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Impact of Stroke in the United States
Recurrent Stroke Prevention:
An Update on the
Evidence and Opportunity in
Ischemic Stroke or TIA
Case-Based Review of Guidelines for
Practitioners Who Care for Patients With
Ischemic Stroke or TIA
y Of all CVDs, stroke is the third leading cause of death
y Annual incidence
– 780,000 strokes
y 600,000 first attacks
y 180,000 recurrent attacks
y 1
15%
% off strokes
k are h
heralded
ld d b
by TIA
y One-third of TIAs may be considered cerebral infarctions
based on diffusion-weighted MRI results
y 90-day risk of stroke after TIA: 3%–17%
– Highest risk within the first 30 days
CVD = cardiovascular disease; MRI = magnetic resonance imaging
American Heart Association. Heart Disease and Stroke Statistics–2008 Update.
Dallas, Texas: American Heart Association; 2008
Rosamond W et al. Circulation. 2008;117(4);e25
Estimates of the Cost of Stroke
Mean lifetime cost
of ischemic stroke
• $140,048
Average cost of ischemic
stroke within 30 days
• $13,019 (mild)
• $20,346 (severe)
$65.5 billion* in 2008
Estimates of Long-term Risk of Stroke
After Ischemic Stroke or TIA
Percentage of Patients Experiencing Stroke
After TIA1
After Stroke2
(%)
(%)
30 days
4–8
4
8
3–10
3
10
1 year
12–13
10–14
5 years
24–29
25–40
Time
*Estimated direct and indirect costs
American Heart Association. Heart Disease and Stroke Statistics–2008 Update.
Dallas, Texas: American Heart Association; 2008;
Rosamond W et al. Circulation. 2008;117(4);e25
Putative Risk Factors for Stroke Recurrence
1. Feinberg WM et al. Stroke. 1994;25(6):1320
2. Sacco RL. Neurology. 1997;49(5 suppl 4):S39
Defining Stroke Subtype Is an Important
Consideration in Recurrent Stroke Prevention
Early stroke recurrence
y Stroke subtype
Other
5%
– High for large artery, extra- and intracranial occlusive disease
y Elevated blood glucose
y HTN
Cryptogenic
30%
Late stroke
k recurrence
y
y
y
y
Age
HTN
Heart disease (CHD, HF, AF)
DM and hyperglycemia
Prior stroke or TIA
AF = atrial fibrillation; CHD = coronary heart disease;
DM = diabetes mellitus; HF = heart failure; HTN = hypertension
Sacco RL et al. Neurology. 1999;53(7 suppl 4):S15
Cardiogenic
embolism
20%
Ischemic stroke
88%
Hemorrhagic stroke
12%
Atherosclerotic
cerebrovascular
disease
20%
Small vessel
disease
“lacunae”
25%
Albers GW et al. Chest. 2004;126(3 suppl):438S
Thom T et al. Circulation. 2006;113(6):e85
1
Prevention of Recurrent Stroke
y Evaluation for risk factors
– HTN, DM, hyperlipidemia
y Evaluation for cause
– Arterial diseases, heart diseases
– Coagulopathies
Case Presentation
y Management of risk factors
– Lifestyle and medications
y Antithrombotic therapy
y Surgical or endovascular interventions
Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman
With 15-Year History of HTN
y Chief complaint
– Presented to the ED after a 30-minute spell of
transient right-sided face and arm weakness after
exercising today
y Past medical history
– HTN ×15 years
y Medications
– HCTZ 25 mg once daily
65-Year-Old Woman
With 15-Year History of HTN
y Physical exam
– BP 149/95 mm Hg; HR 80 BPM and regular
– Neurologic examination normal except for slight
weakness of the right arm and leg
((NIH Stroke Scale score = 2))
y Laboratory examination
– Total cholesterol = 230 mg/dL
– LDL-C = 120 mg/dL
– HDL-C = 39 mg/dL
– Other laboratory tests unremarkable
ED = emergency department; HCTZ = hydrochlorothiazide
65-Year-Old Woman
With 15-Year History of HTN
BP = blood pressure; BPM = beats/minute; HDL-C = high-density lipoprotein
cholesterol; HR = heart rate; LDL-C = low-density lipoprotein cholesterol; NIH =
National Institutes of Health
MRI Diffusion-Weighted Imaging (DWI)
y Diagnostic studies
– EKG normal
– Transthoracic echocardiography showed LVH
– MRA of the head and neck was unremarkable
– MRI of the head
Right
Left
EKG = electrocardiogram
LVH = left ventricular hypertrophy
MRA = magnetic resonance angiography
2
65-Year-Old Woman
With 15-Year History of HTN
y Diagnostic studies
– EKG is normal
– Transthoracic echocardiography showed LVH
– MRA of the head and neck was unremarkable
Guidelines for Management of TIA
– MRI of head shows DWI abnormality
predominantly of left posterior limb of internal
capsule consistent with ischemic injury
Definitions of Classes and Levels of Evidence:
AHA/ASA 2006 Stroke Prevention Guidelines
Class I
Evidence or general agreement that procedure or treatment is useful
and effective
Class II
Conflicting evidence or divergence of opinion of usefulness/efficacy
Class IIa
Weight of evidence or opinion is in favor
Class IIb
Usefulness/efficacy is less well established by evidence or opinion
Class III
Evidence and/or general opinion that usefulness/effectiveness does
not exist and may be harmful
LOE A
Derived from multiple RCTs
LOE B
Derived from a single RCT or nonrandomized studies
LOE C
Expert opinion or case series
AHA/ASA = American Heart Association/American Stroke Association
