak J, Clark AJ, Rod NH. The effect of sleep disordered breathing on
309. Ryan CM, Bayley M, Green R, Murray BJ, Bradley TD. Influence of con- the outcome of stroke and transient ischemic attack: a systematic review.
Downloaded from http://ahajournals.org by on June 12, 2021
tinuous positive airway pressure on outcomes of rehabilitation in stroke J Clin Sleep Med. 2014;10:103–108. doi: 10.5664/jcsm.3376
patients with obstructive sleep apnea. Stroke. 2011;42:1062–1067. doi: 329. Turkington PM, Allgar V, Bamford J, Wanklyn P, Elliott MW. Effect of up-
10.1161/STROKEAHA.110.597468 per airway obstruction in acute stroke on functional outcome at 6 months.
310. Wessendorf TE, Wang YM, Thilmann AF, Sorgenfrei U, Konietzko N, Thorax. 2004;59:367–371. doi: 10.1136/thx.2003.005348
Teschler H. Treatment of obstructive sleep apnoea with nasal continuous 330. Qaseem A, Holty JE, Owens DK, Dallas P, Starkey M, Shekelle P; Clinical
positive airway pressure in stroke. Eur Respir J. 2001;18:623–629. doi: Guidelines Committee of the American College of Physicians. Management
10.1183/09031936.01.00057201 of obstructive sleep apnea in adults: a clinical practice guideline from the
311. Sandberg O, Franklin KA, Bucht G, Eriksson S, Gustafson Y. Nasal con- American College of Physicians. Ann Intern Med. 2013;159:471–483. doi:
tinuous positive airway pressure in stroke patients with sleep apnoea: 10.7326/0003-4819-159-7-201310010-00704
a randomized treatment study. Eur Respir J. 2001;18:630–634. doi: 331. Deleted in proofs.
10.1183/09031936.01.00070301 332. Takala M, Puustinen J, Rauhala E, Holm A. Pre-screening of sleep-
312. Bravata DM, Concato J, Fried T, Ranjbar N, Sadarangani T, McClain V, disordered breathing after stroke: a systematic review. Brain Behav.
Struve F, Zygmunt L, Knight HJ, Lo A, et al. Continuous positive airway 2018;8:e01146. doi: 10.1002/brb3.1146
pressure: evaluation of a novel therapy for patients with acute ischemic 333. Senaratna CV, Perret JL, Matheson MC, Lodge CJ, Lowe AJ, Cassim
stroke. Sleep. 2011;34:1271–1277. doi: 10.5665/SLEEP.1254 R, Russell MA, Burgess JA, Hamilton GS, Dharmage SC. Validity of the
313. Brill AK, Horvath T, Seiler A, Camilo M, Haynes AG, Ott SR, Egger M, Berlin questionnaire in detecting obstructive sleep apnea: a system-
Bassetti CL. CPAP as treatment of sleep apnea after stroke: a meta- atic review and meta-analysis. Sleep Med Rev. 2017;36:116–124. doi:
analysis of randomized trials. Neurology. 2018;90:e1222–e1230. doi: 10.1016/j.smrv.2017.04.001
10.1212/WNL.0000000000005262 334. Kapur VK, Auckley DH, Chowdhuri S, Kuhlmann DC, Mehra R, Ramar
314. Sandberg O, Franklin KA, Bucht G, Gustafson Y. Sleep apnea, delirium, K, Harrod CG. Clinical practice guideline for diagnostic testing for adult
depressed mood, cognition, and ADL ability after stroke. J Am Geriatr Soc. obstructive sleep apnea: an American Academy of Sleep Medicine
2001;49:391–397. doi: 10.1046/j.1532-5415.2001.49081.x clinical practice guideline. J Clin Sleep Med. 2017;13:479–504. doi:
315. Bravata DM, McClain V, Austin C, Ferguson J, Burrus N, Miech EJ, Matthias 10.5664/jcsm.6506
MS, Chumbler N, Ofner S, Foresman B, et al. Diagnosing and managing 335. Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, Frankel
sleep apnea in patients with chronic cerebrovascular disease: a random- MR, Levine SR, Chaturvedi S, Kasner SE, Benesch CG, et al; Warfarin-
ized trial of a home-based strategy. Sleep Breath. 2017;21:713–725. doi: Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison
10.1007/s11325-017-1494-5 of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl
316. Saletu MT, Kotzian ST, Schwarzinger A, Haider S, Spatt J, Saletu B. Sleep J Med. 2005;352:1305–1316. doi: 10.1056/NEJMoa043033
apnea testing is a feasible and accurate method to diagnose obstructive 336. Chimowitz MI, Lynn MJ, Derdeyn CP, Turan TN, Fiorella D, Lane BF, Janis LS,
sleep apnea in stroke patients during in-hospital rehabilitation. J Clin Sleep Lutsep HL, Barnwell SL, Waters MF, et al; SAMMPRIS Trial Investigators.
Med. 2018;14:1495–1501. doi: 10.5664/jcsm.7322 Stenting versus aggressive medical therapy for intracranial arterial steno-
317. Qaseem A, Dallas P, Owens DK, Starkey M, Holty JE, Shekelle P; Clinical sis. N Engl J Med. 2011;365:993–1003. doi: 10.1056/NEJMoa1105335
Guidelines Committee of the American College of Physicians. Diagnosis 337. Chaturvedi S, Turan TN, Lynn MJ, Kasner SE, Romano J, Cotsonis G,
of obstructive sleep apnea in adults: a clinical practice guideline from the Frankel M, Chimowitz MI; WASID Study Group. Risk factor status and vas-
American College of Physicians. Ann Intern Med. 2014;161:210–220. doi: cular events in patients with symptomatic intracranial stenosis. Neurology.
10.7326/M12-3187 2007;69:2063–2068. doi: 10.1212/01.wnl.0000279338.18776.26
338. Liu L, Wong KS, Leng X, Pu Y, Wang Y, Jing J, Zou X, Pan Y, Wang A, Meng 353. Derdeyn CP, Chimowitz MI, Lynn MJ, Fiorella D, Turan TN, Janis LS,
X, et al; CHANCE Investigators. Dual antiplatelet therapy in stroke and Montgomery J, Nizam A, Lane BF, Lutsep HL, et al; Stenting and Aggressive
CLINICAL STATEMENTS
ICAS: subgroup analysis of CHANCE. Neurology. 2015;85:1154–1162. Medical Management for Preventing Recurrent Stroke in Intracranial
AND GUIDELINES
doi: 10.1212/WNL.0000000000001972 Stenosis Trial Investigators. Aggressive medical treatment with or without
339. Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, Han Z, Tan stenting in high-risk patients with intracranial artery stenosis (SAMMPRIS):
KS, Ratanakorn D, Chollate P, et al; CLAIR Study Investigators. Clopidogrel the final results of a randomised trial. Lancet. 2014;383:333–341. doi:
plus aspirin versus aspirin alone for reducing embolisation in patients with 10.1016/S0140-6736(13)62038-3
acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a ran- 354. Miao Z, Jiang L, Wu H, Bao Y, Jiao L, Li S, Wu J, Hua Y, Li Y, Zhu J, et al.
domised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:489– Randomized controlled trial of symptomatic middle cerebral artery steno-
497. doi: 10.1016/S1474-4422(10)70060-0 sis: endovascular versus medical therapy in a Chinese population. Stroke.
340. Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson 2012;43:3284–3290. doi: 10.1161/STROKEAHA.112.662270
M, Ladenvall P, Molina CA, Wang Y, Johnston SC; THALES Steering 355. Zaidat OO, Fitzsimmons BF, Woodward BK, Wang Z, Killer-Oberpfalzer M,
Committee and Investigators. Ticagrelor added to aspirin in acute nonse- Wakhloo A, Gupta R, Kirshner H, Megerian JT, Lesko J, et al; VISSIT Trial
vere ischemic stroke or transient ischemic attack of atherosclerotic origin. Investigators. Effect of a balloon-expandable intracranial stent vs medical
Stroke. 2020;51:3504–3513. doi: 10.1161/STROKEAHA.120.032239 therapy on risk of stroke in patients with symptomatic intracranial stenosis:
341. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, Lee JH, Kim JS. the VISSIT randomized clinical trial. JAMA. 2015;313:1240–1248. doi:
Cilostazol prevents the progression of the symptomatic intracranial arterial 10.1001/jama.2015.1693
stenosis: the multicenter double-blind placebo-controlled trial of cilostazol 356. Lutsep HL, Lynn MJ, Cotsonis GA, Derdeyn CP, Turan TN, Fiorella D, Janis
in symptomatic intracranial arterial stenosis. Stroke. 2005;36:782–786. LS, Lane BF, Montgomery J, Chimowitz MI; SAMMPRIS Investigators.
doi: 10.1161/01.STR.0000157667.06542.b7 Does the stenting versus aggressive medical therapy trial support stenting
342. Kwon SU, Hong KS, Kang DW, Park JM, Lee JH, Cho YJ, Yu KH, Koo JS, for subgroups with intracranial stenosis? Stroke. 2015;46:3282–3284.
Wong KS, Lee SH, et al. Efficacy and safety of combination antiplatelet doi: 10.1161/STROKEAHA.115.009846
therapies in patients with symptomatic intracranial atherosclerotic stenosis. 357. Wabnitz AM, Derdeyn CP, Fiorella DJ, Lynn MJ, Cotsonis GA,
Stroke. 2011;42:2883–2890. doi: 10.1161/STROKEAHA.110.609370 Liebeskind DS, Waters MF, Lutsep H, Lopez-Cancio E, Turan TN, et
343. Uchiyama S, Sakai N, Toi S, Ezura M, Okada Y, Takagi M, Nagai Y, Matsubara al; SAMMPRIS Investigators. Hemodynamic markers in the ante-
Y, Minematsu K, Suzuki N, et al; CATHARSIS Study Group. Final results rior circulation as predictors of recurrent stroke in patients with intra-
of Cilostazol-Aspirin Therapy against Recurrent Stroke with Intracranial cranial stenosis [published online December 11, 2018]. Stroke. doi:
Artery Stenosis (CATHARSIS). Cerebrovasc Dis Extra. 2015;5:1–13. doi: 10.1161/STROKEAHA.118.020840.https://www.ahajournals.org/doi/10.1161/
10.1159/000369610 STROKEAHA.118.020840?url_ver=Z39.88-2003&rfr_id=ori:rid:
344. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, crossref.org&rfr_dat=cr_pub%20%200pubmed
Sakai N, Okada Y, Tanaka K, Origasa H, et al; CSPS.com Trial Investigators. 358. Compter A, van der Worp HB, Schonewille WJ, Vos JA, Boiten J,
Dual antiplatelet therapy using cilostazol for secondary prevention in Nederkoorn PJ, Uyttenboogaart M, Lo RT, Algra A, Kappelle LJ; VAST
patients with high-risk ischaemic stroke in Japan: a multicentre, open- Investigators. Stenting versus medical treatment in patients with symptom-
label, randomised controlled trial. Lancet Neurol. 2019;18:539–548. doi: atic vertebral artery stenosis: a randomised open-label phase 2 trial. Lancet
10.1016/S1474-4422(19)30148-6 Neurol. 2015;14:606–614. doi: 10.1016/S1474-4422(15)00017-4
345. Turan TN, Cotsonis G, Lynn MJ, Chaturvedi S, Chimowitz M; Warfarin- 359. Markus HS, Larsson SC, Kuker W, Schulz UG, Ford I, Rothwell PM, Clifton
Aspirin Symptomatic Intracranial Disease (WASID) Trial Investigators. A; VIST Investigators. Stenting for symptomatic vertebral artery stenosis:
Relationship between blood pressure and stroke recurrence in patients the Vertebral Artery Ischaemia Stenting Trial. Neurology. 2017;89:1229–
Downloaded from http://ahajournals.org by on June 12, 2021
with intracranial arterial stenosis. Circulation. 2007;115:2969–2975. doi: 1236. doi: 10.1212/WNL.0000000000004385
10.1161/CIRCULATIONAHA.106.622464 360. Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ,
346. Yu DD, Pu YH, Pan YS, Zou XY, Soo Y, Leung T, Liu LP, Wang DZ, Wong Hertzberg VS, Frankel MR, Levine SR, Chaturvedi S, Benesch CG, et
KS, Wang YL, et al; Chinese Intracranial Atherosclerosis (CICAS) Study al; Warfarin Aspirin Symptomatic Intracranial Disease Trial Investigators.
Group. High blood pressure increases the risk of poor outcome at dis- Predictors of ischemic stroke in the territory of a symptomatic intracra-
charge and 12-month follow-up in patients with symptomatic intracranial nial arterial stenosis. Circulation. 2006;113:555–563. doi: 10.1161/
large artery stenosis and occlusions: subgroup analysis of the CICAS Study. CIRCULATIONAHA.105.578229
CNS Neurosci Ther. 2015;21:530–535. doi: 10.1111/cns.12400 361. EC/IC Bypass Study Group. Failure of extracranial-intracranial arterial
347. Amin-Hanjani S, Turan TN, Du X, Pandey DK, Rose-Finnell L, Richardson D, bypass to reduce the risk of ischemic stroke. results of an international
Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, et al; VERiTAS Study Group. randomized trial. N Engl J Med. 1985;313:1191–1200. doi: 10.1056/
Higher stroke risk with lower blood pressure in hemodynamic vertebro- NEJM198511073131904
basilar disease: analysis from the VERiTAS study. J Stroke Cerebrovasc Dis. 362. Gorelick PB, Wong KS, Bae HJ, Pandey DK. Large artery intracranial oc-
2017;26:403–410. doi: 10.1016/j.jstrokecerebrovasdis.2016.09.044 clusive disease: a large worldwide burden but a relatively neglected frontier.
348. Park JM, Kim BJ, Kwon SU, Hwang YH, Heo SH, Rha JH, Lee J, Park Stroke. 2008;39:2396–2399. doi: 10.1161/STROKEAHA.107.505776
MS, Kim JT, Song HJ, et al. Intensive blood pressure control may not 363. Amin-Hanjani S, Pandey DK, Rose-Finnell L, Du X, Richardson D, Thulborn
be safe in subacute ischemic stroke by intracranial atherosclerosis: KR, Elkind MS, Zipfel GJ, Liebeskind DS, Silver FL, et al; Vertebrobasilar
a result of randomized trial. J Hypertens. 2018;36:1936–1941. doi: Flow Evaluation and Risk of Transient Ischemic Attack and Stroke Study
10.1097/HJH.0000000000001784 Group. Effect of hemodynamics on stroke risk in symptomatic atheroscle-
349. Zhou P, Lu Z, Gao P, Wang P, Cao Z, Zhang G, Wang S, Feng Y, Wang P. rotic vertebrobasilar occlusive disease. JAMA Neurol. 2016;73:178–185.
Efficacy and safety of intensive statin therapy in Chinese patients with doi: 10.1001/jamaneurol.2015.3772
atherosclerotic intracranial arterial stenosis: a single-center, randomized, 364. López-Cancio E, Matheus MG, Romano JG, Liebeskind DS, Prabhakaran
single-blind, parallel-group study with one-year follow-up. Clin Neurol S, Turan TN, Cotsonis GA, Lynn MJ, Rumboldt Z, Chimowitz MI. Infarct
Neurosurg. 2014;120:6–13. doi: 10.1016/j.clineuro.2014.02.001 patterns, collaterals and likely causative mechanisms of stroke in symp-
350. Alexander MJ, Zauner A, Chaloupka JC, Baxter B, Callison RC, Gupta R, tomatic intracranial atherosclerosis. Cerebrovasc Dis. 2014;37:417–422.
Song SS, Yu W; WEAVE Trial Sites and Interventionalists. WEAVE trial: doi: 10.1159/000362922
final results in 152 on-label patients. Stroke. 2019;50:889–894. doi: 365. Johnston SC, Elm JJ, Easton JD, Farrant M, Barsan WG, Kim AS, Lindblad
10.1161/STROKEAHA.118.023996 AS, Palesch YY, Zurita KG, Albers GW, et al; POINT and Neurological
351. Aghaebrahim A, Agnoletto GJ, Aguilar-Salinas P, Granja MF, Monteiro A, Emergencies Treatment Trials Network Investigators. Time course for
Siddiqui AH, Levy EI, Shallwani H, Kim SJ, Haussen DC, et al. Endovascular benefit and risk of clopidogrel and aspirin after acute transient ischemic
recanalization of symptomatic intracranial arterial stenosis despite aggres- attack and minor ischemic stroke. Circulation. 2019;140:658–664. doi:
sive medical management. World Neurosurg. 2019;123:e693–e699. doi: 10.1161/CIRCULATIONAHA.119.040713
10.1016/j.wneu.2018.12.008 366. US Food and Drug Administration. Use of the Stryker Wingspan stent sys-
352. Lutsep HL, Barnwell SL, Larsen DT, Lynn MJ, Hong M, Turan TN, Derdeyn tem outside of approved indications leads to an increased risk of stroke or
CP, Fiorella D, Janis LS, Chimowitz MI; SAMMPRIS Investigators. death: FDA Safety Communication. 2019. Accessed December 3, 2020.
Outcome in patients previously on antithrombotic therapy in the https://www.fda.gov/medical-devices/medical-device-safety/use-stryker-
SAMMPRIS trial: subgroup analysis. Stroke. 2015;46:775–779. doi: wingspan-stent-system-outside-approved-indications-leads-increased-
10.1161/STROKEAHA.114.007752 risk-stroke-or-death
367. US Food and Drug Administration. Rates of stroke and death: 522 post- double-blind, placebo-controlled trial. Lancet. 2004;364:331–337. doi:
market surveillance studies database. 2013. Accessed December 3, 10.1016/S0140-6736(04)16721-4
CLINICAL STATEMENTS
2020. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pss. 382. SPS3 Investigators; Benavente OR, Hart RG, McClure LA, Szychowski
AND GUIDELINES
cfm?t_id=297&c_id=762 JM, Coffey CS, Pearce LA. Effects of clopidogrel added to aspirin in pa-
368. Gröschel K, Schnaudigel S, Pilgram SM, Wasser K, Kastrup A. A systematic tients with recent lacunar stroke. N Engl J Med. 2012;367:817–825. doi:
review on outcome after stenting for intracranial atherosclerosis. Stroke. 10.1056/NEJMoa1204133
2009;40:e340–e347. doi: 10.1161/STROKEAHA.108.532713 383. Antithrombotic Trialists Collaboration; Baigent C, Blackwell L, Collins
369. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney
Warlow CP, Barnett HJ; Carotid Endarterectomy Trialists’ Collaboration. P, Meade T, et al. Aspirin in the primary and secondary prevention
Analysis of pooled data from the randomised controlled trials of endarter- of vascular disease: collaborative meta-analysis of individual partici-
ectomy for symptomatic carotid stenosis. Lancet. 2003;361:107–116. doi: pant data from randomised trials. Lancet. 2009;373:1849–1860. doi:
10.1016/s0140-6736(03)12228-3 10.1016/S0140-6736(09)60503-1
370. Barnett HJM, Taylor DW, Haynes RB, Sackett DL, Peerless SJ, Ferguson 384. Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim
GG, Fox AJ, Rankin RN, Hachinski VC, Wiebers DO, et al. Beneficial effect AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological
of carotid endarterectomy in symptomatic patients with high-grade carotid Emergencies Treatment Trials Network, and the POINT Investigators.
stenosis. N Engl J Med. 1991;325:445–453. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl
371. Howard G, Roubin GS, Jansen O, Hendrikse J, Halliday A, Fraedrich G, J Med. 2018;379:215–225. doi: 10.1056/NEJMoa1800410
Eckstein HH, Calvet D, Bulbulia R, Bonati LH, et al; Carotid Stenting 385. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of ran-
Trialists’ Collaboration. Association between age and risk of stroke or domised trials of antiplatelet therapy for prevention of death, myocardial
death from carotid endarterectomy and carotid stenting: a meta-analysis of infarction, and stroke in high risk patients. BMJ. 2002;324:71–86. doi:
pooled patient data from four randomised trials. Lancet. 2016;387:1305– 10.1136/bmj.324.7329.7
1311. doi: 10.1016/S0140-6736(15)01309-4 386. Amarenco P, Duyckaerts C, Tzourio C, Hénin D, Bousser MG, Hauw JJ. The
372. Rantner B, Kollerits B, Roubin GS, Ringleb PA, Jansen O, Howard G, prevalence of ulcerated plaques in the aortic arch in patients with stroke. N
Hendrikse J, Halliday A, Gregson J, Eckstein HH, et al; Carotid Stenosis Engl J Med. 1992;326:221–225. doi: 10.1056/NEJM199201233260402
Trialists’ Collaboration. Early endarterectomy carries a lower procedural 387. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G,
risk than early stenting in patients with symptomatic stenosis of the in- Chauvel C, Touboul PJ, Bousser MG. Atherosclerotic disease of the aortic
ternal carotid artery: results from 4 randomized controlled trials. Stroke. arch and the risk of ischemic stroke. N Engl J Med. 1994;331:1474–1479.
2017;48:1580–1587. doi: 10.1161/STROKEAHA.116.016233 doi: 10.1056/NEJM199412013312202
373. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ; Carotid 388. Di Tullio MR, Russo C, Jin Z, Sacco RL, Mohr JP, Homma S; Patent Foramen
Endarterectomy Trialists Collaboration. Endarterectomy for symptomatic Ovale in Cryptogenic Stroke Study Investigators. Aortic arch plaques and
carotid stenosis in relation to clinical subgroups and timing of surgery. risk of recurrent stroke and death. Circulation. 2009;119:2376–2382. doi:
Lancet. 2004;363:915–924. doi: 10.1016/S0140-6736(04)15785-1 10.1161/CIRCULATIONAHA.108.811935
374. Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, 389. Cohen A, Tzourio C, Bertrand B, Chauvel C, Bousser MG, Amarenco P.
