Stroke Prevention 2019

Helmi Lutsep, MD
Vice Chair and Dixon Term Professor,
Department of Neurology, Oregon Health & Science University
Chief of Neurology, VA Portland Health Care System
 Disclosures

Stroke Adjudication Committee, CREST2, NINDS/Mayo

Consultant, Abbott Vascular, Inc.
National Leader, Steering Committee, Bristol Myers Squib
Physician Advisory Board, Coherex Medical
Editorial Board, Medscape Neurology
 Stroke Prevention: Overview

• Small vessel disease

• Large vessel stenosis
• Cryptogenic stroke
• Selection of patients for PFO closure
• Neurologist’s perspective on atrial fibrillation
Causes of Ischemic Stroke

Lancet Neurol 2014;13:429–38

Small Vessel Disease
 Stroke Prevention
Large Small Cryptogenic Cardiogenic
vessel vessel source
stenosis disease
>50%
If internal carotid
artery stenotic,
consider
revascularization

Risk factor Risk factor control,

control, anticoagulation
antiplatelet (antiplatelet or
agent closure for PFO)
 Small Vessel Disease

• Due to thrombosis of a small

perforating artery
– lnfarction deep to the cortex
• Generally <1.5 cm
• Often result in pure
syndromes i.e. pure sensory
or pure motor
 Blood Pressure in Lacunar Strokes

SPS3 Trial
• Lacunar strokes (n=3020) followed mean of 3.7
years
• Blood pressure target of 130-149 systolic vs <130
• Showed strong trend for reduced strokes in lower
blood pressure group (p=0.08)

The Lancet 2013; 382:507-515

 Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

Goals for target BP level or reduction from

pretreatment baseline are uncertain and should
be individualized, but it is reasonable to achieve
a systolic pressure <140 mm Hg and a diastolic
pressure <90 mm Hg (Class IIa; Level of Evidence
B).
For patients with a recent lacunar stroke, it might
be reasonable to target a systolic BP of <130 mm
Hg (Class IIb; Level of Evidence B).
Stroke 2014;45:2160-2236
 Dual Antiplatelets in Lacunar Strokes
SPS3 trial other arm
• Clopidogrel plus aspirin vs aspirin alone
DSMB terminated antiplatelet combination
therapy due to risks and futility
• Risk of major hemorrhage nearly doubled with dual
antiplatelet therapy (p<0.001) and mortality increased
(p=0.004)

NEJM 2012;367:817-25
Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

“The combination of aspirin and clopidogrel …

increases the risk of hemorrhage… and is not
recommended for routine long-term secondary
prevention…”

Stroke 2014;45:2160-2236
 Clicker Question

How long should dual antiplatelet therapy with

aspirin and clopidogrel be continued after an acute
minor stroke or TIA?
A. 21 days
B. 6 months
C. 1 year
Short-Term Dual Antiplatelet (DAPT) Use
CHANCE trial (China)
• Minor stroke and TIA patients randomized within 24
hours
• Randomized to either DAPT for 21 days and then
clopidogrel alone for rest of 90 days, or aspirin alone
for 90 days
• Ischemic or hemorrhagic stroke occurred less often
in DAPT group (8.6% vs 11.7%)

NEJM 2013; 269:11-19

Short-Term Dual Antiplatelet (DAPT) Use
POINT trial (U.S.)
• Minor stroke and TIA patients randomized within 12
hours
• Received either DAPT or to aspirin alone for 90
days
• Results showed benefit, although with an
increased risk of major hemorrhage
– Treat 1000 patients to prevent 15 ischemic strokes and
cause 5 major hemorrhages

NEJM 2018;379:215-225
Short-Term Dual Antiplatelet (DAPT) Use

POINT trial secondary analysis

• Benefit of clopidogrel-aspirin occurred
predominantly within the first 21 says
• Risk of major hemorrhage remained relatively
constant over 90 days
• For 1000 patients treated for 21 days with DAPT,
prevent 20 major ischemic events and cause 2
major hemorrhages

Circulation 2019;140:658-664
 Sweet Spot for DAPT Duration
Meta-analysis of CHANCE, FASTER and POINT
• Clopidogrel-aspirin started within 24 hours of
symptom onset reduced recurrent stroke risk
compared to aspirin alone (1.9% ARR, CI 0.61-0.80)
• DAPT was associated with a likely increase in
moderate or severe extracranial bleeding (ARI 0.2%,
CI 0.92-3.20)
• Most stroke events occurred within 10 days of
randomization and any benefit after 21 days was
extremely unlikely
BMJ 2018;363:k5108
 Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