RCT = randomized clinical trial
LOE = level of evidence
Johnston SC et al. Ann Neurol. 2006;60(3):301
Recent TIA:
A Neurologic Emergency
y Risk of stroke after TIA
– 10.5% occurred within 90 days and half occurred within
2 days (Kaiser-Permanente HMO study)
y Risks may have been previously underestimated
Sacco RL et al. Stroke. 2006;37(2):577
Predicting Risk of Stroke After TIA:
ABCD2 Score for 2- or 7-Day Risk of Stroke
A Age
≥60 years
B Blood pressure
SBP >140 mm Hg or
DBP ≥90 mm Hg
1 point
Unilateral weakness
2 points
C Clinical features
Speech disturbance without
weakness
k
1p
point
Duration of
D
symptoms
≥60 minutes
2 points
10–59 minutes
1 point
D Diabetes
Diabetes
1 point
– 1%─2%
1% 2% at 7 days and 2%
2%─4%
4% at 30 days
y True risk
– Up to 10% at 7 days and as high as 15% at 30 days
y Time window for prevention is brief
Maximum score
– 17% of TIAs occur on the day of stroke
– 43% during the 7 days prior to stroke
Rothwell PM. Nat Clin Pract Neurol. 2006;2(4):174
1 point
7 points
DBP = diastolic blood pressure; SBP = systolic blood pressure
Johnston SC et al. Lancet. 2007;369(9558):283
Rothwell PM et al. Lancet. 2005;366(9479):29
3
ABCD2 Is Predictive of
2-Day Risk of Stroke in Patients With TIA
Traditional TIA Symptoms and Signs*:
Carotid Territory (1974)
Symptom
ABCD2 Score Level of Risk
2-Day Stroke Risk
Weakness, clumsiness, paralysis of 1 or
both limbs on same side
2. Sensory
Numbness, loss of sensation, and
paresthesias of 1 or both limbs on same
side; without spread or march
3. Speech/language
Aphasia
4. Vision
Loss in 1 eye or part of 1 eye
(%)
6–7
High
g
8.1
4–5
Moderate
4.1
0–3
Low
1.0
Sign
1. Motor dysfunction
5. Vision
Homonymous hemianopia
6. Multiple
Combination of above
*Symptoms/sign can last up to 24 hours
Johnston SC et al. Lancet. 2007;369(9558):283
TIA: New Definition Is Proposed (2002)
Definition
y
y
y
y
Brief episode of neurologic dysfunction caused by focal brain or
retinal ischemia
Clinical symptoms typically lasting less than 1 hour
No evidence of cerebral infarction (using advanced neuroimaging
techniques)
q
)
Urgent brain imaging is recommended
Rationale
•
•
Traditional definition is out of date and no longer consistent with current
concepts of brain ischemia
Most TIAs are short lived, and advanced imaging techniques may show
cerebral ischemic injury
Albers GW et al. N Engl J Med. 2002;347(21):1713
NSA Guidelines for the
Management of TIAs: Evaluation
Factor
Comment
General
EKG, CBC, serum electrolytes, creatinine, fasting blood
glucose, lipids
Brain imaging
CT/CTA or MRI/A; TCD is complementary
Carotid imaging
pp ultrasound;; CTA and/or MRA for supra-aortic
p
Doppler
vessels if Doppler not reliable or CEA considered;
conventional angiogram if Doppler and MRA/CTA discordant
or not feasible
Cardiac
evaluation
TTE or TEE in patients younger than 45 years when neck,
brain, and hematology studies negative for cause
CBC = complete blood count
CEA = carotid endarterectomy
TCD = transcranial Doppler
TEE = transesophageal echocardiogram
TTE = transthoracic echocardiogram
Johnston SC et al. Ann Neurol. 2006;60(3):312
Heyman A et al. Stroke.1974;5:277
National Stroke Association (NSA)
Guidelines for the Management of TIAs
Factor
Comment
Hospitalization
• Consider within 24–48 hours of first TIA
• Timely hospital referral of recent (within 1 week) TIA and hospital admission is
generally recommended in the case of crescendo TIAs, symptoms longer than
1 hour, symptomatic carotid stenosis >50%, known cardiac-source embolism,
hypercoagulable state, or appropriate California or ABCD score
• Hospitals/practitioners should have local admission policy and referral policy for
specialists’ assessments
• Local written protocols for diagnostic testing
Clinical evaluation
• Specialized clinic for rapid assessment and evaluation within 24–48 hours
Timing of initial
assessment
• For recent TIA, need same-day access to imaging such as CT/CTA, MRI/A, and/or
CUS
• If not admitted to hospital, rapid (within 12 hours) access to urgent assessment and
investigation
• If TIA occurred in past 2 weeks and the patient was not hospitalized, prompt
(24–48 hour) investigations (CUS, blood work, EKG, echocardiogram) needed
CT/CTA = computed tomography/computed tomographic angiography
CUS = carotid ultrasound
Johnston SC et al. Ann Neurol. 2006;60(3):301
Medical and Surgical Management of TIAs
y NSA and AHA/ASA guidelines for use of
antithrombotic therapies, CEA, EC-IC bypass, and
medical risk-factor modification for TIA patients are
comparable
y These prevention strategies in TIA and ischemic
stroke patients plus angioplasty and stenting are
reviewed in subsequent sections of this activity
according to 2006 and 2008 AHA/ASA guidelines
EC-IC = extracranial-intracranial
Johnston SC et al. Ann Neurol. 2006;60(3):301
Sacco RL et al. Stroke. 2006:37(2):577
Adams RJ et al. Stroke. 2008;39(5);1647
4
Does Rapid Assessment and Treatment of
TIA/Minor Stroke Lead to Improved Outcomes?