Bajwa TK, Whitlow P, Strickman NE, Jaff MR, et al; Stenting and Aortic plaque morphology and vascular events: a follow-up study in patients
Angioplasty with Protection in Patients at High Risk for Endarterectomy with ischemic stroke: FAPS Investigators: French Study of Aortic Plaques in
Investigators. Protected carotid-artery stenting versus endarterec- Stroke. Circulation. 1997;96:3838–3841. doi: 10.1161/01.cir.96.11.3838
tomy in high-risk patients. N Engl J Med. 2004;351:1493–1501. doi: 390. Amarenco P, Cohen A, Hommel M, Moulin T, Leys D, Bousser MG.
10.1056/NEJMoa040127 Atherosclerotic disease of the aortic arch as a risk factor for recurrent
Downloaded from http://ahajournals.org by on June 12, 2021
375. Brott TG, Hobson RW 2nd, Howard G, Roubin GS, Clark WM, Brooks W, ischemic stroke. N Engl J Med. 1996;334:1216–1221.
Mackey A, Hill MD, Leimgruber PP, Sheffet AJ, et al; CREST Investigators. 391. Deng X, Gao F, Zhang D, Zhang Y, Wang R, Wang S, Cao Y, Zhao Y, Pan
Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Y, Liu X, et al. Direct versus indirect bypasses for adult ischemic-type
Engl J Med. 2010;363:11–23. doi: 10.1056/NEJMoa0912321 moyamoya disease: a propensity score-matched analysis. J Neurosurg.
376. Schermerhorn ML, Liang P, Eldrup-Jorgensen J, Cronenwett JL, Nolan 2018;128:1785–1791. doi: 10.3171/2017.2.JNS162405
BW, Kashyap VS, Wang GJ, Motaganahalli RL, Malas MB. Association of 392. Deng X, Gao F, Zhang D, Zhang Y, Wang R, Wang S, Cao Y, Zhao Y, Pan
transcarotid artery revascularization vs transfemoral carotid artery stenting Y, Ye X, et al. Effects of different surgical modalities on the clinical out-
with stroke or death among patients with carotid artery stenosis. JAMA. come of patients with moyamoya disease: a prospective cohort study. J
2019;322:2313–2322. doi: 10.1001/jama.2019.18441 Neurosurg. 2018;128:1327–1337. doi: 10.3171/2016.12.JNS162626
377. Powers WJ, Clarke WR, Grubb RL Jr, Videen TO, Adams HP Jr, Derdeyn 393. Jeon JP, Kim JE, Cho WS, Bang JS, Son YJ, Oh CW. Meta-analysis of
CP; COSS Investigators. Extracranial-intracranial bypass surgery for stroke the surgical outcomes of symptomatic moyamoya disease in adults. J
prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Neurosurg. 2018;128:793–799. doi: 10.3171/2016.11.JNS161688
Surgery Study randomized trial. JAMA. 2011;306:1983–1992. doi: 394. Li Q, Gao Y, Xin W, Zhou Z, Rong H, Qin Y, Li K, Zhou Y, Wang J, Xiong
10.1001/jama.2011.1610 J, et al. Meta-analysis of prognosis of different treatments for symptom-
377a. Amarenco P, Kim JS, Labreuche J, Charles H, Abtan J, Béjot Y, Cabrejo L, atic moyamoya disease. World Neurosurg. 2019;127:354–361. doi:
Cha JK, Ducrocq G, Giroud M, et al; Treat Stroke to Target Investigators. A 10.1016/j.wneu.2019.04.062
comparison of two LDL cholesterol targets after ischemic stroke. N Engl J 395. Sun H, Wilson C, Ozpinar A, Safavi-Abbasi S, Zhao Y, Nakaji P, Wanebo
Med. 2020;382:9. doi: 10.1056/NEJMoa1910355 JE, Spetzler RF. Perioperative complications and long-term outcomes
378. Markus HS, Harshfield EL, Compter A, Kuker W, Kappelle LJ, Clifton after bypasses in adults with moyamoya disease: a systematic re-
A, van der Worp HB, Rothwell P, Algra A; Vertebral Stenosis Trialists’ view and meta-analysis. World Neurosurg. 2016;92:179–188. doi:
Collaboration. Stenting for symptomatic vertebral artery stenosis: a 10.1016/j.wneu.2016.04.083
preplanned pooled individual patient data analysis. Lancet Neurol. 396. Kim H, Jang DK, Han YM, Sung JH, Park IS, Lee KS, Yang JH, Huh PW,
2019;18:666–673. doi: 10.1016/S1474-4422(19)30149-8 Park YS, Kim DS, et al. Direct bypass versus indirect bypass in adult moy-
379. Hanel RA, Brasiliense LB, Spetzler RF. Microsurgical revasculariza- amoya angiopathy with symptoms or hemodynamic instability: a meta-
tion of proximal vertebral artery: a single-center, single-operator analy- analysis of comparative studies. World Neurosurg. 2016;94:273–284. doi:
sis. Neurosurgery. 2009;64:1043–1050. doi: 10.1227/01.NEU. 10.1016/j.wneu.2016.07.009
0000347099.17437.64 397. Jang DK, Lee KS, Rha HK, Huh PW, Yang JH, Park IS, Ahn JG, Sung
380. Amarenco P, Davis S, Jones EF, Cohen AA, Heiss WD, Kaste M, Laouénan JH, Han YM. Bypass surgery versus medical treatment for symptom-
C, Young D, Macleod M, Donnan GA; Aortic Arch Related Cerebral Hazard atic moyamoya disease in adults. J Neurosurg. 2017;127:492–502. doi:
Trial Investigators. Clopidogrel plus aspirin versus warfarin in patients 10.3171/2016.8.JNS152875
with stroke and aortic arch plaques. Stroke. 2014;45:1248–1257. doi: 398. Yamada S, Oki K, Itoh Y, Kuroda S, Houkin K, Tominaga T, Miyamoto S,
10.1161/STROKEAHA.113.004251 Hashimoto N, Suzuki N; Research Committee on Spontaneous Occlusion
381. Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, of Circle of Willis (Moyamoya Disease). Effects of surgery and antiplate-
Leys D, Matias-Guiu J, Rupprecht HJ; MATCH Investigators. Aspirin and let therapy in ten-year follow-up from the registry study of Research
clopidogrel compared with clopidogrel alone after recent ischaemic stroke Committee on Moyamoya Disease in Japan. J Stroke Cerebrovasc Dis.
or transient ischaemic attack in high-risk patients (MATCH): randomised, 2016;25:340–349. doi: 10.1016/j.jstrokecerebrovasdis.2015.10.003
399. Qian C, Yu X, Li J, Chen J, Wang L, Chen G. The efficacy of surgical treat- 418. Smith EE, Saposnik G, Biessels GJ, Doubal FN, Fornage M, Gorelick
ment for the secondary prevention of stroke in symptomatic moyamoya PB, Greenberg SM, Higashida RT, Kasner SE, Seshadri S; on be-
CLINICAL STATEMENTS
disease: a meta-analysis. Medicine (Baltimore). 2015;94:e2218. doi: half of the American Heart Association Stroke Council; Council on
AND GUIDELINES
10.1097/MD.0000000000002218 Cardiovascular Radiology and Intervention; Council on Functional
400. Onozuka D, Hagihara A, Nishimura K, Kada A, Nakagawara J, Ogasawara Genomics and Translational Biology; and Council on Hypertension.
K, Ono J, Shiokawa Y, Aruga T, Miyachi S, et al; J-ASPECT Study Prevention of stroke in patients with silent cerebrovascular disease: a sci-
Collaborators. Prehospital antiplatelet use and functional status on ad- entific statement for healthcare professionals from the American Heart
mission of patients with non-haemorrhagic moyamoya disease: a na- Association/American Stroke Association. Stroke. 2017;48:e44–e71. doi:
tionwide retrospective cohort study (J-ASPECT study). BMJ Open. 10.1161/STR.0000000000000116
2016;6:e009942. doi: 10.1136/bmjopen-2015-009942 419. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in
401. Zhao Y, Zhang Q, Zhang D, Zhao Y. Effect of aspirin in postoperative Atrial Fibrillation study: final results. Circulation. 1991;84:527–39.
management of adult ischemic moyamoya disease. World Neurosurg. 420. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk
2017;105:728–731. doi: 10.1016/j.wneu.2017.06.057 stratification for predicting stroke and thromboembolism in atrial fibrillation
402. Acker G, Goerdes S, Schneider UC, Schmiedek P, Czabanka M, Vajkoczy using a novel risk factor-based approach: the Euro Heart Survey on Atrial
P. Distinct clinical and radiographic characteristics of moyamoya disease Fibrillation. Chest. 2010;137:263–272. doi: 10.1378/chest.09-1584
amongst European Caucasians. Eur J Neurol. 2015;22:1012–1017. doi: 421. Mason PK, Lake DE, DiMarco JP, Ferguson JD, Mangrum JM, Bilchick
10.1111/ene.12702 K, Moorman LP, Moorman JR. Impact of the CHA2DS2-VASc score
403. Baba T, Houkin K, Kuroda S. Novel epidemiological features of moy- on anticoagulation recommendations for atrial fibrillation. Am J Med.
amoya disease. J Neurol Neurosurg Psychiatry. 2008;79:900–904. doi: 2012;125:603.e1–603.e6. doi: 10.1016/j.amjmed.2011.09.030
10.1136/jnnp.2007.130666 422. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the
404. Research Committee on the Pathology and Treatment of Spontaneous CHA2DS2-VASc score for refining stroke risk stratification in patients
Occlusion of the Circle of Willis. Guidelines for diagnosis and treatment of with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study.
moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Thromb Haemost. 2012;107:1172–1179. doi: 10.1160/TH12-03-0175
Med Chir (Tokyo). 2012;52:245–266. doi: 10.2176/nmc.52.245 423. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh
405. Miyamoto S, Yoshimoto T, Hashimoto N, Okada Y, Tsuji I, Tominaga T, A, Pogue J, Reilly PA, Themeles E, Varrone J, et al; RE-LY Steering
Nakagawara J, Takahashi JC; JAM Trial Investigators. Effects of extracra- Committee and Investigators. Dabigatran versus warfarin in patients
nial-intracranial bypass for patients with hemorrhagic moyamoya disease: with atrial fibrillation. N Engl J Med. 2009;361:1139–1151. doi:
results of the Japan Adult Moyamoya Trial. Stroke. 2014;45:1415–1421. 10.1056/NEJMoa0905561
doi: 10.1161/STROKEAHA.113.004386 424. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt
406. Kim DY, Son JP, Yeon JY, Kim GM, Kim JS, Hong SC, Bang OY. Infarct G, Halperin JL, Hankey GJ, Piccini JP, et al; ROCKET AF Investigators.
pattern and collateral status in adult moyamoya disease: a multimodal Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
magnetic resonance imaging study. Stroke. 2017;48:111–116. doi: 2011;365:883–891. doi: 10.1056/NEJMoa1009638
10.1161/STROKEAHA.116.014529 425. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M,
407. Kraemer M, Berlit P, Diesner F, Khan N. What is the expert’s option on an- Al-Khalidi HR, Ansell J, Atar D, Avezum A, et al; ARISTOTLE Committees
tiplatelet therapy in moyamoya disease? Results of a worldwide survey. Eur and Investigators. Apixaban versus warfarin in patients with atrial fibrilla-
J Neurol. 2012;19:163–167. doi: 10.1111/j.1468-1331.2011.03481.x tion. N Engl J Med. 2011;365:981–992. doi: 10.1056/NEJMoa1107039
408. Benavente OR, White CL, Pearce L, Pergola P, Roldan A, Benavente MF, 426. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL,
Coffey C, McClure LA, Szychowski JM, Conwit R, et al; SPS3 Investigators. Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, et al; ENGAGE AF-TIMI 48
Downloaded from http://ahajournals.org by on June 12, 2021
The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N
Stroke. 2011;6:164–175. doi: 10.1111/j.1747-4949.2010.00573.x Engl J Med. 2013;369:2093–2104. doi: 10.1056/NEJMoa1310907
409. Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao 427. Healey JS, Connolly SJ, Gold MR, Israel CW, Van Gelder IC, Capucci A, Lau
X, Meurer WJ, et al. Outcomes associated with clopidogrel-aspirin use in CP, Fain E, Yang S, Bailleul C, et al; ASSERT Investigators. Subclinical atrial
minor stroke or transient ischemic attack: a pooled analysis of Clopidogrel fibrillation and the risk of stroke. N Engl J Med. 2012;366:120–129. doi:
in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events 10.1056/NEJMoa1105575
(CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor 428. Hart RG, Coull BM, Hart D. Early recurrent embolism associated with non-
Ischemic Stroke (POINT) Trials. JAMA Neurol. 2019;76:1466–1473. doi: valvular atrial fibrillation: a retrospective study. Stroke. 1983;14:688–693.
10.1001/jamaneurol.2019.2531 doi: 10.1161/01.str.14.5.688
410. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, 429. Seiffge DJ, Werring DJ, Paciaroni M, Dawson J, Warach S, Milling TJ,
Cui L, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor Engelter ST, Fischer U, Norrving B. Timing of anticoagulation after re-
stroke or transient ischemic attack. N Engl J Med. 2013;369:11–19. doi: cent ischaemic stroke in patients with atrial fibrillation. Lancet Neurol.
10.1056/NEJMoa1215340 2019;18:117–126. doi: 10.1016/S1474-4422(18)30356-9
411. Deleted in proofs. 430. Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, Caso V,
412. Bamford J, Sandercock P, Jones L, Warlow C. The natural history of la- Micheli S, Bertolani L, Venti M, et al. Early hemorrhagic transformation of
cunar infarction: the Oxfordshire Community Stroke Project. Stroke. brain infarction: rate, predictive factors, and influence on clinical outcome:
1987;18:545–551. doi: 10.1161/01.str.18.3.545 results of a prospective multicenter study. Stroke. 2008;39:2249–2256.
413. Jackson C, Sudlow C. Comparing risks of death and recurrent vascular doi: 10.1161/STROKEAHA.107.510321
events between lacunar and non-lacunar infarction. Brain. 2005;128(pt 431. Ahmed N, Steiner T, Caso V, Wahlgren N; ESO-KSU Session Participants.
11):2507–2517. doi: 10.1093/brain/awh636 Recommendations from the ESO-Karolinska Stroke Update Conference,
414. Jacova C, Pearce LA, Costello R, McClure LA, Holliday SL, Hart RG, Stockholm 13-15 November 2016. Eur Stroke J. 2017;2:95–102. doi:
Benavente OR. Cognitive impairment in lacunar strokes: the SPS3 trial. 10.1177/2396987317699144
Ann Neurol. 2012;72:351–362. doi: 10.1002/ana.23733 432. Blackshear JL, Odell JA. Appendage obliteration to reduce stroke in cardi-
415. Makin SD, Turpin S, Dennis MS, Wardlaw JM. Cognitive impairment after ac surgical patients with atrial fibrillation. Ann Thorac Surg. 1996;61:755–
lacunar stroke: systematic review and meta-analysis of incidence, prev- 759. doi: 10.1016/0003-4975(95)00887-X
alence and comparison with other stroke subtypes. J Neurol Neurosurg 433. Holmes DR Jr, Kar S, Price MJ, Whisenant B, Sievert H, Doshi SK, Huber K,
Psychiatry. 2013;84:893–900. doi: 10.1136/jnnp-2012-303645 Reddy VY. Prospective randomized evaluation of the Watchman left atrial
416. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, Shinohara Y, appendage closure device in patients with atrial fibrillation versus long-
Itoh E, Matsuda T, Sawada T, et al. Cilostazol stroke prevention study: a term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64:1–12.
placebo-controlled double-blind trial for secondary prevention of ce- doi: 10.1016/j.jacc.2014.04.029
rebral infarction. J Stroke Cerebrovasc Dis. 2000;9:147–157. doi: 434. Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin
10.1053/jscd.2000.7216 CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the
417. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka left atrial appendage versus warfarin therapy for prevention of stroke in
K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, et al; CSPS 2 Group. patients with atrial fibrillation: a randomised non-inferiority trial. Lancet.
Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin- 2009;374:534–542. doi: 10.1016/S0140-6736(09)61343-X
controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 435. Reddy VY, Doshi SK, Kar S, Gibson DN, Price MJ, Huber K, Horton RP,
2010;9:959–968. doi: 10.1016/S1474-4422(10)70198-8 Buchbinder M, Neuzil P, Gordon NT, et al; PREVAIL and PROTECT AF
Investigators. 5-Year outcomes after left atrial appendage closure: from Association practical guide on the use of non-vitamin K antagonist oral an-
the PREVAIL and PROTECT AF trials. J Am Coll Cardiol. 2017;70:2964– ticoagulants in patients with atrial fibrillation: executive summary. Europace.
CLINICAL STATEMENTS
436. Reddy VY, Sievert H, Halperin J, Doshi SK, Buchbinder M, Neuzil P, Huber 451. Muscari A, Faccioli L, Lega MV, Lorusso A, Masetti M, Pastore Trossello M,
K, Whisenant B, Kar S, Swarup V, et al; PROTECT AF Steering Committee Puddu GM, Spinardi L, Zoli M. Predicting hemorrhagic transformation and
and Investigators. Percutaneous left atrial appendage closure vs warfarin its timing from maximum cerebral lesion diameter in nonlacunar ischemic
for atrial fibrillation: a randomized clinical trial. JAMA. 2014;312:1988– strokes. Brain Behav. 2020;10:e01497. doi: 10.1002/brb3.1497
1998. doi: 10.1001/jama.2014.15192 452. Pan KL, Singer DE, Ovbiagele B, Wu YL, Ahmed MA, Lee M. Effects
437. Abdul-Rahim AH, Fulton RL, Frank B, Tatlisumak T, Paciaroni M, Caso of non-vitamin K antagonist oral anticoagulants versus warfarin in
V, Diener HC, Lees KR; VISTA Collaborators. Association of improved patients with atrial fibrillation and valvular heart disease: a system-
outcome in acute ischaemic stroke patients with atrial fibrillation who atic review and meta-analysis. J Am Heart Assoc. 2017;6:e005835. doi:
receive early antithrombotic therapy: analysis from VISTA. Eur J Neurol. 10.1161/JAHA.117.005835
2015;22:1048–1055. doi: 10.1111/ene.12577 453. Avezum A, Lopes RD, Schulte PJ, Lanas F, Gersh BJ, Hanna M, Pais P,
438. Siontis KC, Zhang X, Eckard A, Bhave N, Schaubel DE, He K, Tilea A, Erol C, Diaz R, Bahit MC, et al. Apixaban in comparison with warfarin in
Stack AG, Balkrishnan R, Yao X, et al. Outcomes associated with apix- patients with atrial fibrillation and valvular heart disease: findings from the
aban use in patients with end-stage kidney disease and atrial fibril- Apixaban for Reduction in Stroke and Other Thromboembolic Events in
lation in the United States. Circulation. 2018;138:1519–1529. doi: Atrial Fibrillation (ARISTOTLE) Trial. Circulation. 2015;132:624–632. doi:
10.1161/CIRCULATIONAHA.118.035418 10.1161/CIRCULATIONAHA.114.014807
439. Gage BF, van Walraven C, Pearce L, Hart RG, Koudstaal PJ, Boode 454. Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP,
BS, Petersen P. Selecting patients with atrial fibrillation for antico- Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, et al;
agulation: stroke risk stratification in patients taking aspirin. Circulation. ROCKET AF Steering Committee & Investigators. Clinical characteristics
2004;110:2287–2292. doi: 10.1161/01.CIR.0000145172.55640.93 and outcomes with rivaroxaban vs. warfarin in patients with non-valvular
440. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. atrial fibrillation but underlying native mitral and aortic valve disease par-
Validation of clinical classification schemes for predicting stroke: results ticipating in the ROCKET AF trial. Eur Heart J. 2014;35:3377–3385. doi:
from the National Registry of Atrial Fibrillation. JAMA. 2001;285:2864– 10.1093/eurheartj/ehu305
2870. doi: 10.1001/jama.285.22.2864 455. Pérez-Gómez F, Alegría E, Berjón J, Iriarte JA, Zumalde J, Salvador A,
441. Gürdoğan M, Ari H, Tenekecioğlu E, Ari S, Bozat T, Koca V, Melek M. Mataix L; NASPEAF Investigators. Comparative effects of antiplatelet,
Predictors of atrial fibrillation recurrence in hyperthyroid and euthyroid pa- anticoagulant, or combined therapy in patients with valvular and nonval-
tients. Arq Bras Cardiol. 2016;106:84–91. doi: 10.5935/abc.20160013 vular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol.