The combination of aspirin and clopidogrel might be

considered for initiation within 24 hours of a minor
ischemic stroke or TIA and for continuation for 90
days (Class Iib; Level of Evidence B)
DAPT continuation for just 21 days

NEJM 2013; 269:11-19; Stroke 2014;45:2160-2236

 Stroke Prevention
Large Small Cryptogenic Cardiogenic
vessel vessel source
stenosis disease
>50%
If internal carotid
artery stenotic,
consider
revascularization

Risk factor Risk factor control,

control, anticoagulation
antiplatelet (antiplatelet or
agent closure for PFO)
 Intracranial Stenosis

*May be the most common cause of stroke worldwide

*Stroke 2008; 39: 2396-2399

 Clicker Question

Should a stent be placed in a 75 year old woman

with severe left middle cerebral artery stenosis and 3
episodes of word finding difficulty despite aspirin?
A. Yes
B. No
 Trial To Explore
Stenting Versus Medical Therapy
SAMMPRIS: Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis

• Patients with stroke or TIA within 30 days attributed

to high grade stenosis of a major intracranial artery
• Study compared stenting plus aggressive medical
management to aggressive medical management
alone
• Outcomes were stroke or death within 30 days, or
strokes in the territory of the qualifying artery
beyond 30 days
NEJM 2011;365:993-1003; Lancet 2014;383:333-41
 SAMMPRIS Randomized Trial
Enrollment halted for high 30-day stroke/death rate in
stenting group after 451 patients were in the trial
30-Day Stroke and Death Rate

14.70% p=0.002

5.80%

Stenting Risk factor control

alone
• Patients continued to be followed
NEJM 2011;365:993-1003
SAMMPRIS: Final Results Show Medical
Therapy Alone Better Than Stenting

More strokes in
group that received
stents (in red)

Lancet 2014;383:333-41
 Implementing Aggressive Medical
Management
Antiplatelet agents
• Aspirin for entire follow-up, clopidogrel for 90 days
Aggressive risk factor management
• Systolic blood pressure <140 mm Hg
• Low density lipoprotein (LDL) <70 mg/dl
• Diabetes control, Hemoglobin A1C <7.0%
• Lifestyle modification
– Exercise, smoking cessation, weight management
Lancet 2014;383:333-41; Stroke 2014;45:2160-2236
 Clicker Question

Treatment of which risk factor was the strongest

predictor of good outcome in intracranial stenosis?
A. Hypertension
B. Hyperlipidemia
C. Lack of exercise
 Risk Factors and Outcomes in
SAMMPRIS
• Reduction of blood pressure and lipid control
were important for reducing vascular events
• However, physical activity was the strongest
predictor of good outcome in the medical arm of
SAMMPRIS
– Recommended at least 30 minutes of moderate intensity
physical exercise most days

Neurology 2017;88:1-7
Carotid Artery Stenosis
Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

Asymptomatic carotid stenosis:

• “It is reasonable to consider performing CEA in
asymptomatic patients who have >70% stenosis of the
ICA if the risk of perioperative stroke, MI, and death is
low (<3%). However, its effectiveness compared with
contemporary best medical management alone is not
well established.
• Prophylactic CAS might be considered in highly
selected patients with asymptomatic carotid stenosis …
but its effectiveness compared with medical therapy
alone in this situation is not well established.”

Stroke 2014;45:3754-3832
 Asymptomatic Carotid Stenosis

CREST 2 trial enrolling (NINDS funded):

• Asymptomatic carotid artery stenosis
• Revascularization plus intensive medical
management versus medical management alone

ClinicalTrials.gov
Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA
Symptomatic carotid stenosis:
• “For patients with a TIA or ischemic stroke within the
past 6 months and ipsilateral severe (70%–99%) carotid
artery stenosis… carotid endarterectomy (CEA) is
recommended if the perioperative morbidity and
mortality risk is estimated to be <6%.”
• “For patients with recent TIA or ischemic stroke and
ipsilateral moderate (50%–69%)…CEA is recommended
depending on patient-specific factors…”
• “Carotid artery stenting (CAS) is indicated as an
alternative to CEA for symptomatic patients at average
or low risk of complications associated with
endovascular intervention…”
Stroke 2014;45:3754-3832
Cryptogenic Stroke
 Stroke Prevention
Large Small Cryptogenic Cardiogenic
vessel vessel source
stenosis disease
>50%
If internal carotid
artery stenotic,
consider
revascularization