EXPRESS Study
Guidelines for Use of Antiplatelet Therapy
in TIA or Ischemic Stroke Prevention
90-Day Risk of Recurrent S
Stroke* (%)
y Urgent assessment and immediate clinical treatment in Oxford
Vascular Study (OXVASC) of those at risk of stroke within 90 days
y Phase 1 (4/1/02–9/30/04); Phase 2 (10/1/04–3/31/07)
12
10.3
10
Early treatment
associated
i t d with
ith
80% reduction
8
6
Resting platelet
4
2
P=.0001
2.1
Activated platelets
(Scanning electron microscopy)
0
Phase 1
Phase 2
*When referred to study clinic
EXPRESS study = Early Use of Existing Preventive Strategies for Stroke study
Rothwell P et al. Lancet. 2007;370(9596):1432
65-Year-Old Woman
With 15-Year History of HTN
y Case impression
– No evidence of cardiac source of embolism or
high-grade carotid stenosis
Which one of the following antiplatelet agents are
acceptable for prevention of recurrent cerebral
ischemia according to current guidelines?
A. Aspirin
B. Aspirin plus extended-release dipyridamole
C. Clopidogrel
D. Aspirin, aspirin plus extended-release
dipyridamole, or clopidogrel
AHA/ASA 2008 Recurrent Stroke
Prevention Guideline Update
y Acceptable antiplatelet options for initial recurrent stroke
prevention (Class I, LOE A)
–
–
–
ASA (50–325 mg/day)
ASA plus ER dipyridamole (25 mg/200 mg bid)
Clopidogrel (75 mg/day)
y Other
Oth recommendations
d ti
–
–
ASA plus ER dipyridamole favored over ASA alone
(Class 1, LOE B; upgraded based on ESPRIT study result)*
ASA added to clopidogrel is not recommended for routine use
“Variable Response”
Preferred Term to “Aspirin Resistance”?
y Variable response
– Occurrence of breakthrough atherothrombotic
events
– Response to ASA differs among patients and
may be attributed to various mechanisms
*New recommendation since 2006 guideline
ASA = aspirin; bid = twice a day; ER = extended release; ESPRIT = European/Australasian Stroke
Prevention in Reversible Ischaemia Trial
Adams RJ et al. Stroke. 2008;39(5);1647; Gorelick PB. AHA Communities
Learning Library. http://pt.wkhealth.com/pt/re/aha/editorial3_5_2008.htm;
jsessionid=Lr9hGX0qz7ynry2TfJTs7r5sGmJbBVyq3ph0xMkhBn2p4T0rGs2Q!20
85969891!181195628!8091!-1. Accessed July 16, 2008
5
Aspirin Resistance:
More Than Just a Laboratory Curiosity?
PRoFESS Trial
Study design
Multinational (more than 21 countries and 600
sites), randomized, double-blind,
placebo-controlled, 2 x 2 factorial design
Study population
20,333 patients with recent stroke
(within 90 days of study entry)
Cellular factors
Genetic
polymorphisms
Insufficient suppression
of COX-1
Clinical factors
Overexpression
of COX-2 mRNA
Noncompliance
COX-1
GP IIIa receptor
Failure to prescribe
Nonabsorption
Collagen receptor
Erythrocyte-induced
platelet activation
Interaction with ibuprofen
vWF receptor
Increased norepinephrine
Interaction with naproxen
Generation of 8-iso-PGF2α
Study drugs
ASA/ER dipyridamole vs clopidogrel and
telmisartan vs placebo
Primary end point
Time to first recurrent stroke
Secondary end point
Stroke, MI, or vascular death; major bleeding;
stroke or major hemorrhage
Anticipated data
2008
ASA resistance
COX = cyclo-oxygenase; GP = glycoprotein; mRNA = messenger ribonucleic acid;
PGF2α = prostaglandin F2 alpha; vWF = von Willebrand factor
MI = myocardial infarction; PRoFESS = Prevention Regimen For Effectively
Avoiding Second Strokes
Adapted with permission from Bhatt DL. J Am Coll Cardiol. 2004;43(6):1127
Diener HC et al. Cerebrovasc Dis. 2007;23:368
PRoFESS Trial: Preliminary Results
y Primary end point
– Across an average observation time of 2.5 years, rates of first
recurrent stroke were similar (9.0% ASA + ER dipyridamole vs
8.8% clopidogrel; HR 1.01, 95% CI 0.92−1.11)
y Bleeding
– More frequent in ASA + ER dipyridamole group
(major hemorrhagic events: 4.1% vs 3.6%; HR 1.15,
95% CI 1.00−1.32, P=.06)
Guidelines for Medical Risk Factor
Management
g
in Patients With
TIA or Ischemic Stroke
y Benefit-risk ratio
– Similar between groups (11.7% ASA + ER dipyridamole vs
11.4% clopidogrel; HR 1.03, 95% CI 0.95−1.11, P=.50)
CI = confidence interval; HR = hazard ratio
Boehringer Ingelheim. News Release. PRoFESS® results announced at XVII
European Stroke Conference. http://www.boehringeringelheim.com/corporate/news/press_releases/detail.asp?ID=5534.