442. Lowres N, Mulcahy G, Jin K, Gallagher R, Neubeck L, Freedman B. 2004;44:1557–1566. doi: 10.1016/j.jacc.2004.05.084
Incidence of postoperative atrial fibrillation recurrence in patients dis- 456. Ezekowitz MD, Nagarakanti R, Noack H, Brueckmann M, Litherland C,
charged in sinus rhythm after cardiac surgery: a systematic review and Jacobs M, Clemens A, Reilly PA, Connolly SJ, Yusuf S, et al. Comparison
meta-analysis. Interact Cardiovasc Thorac Surg. 2018;26:504–511. doi: of dabigatran and warfarin in patients with atrial fibrillation and val-
10.1093/icvts/ivx348 vular heart disease: the RE-LY Trial (Randomized Evaluation of Long-
443. Park-Hansen J, Greve AM, Clausen J, Holme SJ, Carranza CL, Term Anticoagulant Therapy). Circulation. 2016;134:589–598. doi:
Irmukhamedov A, Sabah L, Lin Q, Madsen AS, Domínguez H. New- 10.1161/CIRCULATIONAHA.115.020950
onset of postoperative atrial fibrillation is likely to recur in the absence 457. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein
of other triggers. Ther Clin Risk Manag. 2018;14:1641–1647. doi: AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, et al;
Downloaded from http://ahajournals.org by on June 12, 2021
Cardiovascular Surgery and Anesthesia, American Heart Association: en- 479. Kizer JR, Wiebers DO, Whisnant JP, Galloway JM, Welty TK, Lee ET, Best
dorsed by the Infectious Diseases Society of America [published correc- LG, Resnick HE, Roman MJ, Devereux RB. Mitral annular calcification, aor-
CLINICAL STATEMENTS
tion appears in Circulation. 2005;112:2373, Circulation. 2007;115:e408, tic valve sclerosis, and incident stroke in adults free of clinical cardiovas-
AND GUIDELINES
Circulation. 2007;116:e547, and Circulation. 2008;118:e497]. Circulation. cular disease: the Strong Heart Study. Stroke. 2005;36:2533–2537. doi:
2005;111:e394–e434. doi: 10.1161/CIRCULATIONAHA.105.165564 10.1161/01.STR.0000190005.09442.ad
464. Kang DH, Kim YJ, Kim SH, Sun BJ, Kim DH, Yun SC, Song JM, Choo 480. Orencia AJ, Petty GW, Khandheria BK, O’Fallon WM, Whisnant JP.
SJ, Chung CH, Song JK, et al. Early surgery versus conventional treat- Mitral valve prolapse and the risk of stroke after initial cerebral ischemia.
ment for infective endocarditis. N Engl J Med. 2012;366:2466–2473. doi: Neurology. 1995;45:1083–1086. doi: 10.1212/wnl.45.6.1083
10.1056/NEJMoa1112843 481. Nishimura RA, McGoon MD, Shub C, Miller FA Jr, Ilstrup DM, Tajik AJ.
465. Thuny F, Di Salvo G, Disalvo G, Belliard O, Avierinos JF, Pergola V, Echocardiographically documented mitral-valve prolapse: long-term
Rosenberg V, Casalta JP, Gouvernet J, Derumeaux G, et al. Risk of embo- follow-up of 237 patients. N Engl J Med. 1985;313:1305–1309. doi:
lism and death in infective endocarditis: prognostic value of echocardiog- 10.1056/NEJM198511213132101
raphy: a prospective multicenter study. Circulation. 2005;112:69–75. doi: 482. Hayek E, Griffin B. Mitral valve prolapse: old beliefs yield to new knowl-
10.1161/CIRCULATIONAHA.104.493155 edge. Cleve Clin J Med. 2002;69:889–896. doi: 10.3949/ccjm.69.11.889
466. Eishi K, Kawazoe K, Kuriyama Y, Kitoh Y, Kawashima Y, Omae T. Surgical 483. Zuppiroli A, Rinaldi M, Kramer-Fox R, Favilli S, Roman MJ, Devereux RB.
management of infective endocarditis associated with cerebral complica- Natural history of mitral valve prolapse. Am J Cardiol. 1995;75:1028–
tions: multi-center retrospective study in Japan. J Thorac Cardiovasc Surg. 1032. doi: 10.1016/s0002-9149(99)80718-8
1995;110:1745–1755. doi: 10.1016/S0022-5223(95)70038-2 484. Benjamin EJ, Plehn JF, D’Agostino RB, Belanger AJ, Comai K, Fuller
467. Barsic B, Dickerman S, Krajinovic V, Pappas P, Altclas J, Carosi G, Casabé DL, Wolf PA, Levy D. Mitral annular calcification and the risk of
JH, Chu VH, Delahaye F, Edathodu J, et al; International Collaboration stroke in an elderly cohort. N Engl J Med. 1992;327:374–379. doi:
on Endocarditis–Prospective Cohort Study Investigators. Influence of 10.1056/NEJM199208063270602
the timing of cardiac surgery on the outcome of patients with infec- 485. Kohsaka S, Jin Z, Rundek T, Boden-Albala B, Homma S, Sacco RL, Di Tullio
tive endocarditis and stroke. Clin Infect Dis. 2013;56:209–217. doi: MR. Impact of mitral annular calcification on cardiovascular events in a
10.1093/cid/cis878 multiethnic community: the Northern Manhattan Study. JACC Cardiovasc
468. John S, Walsh KM, Hui FK, Sundararajan S, Silverman S, Bain M. Imaging. 2008;1:617–623. doi: 10.1016/j.jcmg.2008.07.006
Dynamic angiographic nature of cerebral mycotic aneurysms in patients 486. Roldan CA, Gelgand EA, Qualls CR, Sibbitt WL Jr. Valvular heart dis-
with infective endocarditis. Stroke. 2016;47:e8–e10. doi: 10.1161/ ease as a cause of cerebrovascular disease in patients with sys-
STROKEAHA.115.011198 temic lupus erythematosus. Am J Cardiol. 2005;95:1441–1447. doi:
469. Acar J, Iung B, Boissel JP, Samama MM, Michel PL, Teppe JP, Pony JC, 10.1016/j.amjcard.2005.02.010
Breton HL, Thomas D, Isnard R, et al. AREVA: multicenter randomized 487. Khetarpal V, Mahajan N, Madhavan R, Batra S, Mopala P, Sagar A,
comparison of low-dose versus standard-dose anticoagulation in patients Rapolu P, Nangia S, Afonso L. Calcific aortic valve and spontaneous em-
with mechanical prosthetic heart valves. Circulation. 1996;94:2107–2112. bolic stroke: a review of literature. J Neurol Sci. 2009;287:32–35. doi:
doi: 10.1161/01.cir.94.9.2107 10.1016/j.jns.2009.07.018
470. Mérie C, Køber L, Skov Olsen P, Andersson C, Gislason G, Skov Jensen 488. Makkar RR, Fontana G, Jilaihawi H, Chakravarty T, Kofoed KF, De Backer
J, Torp-Pedersen C. Association of warfarin therapy duration after bio- O, Asch FM, Ruiz CE, Olsen NT, Trento A, et al. Possible subclinical leaflet
prosthetic aortic valve replacement with risk of mortality, thromboem- thrombosis in bioprosthetic aortic valves. N Engl J Med. 2015;373:2015–
bolic complications, and bleeding. JAMA. 2012;308:2118–2125. doi: 2024. doi: 10.1056/NEJMoa1509233
10.1001/jama.2012.54506 489. Sundt TM, Zehr KJ, Dearani JA, Daly RC, Mullany CJ, McGregor CG, Puga
Downloaded from http://ahajournals.org by on June 12, 2021
471. Puskas J, Gerdisch M, Nichols D, Quinn R, Anderson C, Rhenman B, FJ, Orszulak TA, Schaff HV. Is early anticoagulation with warfarin necessary
Fermin L, McGrath M, Kong B, Hughes C, et al; PROACT Investigators. after bioprosthetic aortic valve replacement? J Thorac Cardiovasc Surg.
Reduced anticoagulation after mechanical aortic valve replacement: in- 2005;129:1024–1031. doi: 10.1016/j.jtcvs.2004.11.028
terim results from the prospective randomized On-X Valve Anticoagulation 490. Russo A, Grigioni F, Avierinos JF, Freeman WK, Suri R, Michelena H,
Clinical Trial randomized Food and Drug Administration investigational de- Brown R, Sundt TM, Enriquez-Sarano M. Thromboembolic complications
vice exemption trial. J Thorac Cardiovasc Surg. 2014;147:1202–1210. doi: after surgical correction of mitral regurgitation incidence, predictors,
10.1016/j.jtcvs.2014.01.004 and clinical implications. J Am Coll Cardiol. 2008;51:1203–1211. doi:
472. Torella M, Torella D, Chiodini P, Franciulli M, Romano G, De Santo L, De Feo 10.1016/j.jacc.2007.10.058
M, Amarelli C, Sasso FC, Salvatore T, et al. LOWERing the INtensity of 491. Colli A, Mestres CA, Castella M, Gherli T. Comparing warfarin to aspirin
oral anticoaGulant Therapy in patients with bileaflet mechanical aortic (WoA) after aortic valve replacement with the St. Jude Medical Epic heart
valve replacement: results from the “LOWERING-IT” Trial. Am Heart J. valve bioprosthesis: results of the WoA Epic pilot trial. J Heart Valve Dis.
2010;160:171–178. doi: 10.1016/j.ahj.2010.05.005 2007;16:667–671.
473. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic 492. Heras M, Chesebro JH, Fuster V, Penny WJ, Grill DE, Bailey KR, Danielson
and thrombolytic therapy for valvular disease: Antithrombotic Therapy GK, Orszulak TA, Pluth JR, Puga FJ. High risk of thromboemboli early after
and Prevention of Thrombosis, 9th ed: American College of Chest bioprosthetic cardiac valve replacement. J Am Coll Cardiol. 1995;25:1111–
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 1119. doi: 10.1016/0735-1097(94)00563-6
2012;141(suppl):e576S–e600S. doi: 10.1378/chest.11-2305 493. Nuñez L, Gil Aguado M, Larrea JL, Celemín D, Oliver J. Prevention
474. Barnett HJ, Boughner DR, Taylor DW, Cooper PE, Kostuk WJ, Nichol of thromboembolism using aspirin after mitral valve replacement
PM. Further evidence relating mitral-valve prolapse to cerebral isch- with porcine bioprosthesis. Ann Thorac Surg. 1984;37:84–87. doi:
emic events. N Engl J Med. 1980;302:139–144. doi: 10.1056/ 10.1016/s0003-4975(10)60717-5
NEJM198001173020303 494. Meschengieser SS, Fondevila CG, Frontroth J, Santarelli MT, Lazzari MA.
475. Freed LA, Levy D, Levine RA, Larson MG, Evans JC, Fuller DL, Lehman B, Low-intensity oral anticoagulation plus low-dose aspirin versus high-inten-
Benjamin EJ. Prevalence and clinical outcome of mitral-valve prolapse. N sity oral anticoagulation alone: a randomized trial in patients with mechani-
Engl J Med. 1999;341:1–7. doi: 10.1056/NEJM199907013410101 cal prosthetic heart valves. J Thorac Cardiovasc Surg. 1997;113:910–916.
476. Gilon D, Buonanno FS, Joffe MM, Leavitt M, Marshall JE, Kistler JP, doi: 10.1016/S0022-5223(97)70264-2
Levine RA. Lack of evidence of an association between mitral-valve pro- 495. Turpie AG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile F, Klimek M,
lapse and stroke in young patients. N Engl J Med. 1999;341:8–13. doi: Hirsh J. A comparison of aspirin with placebo in patients treated with war-
10.1056/NEJM199907013410102 farin after heart-valve replacement. N Engl J Med. 1993;329:524–529.
477. Orencia AJ, Petty GW, Khandheria BK, Annegers JF, Ballard DJ, Sicks doi: 10.1056/NEJM199308193290802
JD, O’Fallon WM, Whisnant JP. Risk of stroke with mitral valve pro- 496. Goette A, Kalman JM, Aguinaga L, Akar J, Cabrera JA, Chen SA, Chugh SS,
lapse in population-based cohort study. Stroke. 1995;26:7–13. doi: Corradi D, D’Avila A, Dobrev D, et al; Document Reviewers. EHRA/HRS/
10.1161/01.str.26.1.7 APHRS/SOLAECE expert consensus on atrial cardiomyopathies: defini-
478. Rodriguez CJ, Bartz TM, Longstreth WT Jr, Kizer JR, Barasch E, tion, characterization, and clinical implication. Europace. 2016;18:1455–
Lloyd-Jones DM, Gottdiener JS. Association of annular calcification and 1490. doi: 10.1093/europace/euw161
aortic valve sclerosis with brain findings on magnetic resonance imaging 497. Guichard JB, Nattel S. Atrial cardiomyopathy: a useful notion in cardiac dis-
in community dwelling older adults: the Cardiovascular Health Study. J Am ease management or a passing fad? J Am Coll Cardiol. 2017;70:756–765.
Coll Cardiol. 2011;57:2172–2180. doi: 10.1016/j.jacc.2011.01.034 doi: 10.1016/j.jacc.2017.06.033
498. Iung B, Klein I, Mourvillier B, Olivot JM, Détaint D, Longuet P, Ruimy R, direct oral anticoagulants compared with warfarin for left ventricular throm-
Fourchy D, Laurichesse JJ, Laissy JP, et al; Study Group. Respective ef- bi. JAMA Cardiol. 2020;5:685–692. doi: 10.1001/jamacardio.2020.0652
CLINICAL STATEMENTS
fects of early cerebral and abdominal magnetic resonance imaging on 514. Cambronero-Cortinas E, Bonanad C, Monmeneu JV, Lopez-Lereu MP,
AND GUIDELINES
clinical decisions in infective endocarditis. Eur Heart J Cardiovasc Imaging. Gavara J, de Dios E, Rios C, Perez N, Racugno P, Paya A, et al. Incidence,
2012;13:703–710. doi: 10.1093/ehjci/jes023 outcomes, and predictors of ventricular thrombus after reperfused st-seg-
499. Meshaal MS, Kassem HH, Samir A, Zakaria A, Baghdady Y, Rizk ment-elevation myocardial infarction by using sequential cardiac MR imag-
HH. Impact of routine cerebral CT angiography on treatment deci- ing. Radiology. 2017;284:372–380. doi: 10.1148/radiol.2017161898
sions in infective endocarditis. PLoS One. 2015;10:e0118616. doi: 515. Leow AS, Sia CH, Tan BY, Kaur R, Yeo TC, Chan MY, Tay EL, Seet RC,
10.1371/journal.pone.0118616 Loh JP, Yeo LL. Characterisation of acute ischemic stroke in patients with
500. Stortecky S, Franzone A, Heg D, Tueller D, Noble S, Pilgrim T, Jeger R, left ventricular thrombi after myocardial infarction. J Thromb Thrombolysis.
Toggweiler S, Ferrari E, Nietlispach F, et al. Temporal trends in adoption and 2019;48:158–166. doi: 10.1007/s11239-019-01829-6
outcomes of transcatheter aortic valve implantation: a SwissTAVI Registry 516. Boyle AJ, Jorde UP, Sun B, Park SJ, Milano CA, Frazier OH, Sundareswaran
analysis. Eur Heart J Qual Care Clin Outcomes. 2019;5:242–251. doi: KS, Farrar DJ, Russell SD; HeartMate II Clinical Investigators. Pre-operative
10.1093/ehjqcco/qcy048 risk factors of bleeding and stroke during left ventricular assist device sup-
501. Guerrero M, Vemulapalli S, Xiang Q, Wang DD, Eleid M, Cabalka AK, port: an analysis of more than 900 HeartMate II outpatients. J Am Coll
Sandhu G, Salinger M, Russell H, Greenbaum A, et al. Thirty-day out- Cardiol. 2014;63:880–888. doi: 10.1016/j.jacc.2013.08.1656
comes of transcatheter mitral valve replacement for degenerated mi- 517. Frontera JA, Starling R, Cho SM, Nowacki AS, Uchino K, Hussain MS,
tral bioprostheses (valve-in-valve), failed surgical rings (valve-in-ring), Mountis M, Moazami N. Risk factors, mortality, and timing of ischemic
and native valve with severe mitral annular calcification (valve-in-mitral and hemorrhagic stroke with left ventricular assist devices. J Heart Lung
annular calcification) in the United States: data from the Society of Transplant. 2017;36:673–683. doi: 10.1016/j.healun.2016.12.010
Thoracic Surgeons/American College of Cardiology/Transcatheter 518. Harvey L, Holley C, Roy SS, Eckman P, Cogswell R, Liao K, John R.
Valve Therapy Registry. Circ Cardiovasc Interv. 2020;13:e008425. doi: Stroke after left ventricular assist device implantation: outcomes in
10.1161/CIRCINTERVENTIONS.119.008425 the continuous-flow era. Ann Thorac Surg. 2015;100:535–541. doi:
502. Dangas GD, Tijssen JGP, Wöhrle J, Søndergaard L, Gilard M, Möllmann 10.1016/j.athoracsur.2015.02.094
H, Makkar RR, Herrmann HC, Giustino G, Baldus S, et al; GALILEO 519. Tsukui H, Abla A, Teuteberg JJ, McNamara DM, Mathier MA, Cadaret
Investigators. A controlled trial of rivaroxaban after transcatheter LM, Kormos RL. Cerebrovascular accidents in patients with a ventricu-
aortic-valve replacement. N Engl J Med. 2020;382:120–129. doi: lar assist device. J Thorac Cardiovasc Surg. 2007;134:114–123. doi:
10.1056/NEJMoa1911425 10.1016/j.jtcvs.2007.02.044
503. De Backer O, Dangas GD, Jilaihawi H, Leipsic JA, Terkelsen CJ, Makkar R, 520. John R, Naka Y, Park SJ, Sai-Sudhakar C, Salerno C, Sundareswaran KS,
Kini AS, Veien KT, Abdel-Wahab M, Kim WK, et al; GALILEO-4D Investigators. Farrar DJ, Milano CA. Impact of concurrent surgical valve procedures in
Reduced leaflet motion after transcatheter aortic-valve replacement. N patients receiving continuous-flow devices. J Thorac Cardiovasc Surg.
Engl J Med. 2020;382:130–139. doi: 10.1056/NEJMoa1911426 2014;147:581–589. doi: 10.1016/j.jtcvs.2013.10.024
504. Pöss J, Desch S, Eitel C, de Waha S, Thiele H, Eitel I. Left ventricular throm- 521. Aggarwal A, Gupta A, Kumar S, Baumblatt JA, Pauwaa S, Gallagher C,
bus formation after ST-segment-elevation myocardial infarction: insights Treitman A, Pappas P, Tatooles A, Bhat G. Are blood stream infections
from a cardiac magnetic resonance multicenter study. Circ Cardiovasc associated with an increased risk of hemorrhagic stroke in patients
Imaging. 2015;8:e003417. doi: 10.1161/CIRCIMAGING.115.003417 with a left ventricular assist device? ASAIO J. 2012;58:509–513. doi:
505. Phan J, Nguyen T, French J, Moses D, Schlaphoff G, Lo S, Juergens C, 10.1097/MAT.0b013e318260c6a6
Dimitri H, Richards D, Thomas L. Incidence and predictors of left ven- 522. Backes D, van den Bergh WM, van Duijn AL, Lahpor JR, van Dijk D, Slooter
Downloaded from http://ahajournals.org by on June 12, 2021
tricular thrombus formation following acute ST-segment elevation myo- AJ. Cerebrovascular complications of left ventricular assist devices. Eur J
cardial infarction: a serial cardiac MRI study. Int J Cardiol Heart Vasc. Cardiothorac Surg. 2012;42:612–620. doi: 10.1093/ejcts/ezs320
2019;24:100395. doi: 10.1016/j.ijcha.2019.100395 523. Cho SM, Moazami N, Frontera JA. Stroke and intracranial hemorrhage in
506. Vaitkus PT, Barnathan ES. Embolic potential, prevention and man- HeartMate II and HeartWare left ventricular assist devices: a systematic re-
agement of mural thrombus complicating anterior myocardial infarc- view. Neurocrit Care. 2017;27:17–25. doi: 10.1007/s12028-017-0386-7
tion: a meta-analysis. J Am Coll Cardiol. 1993;22:1004–1009. doi: 524. Cleland JG, Findlay I, Jafri S, Sutton G, Falk R, Bulpitt C, Prentice C,
10.1016/0735-1097(93)90409-t Ford I, Trainer A, Poole-Wilson PA. The Warfarin/Aspirin Study in Heart
507. Merkler AE, Alakbarli J, Gialdini G, Navi BB, Murthy SB, Goyal P, Kim J, failure (WASH): a randomized trial comparing antithrombotic strategies
Devereux RB, Safford MM, Iadecola C, et al. Short-term risk of ischemic for patients with heart failure. Am Heart J. 2004;148:157–164. doi:
stroke after detection of left ventricular thrombus on cardiac magnetic 10.1016/j.ahj.2004.03.010
resonance imaging. J Stroke Cerebrovasc Dis. 2019;28:1027–1031. doi: 525. Cokkinos DV, Haralabopoulos GC, Kostis JB, Toutouzas PK; HELAS
10.1016/j.jstrokecerebrovasdis.2018.12.025 Investigators. Efficacy of antithrombotic therapy in chronic heart failure:
508. Velangi PS, Choo C, Chen KA, Kazmirczak F, Nijjar PS, Farzaneh-Far the HELAS study. Eur J Heart Fail. 2006;8:428–432. doi: 10.1016/j.