Risk factor Risk factor control,

control, anticoagulation
antiplatelet (antiplatelet or
agent closure for PFO)
 What is a Cryptogenic Stroke?
• Stroke for which the cause is not found
– Excludes strokes presumed due to small vessel disease,
arterial stenosis of ≥ 50%, major or medium risk
cardioembolic or other causes (such as dissection)
• Accounts for 25% of ischemic strokes

Lancet Neurol 2014;13:429–38

 How Should We Monitor for Atrial
Fibrillation in Cryptogenic Stroke?
30-day event monitor vs second 24-hr monitor
• Patients aged 55 years or older
• Stroke in previous 6 mos; had had 24 hrs monitoring
• AF occurred in 16.1% with 30-day monitor vs 3.2%
6-month insertable monitor vs M.D. discretion
• Patients aged 40 years or older
• Stroke in previous 3 mos; had had 24 hrs monitoring
• AF occurred in 8.9% vs 1.4% (by 12 mos 12.4% vs 2.0%)
NEJM 2014;370:2467-77; NEJM 2014;370:2478-86
 Monitoring For AF – Zio Patch

Review of manufacturer’s monitoring data with

indication of TIA or stroke (n=1171)
• Median monitor wear time was 13.0 days
• Median analyzable time relative to wear time 98.7%
Atrial fibrillation present in 5% of the reports
• 14.3% occurred after the first 48 hours
Frontiers in Neurology; published 12 January 2015
Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

For patients who have experienced an acute

ischemic stroke or TIA with no other apparent
cause, prolonged rhythm monitoring (≈30 days) for
AF is reasonable within 6 months of the index event
(Class IIa, Level of Evidence C).

Stroke 2014;45:2160-2236
 Focused Update of 2014
AHA/ACC/HRS Guideline for
Management of Patients with AF

New:
In patients with cryptogenic stroke (i.e., stroke of
unknown cause) in whom external ambulatory
monitoring is inconclusive, implantation of a
cardiac monitor (loop recorder) is reasonable to
optimize detection of silent AF (IIa, B-R)

Circulation 2019;140:e125-e151
 What is an Embolic Stroke of
Undetermined Source (ESUS)?

• A subset of cryptogenic strokes

• Don’t have a major-risk cardioembolic source but
can have medium-risk cardiac source
– The excluded major risk cardioembolic sources include
AF and left ventricular thrombi

Lancet Neurol 2014;13:429–38

 ESUS: Causes May Be Embolic
• Some potential causes have sufficiently low
inherent risk of thromboembolism that causal role
of stroke at patient level is unclear
Cardiac
• PFO, valvular disease, LV dysfunction
• Rhythm abnormalities: brief AF, sick sinus, etc.
Arterial
• Cerebral artery non-stenotic plaque with ulceration
or aortic arch atherosclerotic plaque

Lancet Neurol 2014;13:429–38

 NOAC No Better Than Aspirin in ESUS
NAVIGATE ESUS
• Recurrent stroke risk, percent per year
– Rivaroxaban 5.1% vs. aspirin 4.8%, p=0.52
• Major bleeding, percent per year
– Rivaroxaban 1.8% vs. aspirin 0.7%, p<0.001
RESPECT ESUS
• Recurrent stroke risk, percent per year
– Dabigatran 4.1% vs. aspirin 4.8%, p=0.10
• Major bleeding, percent per year
– Dabigatran 1.7% vs. aspirin 1.4%, p=0.30
NEJM 2018;378:2191-2201; NEJM 2019;380:1906-1917
 Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

For patients with noncardioembolic ischemic stroke

or TIA, the use of antiplatelet agents rather than
oral anticoagulation is recommended to reduce the
risk of recurrent stroke and other cardiovascular
events (Class I; Level of Evidence A).