Accessed August 12, 2008
65-Year-Old Woman
With 15-Year History of HTN
y Diagnosis
– Patient was diagnosed with a lacunar or small artery
territory infarction syndrome
y Treatment
– She did not receive intravenous tPA therapy since she had
only a very minor neurologic impairment
– After the MRI head study was reviewed in the ED, she was
treated with ASA 81 mg/day
When it is deemed safe to lower BP following the
initial phase of acute ischemic stroke, what is
the long-term target BP?
A. <140/90 mm Hg
B. <130/80 mm Hg
C. <120/70 mm Hg
D. <110/75 mm Hg
– Her BP was initially not treated
y Within 48 hours of the neurologic symptoms,
her neurologic examination was normal
tPA = tissue plasminogen activator
6
Which one of the following statements best
characterizes the use of statin therapy for
recurrent stroke prevention?
Which one of the following statements
best characterizes smoking as a
risk factor for stroke?
A. There is no proof that statin therapy reduces
stroke risk
A. Environmental (passive) smoke increases the risk
of stroke
py reduces stroke risk,, but is not
B. Statin therapy
safe; fatal liver disease is common
g is a risk factor for ischemic,, but not
B. Smoking
hemorrhagic stroke
C. Statin therapy reduces stroke and major
cardiovascular risks
C. Smoking increases the relative risk of stroke by
5 to 10 times
D. Statin therapy reduces stroke risk, but does not
reduce major cardiovascular risks
D. Smoking cessation leads to reversal of stroke
risk after 20 years
AHA/ASA 2008 Recurrent Stroke
Prevention Guideline Update
AHA/ASA 2006 Recommendations for Lifestyle and
Risk Factor Management in TIA or Ischemic Stroke
Factor
y Statin therapy and lipid lowering
– Based on the SPARCL results, statin therapy with intensive lipidlowering effects is indicated for patients with LDL-C in the
100–190 mg/dL range, atherosclerotic ischemic stroke
or TIA, and no known CHD to reduce occurrence of stroke and
vascular events (Class I, LOE B)*
– Target goal for cholesterol lowering for those with CHD or
symptomatic atherosclerotic disease
Recommendation
Initiate Rx when safe; individualize Rx; consider BP
reduction of 10/5 mm Hg with a diuretic and ACEI
Class I, LOE A
DM
Rigorous control of BP and lipids; aim for hemoglobin
A1c ≤7%
Class I, LOE A
Class IIa, LOE B
Smoking
Discontinue smoking
Counseling, NRT, and oral smoking-cessation
medications
Class I, LOE C
Class IIa, LOE B
Alcohol use
Eliminate heavy drinking or reduce
Men ≤2 drinks/day and non-pregnant women
1 drink/day
Class I, LOE A
Class IIb, LOE C
Obesity
Goal BMI 18.5 to 24.9 kg/m2 and waist circumference
women (<35 inches) and men (<40 inches)
Class IIb, LOE C
Physical activity
If capable, at least 30 minutes of moderate-intensity
exercise daily
Class IIb, LOE C
y LDL-C level of <100 mg/dL or
y LDL-C <70 mg/dL for very high-risk persons (those with
multiple risk factors)
*New recommendation since 2006 guideline
SPARCL = Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial
Adams RJ et al. Stroke. 2008;39(5);1647; Gorelick PB. AHA Communities Learning
Library. http://pt.wkhealth.com/pt/re/aha/editorial3_5_2008.htm;jsessionid=Lr9hG
X0qz7ynry2TfJTs7r5sGmJbBVyq3ph0xMkhBn2p4T0rGs2Q!2085969891!1811956
28!8091!-1. Accessed July 16, 2008
LOE
HTN
ACEI = angiotensin-converting enzyme inhibitor; BMI = body mass
index; NRT = nicotine replacement therapy; Rx = treatment
Sacco RL et al. Stroke. 2006:37(2):577
Established Therapies Are Consistently
Underused in all Patient Types
Patients
s Not Receiving
Prove
en Therapy (%)
Improving Patient Adherence
Lipid lowering
Antiplatelets
60
50
46
44
39
40
36
30
30
20
Statin
28
24
19
18
18
19
14
10
0
CAD
(n=40,258)
CVD
(n=18,843)
PAD
(n=8273)
Multiple Risk Factors
(n=12,389)
CAD = coronary artery disease; PAD = peripheral artery disease
Bhatt DL et al. JAMA. 2006;295(2):180
7
65-Year-Old Woman
With 15-Year History of HTN
y Patient is now taking a diuretic, ACEI, statin,
and ASA plus ER dipyridamole for recurrent
stroke prevention
Steps to Consider to Enhance Adherence to
TIA or Recurrent Stroke Prevention Regimen
y Awareness or recognition of stroke risk and
risk factors
y Qualitative determination of recurrent stroke risk
y Awareness of risk factor numbers ((eg,
g BP, blood
glucose, serum cholesterol)
What steps might be taken to assure adherence to
the treatment regimen?
y Establish multimodality maintenance approach
American Stroke Association broadcast on Primary Stroke Prevention, October 2007
Recurrent Stroke Prevention
Successful Maintenance of Treatment by
Multimodality Approach
y Motivation from family members
y Reminders and encouragement from medical
office staff
y Pharmacy reminders to renew medications
y Physician report cards: Is the patient meeting
target numbers?