A, Okasha O, Akçakaya M, Weinsaft JW, Shenoy C. Long-term embolic ejheart.2006.02.012
outcomes after detection of left ventricular thrombus by late gado- 526. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink
linium enhancement cardiovascular magnetic resonance imaging: a JR, Ammon SE, Graham S, Sacco RL, Mann DL, et al; WARCEF Investigators.
matched cohort study. Circ Cardiovasc Imaging. 2019;12:e009723. doi: Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl
10.1161/CIRCIMAGING.119.009723 J Med. 2012;366:1859–1869. doi: 10.1056/NEJMoa1202299
509. Fleddermann AM, Hayes CH, Magalski A, Main ML. Efficacy of direct 527. Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz
acting oral anticoagulants in treatment of left ventricular thrombus. Am J M, Jafri SM, Krol WF, O’Connor CM, Schulman KA, et al; WATCH Trial
Cardiol. 2019;124:367–372. doi: 10.1016/j.amjcard.2019.05.009 Investigators. Randomized trial of warfarin, aspirin, and clopidogrel in pa-
510. Witt BJ, Brown RD Jr, Jacobsen SJ, Weston SA, Yawn BP, Roger VL. tients with chronic heart failure: the Warfarin and Antiplatelet Therapy in
A community-based study of stroke incidence after myocardial in- Chronic Heart Failure (WATCH) trial. Circulation. 2009;119:1616–1624.
farction. Ann Intern Med. 2005;143:785–792. doi: 10.7326/0003- doi: 10.1161/CIRCULATIONAHA.108.801753
4819-143-11-200512060-00006 528. Zannad F, Anker SD, Byra WM, Cleland JGF, Fu M, Gheorghiade M,
511. Weinsaft JW, Kim J, Medicherla CB, Ma CL, Codella NC, Kukar N, Alaref Lam CSP, Mehra MR, Neaton JD, Nessel CC, et al; COMMANDER HF
S, Kim RJ, Devereux RB. Echocardiographic algorithm for post-myocar- Investigators. Rivaroxaban in patients with heart failure, sinus rhythm,
dial infarction LV thrombus: a gatekeeper for thrombus evaluation by de- and coronary disease. N Engl J Med. 2018;379:1332–1342. doi:
layed enhancement CMR. JACC Cardiovasc Imaging. 2016;9:505–515. 10.1056/NEJMoa1808848
doi: 10.1016/j.jcmg.2015.06.017 529. Andreas M, Moayedifar R, Wieselthaler G, Wolzt M, Riebandt J,
512. Weinsaft JW, Kim HW, Crowley AL, Klem I, Shenoy C, Van Assche L, Haberl T, Angleitner P, Schloglhofer T, Wiedemann D, Schima H, et al.
Brosnan R, Shah DJ, Velazquez EJ, Parker M, et al. LV thrombus detection Increased thromboembolic events with dabigatran compared with vi-
by routine echocardiography: insights into performance characteristics us- tamin K antagonism in left ventricular assist device patients: a ran-
ing delayed enhancement CMR. JACC Cardiovasc Imaging. 2011;4:702– domized controlled pilot trial. Circ Heart Fail. 2017;10:e003709. doi:
712. doi: 10.1016/j.jcmg.2011.03.017 10.1161/CIRCHEARTFAILURE.116.003709
513. Robinson AA, Trankle CR, Eubanks G, Schumann C, Thompson P, Wallace 530. Wada H, Yasu T, Sakakura K, Hayakawa Y, Ishida T, Kobayashi N, Kubo
RL, Gottiparthi S, Ruth B, Kramer CM, Salerno M, et al. Off-label use of N, Ako J, Momomura S. Contrast echocardiography for the diagnosis of
left ventricular thrombus in anterior myocardial infarction. Heart Vessels. of left ventricular non-compaction in adults. Eur Heart J. 2020;41:1428–
2014;29:308–312. doi: 10.1007/s00380-013-0363-9 1436. doi: 10.1093/eurheartj/ehz317
CLINICAL STATEMENTS
531. Meurin P, Brandao Carreira V, Dumaine R, Shqueir A, Milleron O, Safar 549. Ritter M, Oechslin E, Sütsch G, Attenhofer C, Schneider J, Jenni R. Isolated
AND GUIDELINES
B, Perna S, Smadja C, Genest M, Garot J, et al; College National des noncompaction of the myocardium in adults. Mayo Clin Proc. 1997;72:26–
Cardiologues Français; Collège National des Cardiologues des Hôpitaux 31. doi: 10.4065/72.1.26
Français, Paris, France. Incidence, diagnostic methods, and evolution of left 550. Di Tullio MR, Qian M, Thompson JL, Labovitz AJ, Mann DL, Sacco RL,
ventricular thrombus in patients with anterior myocardial infarction and low Pullicino PM, Freudenberger RS, Teerlink JR, Graham S, et al; WARCEF
left ventricular ejection fraction: a prospective multicenter study. Am Heart Investigators. Left ventricular ejection fraction and risk of stroke and
J. 2015;170:256–262. doi: 10.1016/j.ahj.2015.04.029 cardiac events in heart failure: data from the Warfarin Versus Aspirin
532. Roifman I, Connelly KA, Wright GA, Wijeysundera HC. Echocardiography in Reduced Ejection Fraction trial. Stroke. 2016;47:2031–2037. doi:
vs. cardiac magnetic resonance imaging for the diagnosis of left ventricu- 10.1161/STROKEAHA.116.013679
lar thrombus: a systematic review. Can J Cardiol. 2015;31:785–791. doi: 551. Meurin P, Tabet JY, Renaud N, Weber H, Grosdemouge A, Bourmayan
10.1016/j.cjca.2015.01.011 C, Driss AB. Treatment of left ventricular thrombi with a low molecular
533. Muser D, Nucifora G, Gianfagna E, Pavoni D, Rebellato L, Facchin D, weight heparin. Int J Cardiol. 2005;98:319–323. doi: 10.1016/j.ijcard.
Daleffe E, Proclemer A. Clinical spectrum of isolated left ventricular non- 2004.02.014
compaction: thromboembolic events, malignant left ventricular arrhyth- 552. Kent DM, Dahabreh IJ, Ruthazer R, Furlan AJ, Reisman M, Carroll JD,
mias, and refractory heart failure. J Am Coll Cardiol. 2014;63:e39. doi: Saver JL, Smalling RW, Jüni P, Mattle HP, et al. Device closure of
10.1016/j.jacc.2013.11.063 patent foramen ovale after stroke: pooled analysis of completed ran-
534. Oechslin EN, Attenhofer Jost CH, Rojas JR, Kaufmann PA, Jenni R. domized trials. J Am Coll Cardiol. 2016;67:907–917. doi: 10.1016/j.
Long-term follow-up of 34 adults with isolated left ventricular noncom- jacc.2015.12.023
paction: a distinct cardiomyopathy with poor prognosis. J Am Coll Cardiol. 553. Lee PH, Song JK, Kim JS, Heo R, Lee S, Kim DH, Song JM, Kang DH,
2000;36:493–500. doi: 10.1016/s0735-1097(00)00755-5 Kwon SU, Kang DW, et al. Cryptogenic stroke and high-risk patent foramen
535. Stöllberger C, Blazek G, Dobias C, Hanafin A, Wegner C, Finsterer J. ovale: the DEFENSE-PFO trial. J Am Coll Cardiol. 2018;71:2335–2342.
Frequency of stroke and embolism in left ventricular hypertrabecu- doi: 10.1016/j.jacc.2018.02.046
lation/noncompaction. Am J Cardiol. 2011;108:1021–1023. doi: 554. Mas JL, Derumeaux G, Guillon B, Massardier E, Hosseini H, Mechtouff L,
10.1016/j.amjcard.2011.05.039 Arquizan C, Béjot Y, Vuillier F, Detante O, et al; CLOSE Investigators. Patent
536. Feldman D, Pamboukian SV, Teuteberg JJ, Birks E, Lietz K, Moore SA, foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N
Morgan JA, Arabia F, Bauman ME, Buchholz HW, et al; International Society Engl J Med. 2017;377:1011–1021. doi: 10.1056/NEJMoa1705915
for Heart and Lung Transplantation. The 2013 International Society for 555. Saver JL, Carroll JD, Thaler DE, Smalling RW, MacDonald LA, Marks
Heart and Lung Transplantation guidelines for mechanical circulatory sup- DS, Tirschwell DL; RESPECT Investigators. Long-term outcomes of pat-
port: executive summary. J Heart Lung Transplant. 2013;32:157–187. doi: ent foramen ovale closure or medical therapy after stroke. N Engl J Med.
10.1016/j.healun.2012.09.013 2017;377:1022–1032. doi: 10.1056/NEJMoa1610057
537. Lee JM, Park JJ, Jung HW, Cho YS, Oh IY, Yoon CH, Suh JW, Chun EJ, 556. Søndergaard L, Kasner SE, Rhodes JF, Andersen G, Iversen HK,
Choi SI, Youn TJ, et al. Left ventricular thrombus and subsequent thrombo- Nielsen-Kudsk JE, Settergren M, Sjöstrand C, Roine RO, Hildick-Smith
embolism, comparison of anticoagulation, surgical removal, and antiplatelet D, et al; Gore REDUCE Clinical Study Investigators. Patent foramen ova-
agents. J Atheroscler Thromb. 2013;20:73–93. doi: 10.5551/jat.13540 le closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med.
538. Lanzillo C, Di Roma M, Sciahbasi A, Minati M, Maresca L, Pendenza G, 2017;377:1033–1042. doi: 10.1056/NEJMoa1707404
Romagnoli E, Summaria F, Patrizi R, Di Luozzo M, et al. Cardiac mag- 557. Turc G, Lee JY, Brochet E, Kim JS, Song JK, Mas JL; CLOSE and
Downloaded from http://ahajournals.org by on June 12, 2021
netic resonance detection of left ventricular thrombus in acute myo- DEFENSE-PFO Trial Investigators. Atrial septal aneurysm, shunt size,
cardial infarction. Acute Card Care. 2013;15:11–16. doi: 10.3109/ and recurrent stroke risk in patients with patent foramen ovale. J Am Coll
17482941.2012.741248 Cardiol. 2020;75:2312–2320. doi: 10.1016/j.jacc.2020.02.068
539. Johannessen KA, Nordrehaug JE, von der Lippe G. Left ventricular thrombi 558. Carroll JD, Saver JL, Thaler DE, Smalling RW, Berry S, MacDonald LA,
after short-term high-dose anticoagulants in acute myocardial infarction. Eur Marks DS, Tirschwell DL; RESPECT Investigators. Closure of patent fora-
Heart J. 1987;8:975–980. doi: 10.1093/oxfordjournals.eurheartj.a062374 men ovale versus medical therapy after cryptogenic stroke. N Engl J Med.
540. Kolekar S, Munjewar C, Sharma S. Dabigatran for left ventricular thrombus. 2013;368:1092–1100. doi: 10.1056/NEJMoa1301440
Indian Heart J. 2015;67:495–496. doi: 10.1016/j.ihj.2015.06.010 559. Furlan AJ, Reisman M, Massaro J, Mauri L, Adams H, Albers GW, Felberg R,
541. Chung K, Paek YM, Lee HJ, Hong KS. Dabigatran effect on left ventricular Herrmann H, Kar S, Landzberg M, et al; CLOSURE I Investigators. Closure
thrombus in a patient with acute ischemic stroke. J Stroke. 2015;17:366– or medical therapy for cryptogenic stroke with patent foramen ovale. N
368. doi: 10.5853/jos.2015.17.3.366 Engl J Med. 2012;366:991–999. doi: 10.1056/NEJMoa1009639
542. Ohashi N, Okada T, Uchida M, Amioka M, Fujiwara M, Kaseda S. 560. Meier B, Kalesan B, Mattle HP, Khattab AA, Hildick-Smith D, Dudek
Effects of dabigatran on the resolution of left ventricular thrombus af- D, Andersen G, Ibrahim R, Schuler G, Walton AS, et al; PC Trial
ter acute myocardial infarction. Intern Med. 2015;54:1761–1763. doi: Investigators. Percutaneous closure of patent foramen ovale in crypto-
10.2169/internalmedicine.54.4191 genic embolism. N Engl J Med. 2013;368:1083–1091. doi: 10.1056/
543. Nagamoto Y, Shiomi T, Matsuura T, Okahara A, Takegami K, Mine D, NEJMoa1211716
Shirahama T, Koga Y, Yoshida K, Sadamatsu K, et al. Resolution of a 561. Turc G, Calvet D, Guerin P, Sroussi M, Chatellier G, Mas JL; CLOSE
left ventricular thrombus by the thrombolytic action of dabigatran. Heart Investigators. Closure, anticoagulation, or antiplatelet therapy for crypto-
Vessels. 2014;29:560–562. doi: 10.1007/s00380-013-0403-5 genic stroke with patent foramen ovale: systematic review of randomized
544. Nakasuka K, Ito S, Noda T, Hasuo T, Sekimoto S, Ohmori H, Inomata M, trials, sequential meta-analysis, and new insights from the CLOSE study. J
Yoshida T, Tamai N, Saeki T, et al. Resolution of left ventricular thrombus Am Heart Assoc. 2018;7:e008356. doi: 10.1161/JAHA.117.008356
secondary to tachycardia-induced heart failure with rivaroxaban. Case Rep 562. Merkler AE, Gialdini G, Yaghi S, Okin PM, Iadecola C, Navi BB, Kamel
Med. 2014;2014:814524. doi: 10.1155/2014/814524 H. Safety outcomes after percutaneous transcatheter closure of pat-
545. Padilla Pérez M, Salas Bravo D, Garcelán Trigo JA, Vazquez Ruiz de Castroviejo ent foramen ovale. Stroke. 2017;48:3073–3077. doi: 10.1161/
E, Torres Llergo J, Lozano Cabezas C, Fernández Guerrero JC. Resolution STROKEAHA.117.018501
of left ventricular thrombus by rivaroxaban. Future Cardiol. 2014;10:333– 563. Mas JL, Derex L, Guérin P, Guillon B, Habib G, Juliard JM, Marijon E,
336. doi: 10.2217/fca.14.12 Massardier E, Meneveau N, Vuillier F. Transcatheter closure of patent fora-
546. Mano Y, Koide K, Sukegawa H, Kodaira M, Ohki T. Successful resolu- men ovale to prevent stroke recurrence in patients with otherwise unex-
tion of a left ventricular thrombus with apixaban treatment following plained ischaemic stroke: expert consensus of the French Neurovascular
acute myocardial infarction. Heart Vessels. 2016;31:118–123. doi: Society and the French Society of Cardiology. Arch Cardiovasc Dis.
10.1007/s00380-014-0562-z 2019;112:532–542. doi: 10.1016/j.acvd.2019.06.002
547. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. 564. Pristipino C, Sievert H, D’Ascenzo F, Louis Mas J, Meier B, Scacciatella
Echocardiographic and pathoanatomical characteristics of isolated left P, Hildick-Smith D, Gaita F, Toni D, Kyrle P, et al; Evidence Synthesis
ventricular non-compaction: a step towards classification as a distinct car- Team; EAPCI Scientific Documents and Initiatives Committee; International
diomyopathy. Heart. 2001;86:666–671. doi: 10.1136/heart.86.6.666 Experts. European position paper on the management of patients with pat-
548. Ross SB, Jones K, Blanch B, Puranik R, McGeechan K, Barratt A, ent foramen ovale. General approach and left circulation thromboembolism.
Semsarian C. A systematic review and meta-analysis of the prevalence Eur Heart J. 2019;40:3182–3195. doi: 10.1093/eurheartj/ehy649
565. Kamel H, Merkler AE, Iadecola C, Gupta A, Navi BB. Tailoring the ap- 583. Yang H, Bouma BJ, Mulder BJM; Non vitamin K antagonist Oral anti-
proach to embolic stroke of undetermined source: a review. JAMA Neurol. coagulants for ThromboEmbolic prevention in adult congenital heart
CLINICAL STATEMENTS
2019;76:855–861. doi: 10.1001/jamaneurol.2019.0591 disease (NOTE) Investigators. Is initiating NOACs for atrial arrhythmias
AND GUIDELINES
566. Kent DM, Ruthazer R, Weimar C, Mas JL, Serena J, Homma S, safe in adults with congenital heart disease? Cardiovasc Drugs Ther.
Di Angelantonio E, Di Tullio MR, Lutz JS, Elkind MS, et al. An index 2017;31:413–417. doi: 10.1007/s10557-017-6745-y
to identify stroke-related vs incidental patent foramen ovale in cryp- 584. Rychik J, Atz AM, Celermajer DS, Deal BJ, Gatzoulis MA, Gewillig MH, Hsia
togenic stroke. Neurology. 2013;81:619–625. doi: 10.1212/WNL. T-Y, Hsu DT, Kovacs AH, McCrindle BW, et al; on behalf of the American
0b013e3182a08d59 Heart Association Council on Cardiovascular Disease in the Young and
567. Kuijpers T, Spencer FA, Siemieniuk RAC, Vandvik PO, Otto CM, Lytvyn L, Council on Cardiovascular and Stroke Nursing. Evaluation and manage-
Mir H, Jin AY, Manja V, Karthikeyan G, et al. Patent foramen ovale closure, ment of the child and adult with Fontan circulation: a scientific statement
antiplatelet therapy or anticoagulation therapy alone for management of from the American Heart Association. Circulation. 2019;140:e234–e284.
cryptogenic stroke? A clinical practice guideline. BMJ. 2018;362:k2515. doi: 10.1161/CIR.0000000000000696
doi: 10.1136/bmj.k2515 585. Goff DA, Blume ED, Gauvreau K, Mayer JE, Lock JE, Jenkins KJ. Clinical
568. Kent DM, Saver JL, Ruthazer R, Furlan AJ, Reisman M, Carroll JD, Smalling outcome of fenestrated Fontan patients after closure: the first 10 years.
RW, Jüni P, Mattle HP, Meier B, et al. Risk of Paradoxical Embolism (RoPE)- Circulation. 2000;102:2094–2099. doi: 10.1161/01.cir.102.17.2094
estimated attributable fraction correlates with the benefit of patent fora- 585a. International Society for Adult Congenital Heart Disease. NOTE Registry.
men ovale closure: an analysis of 3 trials. Stroke. 2020;51:3119–3123. Accessed December 1, 2019. http://www.isachd.org/content/note-registry
doi: 10.1161/STROKEAHA.120.029350 586. Elbardissi AW, Dearani JA, Daly RC, Mullany CJ, Orszulak TA, Puga
569. Mazzucco S, Li L, Rothwell PM. Prognosis of cryptogenic stroke with pat- FJ, Schaff HV. Embolic potential of cardiac tumors and outcome af-
ent foramen ovale at older ages and implications for trials: a population- ter resection: a case-control study. Stroke. 2009;40:156–162. doi:
based study and systematic review. JAMA Neurol. 2020;77:1–9. doi: 10.1161/STROKEAHA.108.525709
10.1001/jamaneurol.2020.1948 587. Grinda JM, Couetil JP, Chauvaud S, D’Attellis N, Berrebi A, Fabiani JN,
570. Deng W, Yin S, McMullin D, Inglessis-Azuaje I, Elmariah S, Hung J, Lo Deloche A, Carpentier A. Cardiac valve papillary fibroelastoma: surgical
EH, Palacios IF, Buonanno FS, Ning M. Residual shunt after patent fo- excision for revealed or potential embolization. J Thorac Cardiovasc Surg.
ramen ovale closure and long-term stroke recurrence. Ann Intern Med. 1999;117:106–110. doi: 10.1016/s0022-5223(99)70474-5
2020;173:946–947. doi: 10.7326/L20-1274 588. Gowda RM, Khan IA, Nair CK, Mehta NJ, Vasavada BC, Sacchi TJ. Cardiac
571. Messé SR, Gronseth GS, Kent DM, Kizer JR, Homma S, Rosterman L, papillary fibroelastoma: a comprehensive analysis of 725 cases. Am Heart
Carroll JD, Ishida K, Sangha N, Kasner SE. Practice advisory update J. 2003;146:404–410. doi: 10.1016/S0002-8703(03)00249-7
summary: patent foramen ovale and secondary stroke prevention: report 589. Reynen K. Frequency of primary tumors of the heart. Am J Cardiol.
of the Guideline Subcommittee of the American Academy of Neurology. 1996;77:107. doi: 10.1016/s0002-9149(97)89149-7
Neurology. 2020;94:876–885. doi: 10.1212/WNL.0000000000009443 590. Lai MM, Li TC, Lin CL, Sung FC, Lin CC, Liu CS, Kao CH. Benign neoplasm
572. Seipelt RG, Franke A, Vazquez-Jimenez JF, Hanrath P, von Bernuth G, of the heart increases the risk of first ischemic stroke: a population-based
Messmer BJ, Mühler EG. Thromboembolic complications after Fontan cohort study. Int J Stroke. 2015;10:202–206. doi: 10.1111/ijs.12314
procedures: comparison of different therapeutic approaches. Ann Thorac 591. Valente M, Basso C, Thiene G, Bressan M, Stritoni P, Cocco P, Fasoli G.
Surg. 2002;74:556–562. doi: 10.1016/s0003-4975(02)03677-9 Fibroelastic papilloma: a not-so-benign cardiac tumor. Cardiovasc Pathol.
573. Monagle P, Cochrane A, Roberts R, Manlhiot C, Weintraub R, Szechtman 1992;1:161–166. doi: 10.1016/1054-8807(92)90020-O
B, Hughes M, Andrew M, McCrindle BW; Fontan Anticoagulation Study 592. Tamin SS, Maleszewski JJ, Scott CG, Khan SK, Edwards WD, Bruce CJ, Oh
Group. A multicenter, randomized trial comparing heparin/warfarin and JK, Pellikka PA, Klarich KW. Prognostic and bioepidemiologic implications
Downloaded from http://ahajournals.org by on June 12, 2021
acetylsalicylic acid as primary thromboprophylaxis for 2 years after the of papillary fibroelastomas. J Am Coll Cardiol. 2015;65:2420–2429. doi:
Fontan procedure in children. J Am Coll Cardiol. 2011;58:645–651. doi: 10.1016/j.jacc.2015.03.569
10.1016/j.jacc.2011.01.061 593. Markus HS, Hayter E, Levi C, Feldman A, Venables G, Norris J. Antiplatelet
574. Lanz J, Brophy JM, Therrien J, Kaouache M, Guo L, Marelli AJ. Stroke treatment compared with anticoagulation treatment for cervical artery dis-
in adults with congenital heart disease: incidence, cumulative risk, section (CADISS): a randomised trial. Lancet Neurol. 2015;14:361–367.
and predictors. Circulation. 2015;132:2385–2394. doi: 10.1161/ doi: 10.1016/S1474-4422(15)70018-9
CIRCULATIONAHA.115.011241 594. Markus HS, Levi C, King A, Madigan J, Norris J; Cervical Artery Dissection
575. Mandalenakis Z, Rosengren A, Lappas G, Eriksson P, Hansson PO, in Stroke Study (CADISS) Investigators. Antiplatelet therapy vs anticoagu-
Dellborg M. Ischemic stroke in children and young adults with congeni- lation therapy in cervical artery dissection: the Cervical Artery Dissection in
tal heart disease. J Am Heart Assoc. 2016;5:e003071. doi: 10.1161/ Stroke Study (CADISS) randomized clinical trial final results. JAMA Neurol.