Stroke 2014;45:2160-2236
 PFO in ESUS:
Now “PFO-Associated Stroke”?
Patent Foramen Ovale Prevalence

General population
• PFO present in 20-25%
Young and middle-aged patients with
cryptogenic stroke
• PFO present in 50-60%

Stroke 2009;40:2349-44
 Early Randomized Trials of PFO Closure
Trial Year PFO Device Control Primary Age n Mean Results
Endpoint Follow-
up

CLOSURE 2012 STARFlex Aspirin and/or Composite of 18-60 909 2 yrs HR 0.78
(NMT Medical) warfarin (INR stroke/TIA, all-cause 95% CI 0.45-
2-3) mortality, death from 1.35
neurologic causes P=0.37

PC Trial 2013 Amplatzer Antiplatelet or Composite of death, <60 414 4.1 HR 0.63
PFO Occluder anticoagulation nonfatal stroke, TIA, 95% CI 0.24-
(Abbott or peripheral 1.72 P=0.34
Structural) embolism

RESPECT 2013 Amplatzer Antiplatelet or Composite of 18-60 980 2.6 HR 0.49

PFO Occluder warfarin recurrent nonfatal 95% CI 0.22-
(Abbott ischemic stroke, 1.11
Structural) fatal ischemic P=0.08
stroke, or early
death after HR, 0.27
randomization 95% CI 0.10-
0.75
P=0.007, as-
treated

NEJM 2012;368:1083-91; NEJM 2013;368:1083-91; NEJM 2013;368:1092-1100

 Recent Randomized Trials of PFO Closure
Trial Year PFO Device Control Primary Endpoint Age n Mean Results
Follow-up
RESPECT 2017 Amplatzer PFO Antiplatelet or Composite of recurrent 18-60 980 5.9 yrs HR 0.55
(Long-term Occluder (Abbott warfarin nonfatal ischemic stroke, 95% CI 0.31-
Structural) fatal ischemic stroke, or 1.0
follow-up) early death after
P=0.046
randomization

CLOSE 2017 Any CE marked 1) Antiplatelet arm Recurrent fatal or 16-60 663 5.3 Closure vs.
PFO device 2) Oral nonfatal stroke antiplatelet
anticoagulant arm: therapy:
Vitamin K HR 0.03
antagonists or 95% CI 0-0.26
NOACs P<0.001

REDUCE 2017 Helex Septal Antiplatelet 1) Recurrent stroke 18-59 664 3.2 HR 0.23
Occluder and 2) New brain infarct 95% CI 0.09-
Cardioform inclusive of silent brain 0.62
Septal Occluder infarct (SBI) P=0.002
(W.L. Gore &
 
Associates)
HR 0.51
95% CI 0.29-
0.91
P=0.04

DEFENSE- 2018 Amplatzer PFO Antiplatelet or Stroke, vascular death or 18-80 120 2.8 Log-rank
PFO Occluder (Abbott warfarin TIMI-defined major
Structural) bleeding
P=0.013

NEJM 2017;377:1022-32; NEJM 2017;377:1011-21; NEJM 2017;377:1033-42;

J Am Coll Cardiol 2018;71:2335-42
 Trials Comparing PFO Closure Plus
Antithrombotic to Antithrombotic Alone

Device Medical
Therapy
Stroke 2018;49:1541-48
 PFO and Recurrent Stroke Rates
• Recurrent stroke rates are low on medical therapy
alone
– 1.2% per year across the 6 trials
• In patients randomized to device closure plus
antiplatelet therapy versus antiplatelet therapy
alone:
– Number needed to treat to prevent 1 recurrent ischemic
stroke over 5 years was 24 -- lower if atrial septal
aneurysm or moderate-substantial shunt present
• Treatment decisions should be patient centric
Stroke 2018;49:1541-48
Warfarin vs. Aspirin in Cryptogenic Stroke with PFO

Studies have shown no difference in stroke risk

with warfarin but uncertainty remains
• PFO in Cryptogenic Stroke Study (PICCS)
– Sub-study of the Warfarin-Aspirin Recurrent Stroke Study
• CLOSE trial
– Underpowered for this comparison
• Individual participant data meta-analysis of 12 trials
– Imprecise
Circulation 2002;105:2625-31; NEJM 2017;377-1011-1021;
Eur Heart J 2015;36:23881-89
Guidelines for the Prevention of Stroke
in Patients With Stroke and TIA

There are insufficient data to establish whether

anticoagulation is equivalent or superior to aspirin
for secondary stroke prevention in patients with
PFO (Class IIb; Level of Evidence B).