American Stroke Association broadcast on Primary Stroke Prevention, October 2007
What Can Stroke Teams Do?
y In-hospital initiation of secondary prevention
therapies to increase treatment utilization and
adherence in the long term
y Adopt a systematic management approach in
coordination with primary care physicians to
help optimize post-stroke care
Ovbiagele B et al. Neurology. 2004;63(7):1217; Ovbiagele B et al.
Stroke. 2004;35(12):2879; Ovbiagele B et al. Stroke. 2008;39(6):1850
65-Year-Old Woman
With 15-Year History of HTN
y On physical examination, the patient’s pulse is noted
to be irregularly irregular. A bedside EKG is ordered
Cardioembolic Stroke Management
y Patient is diagnosed with cardioembolic stroke
secondary to AF
8
Which one of the following therapies is
recommended to prevent stroke recurrence for
a high-risk patient with atrial fibrillation?
A. Aspirin
Secondary Stroke Prevention:
Cardioembolic Stroke
y Cardioembolic stroke is responsible for ~20% of
ischemic strokes
y High risk of recurrence if not treated properly
B. Clopidogrel
y Underlying cardiac disease*
– Nonvalvular AF (50%)
C. Ximelagatran
– LVT (33%)
D. Warfarin
– Valvular heart disease (25%)
– Cardiomyopathy with low EF (25%)
*Patients may have more than 1 underlying cardiac condition
EF = ejection fraction; LVT = left ventricular thrombus
Cerebral Embolism Task Force. Arch Neurol. 1989;46(7):727
Pujadas Capmany R et al. Int J Cardiol. 2004;95(2-3):129
Cardioembolic Stroke: AF
y Persistent and paroxysmal AF are potent
risk factors for recurrent stroke
Risk factors for recurrent stroke in patients with AF
Age
CHF
HTN
DM
Prior thromboembolism (TIA or stroke)
Anticoagulation
y Warfarin1
Outcome
Stroke reduction (%)
Warfarin
(INR goal of 2–3)
Antiplatelet agents
64 (95% CI 49-74%)
22 (95% CI 6-35%)
14
34
NNT for 1 year for secondary
stroke prevention (n)
y Ximelagatran (investigational)
– Oral direct thrombin inhibitor that does not require coagulation
monitoring
– SPORTIF-V: 36 mg twice daily was not inferior to warfarin (INR,
2–3) for stroke prevention in AF2
– Potential risk of hepatotoxicity
– Not approved by FDA for use
FDA = US Food and Drug Administration; INR = international normalized ratio;
SPORTIF-V = Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation V
CHF = congestive heart failure
AHA/ASA 2006 Guideline Recommendations
for Antithrombotic Therapy in AF
1. For patients with ischemic stroke or TIA with
persistent or paroxysmal (intermittent) AF,
anticoagulation with adjusted-dose warfarin (target
INR, 2.5; range, 2–3) is recommended
(Class II, LOE A)
2. For patients unable to take oral anticoagulants,
ASA 325 mg/day is recommended (Class I, LOE A)
Sacco RL et al. Stroke. 2006;37(2):577
1. Hart RG et al. Ann Intern Med. 2007;146(12):857
2. Albers GW et al. JAMA. 2005;293(6);690
AHA/ASA 2006 Guideline Recommendations
for Antithrombotic Therapy
in Acute MI With LVT
1. For patients with an ischemic stroke or TIA caused by an
acute MI in whom LVT is identified by echocardiography
or another form of cardiac imaging, oral anticoagulation
is reasonable, aiming for an INR of 2–3 for at least
3 months and up to 1 year (Class IIa, LOE B)
2. ASA should be used concurrently for ischemic CAD
during oral anticoagulant therapy in doses up to
162 mg/day (Class IIa, LOE A)
Sacco RL et al. Stroke. 2006;37(2):577
9
65-Year-Old Woman
With 15-Year History of HTN
y On physical examination, a carotid bruit is heard
on the left side
Guidelines for Symptomatic
Extracranial Carotid Occlusive
Disease Management
y CTA of the neck shows 70%–99% stenosis of the
proximal portion of the left ICA
ICA = internal carotid artery
65-Year-Old Woman
With 15-Year History of HTN
Which of the following is recommended as
first-line treatment of high-grade, symptomatic,
extracranial carotid artery stenosis?
A. Extracranial to intracranial bypass
B. Warfarin
C. Carotid endarterectomy
D. Aspirin plus extended-release dipyridamole
y Diagnosis: symptomatic left extracranial ICA stenosis
Secondary Stroke Prevention: Symptomatic
Extracranial Carotid Occlusive Disease
North American Symptomatic Carotid Endarterectomy Trial (NASCET)1
AHA/ASA 2006 Guideline
Recommendations for CEA
1.