JAHA.115.003071 2019;76:657–664. doi: 10.1001/jamaneurol.2019.0072
576. Hoffmann A, Chockalingam P, Balint OH, Dadashev A, Dimopoulos 595. Moon K, Albuquerque FC, Cole T, Gross BA, McDougall CG. Stroke
K, Engel R, Schmid M, Schwerzmann M, Gatzoulis MA, Mulder B, et al. prevention by endovascular treatment of carotid and vertebral ar-
Cerebrovascular accidents in adult patients with congenital heart disease. tery dissections. J Neurointerv Surg. 2017;9:952–957. doi: 10.1136/
Heart. 2010;96:1223–1226. doi: 10.1136/hrt.2010.196147 neurintsurg-2016-012565
577. Nattel SN, Adrianzen L, Kessler EC, Andelfinger G, Dehaes M, 596. Spanos K, Karathanos C, Stamoulis K, Giannoukas AD. Endovascular
Côté-Corriveau G, Trelles MP. Congenital heart disease and neurodevelop- treatment of traumatic internal carotid artery pseudoaneurysm. Injury.
ment: clinical manifestations, genetics, mechanisms, and implications. Can 2016;47:307–312. doi: 10.1016/j.injury.2015.09.015
J Cardiol. 2017;33:1543–1555. doi: 10.1016/j.cjca.2017.09.020 597. Redekop GJ. Extracranial carotid and vertebral artery dissection: a review.
578. Hebson CL, McCabe NM, Elder RW, Mahle WT, McConnell M, Kogon BE, Can J Neurol Sci. 2008;35:146–152. doi: 10.1017/s0317167100008556
Veledar E, Jokhadar M, Vincent RN, Sahu A, et al. Hemodynamic phenotype 598. Morel A, Naggara O, Touzé E, Raymond J, Mas JL, Meder JF, Oppenheim
of the failing Fontan in an adult population. Am J Cardiol. 2013;112:1943– C. Mechanism of ischemic infarct in spontaneous cervical artery dissection.
1947. doi: 10.1016/j.amjcard.2013.08.023 Stroke. 2012;43:1354–1361. doi: 10.1161/STROKEAHA.111.643338
579. Triedman JK. Arrhythmias in adults with congenital heart disease. Heart. 599. Weimar C, Kraywinkel K, Hagemeister C, Haass A, Katsarava Z, Brunner F,
2002;87:383–389. doi: 10.1136/heart.87.4.383 Haverkamp C, Schmid E, Diener HC; German Stroke Study Collaboration.
580. de Groot NM, Atary JZ, Blom NA, Schalij MJ. Long-term outcome af- Recurrent stroke after cervical artery dissection. J Neurol Neurosurg
ter ablative therapy of postoperative atrial tachyarrhythmia in patients Psychiatry. 2010;81:869–873. doi: 10.1136/jnnp.2009.192153
with congenital heart disease and characteristics of atrial tachyarrhyth- 600. Vossen CY, Rosendaal FR; EPCOT Study Group. Risk of arterial thrombo-
mia recurrences. Circ Arrhythm Electrophysiol. 2010;3:148–154. doi: sis in carriers of familial thrombophilia. J Thromb Haemost. 2006;4:916–
10.1161/CIRCEP.109.909838 918. doi: 10.1111/j.1538-7836.2006.01838.x
581. McRae ME. Long-term issues after the Fontan procedure. AACN Adv Crit 601. Mahmoodi BK, Brouwer JL, Veeger NJ, van der Meer J. Hereditary deficiency
Care. 2013;24:264–282. doi: 10.1097/NCI.0b013e31829744c7 of protein C or protein S confers increased risk of arterial thromboembolic
582. Georgekutty J, Kazerouninia A, Wang Y, Ermis PR, Parekh DR, Franklin events at a young age: results from a large family cohort study. Circulation.
WJ, Lam WW. Novel oral anticoagulant use in adult Fontan patients: a 2008;118:1659–1667. doi: 10.1161/CIRCULATIONAHA.108.780759
single center experience. Congenit Heart Dis. 2018;13:541–547. doi: 602. Kenet G, Lütkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao
10.1111/chd.12603 L, Chabrier S, Chan A, deVeber G, Fiedler B, et al. Impact of
thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous lipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019;
thrombosis in neonates and children: a systematic review and meta- 171:685–694. doi: 10.7326/M19-0291
CLINICAL STATEMENTS
analysis of observational studies. Circulation. 2010;121:1838–1847. doi: 618. Dufrost V, Risse J, Reshetnyak T, Satybaldyeva M, Du Y, Yan XX, Salta S,
AND GUIDELINES
10.1161/CIRCULATIONAHA.109.913673 Gerotziafas G, Jing ZC, Elalamy I, et al. Increased risk of thrombosis in
603. Pezzini A, Grassi M, Zotto ED, Giossi A, Volonghi I, Costa P, Grau A, Magoni antiphospholipid syndrome patients treated with direct oral anticoagulants:
M, Padovani A, Lichy C. Do common prothrombotic mutations influence the results from an international patient-level data meta-analysis. Autoimmun
risk of cerebral ischaemia in patients with patent foramen ovale? Systematic Rev. 2018;17:1011–1021. doi: 10.1016/j.autrev.2018.04.009
review and meta-analysis. Thromb Haemost. 2009;101:813–817. 619. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R,
604. Schellekens MMI, van Alebeek ME, Arntz RM, Synhaeve NE, Maaijwee Derksen RH, DE Groot PG, Koike T, Meroni PL, et al. International con-
NAMM, Schoonderwaldt HC, van der Vlugt MJ, van Dijk EJ, Rutten-Jacobs sensus statement on an update of the classification criteria for definite
LCA, de Leeuw FE. Prothrombotic factors do not increase the risk antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4:295–306.
of recurrent ischemic events after cryptogenic stroke at young age: doi: 10.1111/j.1538-7836.2006.01753.x
the FUTURE study. J Thromb Thrombolysis. 2018;45:504–511. doi: 620. Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G,
10.1007/s11239-018-1631-4 Erkan D. Estimated frequency of antiphospholipid antibodies in patients
605. Chiasakul T, De Jesus E, Tong J, Chen Y, Crowther M, Garcia D, with pregnancy morbidity, stroke, myocardial infarction, and deep vein
Chai-Adisaksopha C, Messé SR, Cuker A. Inherited thrombophilia and the thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken).
risk of arterial ischemic stroke: a systematic review and meta-analysis. J 2013;65:1869–1873. doi: 10.1002/acr.22066
Am Heart Assoc. 2019;8:e012877. doi: 10.1161/JAHA.119.012877 621. Cervera R, Piette JC, Font J, Khamashta MA, Shoenfeld Y, Camps
606. Mazzolai L, Aboyans V, Ageno W, Agnelli G, Alatri A, Bauersachs R, MT, Jacobsen S, Lakos G, Tincani A, Kontopoulou-Griva I, et al; Euro-
Brekelmans MPA, Büller HR, Elias A, Farge D, et al. Diagnosis and man- Phospholipid Project Group. Antiphospholipid syndrome: clinical and
agement of acute deep vein thrombosis: a joint consensus document from immunologic manifestations and patterns of disease expression in a
the European Society of Cardiology working groups of aorta and peripheral cohort of 1,000 patients. Arthritis Rheum. 2002;46:1019–1027. doi:
vascular diseases and pulmonary circulation and right ventricular function. 10.1002/art.10187
Eur Heart J. 2018;39:4208–4218. doi: 10.1093/eurheartj/ehx003 622. Nojima J, Kuratsune H, Suehisa E, Kitani T, Iwatani Y, Kanakura Y. Strong
607. Folsom AR, Rosamond WD, Shahar E, Cooper LS, Aleksic N, Nieto FJ, correlation between the prevalence of cerebral infarction and the pres-
Rasmussen ML, Wu KK. Prospective study of markers of hemostatic func- ence of anti-cardiolipin/beta2-glycoprotein I and anti-phosphatidylserine/
tion with risk of ischemic stroke: the Atherosclerosis Risk in Communities prothrombin antibodies: co-existence of these antibodies enhances ADP-
(ARIC) Study Investigators. Circulation. 1999;100:736–742. doi: induced platelet activation in vitro. Thromb Haemost. 2004;91:967–976.
10.1161/01.cir.100.7.736 doi: 10.1160/TH03-10-0608
608. Zakai NA, Judd SE, Kissela B, Howard G, Safford MM, Cushman M. Factor 623. Tektonidou MG, Andreoli L, Limper M, Amoura Z, Cervera R, Costedoat-
VIII, protein C and cardiovascular disease risk: the REasons for Geographic Chalumeau N, Cuadrado MJ, Dörner T, Ferrer-Oliveras R, Hambly K, et
and Racial Differences in Stroke Study (REGARDS). Thromb Haemost. al. EULAR recommendations for the management of antiphospholipid
2018;118:1305–1315. doi: 10.1055/s-0038-1655766 syndrome in adults. Ann Rheum Dis. 2019;78:1296–1304. doi: 10.1136/
609. Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic ap- annrheumdis-2019-215213
proach to laboratory testing and update on monitoring of direct oral antico- 624. Woller SC, Stevens SM, Kaplan DA, Branch DW, Aston VT, Wilson EL, Gallo
agulants. Blood Res. 2014;49:85–94. doi: 10.5045/br.2014.49.2.85 HM, Johnson EG, Rondina MT, Lloyd JF, et al. Apixaban for the Secondary
610. Gouse BM, Boehme AK, Monlezun DJ, Siegler JE, George AJ, Brag K, Prevention of Thrombosis Among Patients With Antiphospholipid
Albright KC, Beasley TM, Leissinger C, El Khoury R, et al. New thrombotic Syndrome: study rationale and design (ASTRO-APS). Clin Appl Thromb
Downloaded from http://ahajournals.org by on June 12, 2021
events in ischemic stroke patients with elevated factor VIII. Thrombosis. Hemost. 2016;22:239–247. doi: 10.1177/1076029615615960
2014;2014:302861. doi: 10.1155/2014/302861 625. VITATOPS Trial Study Group. B vitamins in patients with recent transient
611. Raffield LM, Lu AT, Szeto MD, Little A, Grinde KE, Shaw J, Auer PL, ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS)
Cushman M, Horvath S, Irvin MR, et al; NHLBI Trans-Omics for Precision trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet
Medicine (TOPMed) Consortium, TOPMed Hematology & Hemostasis Neurol. 2010;9:855–865. doi: 10.1016/S1474-4422(10)70187-3
Working Group. Coagulation factor VIII: Relationship to cardiovascular 626. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard
disease risk and whole genome sequence and epigenome-wide analy- VJ, Sides EG, Wang CH, Stampfer M. Lowering homocysteine in patients
sis in African Americans. J Thromb Haemost. 2020;18:1335–1347. doi: with ischemic stroke to prevent recurrent stroke, myocardial infarction, and
10.1111/jth.14741 death: the Vitamin Intervention for Stroke Prevention (VISP) randomized
612. Levine SR, Brey RL, Tilley BC, Thompson JL, Sacco RL, Sciacca RR, controlled trial. JAMA. 2004;291:565–575. doi: 10.1001/jama.291.5.565
Murphy A, Lu Y, Costigan TM, Rhine C, et al; APASS Investigators. 627. Galan P, Kesse-Guyot E, Czernichow S, Briancon S, Blacher J, Hercberg
Antiphospholipid antibodies and subsequent thrombo-occlusive events S; SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega 3
in patients with ischemic stroke. JAMA. 2004;291:576–584. doi: fatty acids on cardiovascular diseases: a randomised placebo controlled
10.1001/jama.291.5.576 trial. BMJ. 2010;341:c6273. doi: 10.1136/bmj.c6273
613. Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, 628. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen
Baudo F, Berrettini M, Testa S, D’Angelo A, et al. A randomized clinical MJ, Probstfield J, Fodor G, Held C, Euro-Phospholipid; Heart Outcomes
trial of high-intensity warfarin vs. conventional antithrombotic therapy Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lower-
for the prevention of recurrent thrombosis in patients with the antiphos- ing with folic acid and B vitamins in vascular disease. N Engl J Med.
pholipid syndrome (WAPS). J Thromb Haemost. 2005;3:848–853. doi: 2006;354:1567–1577. doi: 10.1056/NEJMoa060900
10.1111/j.1538-7836.2005.01340.x 629. Hsu CY, Chiu SW, Hong KS, Saver JL, Wu YL, Lee JD, Lee M, Ovbiagele
614. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin B. Folic acid in stroke prevention in countries without mandatory folic acid
C, Fortin P, Anderson D, Kearon C, et al. A comparison of two intensities of food fortification: a meta-analysis of randomized controlled trials. J Stroke.
warfarin for the prevention of recurrent thrombosis in patients with the an- 2018;20:99–109. doi: 10.5853/jos.2017.01522
tiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133–1138. 630. Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB. Folic acid supplemen-
doi: 10.1056/NEJMoa035241 tation and the risk of cardiovascular diseases: a meta-analysis of ran-
615. Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison be- domized controlled trials. J Am Heart Assoc. 2016;5:e003768. doi:
tween single antiplatelet therapy and combination of antiplatelet and 10.1161/JAHA.116.003768
anticoagulation therapy for secondary prevention in ischemic stroke pa- 631. Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering in-
tients with antiphospholipid syndrome. Int J Med Sci. 2009;7:15–18. doi: terventions for preventing cardiovascular events. Cochrane Database Syst
10.7150/ijms.7.15 Rev. 2017;8:CD006612. doi: 10.1002/14651858.CD006612.pub5
616. Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli 632. Park JH, Saposnik G, Ovbiagele B, Markovic D, Towfighi A. Effect of
L, Tincani A, Cenci C, Prisco D, et al. Rivaroxaban vs warfarin in high-risk B-vitamins on stroke risk among individuals with vascular disease who are
patients with antiphospholipid syndrome. Blood. 2018;132:1365–1371. not on antiplatelets: a meta-analysis. Int J Stroke. 2016;11:206–211. doi:
doi: 10.1182/blood-2018-04-848333 10.1177/1747493015616512
617. Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, 633. Spence JD, Yi Q, Hankey GJ. B vitamins in stroke prevention: time to
Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana reconsider. Lancet Neurol. 2017;16:750–760. doi: 10.1016/S1474-
M, Solé C, et al. Rivaroxaban versus vitamin K antagonist in antiphospho- 4422(17)30180-1
634. Tian T, Yang KQ, Cui JG, Zhou LL, Zhou XL. Folic acid supplementation for 655. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud
stroke prevention in patients with cardiovascular disease. Am J Med Sci. M, Gallagher D, Kutlar A, Nichols FT, et al. Prevention of a first stroke by
CLINICAL STATEMENTS
2017;354:379–387. doi: 10.1016/j.amjms.2017.05.020 transfusions in children with sickle cell anemia and abnormal results on
AND GUIDELINES
635. Zeng R, Xu CH, Xu YN, Wang YL, Wang M. The effect of folate fortifica- transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5–11. doi:
tion on folic acid-based homocysteine-lowering intervention and stroke 10.1056/NEJM199807023390102
risk: a meta-analysis. Public Health Nutr. 2015;18:1514–1521. doi: 656. Russell MO, Goldberg HI, Hodson A, Kim HC, Halus J, Reivich M, Schwartz
10.1017/S1368980014002134 E. Effect of transfusion therapy on arteriographic abnormalities and on re-
636. Zhao M, Wu G, Li Y, Wang X, Hou FF, Xu X, Qin X, Cai Y. Meta- currence of stroke in sickle cell disease. Blood. 1984;63:162–169.
analysis of folic acid efficacy trials in stroke prevention: in- 657. Pegelow CH, Adams RJ, McKie V, Abboud M, Berman B, Miller ST, Olivieri
sight into effect modifiers. Neurology. 2017;88:1830–1838. doi: N, Vichinsky E, Wang W, Brambilla D. Risk of recurrent stroke in patients
10.1212/WNL.0000000000003909 with sickle cell disease treated with erythrocyte transfusions. J Pediatr.
637. Zhao M, Wang X, He M, Qin X, Tang G, Huo Y, Li J, Fu J, Huang X, Cheng 1995;126:896–899. doi: 10.1016/s0022-3476(95)70204-0
X, et al. Homocysteine and stroke risk: modifying effect of methylenetet- 658. Estcourt LJ, Fortin PM, Hopewell S, Trivella M, Wang WC. Blood trans-
rahydrofolate reductase C677T polymorphism and folic acid intervention. fusion for preventing primary and secondary stroke in people with sick-
Stroke. 2017;48:1183–1190. doi: 10.1161/STROKEAHA.116.015324 le cell disease. Cochrane Database Syst Rev. 2017;1:CD003146. doi:
638. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke 10.1002/14651858.CD003146.pub3
in people with migraine: systematic review and meta-analysis of observa- 659. Ware RE, Helms RW; SWiTCH Investigators. Stroke With Transfusions
tional studies. BMJ. 2005;330:63. doi: 10.1136/bmj.38302.504063.8F Changing to Hydroxyurea (SWiTCH). Blood. 2012;119:3925–3932. doi:
639. Bashir A, Lipton RB, Ashina S, Ashina M. Migraine and structural 10.1182/blood-2011-11-392340
changes in the brain: a systematic review and meta-analysis. Neurology. 660. Ali SB, Moosang M, King L, Knight-Madden J, Reid M. Stroke recurrence
2013;81:1260–1268. doi: 10.1212/WNL.0b013e3182a6cb32 in children with sickle cell disease treated with hydroxyurea following first
640. Serrano F, Arauz A, Uribe R, Becerra LC, Mantilla K, Zermeño F. Long-term clinical stroke. Am J Hematol. 2011;86:846–850. doi: 10.1002/ajh.22142
follow-up of patients with migrainous infarction. Clin Neurol Neurosurg. 661. Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I,
2018;165:7–9. doi: 10.1016/j.clineuro.2017.12.008 Fuh B, George A, Owen W, et al. Hydroxycarbamide versus chronic trans-
641. Hoekstra-van Dalen RA, Cillessen JP, Kappelle LJ, van Gijn J. Cerebral fusion for maintenance of transcranial Doppler flow velocities in children
infarcts associated with migraine: clinical features, risk factors and follow- with sickle cell anaemia: TCD With Transfusions Changing to Hydroxyurea
up. J Neurol. 1996;243:511–515. doi: 10.1007/BF00886872 (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet.
642. Rothrock J, North J, Madden K, Lyden P, Fleck P, Dittrich H. Migraine and 2016;387:661–670. doi: 10.1016/S0140-6736(15)01041-7
migrainous stroke: risk factors and prognosis. Neurology. 1993;43:2473– 662. Lucarelli G, Gaziev J, Isgrò A, Sodani P, Paciaroni K, Alfieri C, De Angelis G,
2476. doi: 10.1212/wnl.43.12.2473 Marziali M, Simone MD, Gallucci C, et al. Allogeneic cellular gene therapy in
643. Kellner-Weldon F, El-Koussy M, Jung S, Jossen M, Klinger-Gratz PP, Wiest hemoglobinopathies: evaluation of hematopoietic SCT in sickle cell anemia.
R. Cerebellar hypoperfusion in migraine attack: incidence and significance. Bone Marrow Transplant. 2012;47:227–230. doi: 10.1038/bmt.2011.79
AJNR Am J Neuroradiol. 2018;39:435–440. doi: 10.3174/ajnr.A5508 663. Walters MC, Patience M, Leisenring W, Rogers ZR, Aquino VM, Buchanan
644. Sheikh HU, Pavlovic J, Loder E, Burch R. Risk of stroke associated with GR, Roberts IA, Yeager AM, Hsu L, Adamkiewicz T, et al; Multicenter
use of estrogen containing contraceptives in women with migraine: a sys- Investigation of Bone Marrow Transplantation for Sickle Cell Disease.
tematic review. Headache. 2018;58:5–21. doi: 10.1111/head.13229 Stable mixed hematopoietic chimerism after bone marrow transplantation
645. Roberto G, Raschi E, Piccinni C, Conti V, Vignatelli L, D’Alessandro R, for sickle cell anemia. Biol Blood Marrow Transplant. 2001;7:665–673. doi:
De Ponti F, Poluzzi E. Adverse cardiovascular events associated with 10.1053/bbmt.2001.v7.pm11787529
Downloaded from http://ahajournals.org by on June 12, 2021
triptans and ergotamines for treatment of migraine: systematic re- 664. Fryer RH, Anderson RC, Chiriboga CA, Feldstein NA. Sickle cell anemia
view of observational studies. Cephalalgia. 2015;35:118–131. doi: with moyamoya disease: outcomes after EDAS procedure. Pediatr Neurol.