Stroke 2014;45:2160-2236
 Patent Foramen Ovale Closure

Indications for both the Amplatzer and Gore

Cardioform devices
• “…Patients, predominantly between the ages of 18
and 60 years, who have had a cryptogenic stroke due
to a presumed paradoxical embolism, as determined
by a neurologist and cardiologist…”
 Neurologist Approach to Patient
Assessment for PFO Closure
Cryptogenic stroke in
patient generally <60
years of age
• RoPE score (MDCalc)
– Emphasizes younger age,
cortical infarcts, lack of usual
risk factors
– Score of >6 suggests
probable PFO-related stroke

Neurology 2013;81:619-625;
Neurology 2014;83:221-226
Other Clues to Paradoxical Embolism

Possible PFO-related stroke

• History of DVT or PE
• Recent prolonged travel
• Migraine
• Valsalva preceding the onset
• Waking up with the stroke

J Neurol Sci 2008:275:121-127

 Atrial Fibrillation
Neurologist’s Perspective
 Stroke Prevention
Large Small Cryptogenic Cardiogenic
vessel vessel source
stenosis disease
>50%
If internal carotid
artery stenotic,
consider
revascularization

Risk factor Risk factor control,

control, anticoagulation
antiplatelet (antiplatelet or
agent closure for PFO)
Stroke Prevention in Atrial Fibrillation

75 year old man has hypertension, diabetes

and atrial fibrillation

Developed the acute onset of left-sided

sensory loss and mild weakness
Thalamic Hemorrhage
 Clicker Question
Should an antithrombotic be considered in the
future in this 75 year-old man with a history of
thalamic hemorrhage, hypertension, diabetes
and atrial fibrillation?

A. Yes
B. No
 Hemorrhage: Risk of Recurrence
Deep location
• Most often hypertensive in etiology
• Risk of recurrence low over a lifetime if blood
pressure controlled
Lobar hemorrhage
• In older patients most often due to cerebral
amyloid angiopathy
• Risk of early recurrence high – 20%
(Consider coagulopathy, neoplasm, AVM,
drug use, etc. in all patients)
 Atrial Fibrillation: Assessment of
Stroke Risk
CHADS2:
•C Congestive heart failure
•H Hypertension history
•A Age > 75 years
•D Diabetes
•S Stroke or TIA history (counts as 2 risk points)

• Recommend anticoagulation when 1 risk or more present

• Recommend aspirin + clopidogrel rather than aspirin if
anticoagulation not used (for reasons other than major
bleeding concerns) CHEST Supplement 2012;141:e556S
 Clicker Question
Which antithrombotic should be used in this patient
with AF when the hemorrhage has resolved?

A. Aspirin
B. Warfarin
C. Novel oral anticoagulant
Antithrombotic Therapy for Atrial Fibrillation: CHEST Guideline and Expert Panel Report

In patients with AF and high ischemic stroke risk,

we suggest anticoagulation with an NOAC after
acute spontaneous ICH (which includes subdural,
subarachnoid, and intracerebral hemorrhages)
after careful consideration of the risks and benefits
In ICH survivors at high risk of recurrent ICH (eg,
those with probable cerebral amyloid angiopathy),
we suggest left atrial appendage occlusion

CHEST 2018;154:1121-1201
 Anticoagulation: Oral Agents
Mechanisms of action
• Warfarin
– Vitamin K antagonist affecting activity of factors II, VII,
IX and X
• Dabigatran
– Direct thrombin inhibitor
• Rivaroxaban, apixaban, edoxaban
– Factor Xa inhibitors
– (Edoxaban has reduced efficacy with CrCL > 95
mL/min)

NEJM 2009;361:1139-51; NEJM 2011;365:883-91; NEJM 2011;365:981-92;

NEJM 2013; 369:2093-2104
How To Choose Between Anticoagulants?
Patient co-morbidities
• Consider new oral anticoagulants in those at higher risk of
intracranial bleeding – all associated with lower ICH risk
than warfarin
• Consider apixaban in those with GI bleeding risk – GI
bleeding non-significantly lower with apixaban than warfarin
(higher with dabigatran and rivaroxaban than warfarin)
• Creatinine clearance 30-50 mL/min may want to avoid
dabigatran
• Dyspepsia highest with dabigatran (10%)
Neurology 2014;82:716-724; Hematology Am Soc Hematol Educ
Program 2012;2012:536-40;
Thank you!