For patients with recent TIA or ischemic stroke within the last 6 months and
ipsilateral severe (70%–99%) carotid artery stenosis, CEA by a surgeon with
a perioperative morbidity and mortality rate of <6% is recommended
(Class I, LOE A)
2.
For patients with recent TIA or ischemic stroke and ipsilateral moderate
(50%–69%) carotid stenosis, CEA is recommended depending on patientspecific factors such as age, gender, comorbidities, and severity of initial
symptoms (Class I, LOE A)
3.
When the degree of stenosis is <50%, CEA is not routinely indicated
(Class III, LOE A)
4.
When CEA is indicated for patients with TIA or stroke, surgery within
2 weeks is suggested rather than delaying surgery (Class IIa, LOE B)
• 659 patients with symptomatic stenosis randomized to CEA or medical management
• Only patients with ≥5-years life expectancy were included
• Perioperative stroke/death rate 5.8%
Stenosis (%)
Results
70–99
2-year risk of stroke was 9% with CEA and 26% with medical therapy
50–69
5-year
5
year risk of stroke was 15.7%
15 7% with CEA and 22.2%
22 2% with medical
therapy
Less benefit for women and patients with retinal stroke/TIA
<50
No significant benefit of CEA
Carotid Endarterectomy Trialist
Collaboration2
• Pooled data from European Carotid Surgery Trial and NASCET
• In the CEA arm, benefits were greatest among patients randomized within
2 weeks of symptoms
1. North American Symptomatic Carotid Endarterectomy Trial Collaborators.
N Engl J Med. 1991;325(7):445
2. Rothwell PM et al. Lancet. 2004;363(9413):915
Sacco RL et al. Stroke. 2006; 37(2):577
10
AHA/ASA 2006 Guideline Recommendations
for Carotid Angioplasty and Stenting
Among patients with symptomatic severe stenosis (>70%) in whom the
stenosis is difficult to access surgically, medical conditions are present that
greatly increase the risk for surgery, or other specific circumstances exist such
as radiation-induced stenosis or restenosis after CEA, CAS is not inferior to
endarterectomy and may be considered (Class IIb, LOE B). CAS is reasonable
when performed by operators with established periprocedural morbidity and
mortality rates of 4% to 6%, similar to that observed in trials of CEA and CAS
(Class IIa, LOE B)
Special Note:
The results of the EVA-3S and SPACE studies were published after the 2006 AHA/ASA
guidelines became available. EVA-3S and SPACE have added data which support clinical
equipoise in relation to CAS. We await the results of Carotid Revascularization
Endarterectomy Versus Stenting Trial (CREST) to clarify the role of CAS in the
management of patients with extracranial occlusive disease.
Guidelines for Symptomatic
Intracranial Carotid Occlusive
Disease Management
Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman
With 15-Year History of HTN
65-Year-Old Woman
With 15-Year History of HTN
y Physical examination is unremarkable
y Cerebral vascular diagnostic workup shows no
cardiac source of embolism, and both carotid
arteries are patent with no evidence of
h
hemodynamically
d
i ll significant
i ifi
t stenosis
t
i
y Head MRA is ordered, which shows a proximal
left MCA stenosis
y Diagnosis: large artery intracranial occlusive disease
(LAICOD)
MCA = middle cerebral artery
Which one of the following is recommended as
first-line treatment for large artery intracranial
occlusive disease?
A. Antiplatelet therapy
Secondary Stroke Prevention:
Symptomatic Intracranial
Carotid Occlusive Disease
y Worldwide LAICOD is a common and well-defined stroke subtype
y Certain population groups may be at higher risk for LAICOD
B. Anticoagulant therapy
Ethnic Group
Reported Frequency of LAICOD in
Patients With Stroke (%)
C. Angioplasty and stenting
Chinese
Korean
South Asian
Thai
35–50
56
54
47
D. Extracranial to intracranial bypass
y Relative risk of intracranial atherosclerotic stroke in the
United States
– Hispanics vs whites: 5.00 (95% CI 1.69 to 14.76)
– African Americans vs whites: 5.85 (95% CI 1.82 to 18.73)
Gorelick PB et al. Stroke. 2008;39(8):2396
11
AHA/ASA 2006 Guideline Recommendations
for Treatment of LAICOD
With Endovascular Therapy
LAICOD: Risk of Recurrent Cerebral
Ischemic Stroke in Key Clinical Trials
y
y
EC-IC Bypass Study1
– 1377 patients with symptomatic ICA or MCA stenosis randomized to
either surgery or medical management
– Patients with symptomatic carotid siphon or MCA stenosis had an
annual stroke rate of 8%–10%
– No significant benefit for EC-IC was shown
Warfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID)2
– 569 patients with symptomatic 50%–99% IC stenosis
– INR goal of 2–3
– Mean follow up of 1.8 years
Outcomes in WASID
ASA (%)
For patients with hemodynamically significant intracranial
stenosis who have symptoms despite medical therapies
(antithrombotics, statins, and other treatments for risk factors),
the usefulness of endovascular therapy (angioplasty and/or stent
placement) is uncertain and is considered investigational
(Class IIb, LOE C)1
Special Note:
The results of the NIH registry on use of Wingspan stent for symptomatic 70%–99%
intracranial arterial stenosis were published after the 2006 AHA/ASA guidelines. Based on
these results, NIH has funded a study called Stenting vs Aggressive Medical Management
for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS)2 to study the
possible benefit of stenting for symptomatic intracranial artery stenosis.