10.1177/0333102414550416 2003;29:124–130. doi: 10.1016/s0887-8994(03)00047-x
646. Aradi S, Kaiser E, Cucchiara B. Ischemic stroke associated with cal- 665. Hankinson TC, Bohman LE, Heyer G, Licursi M, Ghatan S, Feldstein
citonin gene-related peptide inhibitor therapy for migraine: a case re- NA, Anderson RC. Surgical treatment of moyamoya syndrome in pa-
port. J Stroke Cerebrovasc Dis. 2019;28:104286. doi: 10.1016/j. tients with sickle cell anemia: outcome following encephaloduroarte-
jstrokecerebrovasdis.2019.07.002 riosynangiosis. J Neurosurg Pediatr. 2008;1:211–216. doi: 10.3171/
647. Chen ST, Hellkamp AS, Becker RC, Berkowitz SD, Breithardt G, Fox KAA, PED/2008/1/3/211
Hacke W, Halperin JL, Hankey GJ, Mahaffey KW, et al. Efficacy and safety 666. Pleasants S. Epidemiology: a moving target. Nature. 2014;515:S2–S3. doi:
of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and 10.1038/515S2a
a history of cancer: observations from ROCKET AF. Eur Heart J Qual Care 667. Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease.
Clin Outcomes. 2019;5:145–152. doi: 10.1093/ehjqcco/qcy040 Lancet. 2017;390:311–323. doi: 10.1016/S0140-6736(17)30193-9
648. Melloni C, Dunning A, Granger CB, Thomas L, Khouri MG, Garcia DA, Hylek 668. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, Temperley
EM, Hanna M, Wallentin L, Gersh BJ, et al. Efficacy and safety of apixaban WH, Williams TN, Weatherall DJ, Hay SI. Global epidemiology of sickle
versus warfarin in patients with atrial fibrillation and a history of cancer: haemoglobin in neonates: a contemporary geostatistical model-based
insights from the ARISTOTLE Trial. Am J Med. 2017;130:1440–1448.e1. map and population estimates. Lancet. 2013;381:142–151. doi:
doi: 10.1016/j.amjmed.2017.06.026 10.1016/S0140-6736(12)61229-X
649. Shah S, Norby FL, Datta YH, Lutsey PL, MacLehose RF, Chen LY, Alonso 669. Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE. Cerebral in-
A. Comparative effectiveness of direct oral anticoagulants and warfarin in farction in sickle cell anemia: mechanism based on CT and MRI. Neurology.
patients with cancer and atrial fibrillation. Blood Adv. 2018;2:200–209. 1988;38:1012–1017. doi: 10.1212/wnl.38.7.1012
doi: 10.1182/bloodadvances.2017010694 670. Mack AK, Thompson AA. Primary and secondary stroke prevention in chil-
650. Yang P, Zhu D, Xu X, Shen W, Wang C, Jiang Y, Xu G, Wu Q. Efficacy dren with sickle cell disease. J Pediatr Health Care. 2017;31:145–154.
and safety of oral anticoagulants in atrial fibrillation patients with can- doi: 10.1016/j.pedhc.2016.06.005
cer: a network meta-analysis. Heart Fail Rev. 2020;25:823–831. doi: 671. DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik
10.1007/s10741-019-09844-8 SA, Meier ER, Howard TH, Majumdar S, Inusa BP, et al. Controlled trial of
651. Dardiotis E, Aloizou AM, Markoula S, Siokas V, Tsarouhas K, Tzanakakis transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med.
G, Libra M, Kyritsis AP, Brotis AG, Aschner M, et al. Cancer-associated 2014;371:699–710. doi: 10.1056/NEJMoa1401731
stroke: pathophysiology, detection and management (review). Int J Oncol. 672. Brekke LK, Diamantopoulos AP, Fevang BT, Aβmus J, Esperø E,
2019;54:779–796. doi: 10.3892/ijo.2019.4669 Gjesdal CG. Incidence of giant cell arteritis in western Norway 1972-
652. Adams HP Jr. Cancer and cerebrovascular disease. Curr Neurol Neurosci 2012: a retrospective cohort study. Arthritis Res Ther. 2017;19:278. doi:
Rep. 2019;19:73. doi: 10.1007/s11910-019-0985-0 10.1186/s13075-017-1479-6
653. Hiatt BK, Lentz SR. Prothrombotic states that predispose to stroke. Curr Treat 673. Salvarani C, Macchioni PL, Tartoni PL, Rossi F, Baricchi R, Castri C,
Options Neurol. 2002;4:417–425. doi: 10.1007/s11940-002-0009-1 Chiaravalloti F, Portioli I. Polymyalgia rheumatica and giant cell arteritis:
654. Navi BB, Marshall RS, Bobrow D, Singer S, Stone JB, DeSancho MT, a 5-year epidemiologic and clinical study in Reggio Emilia, Italy. Clin Exp
DeAngelis LM. Enoxaparin vs aspirin in patients with cancer and isch- Rheumatol. 1987;5:205–215.
emic stroke: the TEACH pilot randomized clinical trial. JAMA Neurol. 674. Samson M, Jacquin A, Audia S, Daubail B, Devilliers H, Petrella T, Martin
2018;75:379–381. doi: 10.1001/jamaneurol.2017.4211 L, Durier J, Besancenot JF, Lorcerie B, et al. Stroke associated with giant
cell arteritis: a population-based study. J Neurol Neurosurg Psychiatry. of parenchymal, meningeal, and vascular lesions at baseline. Stroke.
2015;86:216–221. doi: 10.1136/jnnp-2014-307614 2017;48:1248–1255. doi: 10.1161/STROKEAHA.116.016194
CLINICAL STATEMENTS
675. Chevalet P, Barrier JH, Pottier P, Magadur-Joly G, Pottier MA, Hamidou 693. Hutchinson C, Elbers J, Halliday W, Branson H, Laughlin S, Armstrong D,
AND GUIDELINES
M, Planchon B, El Kouri D, Connan L, Dupond JL, et al. A randomized, Hawkins C, Westmacott R, Benseler SM. Treatment of small vessel pri-
multicenter, controlled trial using intravenous pulses of methylprednisolone mary CNS vasculitis in children: an open-label cohort study. Lancet Neurol.
in the initial treatment of simple forms of giant cell arteritis: a one year fol- 2010;9:1078–1084. doi: 10.1016/S1474-4422(10)70243-X
lowup study of 164 patients. J Rheumatol. 2000;27:1484–1491. 694. Salvarani C, Brown RD Jr, Christianson TJ, Huston J 3rd, Giannini C, Miller
676. Diamantopoulos AP, Haugeberg G, Lindland A, Myklebust G. The fast- DV, Hunder GG. Adult primary central nervous system vasculitis treat-
track ultrasound clinic for early diagnosis of giant cell arteritis significantly ment and course: analysis of one hundred sixty-three patients. Arthritis
reduces permanent visual impairment: towards a more effective strategy Rheumatol. 2015;67:1637–1645. doi: 10.1002/art.39068
to improve clinical outcome in giant cell arteritis? Rheumatology (Oxford). 695. de Boysson H, Arquizan C, Touzé E, Zuber M, Boulouis G, Naggara O,
2016;55:66–70. doi: 10.1093/rheumatology/kev289 Guillevin L, Aouba A, Pagnoux C. Treatment and long-term outcomes of
677. González-Gay MA, Blanco R, Rodríguez-Valverde V, Martínez-Taboada primary central nervous system vasculitis. Stroke. 2018;49:1946–1952.
VM, Delgado-Rodriguez M, Figueroa M, Uriarte E. Permanent visual doi: 10.1161/STROKEAHA.118.021878
loss and cerebrovascular accidents in giant cell arteritis: predictors and 696. Schuster S, Ozga AK, Stellmann JP, Deb-Chatterji M, Häußler V, Matschke
response to treatment. Arthritis Rheum. 1998;41:1497–1504. doi: J, Gerloff C, Thomalla G, Magnus T. Relapse rates and long-term outcome in
10.1002/1529-0131(199808)41:8<1497::AID-ART22>3.0.CO;2-Z primary angiitis of the central nervous system. J Neurol. 2019;266:1481–
678. Mazlumzadeh M, Hunder GG, Easley KA, Calamia KT, Matteson EL, Griffing 1489. doi: 10.1007/s00415-019-09285-1
WL, Younge BR, Weyand CM, Goronzy JJ. Treatment of giant cell arteri- 697. Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone
tis using induction therapy with high-dose glucocorticoids: a double-blind, JH, Salvarani C, Xu W, Visvanathan S, Rahman MU; Infliximab-GCA Study
placebo-controlled, randomized prospective clinical trial. Arthritis Rheum. Group. Infliximab for maintenance of glucocorticosteroid-induced remission
2006;54:3310–3318. doi: 10.1002/art.22163 of giant cell arteritis: a randomized trial. Ann Intern Med. 2007;146:621–
679. Lopez-Diaz MJ, Llorca J, Gonzalez-Juanatey C, Peña-Sagredo JL, 630. doi: 10.7326/0003-4819-146-9-200705010-00004
Martin J, Gonzalez-Gay MA. The erythrocyte sedimentation rate is as- 698. Liou TH, Huang SW, Lin JW, Chang YS, Wu CW, Lin HW. Risk of stroke
sociated with the development of visual complications in biopsy-proven in patients with rheumatism: a nationwide longitudinal population-based
giant cell arteritis. Semin Arthritis Rheum. 2008;38:116–123. doi: study. Sci Rep. 2014;4:5110. doi: 10.1038/srep05110
10.1016/j.semarthrit.2007.10.014 699. Stojan G, Petri M. Atherosclerosis in systemic lupus erythemato-
680. Fernández-Fernández E, Monjo-Henry I, Bonilla G, Plasencia C, sus. J Cardiovasc Pharmacol. 2013;62:255–262. doi: 10.1097/
Miranda-Carús ME, Balsa A, De Miguel E. False positives in the ultra- FJC.0b013e31829dd857
sound diagnosis of giant cell arteritis: some diseases can also show the 700. Moyssakis I, Tektonidou MG, Vasilliou VA, Samarkos M, Votteas V,
halo sign. Rheumatology (Oxford). 2020;59:2443–2447. doi: 10.1093/ Moutsopoulos HM. Libman-Sacks endocarditis in systemic lupus
rheumatology/kez641 erythematosus: prevalence, associations, and evolution. Am J Med.
681. van der Geest KSM, Borg F, Kayani A, Paap D, Gondo P, Schmidt W, 2007;120:636–642. doi: 10.1016/j.amjmed.2007.01.024
Luqmani RA, Dasgupta B. Novel ultrasonographic Halo Score for gi- 701. Fasano S, Pierro L, Pantano I, Iudici M, Valentini G. Longterm hydroxy-
ant cell arteritis: assessment of diagnostic accuracy and associa- chloroquine therapy and low-dose aspirin may have an additive effective-
tion with ocular ischaemia. Ann Rheum Dis. 2020;79:393–399. doi: ness in the primary prevention of cardiovascular events in patients with
10.1136/annrheumdis-2019-216343 systemic lupus erythematosus. J Rheumatol. 2017;44:1032–1038. doi:
682. Mahr AD, Jover JA, Spiera RF, Hernández-García C, Fernández-Gutiérrez 10.3899/jrheum.161351
Downloaded from http://ahajournals.org by on June 12, 2021
B, Lavalley MP, Merkel PA. Adjunctive methotrexate for treatment of gi- 702. Law ST, Ma KM, Li KK. Clinical characteristics of concurrent and se-
ant cell arteritis: an individual patient data meta-analysis. Arthritis Rheum. quentially presented lupus-related protein-losing enteropathy: what
2007;56:2789–2797. doi: 10.1002/art.22754 are their differences? Rheumatol Int. 2013;33:85–92. doi: 10.1007/
683. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, s00296-011-2356-2
Brouwer E, Cid MC, Dasgupta B, Rech J, et al. Trial of tocilizumab in giant-cell 703. Shapiro M, Levy Y. The association between hydroxychloroquine treat-
arteritis. N Engl J Med. 2017;377:317–328. doi: 10.1056/NEJMoa1613849 ment and cardiovascular morbidity among rheumatoid arthritis patients.
684. Villiger PM, Adler S, Kuchen S, Wermelinger F, Dan D, Fiege V, Bütikofer Oncotarget. 2018;9:6615–6622. doi: 10.18632/oncotarget.23570
L, Seitz M, Reichenbach S. Tocilizumab for induction and maintenance 704. Sharma TS, Wasko MCM, Tang X, Vedamurthy D, Yan X, Cote J, Bili A.
of remission in giant cell arteritis: a phase 2, randomised, double-blind, Hydroxychloroquine use is associated with decreased incident car-
placebo-controlled trial. Lancet. 2016;387:1921–1927. doi: 10.1016/ diovascular events in rheumatoid arthritis patients. J Am Heart Assoc.
S0140-6736(16)00560-2 2016;5:e002867. doi: 10.1161/JAHA.115.002867
685. Onen F, Akkoc N. Epidemiology of Takayasu arteritis. Presse Med. 705. Varona JF, Guerra JM, Bermejo F, Molina JA, Gomez de la Cámara A.
2017;46(pt 2):e197–e203. doi: 10.1016/j.lpm.2017.05.034 Causes of ischemic stroke in young adults, and evolution of the etio-
686. Bond KM, Nasr D, Lehman V, Lanzino G, Cloft HJ, Brinjikji W. Intracranial logical diagnosis over the long term. Eur Neurol. 2007;57:212–218. doi:
and extracranial neurovascular manifestations of Takayasu arteritis. AJNR 10.1159/000099161
Am J Neuroradiol. 2017;38:766–772. doi: 10.3174/ajnr.A5095 706. Emmi G, Silvestri E, Squatrito D, Amedei A, Niccolai E, D’Elios MM,
687. Hoffman GS, Leavitt RY, Kerr GS, Rottem M, Sneller MC, Fauci AS. Treatment Della Bella C, Grassi A, Becatti M, Fiorillo C, et al. Thrombosis in vas-
of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrex- culitis: from pathogenesis to treatment. Thromb J. 2015;13:15. doi:
ate. Arthritis Rheum. 1994;37:578–582. doi: 10.1002/art.1780370420 10.1186/s12959-015-0047-z
688. Valsakumar AK, Valappil UC, Jorapur V, Garg N, Nityanand S, Sinha N. Role 707. Weyand CM, Goronzy JJ. Immune mechanisms in medium and
of immunosuppressive therapy on clinical, immunological, and angiographic large-vessel vasculitis. Nat Rev Rheumatol. 2013;9:731–740. doi:
outcome in active Takayasu’s arteritis. J Rheumatol. 2003;30:1793–1798. 10.1038/nrrheum.2013.161
689. de Souza AW, de Almeida Agustinelli R, de Cinque Almeida H, Oliveira PB, 708. Stamatis P. Giant cell arteritis versus Takayasu arteritis: an update. Mediterr
Pinheiro FA, Oliveira AC, Sato EI. Leflunomide in Takayasu arteritis: a long J Rheumatol. 2020;31:174–182. doi: 10.31138/mjr.31.2.174
term observational study. Rev Bras Reumatol Engl Ed. 2016;56:371–375. 709. Hellmich B, Agueda A, Monti S, Buttgereit F, de Boysson H, Brouwer E,
doi: 10.1016/j.rbre.2016.02.003 Cassie R, Cid MC, Dasgupta B, Dejaco C, et al. 2018 Update of the EULAR
690. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumat- recommendations for the management of large vessel vasculitis. Ann
ica and giant-cell arteritis. N Engl J Med. 2002;347:261–271. doi: Rheum Dis. 2020;79:19–30. doi: 10.1136/annrheumdis-2019-215672
10.1056/NEJMra011913 710. Gutierrez J, Ortiz G. HIV/AIDS patients with HIV vasculopathy and
691. Salvarani C, Brown RD Jr, Calamia KT, Christianson TJ, Weigand SD, VZV vasculitis: a case series. Clin Neuroradiol. 2011;21:145–151. doi:
Miller DV, Giannini C, Meschia JF, Huston J 3rd, Hunder GG. Primary 10.1007/s00062-011-0087-0
central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 711. Lanthier S, Armstrong D, Domi T, deVeber G. Post-varicella arteriopathy of
2007;62:442–451. doi: 10.1002/ana.21226 childhood: natural history of vascular stenosis. Neurology. 2005;64:660–
692. Boulouis G, de Boysson H, Zuber M, Guillevin L, Meary E, Costalat V, 663. doi: 10.1212/01.WNL.0000151851.66154.27
Pagnoux C, Naggara O; French Vasculitis Group. Primary angiitis of 712. Nagel MA, Forghani B, Mahalingam R, Wellish MC, Cohrs RJ, Russman
the central nervous system: magnetic resonance imaging spectrum AN, Katzan I, Lin R, Gardner CJ, Gilden DH. The value of detecting
anti-VZV IgG antibody in CSF to diagnose VZV vasculopathy. Neurology. of positive syphilis serology and meningovascular neurosyphilis in patients
2007;68:1069–1073. doi: 10.1212/01.wnl.0000258549.13334.16 admitted with stroke and TIA from a culturally diverse population (2005-
CLINICAL STATEMENTS
713. Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC, Forghani B, Schiller A, 09). J Clin Neurosci. 2013;20:943–947. doi: 10.1016/j.jocn.2012.08.011
AND GUIDELINES
Safdieh JE, Kamenkovich E, Ostrow LW, Levy M, et al. The varicella zoster vi- 734. Mishra AK, Arvind VH, Muliyil D, Kuriakose CK, George AA, Karuppusami
rus vasculopathies: clinical, CSF, imaging, and virologic features. Neurology. R, Benton Carey RA, Mani S, Hansdak SG. Cerebrovascular in-
2008;70:853–860. doi: 10.1212/01.wnl.0000304747.38502.e8 jury in cryptococcal meningitis. Int J Stroke. 2018;13:57–65. doi:
714. Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC 3rd. 10.1177/1747493017706240
Treatment of adult varicella with oral acyclovir: a randomized, pla- 735. Workowski KA, Bolan GA; Centers for Disease Control and Prevention.
cebo-controlled trial. Ann Intern Med. 1992;117:358–363. doi: Sexually transmitted diseases treatment guidelines, 2015. MMWR
10.7326/0003-4819-117-5-358 Recomm Rep. 2015;64:1–137.
715. Blocker ME, Levine WC, St Louis ME. HIV prevalence in patients 736. Fonkem E, Dayawansa S, Stroberg E, Lok E, Bricker PC, Kirmani B,
with syphilis, United States. Sex Transm Dis. 2000;27:53–59. doi: Wong ET, Huang JH. Neurological presentations of intravascular lym-
10.1097/00007435-200001000-00011 phoma (IVL): meta-analysis of 654 patients. BMC Neurol. 2016;16:9. doi:
716. Callegari FM, Pinto-Neto LF, Medeiros CJ, Scopel CB, Page K, Miranda AE. 10.1186/s12883-015-0509-8
Syphilis and HIV co-infection in patients who attend an AIDS outpatient 737. Patil A, Shree R, Naheed D, Goyal MK, Mehta S, Ahuja CK, Radotra BD, Lal
clinic in Vitoria, Brazil. AIDS Behav. 2014;18(suppl 1):S104–S109. doi: V. Pearls & oy-sters: paraneoplastic cerebral vasculitis: rare cause of spon-
10.1007/s10461-013-0533-x taneous convexity subarachnoid hemorrhage. Neurology. 2018;90:e815–
717. Günthard HF, Aberg JA, Eron JJ, Hoy JF, Telenti A, Benson CA, Burger e817. doi: 10.1212/WNL.0000000000005025
DM, Cahn P, Gallant JE, Glesby MJ, et al; International Antiviral Society- 738. Quinones E, Potes LI, Silva N, Lobato-Polo J. Lymphomatoid granulomato-
USA Panel. Antiretroviral treatment of adult HIV infection: 2014 recom- sis of the brain: a case report. Surg Neurol Int. 2016;7(suppl 23):S612–
mendations of the International Antiviral Society-USA Panel. JAMA. S616. doi: 10.4103/2152-7806.189732
2014;312:410–425. doi: 10.1001/jama.2014.8722 739. Yap S, Naughten E. Homocystinuria due to cystathionine beta-synthase de-
718. Connor M. Human immunodeficiency virus (HIV) and stroke: tar- ficiency in Ireland: 25 years’ experience of a newborn screened and treat-
gets for intervention. Infect Disord Drug Targets. 2010;10:76–83. doi: ed population with reference to clinical outcome and biochemical control. J
10.2174/187152610790963483 Inherit Metab Dis. 1998;21:738–747. doi: 10.1023/a:1005445132327
719. Connor MD. Treatment of HIV associated cerebral vasculopathy. J Neurol 740. Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH. Vascular
Neurosurg Psychiatry. 2009;80:831. doi: 10.1136/jnnp.2008.169490 complications of severe hyperhomocysteinemia in patients with ho-
720. Cutfield NJ, Steele H, Wilhelm T, Weatherall MW. Successful treatment of mocystinuria due to cystathionine beta-synthase deficiency: effects of ho-
HIV associated cerebral vasculopathy with HAART. J Neurol Neurosurg mocysteine-lowering therapy. Semin Thromb Hemost. 2000;26:335–340.