Warfarin (%)
Ischemic stroke
20.4
17.0
Ischemic stroke in the territory of the
stenotic vessel
15.0
12.1
Disabling or fatal ischemic stroke
8.9
6.2
1. Sacco et al. Stroke. 2006; 37(2):577
2. Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in
Intracranial Stenosis.
http://clinicaltrials.gov/ct2/show/NCT00576693?term=SAMMPRIS&rank=1.
Accessed August 21, 2008.
1. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):1191
2. Chimowitz MI et al. N Engl J Med. 2005;352(13):1305
Conclusions
y TIA and ischemic stroke are important risk factors
for recurrent cerebral ischemia
y Recurrent stroke is preventable
Appendix I
Additional Slides
y NSA guidelines for the management of patients
with TIA and AHA/ASA guidelines for recurrent
stroke prevention are useful clinical tools to reduce
the risk of recurrent cerebral ischemia
y
12 meta-analyses (106 studies,
210,926 patients)
y
Combination of
– Diet
– Exercise
– ASA (ASA + dipyridamole)
– Statin (high dose)
– Antihypertensive
A tih
t
i d
drug
(aggressive BP lowering)
y
Predicted 5-year
major vascular event rate
– RRR 80% (90%)
– ARR 20% (22%)
– NNT 5 (5)
– Residual 5-year risk 5% (3%)
5-Yearr Major Vascular Event Rate (%)
Polytherapy for Recurrent Stroke Prevention:
Opportunity for Reduction of Subsequent Stroke Risk
90
Untreated
80
70
Predicting Stroke Risk in AF:
Who Benefits Most?
Multivariate Analysis of Pooled Data
Treated
60
50
Clinical Risk Factors
40
30
20
10
0
Cartoid
stenosis
AF
Diabetes
Smoking
RRR (%)
90
86
84
87
ARR (%)
41
67
27
25
NNT (n)
2
1
4
4
RR
Previous stroke or TIA
2.5 ×
History of HTN
1.6 ×
Diabetes
1.7 ×
Increasing age (per decade)
1.4 ×
Benefits of combination therapy in patients with CVD and specific
subtypes or comorbidities
ARR = absolute risk reduction; NNT = number needed to treat;
RRR = relative risk reduction
RR = relative risk
Adapted with permission from Hackam DG, Spence JD. Stroke. 2007;38(6):1881
Hughes M et al. Thromb Haemost. 2008;99(2):295
12
Initiation of Anticoagulation Therapy in
AF Patient With Acute TIA or Stroke
y Controversy exists regarding the timing of treatment
Cardioembolic Stroke: Acute MI and LVT
y Acute MI and LVT
y Patients with TIA
– May receive anticoagulation immediately if not contraindicated by
CT, MRI brain, or otherwise
– Stroke and systemic embolism can occur in up to
12% of patients with LVT post MI
– Risk of LVT is higher in anterior MI
y Patients with ischemic stroke
– Initiate anticoagulation within 2 weeks of ischemic stroke or
sooner depending on CT or MRI brain findings, neurologic
examination findings (size and severity of infarct to be
considered), and urgency of anticoagulation (eg, mechanical heart
valve)
– Risk of stroke is higher during the first 3 months
– In one-third of patients, LVT may remain
echcardiographically apparent for 1 year after MI
– Delaying anticoagulation may be reasonable in patients with
uncontrolled HTN and large infarcts
Albers GW et al. Chest. 2004;126(3 suppl):483S
Visser CA et al. Chest. 1984;86(4):532
Cardioembolic Stroke: Cardiomyopathy
y Cardiomyopathy
AHA/ASA 2006 Guideline Recommendations
for Antithrombotic Therapy
in Cardiomyopathy
– Significantly reduced LV systolic function causes relative stasis
– Annual stroke rate in the Survival And Ventricular Enlargement
(SAVE) study1
y 0.8% in patients with EF of 29%–35%
y 1.7% in those with EF ≤28%
– N
No study
t d h
has d
definitively
fi iti l proven th
the efficacy
ffi
off warfarin
f i or ASA iin
stroke prevention in patients with cardiomyopathy
For patients with ischemic stroke or TIA who have
dilated cardiomyopathy, either warfarin (INR, 2–3) or
antiplatelet therapy may be considered for prevention
of recurrent events (Class IIb,
IIb LOE C)
– In practice, patients with thromboembolism suspected of
cardioembolic origin with EF below 30% are usually managed with
warfarin (INR, 2–3)
– WARCEF (Warfarin versus Aspirin for Reduced Cardiac Ejection
Fraction) study is in progress2
1. Pfeffer MA et al. N Engl J Med. 1992;327(10):669
2. Pullicino P et al. J Card Fail. 2006;12(1):39
Sacco RL et al. Stroke. 2006;37(2):577
Cardioembolic Stroke:
Valvular Disease
Cardioembolic Stroke: Valvular Disease
Valvular
Disorder
y PHV
– Warfarin (INR, 1.8–2.5) versus antiplatelet agents1
Treatment
Warfarin
ASA-dipyridamole
Pentoxifylline-ASA
Rheumatic
valve disease
Thromboembolism
(100 patient-years) (%)
2
9.8
7.9
•
– Warfarin (INR, 3.0–4.5) vs warfarin plus ASA (100 mg daily)2
Treatment
Warfarin
+ placebo
+ ASA
Annual Rate of Embolic Events