Psychiatry. 2009;80:936–937. doi: 10.1136/jnnp.2008.165852 doi: 10.1055/s-2000-8100
721. Martínez-Longoria CA, Morales-Aguirre JJ, Villalobos-Acosta CP, 741. El Dib R, Gomaa H, Carvalho RP, Camargo SE, Bazan R, Barretti
Gómez-Barreto D, Cashat-Cruz M. Occurrence of intracerebral aneurysm P, Barreto FC. Enzyme replacement therapy for Anderson-Fabry
in an HIV-infected child: a case report. Pediatr Neurol. 2004;31:130–132. disease. Cochrane Database Syst Rev. 2016;7:CD006663. doi:
doi: 10.1016/j.pediatrneurol.2004.02.008 10.1002/14651858.CD006663.pub4
722. Benjamin LA, Allain TJ, Mzinganjira H, Connor MD, Smith C, Lucas S, 742. Germain DP, Elliott PM, Falissard B, Fomin VV, Hilz MJ, Jovanovic A,
Joekes E, Kampondeni S, Chetcuti K, Turnbull I, et al. The role of human Kantola I, Linhart A, Mignani R, Namdar M, et al. The effect of enzyme
immunodeficiency virus-associated vasculopathy in the etiology of stroke. replacement therapy on clinical outcomes in male patients with Fabry dis-
J Infect Dis. 2017;216:545–553. doi: 10.1093/infdis/jix340 ease: a systematic literature review by a European panel of experts. Mol
Downloaded from http://ahajournals.org by on June 12, 2021
723. Goldstein DA, Timpone J, Cupps TR. HIV-associated intracranial an- Genet Metab Rep. 2019;19:100454. doi: 10.1016/j.ymgmr.2019.100454
eurysmal vasculopathy in adults. J Rheumatol. 2010;37:226–233. doi: 743. Rolfs A, Böttcher T, Zschiesche M, Morris P, Winchester B, Bauer P, Walter
10.3899/jrheum.090643 U, Mix E, Löhr M, Harzer K, et al. Prevalence of Fabry disease in patients
724. Saraya T, Shimura C, Wada H, Aoshima M, Goto H. Evidence for vascular with cryptogenic stroke: a prospective study. Lancet. 2005;366:1794–
spread of varicella zoster-associated vasculopathy. Ann Intern Med. 2006; 1796. doi: 10.1016/S0140-6736(05)67635-0
144:535–537. doi: 10.7326/0003-4819-144-7-200604040-00022 744. Wozniak MA, Kittner SJ, Tuhrim S, Cole JW, Stern B, Dobbins M, Grace
725. WHO Secretariat. Chagas disease: control and elimination. 63th World ME, Nazarenko I, Dobrovolny R, McDade E, et al. Frequency of unrec-
Health Assembly. 2010. Provisional agenda item 11.14. Accessed ognized Fabry disease among young European-American and African-
December 1, 2019. https://apps.who.int/gb/ebwha/pdf_files/WHA63/ American men with first ischemic stroke. Stroke. 2010;41:78–81. doi:
A63_17-en.pdf 10.1161/STROKEAHA.109.558320
726. Carod-Artal FJ, Gascon J. Chagas disease and stroke. Lancet Neurol. 745. Bersano A, Kraemer M, Burlina A, Mancuso M, Finsterer J, Sacco
2010;9:533–542. doi: 10.1016/S1474-4422(10)70042-9 S, Salvarani C, Caputi L, Chabriat H, Oberstein SL, et al. Heritable
727. Lima-Costa MF, Matos DL, Ribeiro AL. Chagas disease predicts and non-heritable uncommon causes of stroke [published on-
10-year stroke mortality in community-dwelling elderly: the Bambui line April 21, 2020]. J Neurol. doi: 10.1007/s00415-020-09836-x.
Cohort Study of Aging. Stroke. 2010;41:2477–2482. doi: 10.1161/ https://link.springer.com/article/10.1007/s00415-020-09836-x
STROKEAHA.110.588061 746. Koga Y, Povalko N, Inoue E, Nakamura H, Ishii A, Suzuki Y, Yoneda M,
728. de Sousa AS, Xavier SS, Rodriguez de Freitas GR, Hasslocher-Moreno Kanda F, Kubota M, Okada H, et al. Therapeutic regimen of L-arginine
A. Prevention strategies of cardioembolic ischemic stroke in Chagas’ for MELAS: 9-year, prospective, multicenter, clinical research. J Neurol.
disease. Arq Bras Cardiol. 2008;91:306–310. doi: 10.1590/s0066- 2018;265:2861–2874. doi: 10.1007/s00415-018-9057-7
782x2008001700004 747. El-Hattab AW, Almannai M, Scaglia F. Arginine and citrulline for the treat-
729. Connor MD, Lammie GA, Bell JE, Warlow CP, Simmonds P, Brettle ment of MELAS syndrome. J Inborn Errors Metab Screen. 2017;5:10.1177
RD. Cerebral infarction in adult AIDS patients: observations from the /2326409817697399. doi: 10.1177/2326409817697399
Edinburgh HIV Autopsy Cohort. Stroke. 2000;31:2117–2126. doi: 748. Haussen DC, Grossberg JA, Bouslama M, Pradilla G, Belagaje S, Bianchi
10.1161/01.str.31.9.2117 N, Allen JW, Frankel M, Nogueira RG. Carotid web (intimal fibromuscular
730. Morgello S, Mahboob R, Yakoushina T, Khan S, Hague K. Autopsy find- dysplasia) has high stroke recurrence risk and is amenable to stenting.
ings in a human immunodeficiency virus-infected population over Stroke. 2017;48:3134–3137. doi: 10.1161/STROKEAHA.117.019020
2 decades: influences of gender, ethnicity, risk factors, and time. 749. Haussen DC, Grossberg JA, Koch S, Malik A, Yavagal D, Gory B, Leesch
Arch Pathol Lab Med. 2002;126:182–190. doi: 10.1043/0003- W, Hassan AE, Derelle AL, Richard S, et al. Multicenter experience with
9985(2002)126<0182:AFIAHI>2.0.CO;2 stenting for symptomatic carotid web. Interv Neurol. 2018;7:413–418. doi:
731. Misra UK, Kalita J, Maurya PK. Stroke in tuberculous meningitis. J Neurol 10.1159/000489710
Sci. 2011;303:22–30. doi: 10.1016/j.jns.2010.12.015 750. Zhang AJ, Dhruv P, Choi P, Bakker C, Koffel J, Anderson D, Kim J,
732. Anderson NE, Somaratne J, Mason DF, Holland D, Thomas MG. Jagadeesan B, Menon BK, Streib C. A systematic literature review of pa-
Neurological and systemic complications of tuberculous meningitis and tients with carotid web and acute ischemic stroke. Stroke. 2018;49:2872–
its treatment at Auckland City Hospital, New Zealand. J Clin Neurosci. 2876. doi: 10.1161/STROKEAHA.118.021907
2010;17:1114–1118. doi: 10.1016/j.jocn.2010.01.006 751. Coutinho JM, Derkatch S, Potvin AR, Tomlinson G, Casaubon LK, Silver FL,
733. Cordato DJ, Djekic S, Taneja SR, Maley M, Beran RG, Cappelen-Smith C, Mandell DM. Carotid artery web and ischemic stroke: a case-control study.
Griffith NC, Hanna IY, Hodgkinson SJ, Worthington JM, et al. Prevalence Neurology. 2017;88:65–69. doi: 10.1212/WNL.0000000000003464
752. Gornik HL, Persu A, Adlam D, Aparicio LS, Azizi M, Boulanger M, Bruno stroke: a population-based study. Neurology. 1998;50:1694–1698. doi:
RM, de Leeuw P, Fendrikova-Mahlay N, Froehlich J, et al. First international 10.1212/wnl.50.6.1694
CLINICAL STATEMENTS
consensus on the diagnosis and management of fibromuscular dysplasia. 770. Xu DS, Levitt MR, Kalani MYS, Rangel-Castilla L, Mulholland CB, Abecassis
AND GUIDELINES
Vasc Med. 2019;24:164–189. doi: 10.1177/1358863X18821816 IJ, Morton RP, Nerva JD, Siddiqui AH, Levy EI, et al. Dolichoectatic an-
753. Weinberg I, Gu X, Giri J, Kim SE, Bacharach MJ, Gray BH, Katzen BT, eurysms of the vertebrobasilar system: clinical and radiographic fac-
Matsumoto AH, Chi YW, Rogers KR, et al. Anti-platelet and anti-hyper- tors that predict poor outcomes. J Neurosurg. 2018;128:560–566. doi:
tension medication use in patients with fibromuscular dysplasia: results 10.3171/2016.10.JNS161041
from the United States Registry for Fibromuscular Dysplasia. Vasc Med. 771. Ubogu EE, Zaidat OO. Vertebrobasilar dolichoectasia diagnosed by mag-
2015;20:447–453. doi: 10.1177/1358863X15584982 netic resonance angiography and risk of stroke and death: a cohort study.
754. Smith LL, Smith DC, Killeen JD, Hasso AN. Operative balloon angioplasty J Neurol Neurosurg Psychiatry. 2004;75:22–26.
in the treatment of internal carotid artery fibromuscular dysplasia. J Vasc 772. Flemming KD, Wiebers DO, Brown RD Jr, Link MJ, Huston J 3rd,
Surg. 1987;6:482–487. doi: 10.1067/mva.1987.avs0060482 McClelland RL, Christianson TJ. The natural history of radiographically de-
755. Olin JW, Gornik HL, Bacharach JM, Biller J, Fine LJ, Gray BH, Gray WA, fined vertebrobasilar nonsaccular intracranial aneurysms. Cerebrovasc Dis.
Gupta R, Hamburg NM, Katzen BT, et al; on behalf of the American Heart 2005;20:270–279. doi: 10.1159/000087710
Association Council on Peripheral Vascular Disease; American Heart 773. Bhogal P, Pérez MA, Ganslandt O, Bäzner H, Henkes H, Fischer S.
Association Council on Clinical Cardiology; American Heart Association Treatment of posterior circulation non-saccular aneurysms with flow divert-
Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; ers: a single-center experience and review of 56 patients. J Neurointerv
American Heart Association Council on Cardiovascular Disease in Surg. 2017;9:471–481. doi: 10.1136/neurintsurg-2016-012781
the Young; American Heart Association Council on Cardiovascular 774. Siddiqui AH, Abla AA, Kan P, Dumont TM, Jahshan S, Britz GW, Hopkins
Radiology and Intervention; American Heart Association Council on LN, Levy EI. Panacea or problem: flow diverters in the treatment of symp-
Epidemiology and Prevention; American Heart Association Council tomatic large or giant fusiform vertebrobasilar aneurysms. J Neurosurg.
on Functional Genomics and Translational Biology; American Heart 2012;116:1258–1266. doi: 10.3171/2012.2.JNS111942
Association Council for High Blood Pressure Research; American Heart 775. Drake CG, Peerless SJ. Giant fusiform intracranial aneurysms: review
Association Council on the Kidney in Cardiovascular Disease; American of 120 patients treated surgically from 1965 to 1992. J Neurosurg.
Heart Association Stroke Council. Fibromuscular dysplasia: state of the 1997;87:141–162. doi: 10.3171/jns.1997.87.2.0141
science and critical unanswered questions: a scientific statement from 776. Anson JA, Lawton MT, Spetzler RF. Characteristics and surgical treatment
the American Heart Association. Circulation. 2014;129:1048–1078. doi: of dolichoectatic and fusiform aneurysms. J Neurosurg. 1996;84:185–
10.1161/01.cir.0000442577.96802.8c 193. doi: 10.3171/jns.1996.84.2.0185
756. Olin JW, Froehlich J, Gu X, Bacharach JM, Eagle K, Gray BH, 777. Coert BA, Chang SD, Do HM, Marks MP, Steinberg GK. Surgical and endo-
Jaff MR, Kim ES, Mace P, Matsumoto AH, et al. The United vascular management of symptomatic posterior circulation fusiform aneu-
States Registry for Fibromuscular Dysplasia: results in the first rysms. J Neurosurg. 2007;106:855–865. doi: 10.3171/jns.2007.106.5.855
447 patients. Circulation. 2012;125:3182–3190. doi: 10.1161/ 778. Zhang H, Shi M, Tong X. Treatment of symptomatic dolichoectatic verte-
CIRCULATIONAHA.112.091223 brobasilar aneurysms: a single-center experience with 12 patients. World
757. De Groote M, Van der Niepen P, Hemelsoet D, Callewaert B, Vermassen F, Neurosurg. 2018;119:e407–e416. doi: 10.1016/j.wneu.2018.07.176
Billiouw JM, De Vriese A, Donck J, De Backer T. Fibromuscular dysplasia: 779. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD,
results of a multicentre study in Flanders. Vasa. 2017;46:211–218. doi: Swaminathan B, Lavados P, Wang Y, Wang Y, et al; NAVIGATE ESUS
10.1024/0301-1526/a000613 Investigators. Rivaroxaban for stroke prevention after embolic stroke
758. Schievink WI. Spontaneous dissection of the carotid and verte- of undetermined source. N Engl J Med. 2018;378:2191–2201. doi:
Downloaded from http://ahajournals.org by on June 12, 2021
Device-Detected Sub-Clinical Atrial Fibrillation (ARTESiA) trial. Am Heart 805. Kheiri B, Osman M, Abdalla A, Haykal T, Swaid B, Ahmed S, Chahine A,
J. 2017;189:137–145. doi: 10.1016/j.ahj.2017.04.008 Hassan M, Bachuwa G, Al Qasmi M, et al. Clopidogrel and aspirin after
CLINICAL STATEMENTS
788. Ratajczak-Tretel B, Lambert AT, Johansen H, Halvorsen B, Bjerkeli V, ischemic stroke or transient ischemic attack: an updated systematic review
AND GUIDELINES
Russell D, Sandset EC, Ihle-Hansen H, Eriksen E, Næss H, et al. Atrial and meta-analysis of randomized clinical trials. J Thromb Thrombolysis.
fibrillation in cryptogenic stroke and transient ischaemic attack: the Nordic 2019;47:233–247. doi: 10.1007/s11239-018-1786-z
Atrial Fibrillation and Stroke (NOR-FIB) study: rationale and design. Eur 806. Patti G, Sticchi A, Bisignani A, Pelliccia F, Pasceri V, Speciale G, Penco M.
Stroke J. 2019;4:172–180. doi: 10.1177/2396987319837089 Meta-regression to identify patients deriving the greatest benefit from dual
789. De Schryver EL, Algra A, Kappelle LJ, van Gijn J, Koudstaal PJ. antiplatelet therapy after stroke or transient ischemic attack without throm-
Vitamin K antagonists versus antiplatelet therapy after transient isch- bolytic or thrombectomy treatment. Am J Cardiol. 2019;124:627–635. doi:
aemic attack or minor ischaemic stroke of presumed arterial origin. 10.1016/j.amjcard.2019.05.013
Cochrane Database Syst Rev. 2012;2012:CD001342. doi: 10.1002/ 807. Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans
14651858.CD001342.pub3 SR, Held P, Jonasson J, Minematsu K, Molina CA, et al; SOCRATES
790. Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Steering Committee and Investigators. Ticagrelor versus aspirin in acute
Albers GW, Pettigrew LC, Adams HP Jr, et al; Warfarin-Aspirin Recurrent stroke or transient ischemic attack. N Engl J Med. 2016;375:35–43. doi:
Stroke Study Group. A comparison of warfarin and aspirin for the preven- 10.1056/NEJMoa1603060
tion of recurrent ischemic stroke. N Engl J Med. 2001;345:1444–1451. 808. Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M,
doi: 10.1056/NEJMoa011258 Ladenvall P, Molina CA, Wang Y, Johnston SC. Ticagrelor added to aspirin
791. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. in acute ischemic stroke or transient ischemic attack in prevention of dis-
European Stroke Prevention Study, 2: dipyridamole and acetylsalicylic acid abling stroke: a randomized clinical trial. JAMA Neurol. 2020;78:1–9. doi:
in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13. doi: 10.1001/jamaneurol.2020.4396
10.1016/s0022-510x(96)00308-5 809. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG,
792. ESPRIT Study Group; Halkes PH, van Gijn J, Kappelle LJ, Koudstaal Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, et al;
PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral COMPASS Investigators. Rivaroxaban with or without aspirin in stable
ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. cardiovascular disease. N Engl J Med. 2017;377:1319–1330. doi:
2006;367:1665–1673. doi: 10.1016/S0140-6736(06)68734-5 10.1056/NEJMoa1709118
793. Kwok CS, Shoamanesh A, Copley HC, Myint PK, Loke YK, Benavente OR. 810. Joubert J, Reid C, Barton D, Cumming T, McLean A, Joubert L, Barlow J,
Efficacy of antiplatelet therapy in secondary prevention following lacunar Ames D, Davis S. Integrated care improves risk-factor modification after
stroke: pooled analysis of randomized trials. Stroke. 2015;46:1014–1023. stroke: initial results of the Integrated Care for the Reduction of Secondary
doi: 10.1161/STROKEAHA.114.008422 Stroke model. J Neurol Neurosurg Psychiatry. 2009;80:279–284. doi:
794. Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch 10.1136/jnnp.2008.148122
Y, Martin RH, Albers GW, Bath P, et al; PRoFESS Study Group. Aspirin and 811. Joubert J, Davis SM, Donnan GA, Levi C, Gonzales G, Joubert
extended-release dipyridamole versus clopidogrel for recurrent stroke. N L, Hankey GJ. ICARUSS: An effective model for risk factor man-
Engl J Med. 2008;359:1238–1251. doi: 10.1056/NEJMoa0805002 agement in stroke survivors. Int J Stroke. 2020;15:438–453. doi:
795. Albay CEQ, Leyson FGD, Cheng FC. Dual versus mono antiplatelet therapy 10.1177/1747493019830582
for acute non- cardio embolic ischemic stroke or transient ischemic at- 812. Irewall AL, Ögren J, Bergström L, Laurell K, Söderström L, Mooe T.
tack, an efficacy and safety analysis: updated meta-analysis. BMC Neurol. Nurse-led, telephone-based, secondary preventive follow-up after stroke
2020;20:224. doi: 10.1186/s12883-020-01808-y or transient ischemic attack improves blood pressure and LDL cho-
796. Naqvi IA, Kamal AK, Rehman H. Multiple versus fewer antiplatelet agents lesterol: results from the first 12 months of the randomized, controlled
Downloaded from http://ahajournals.org by on June 12, 2021
for preventing early recurrence after ischaemic stroke or transient isch- NAILED stroke risk factor trial. PLoS One. 2015;10:e0139997. doi:
aemic attack. Cochrane Database Syst Rev. 2020;8:CD009716. doi: 10.1371/journal.pone.0139997
10.1002/14651858.CD009716.pub2 813. Ögren J, Irewall AL, Söderström L, Mooe T. Long-term, telephone-based
797. Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James follow-up after stroke and TIA improves risk factors: 36-month results from
S, Knutsson M, Ladenvall P, Molina CA, Wang Y; THALES Investigators. the randomized controlled NAILED stroke risk factor trial. BMC Neurol.
Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N 2018;18:153. doi: 10.1186/s12883-018-1158-5
Engl J Med. 2020;383:207–217. doi: 10.1056/NEJMoa1916870 814. McAlister FA, Majumdar SR, Padwal RS, Fradette M, Thompson A,
798. Côté R, Zhang Y, Hart RG, McClure LA, Anderson DC, Talbert RL, Buck B, Dean N, Bakal JA, Tsuyuki R, Grover S, et al. Case manage-
Benavente OR. ASA failure: does the combination ASA/clopidogrel confer ment for blood pressure and lipid level control after minor stroke:
better long-term vascular protection? Neurology. 2014;82:382–389. doi: PREVENTION randomized controlled trial. CMAJ. 2014;186:577–584.
10.1212/WNL.0000000000000076 doi: 10.1503/cmaj.140053
799. Kim JT, Park MS, Choi KH, Cho KH, Kim BJ, Han MK, Park TH, Park SS, 815. Cheng EM, Cunningham WE, Towfighi A, Sanossian N, Bryg RJ,
Lee KB, Lee BC, et al. Different antiplatelet strategies in patients with Anderson TL, Barry F, Douglas SM, Hudson L, Ayala-Rivera M, et al.
new ischemic stroke while taking aspirin. Stroke. 2016;47:128–134. doi: Efficacy of a chronic care-based intervention on secondary stroke
10.1161/STROKEAHA.115.011595 prevention among vulnerable stroke survivors: a randomized con-
800. Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Antiplatelet trolled trial. Circ Cardiovasc Qual Outcomes. 2018;11:e003228. doi:
regimen for patients with breakthrough strokes while on aspirin: a sys- 10.1161/CIRCOUTCOMES.116.003228
tematic review and meta-Analysis. Stroke. 2017;48:2610–2613. doi: 816. Webster F, Saposnik G, Kapral MK, Fang J, O’Callaghan C, Hachinski V.
10.1161/STROKEAHA.117.017895 Organized outpatient care: stroke prevention clinic referrals are associated
801. Bath PM, Woodhouse LJ, Appleton JP, Beridze M, Christensen H, Dineen with reduced mortality after transient ischemic attack and ischemic stroke.
RA, Duley L, England TJ, Flaherty K, Havard D, et al; TARDIS Investigators. Stroke. 2011;42:3176–3182. doi: 10.1161/STROKEAHA.111.621524
Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopi- 817. Ireland SE, Arthur HM, Gunn EA, Oczkowski W. Stroke prevention care
dogrel alone or aspirin and dipyridamole in patients with acute cerebral delivery: predictors of risk factor management outcomes. Int J Nurs Stud.
ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. 2011;48:156–164. doi: 10.1016/j.ijnurstu.2010.07.003
Lancet. 2018;391:850–859. doi: 10.1016/S0140-6736(17)32849-0 818. Ranta A, Dovey S, Weatherall M, O’Dea D, Gommans J, Tilyard
802. Hao Q, Tampi M, O’Donnell M, Foroutan F, Siemieniuk RA, Guyatt G. M. Cluster randomized controlled trial of TIA electronic deci-
Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic sion support in primary care. Neurology. 2015;84:1545–1551. doi:
stroke or high risk transient ischaemic attack: systematic review and meta- 10.1212/WNL.0000000000001472
analysis. BMJ. 2018;363:k5108. doi: 10.1136/bmj.k5108 819. Brenner DA, Zweifler RM, Gomez CR, Kissela BM, Levine D, Howard G,
803. Rothwell PM, Cook NR, Gaziano JM, Price JF, Belch JFF, Roncaglioni Coull B, Howard VJ. Awareness, treatment, and control of vascular risk fac-
MC, Morimoto T, Mehta Z. Effects of aspirin on risks of vascular events tors among stroke survivors. J Stroke Cerebrovasc Dis. 2010;19:311–320.
and cancer according to bodyweight and dose: analysis of individual doi: 10.1016/j.jstrokecerebrovasdis.2009.07.001
patient data from randomised trials. Lancet. 2018;392:387–399. doi: 820. Hillen T, Coshall C, Tilling K, Rudd AG, McGovern R, Wolfe CD; South
10.1016/S0140-6736(18)31133-4 London Stroke Register. Cause of stroke recurrence is multifacto-
804. Ding L, Peng B. Efficacy and safety of dual antiplatelet therapy in the el- rial: patterns, risk factors, and outcomes of stroke recurrence in the
derly for stroke prevention: a systematic review and meta-analysis. Eur J South London Stroke Register. Stroke. 2003;34:1457–1463. doi:
Neurol. 2018;25:1276–1284. doi: 10.1111/ene.13695 10.1161/01.STR.0000072985.24967.7F
821. Kohok DD, Sico JJ, Baye F, Myers L, Coffing J, Kamalesh M, Bravata stroke transitional care: the COMPASS study. Circ Cardiovasc Qual Outcomes.
DM. Post-stroke hypertension control and receipt of health care services 2020;13:e006285. doi: 10.1161/CIRCOUTCOMES.119.006285
CLINICAL STATEMENTS
among veterans. J Clin Hypertens (Greenwich). 2018;20:382–387. doi: 839. Wechsler LR, Demaerschalk BM, Schwamm LH, Adeoye OM, Audebert
AND GUIDELINES
10.1111/jch.13194 HJ, Fanale CV, Hess DC, Majersik JJ, Nystrom KV, Reeves MJ, et al;
822. Mouradian MS, Majumdar SR, Senthilselvan A, Khan K, Shuaib A. How well on behalf of the American Heart Association Stroke Council; Council
are hypertension, hyperlipidemia, diabetes, and smoking managed after a on Epidemiology and Prevention; Council on Quality of Care and
stroke or transient ischemic attack? Stroke. 2002;33:1656–1659. doi: Outcomes Research. Telemedicine quality and outcomes in stroke: a sci-
10.1161/01.str.0000017877.62543.14 entific statement for healthcare professionals from the American Heart
823. Nguyen-Huynh MN, Hills NK, Sidney S, Klingman JG, Johnston SC. Association/American Stroke Association. Stroke. 2017;48:e3–e25. doi:
Race-ethnicity on blood pressure control after ischemic stroke: a pro- 10.1161/STR.0000000000000114
spective cohort study. J Am Soc Hypertens. 2017;11:38–44. doi: 840. Lawrence M, Pringle J, Kerr S, Booth J, Govan L, Roberts NJ. Multimodal
10.1016/j.jash.2016.11.002 secondary prevention behavioral interventions for TIA and stroke: a sys-
824. Ogilvie IM, Welner SA, Cowell W, Lip GY. Characterization of the proportion tematic review and meta-analysis. PLoS One. 2015;10:e0120902. doi:
of untreated and antiplatelet therapy treated patients with atrial fibrillation. 10.1371/journal.pone.0120902
Am J Cardiol. 2011;108:151–161. doi: 10.1016/j.amjcard.2011.02.353 841. Sakakibara BM, Kim AJ, Eng JJ. A systematic review and meta-analysis on
825. White CL, Pergola PE, Szychowski JM, Talbert R, Cervantes-Arriaga self-management for improving risk factor control in stroke patients. Int J
A, Clark HD, Del Brutto OH, Godoy IE, Hill MD, Pelegrí A, et al; SPS3 Behav Med. 2017;24:42–53. doi: 10.1007/s12529-016-9582-7
Investigators. Blood pressure after recent stroke: baseline findings 842. Barker-Collo S, Krishnamurthi R, Witt E, Feigin V, Jones A, McPherson
from the Secondary Prevention of Small Subcortical Strokes trial. Am J K, Starkey N, Parag V, Jiang Y, Barber PA, et al. Improving adherence
Hypertens. 2013;26:1114–1122. doi: 10.1093/ajh/hpt076 to secondary stroke prevention strategies through motivational inter-
826. Johansson T, Wild C. Telemedicine in acute stroke management: system- viewing: randomized controlled trial. Stroke. 2015;46:3451–3458. doi:
atic review. Int J Technol Assess Health Care. 2010;26:149–155. doi: 10.1161/STROKEAHA.115.011003
10.1017/S0266462310000139 843. Kamal AK, Shaikh Q, Pasha O, Azam I, Islam M, Memon AA, Rehman H,
827. Lyerly MJ, Wu TC, Mullen MT, Albright KC, Wolff C, Boehme AK, Branas Akram MA, Affan M, Nazir S, et al. A randomized controlled behavioral in-
CC, Grotta JC, Savitz SI, Carr BG. The effects of telemedicine on racial tervention trial to improve medication adherence in adult stroke patients
and ethnic disparities in access to acute stroke care. J Telemed Telecare. with prescription tailored short messaging service (SMS): SMS4Stroke
2016;22:114–120. doi: 10.1177/1357633X15589534 study. BMC Neurol. 2015;15:212. doi: 10.1186/s12883-015-0471-5
828. Stroke Unit Trialists’ Collaboration. Organised inpatient (stroke unit) 844. Cuccurullo SJ, Fleming TK, Kostis WJ, Greiss C, Gizzi MS, Eckert A, Ray
care for stroke. Cochrane Database Syst Rev. 2007:CD000197. doi: AR, Scarpati R, Cosgrove NM, Beavers T, et al. Impact of a stroke recovery
10.1002/14651858.CD000197.pub2 program integrating modified cardiac rehabilitation on all-cause mortality,
829. Bridgwood B, Lager KE, Mistri AK, Khunti K, Wilson AD, Modi P. cardiovascular performance and functional performance. Am J Phys Med
Interventions for improving modifiable risk factor control in the secondary Rehabil. 2019;98:953–963. doi: 10.1097/PHM.0000000000001214
prevention of stroke. Cochrane Database Syst Rev. 2018;5:CD009103. 845. Olaiya MT, Cadilhac DA, Kim J, Nelson MR, Srikanth VK, Gerraty RP,
doi: 10.1002/14651858.CD009103.pub3 Bladin CF, Fitzgerald SM, Phan T, Frayne J, et al. Community-based in-
830. Wensing M, Wollersheim H, Grol R. Organizational interventions to im- tervention to improve cardiometabolic targets in patients with stroke: a
plement improvements in patient care: a structured review of reviews. randomized controlled trial. Stroke. 2017;48:2504–2510. doi: 10.1161/
Implement Sci. 2006;1:2. doi: 10.1186/1748-5908-1-2 STROKEAHA.117.017499
831. Ormseth CH, Sheth KN, Saver JL, Fonarow GC, Schwamm LH. The 846. O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, Rao-Melacini
Downloaded from http://ahajournals.org by on June 12, 2021
American Heart Association’s Get With The Guidelines (GWTG)-Stroke P, Zhang X, Pais P, Agapay S, et al; INTERSTROKE Investigators. Global
development and impact on stroke care. Stroke Vasc Neurol. 2017;2:94– and regional effects of potentially modifiable risk factors associated with
105. doi: 10.1136/svn-2017-000092 acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet.
832. Ireland S, MacKenzie G, Gould L, Dassinger D, Koper A, LeBlanc K. Nurse 2016;388:761–775. doi: 10.1016/S0140-6736(16)30506-2
case management to improve risk reduction outcomes in a stroke preven- 847. Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR,
tion clinic. Can J Neurosci Nurs. 2010;32:7–13. Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, et al; American
833. Sharrief AZ, Hinojosa E, Cooksey G, Okpala MN, Avritscher EB, Pedroza Heart Association Council on Epidemiology and Prevention Statistics
C, Denny MC, Samuels J, Tyson JE, Savitz SI. Does care in a special- Committee and Stroke Statistics Subcommittee. Heart disease and stroke
ised stroke prevention clinic improve poststroke blood pressure control: statistics–2018 update: a report from the American Heart Association
a protocol for a randomised comparative effectiveness study. BMJ Open. [published correction appears in Circulation. 2018;137:e493]. Circulation.
2019;9:e024695. doi: 10.1136/bmjopen-2018-024695 2018;137:e67–e492. doi: 10.1161/CIR.0000000000000558
834. Dromerick AW, Gibbons MC, Edwards DF, Farr DE, Giannetti ML, Sánchez 848. Riegel B, Moser DK, Buck HG, Dickson VV, Dunbar SB, Lee CS,
B, Shara NM, Fokar A, Jayam-Trouth A, Ovbiagele B, et al. Preventing Lennie TA, Lindenfeld J, Mitchell JE, Treat-Jacobson DJ, et al. Self-
recurrence of thromboembolic events through coordinated treatment in care for the prevention and management of cardiovascular disease
the District of Columbia. Int J Stroke. 2011;6:454–460. doi: 10.1111/j. and stroke: a scientific statement for healthcare professionals from the
1747-4949.2011.00654.x American Heart Association. J Am Heart Assoc. 2017;6:e006997. doi:
835. Toell T, Boehme C, Mayer L, Krebs S, Lang C, Willeit K, Prantl B, 10.1161/JAHA.117.006997
Knoflach M, Rumpold G, Schoenherr G, et al. Pragmatic trial of mul- 849. Lennon O, Blake C, Booth J, Pollock A, Lawrence M. Interventions for
tifaceted intervention (STROKE-CARD care) to reduce cardiovascular behaviour change and self-management in stroke secondary preven-
risk and improve quality-of-life after ischaemic stroke and transient tion: protocol for an overview of reviews. Syst Rev. 2018;7:231. doi:
ischaemic attack -study protocol. BMC Neurol. 2018;18:187. doi: 10.1186/s13643-018-0888-1
10.1186/s12883-018-1185-2 850. Linden B. NICE public health guidance: individual approaches to behaviour
836. Leistner S, Michelson G, Laumeier I, Ahmadi M, Smyth M, Nieweler G, change. Br J Card Nurs. 2014;9:112–113.
Doehner W, Sobesky J, Fiebach JB, Marx P, et al. Intensified Secondary 851. Lawrence M, Asaba E, Duncan E, Elf M, Eriksson G, Faulkner J,
Prevention Intending a Reduction of Recurrent Events in TIA and Minor Guidetti S, Johansson B, Kruuse C, Lambrick D, et al. Stroke second-
Stroke Patients (INSPiRE-TMS): a protocol for a randomised controlled ary prevention, a non-surgical and non-pharmacological consensus
trial. BMC Neurol. 2013;13:11. doi: 10.1186/1471-2377-13-11 definition: results of a Delphi study. BMC Res Notes. 2019;12:823. doi:
837. Cheng EM, Cunningham WE, Towfighi A, Sanossian N, Bryg RJ, 10.1186/s13104-019-4857-0
Anderson TL, Guterman JJ, Gross-Schulman SG, Beanes S, Jones AS, 852. Oikarinen A, Engblom J, Kyngäs H, Kääriäinen M. A study of the relation-
et al. Randomized, controlled trial of an intervention to enable stroke ship between the quality of lifestyle counselling and later adherence to
survivors throughout the Los Angeles County safety net to “stay with the lifestyle changes based on patients with stroke and TIA. Clin Rehabil.
the guidelines.” Circ Cardiovasc Qual Outcomes. 2011;4:229–234. doi: 2018;32:557–567. doi: 10.1177/0269215517733794
10.1161/CIRCOUTCOMES.110.951012 853. Kronish IM, Diefenbach MA, Edmondson DE, Phillips LA, Fei K, Horowitz
838. Duncan PW, Bushnell CD, Jones SB, Psioda MA, Gesell SB, D’Agostino CR. Key barriers to medication adherence in survivors of strokes and
RB Jr, Sissine ME, Coleman SW, Johnson AM, Barton-Percival BF, et al; transient ischemic attacks. J Gen Intern Med. 2013;28:675–682. doi:
COMPASS Site Investigators and Teams. Randomized pragmatic trial of 10.1007/s11606-012-2308-x
854. Anderson L, Oldridge N, Thompson DR, Zwisler AD, Rees K, Martin N, 868. Harrington RA, Califf RM, Balamurugan A, Brown N, Benjamin RM, Braund
Taylor RS. Exercise-based cardiac rehabilitation for coronary heart dis- WE, Hipp J, Konig M, Sanchez E, Joynt Maddox KE. Call to action: ru-
CLINICAL STATEMENTS
ease: Cochrane systematic review and meta-analysis. J Am Coll Cardiol. ral health: a presidential advisory from the American Heart Association
AND GUIDELINES
2016;67:1–12. doi: 10.1016/j.jacc.2015.10.044 and American Stroke Association. Circulation. 2020;141:e615–e644. doi:
855. Mackay-Lyons M, Thornton M, Ruggles T, Che M. Non-pharmacological 10.1161/CIR.0000000000000753
interventions for preventing secondary vascular events after stroke or tran- 869. Caceres BA, Streed CG Jr, Corliss HL, Lloyd-Jones DM, Matthews PA,
sient ischemic attack. Cochrane Database Syst Rev. 2013:CD008656. Mukherjee M, Poteat T, Rosendale N, Ross LM; on behalf of the American
856. Feldman PH, McDonald MV, Trachtenberg M, Trifilio M, Onorato N, Heart Association Council on Cardiovascular and Stroke Nursing; Council
Sridharan S, Silver S, Eimicke J, Teresi J. Reducing hypertension in a on Hypertension; Council on Lifestyle and Cardiometabolic Health; Council
poststroke black and hispanic home care population: results of a prag- on Peripheral Vascular Disease; and Stroke Council. Assessing and ad-
matic randomized controlled trial. Am J Hypertens. 2020;33:362–370. doi: dressing cardiovascular health in LGBTQ adults: a scientific statement
10.1093/ajh/hpz148 from the American Heart Association. Circulation. 2020;142:e321–e332.
857. Boden-Albala B, Goldmann E, Parikh NS, Carman H, Roberts ET, Lord doi: 10.1161/CIR.0000000000000914
AS, Torrico V, Appleton N, Birkemeier J, Parides M, et al. Efficacy of a 870. Addo J, Ayerbe L, Mohan KM, Crichton S, Sheldenkar A, Chen R, Wolfe CD,
discharge educational strategy vs standard discharge care on reduction McKevitt C. Socioeconomic status and stroke: an updated review. Stroke.
of vascular risk in patients with stroke and transient ischemic attack: the 2012;43:1186–1191. doi: 10.1161/STROKEAHA.111.639732
DESERVE randomized clinical trial. JAMA Neurol. 2019;76:20–27. doi: 871. Marshall IJ, Wang Y, Crichton S, McKevitt C, Rudd AG, Wolfe CD. The ef-
10.1001/jamaneurol.2018.2926 fects of socioeconomic status on stroke risk and outcomes. Lancet Neurol.
858. Kronish IM, Goldfinger JZ, Negron R, Fei K, Tuhrim S, Arniella G, 2015;14:1206–1218. doi: 10.1016/S1474-4422(15)00200-8
Horowitz CR. Effect of peer education on stroke prevention: the pre- 872. Avan A, Digaleh H, Di Napoli M, Stranges S, Behrouz R, Shojaeianbabaei
vent recurrence of all inner-city strokes through education random- G, Amiri A, Tabrizi R, Mokhber N, Spence JD, et al. Socioeconomic status
ized controlled trial. Stroke. 2014;45:3330–3336. doi: 10.1161/ and stroke incidence, prevalence, mortality, and worldwide burden: an eco-
STROKEAHA.114.006623 logical analysis from the Global Burden of Disease Study 2017. BMC Med.
859. Towfighi A, Cheng EM, Ayala-Rivera M, McCreath H, Sanossian N, 2019;17:191. doi: 10.1186/s12916-019-1397-3
Dutta T, Mehta B, Bryg R, Rao N, Song S, et al. Randomized controlled 873. Schultz WM, Kelli HM, Lisko JC, Varghese T, Shen J, Sandesara P,
trial of a coordinated care intervention to improve risk factor control af- Quyyumi AA, Taylor HA, Gulati M, Harold JG, et al. Socioeconomic status
ter stroke or transient ischemic attack in the safety net: Secondary and cardiovascular outcomes: challenges and interventions. Circulation.
stroke prevention by Uniting Community and Chronic care model teams 2018;137:2166–2178. doi: 10.1161/CIRCULATIONAHA.117.029652
Early to End Disparities (SUCCEED). BMC Neurol. 2017;17:24. doi: 874. Trivedi AN, Nsa W, Hausmann LR, Lee JS, Ma A, Bratzler DW, Mor MK,
10.1186/s12883-017-0792-7 Baus K, Larbi F, Fine MJ. Quality and equity of care in U.S. hospitals. N Engl
860. Churchwell K, Elkind MSV, Benjamin RM, Carson AP, Chang EK, J Med. 2014;371:2298–2308. doi: 10.1056/NEJMsa1405003
Lawrence W, Mills A, Odom TM, Rodriguez CJ, Rodriguez F, et al; 875. Beauchamp A, Peeters A, Tonkin A, Turrell G. Best practice for pre-
American Heart Association. Call to action: structural racism as a fun- vention and treatment of cardiovascular disease through an equity
damental driver of health disparities: a presidential advisory from the lens: a review. Eur J Cardiovasc Prev Rehabil. 2010;17:599–606. doi:
American Heart Association. Circulation. 2020;142:e454–e468. doi: 10.1097/HJR.0b013e328339cc99
10.1161/CIR.0000000000000936 876. Malambo P, Kengne AP, De Villiers A, Lambert EV, Puoane T. Built en-
861. Lawrence K, Keleher T. Structural Racism. Paper presented at: Race and vironment, selected risk factors and major cardiovascular disease
Public Policy Conference; November 11–13, 2004; Berkeley, CA. outcomes: a systematic review. PLoS One. 2016;11:e0166846. doi:
Downloaded from http://ahajournals.org by on June 12, 2021
862. Lisabeth LD, Smith MA, Brown DL, Moyé LA, Risser JM, Morgenstern LB. 10.1371/journal.pone.0166846
Ethnic differences in stroke recurrence. Ann Neurol. 2006;60:469–475. 877. Billioux AK, Verlander K, Anthony S, Alley D. 2017. Standardized screening
doi: 10.1002/ana.20943 for health-related social needs in clinical settings: the accountable health
863. Park JH, Ovbiagele B. Association of black race with recurrent stroke risk. communities screening tool. NAM Perspectives. Discussion Paper, National
J Neurol Sci. 2016;365:203–206. doi: 10.1016/j.jns.2016.04.012 Academy of Medicine, Washington, DC. Accessed December 1, 2019.
864. Schwamm LH, Reeves MJ, Pan W, Smith EE, Frankel MR, Olson D, https://doi.org/10.31478/201705b
Zhao X, Peterson E, Fonarow GC. Race/ethnicity, quality of care, and 878. Morgenstern LB, Dohodwala N, Frontera-Roura W, Nath A, Ovbiagele B,
outcomes in ischemic stroke. Circulation. 2010;121:1492–1501. doi: Ramirez A, Trevathan E, Vickrey B. Report from the Strategic Planning
10.1161/CIRCULATIONAHA.109.881490 Advisory Panel on Health Disparities: report of the NINDS Advisory
865. Kim O, Ovbiagele B, Valle N, Markovic D, Towfighi A. Race-ethnic Panel on Health Disparities Research. 2010. Accessed December 1,
disparities in cardiometabolic risk profiles among stroke survivors 2019. https://www.ninds.nih.gov/sites/default/files/NINDS_health_
with undiagnosed diabetes and prediabetes in the United States. disparities_rpt.pdf
J Stroke Cerebrovasc Dis. 2017;26:2727–2733. doi: 10.1016/j. 879. Brega A, Barnard J, Mabachi N, Weiss B, DeWalt D, Brach C, Cifuentes M,
jstrokecerebrovasdis.2017.06.037 Albright K, West D. AHRQ Health Literacy Universal Precautions Toolkit.
866. Cruz-Flores S, Rabinstein A, Biller J, Elkind MS, Griffith P, Gorelick PB, Accessed December 1, 2019. https://www.ahrq.gov/sites/default/files/
Howard G, Leira EC, Morgenstern LB, Ovbiagele B, et al; on behalf of wysiwyg/professionals/quality-patient-safety/quality-resources/tools/
American Heart Association Stroke Council; Council on Cardiovascular literacy-toolkit/healthlittoolkit2.pdf
Nursing; Council on Epidemiology and Prevention; Council on Quality of 880. Magnani JW, Mujahid MS, Aronow HD, Cené CW, Dickson VV, Havranek
Care and Outcomes Research. Racial-ethnic disparities in stroke care: E, Morgenstern LB, Paasche-Orlow MK, Pollak A, Willey JZ; on behalf of
the American experience: a statement for healthcare professionals from the American Heart Association Council on Epidemiology and Prevention;
the American Heart Association/American Stroke Association. Stroke. Council on Cardiovascular Disease in the Young; Council on Cardiovascular
2011;42:2091–2116. doi: 10.1161/STR.0b013e3182213e24 and Stroke Nursing; Council on Peripheral Vascular Disease; Council on
867. Reeves MJ, Fonarow GC, Zhao X, Smith EE, Schwamm LH; Get With Quality of Care and Outcomes Research; and Stroke Council. Health literacy
The Guidelines-Stroke Steering Committee and Investigators. Quality and cardiovascular disease: fundamental relevance to primary and second-
of care in women with ischemic stroke in the GWTG program. Stroke. ary prevention: a scientific statement from the American Heart Association.
2009;40:1127–1133. doi: 10.1161/STROKEAHA.108.543157 Circulation. 2018;137:e48– e74. doi: 10.1161/CIR.0000000000000579