or Vascular Death (%)
9.8
7.9
1. Mok CK et al. Circulation. 1985;72(5):1059
2. Turpie AG et al. N Engl J Med. 1993;329(8):524
RR
(%) (95% CI)
77 (44%–91%)
P<.001
Bleeding
(%)
22
35
Comments
•
•
Increase in Risk
(%) (95% CI)
55 (8%–124%)
P=.02
Recurrent stroke occurs in 30%–65% of patients
Valvulplasty does not eliminate the risk of recurrent
thromboembolism
Observational studies show that long-term anticoagulation
significantly reduces the risk of recurrent stroke
Treatment and LOE
Warfarin (INR, 2–3)
(Class IIa, LOE C)
Consider adding ASA
(81 mg/day) if recurrent embolism
while on warfarin
(Class IIa, LOE C)
Mitral valve
prolapse
•
•
Most common form of valve disease, usually innocuous
No large-scale, randomized trials have addressed the
efficacy of major antithrombotics for secondary prevention
Antiplatelet agent
(Class IIa, LOE C)
Aortic valve
disease
•
Associated with small and often clinically silent
microthrombi or calcific embolism
Antiplatelet agent
(Class IIb, LOE C)
Mitral annular
calcification
(MAC)
•
•
•
Considered a form of atherosclerosis
Associated with mitral regurgitation or stenosis
Endocarditis, arrhythmia, and embolic phenomenon may
occur (thromboembolism vs fibro-calcified material)
Antiplatelet agent
(Class IIb, LOE C)
Antiplatelet agent or warfarin may be
considered in patients with mitral
regurgitation caused by MAC
(Class IIb, LOE C)
Sacco RL et al. Stroke. 2006;37(2):577
13
AHA/ASA 2006 Guideline Recommendations
for Antithrombotic Therapy in Valvular Disease
y PFO
1. For patients with ischemic stroke or TIA who have modern
mechanical PHVs, oral anticoagulants are recommended,
with an INR target of 3.0 (range, 2.5–3.5) (Class I, LOE B)
2. For patients with mechanical PHV who have an ischemic stroke
or systemic embolism despite adequate therapy with oral
anticoagulants, ASA 75
75–100
100 mg/day in addition to oral,
anticoagulants and maintenance of the INR at a target of 3.0
(range 2.5–3.5) are reasonable (Class IIa, LOE B)
3. For patients with ischemic stroke or TIA who have bioprosthetic heart
valves with no other source of thromboembolism, anticoagulation with
warfarin (INR, 2–3) may be considered (Class IIb, LOE C)
Cardioembolic Stroke:
PFO
– Prevalence in patients ≥45 years is ~26%
– Atrial septal aneurysm affects ~2%
– 4-year risk of stroke recurrence
y 2.3% in patients with PFO
y 15.2% in patients with PFO and atrial septal aneurysm
– Increased risk of stroke in patients with large right-to-left shunt
– Higher prevalence of PFO in patients with cryptogenic stroke
– PFO in Cryptogenic Stroke Study
y No statistically significant difference in the rate of recurrent stroke in patients
with or without PFO or among those treated with ASA or warfarin
– Randomized Evaluation of Recurrent Stroke Comparing PFO
Closure to Established Current Standard of Care Treatment (RESPECT)
study and others are comparing percutaneous PFO closure versus medical
treatment for recurrent stroke prevention
PHV = prosthetic heart valve
Sacco RL et al. Stroke. 2006;37(2):577
Cruz-González I et al. Rev Esp Cardiol. 2008;61(7):738
AHA/ASA 2006 Guideline Recommendations
for Recurrent Stroke Prevention for PFO
1. Antiplatelet therapy is reasonable to prevent a recurrent event
(Class IIa, LOE B)
2. Warfarin is reasonable for high-risk patients who have other
indications for oral anticoagulation (Class IIa, LOE C)
3. Insufficient data exist to make a recommendation about PFO
closure in patients with a first stroke and PFO
Guidelines for Carotid Dissection
Stroke Management
4. PFO closure may be considered for patients with recurrent
cryptogenic stroke despite optimal medical therapy
(Class IIb, LOE C)
PFO = patent foramen ovale
Sacco RL et al. Stroke. 2006;37(2):577
65-Year-Old Woman
With 15-Year History of HTN
65-Year-Old Woman
With 15-Year History of HTN
y Patient complains of neck pain on the left side
y On physical examination, there is a left partial
Horner syndrome (ptosis and miosis)
y Bedside carotid duplex
p
is p
performed
y Bedside carotid duplex shows a double lumen
in the proximal left ICA (picture above)
y Diagnosis: left extracranial ICA dissection
How should subsequent cerebral ischemia
be prevented in a patient with a symptomatic
carotid artery dissection?
14
Arterial Dissections:
Pathophysiology
Secondary Stroke Prevention:
Arterial Dissections
y Extracranial arterial dissections
– Common with atherosclerotic disease
y
Tear in tunica media results in bleeding in
arterial wall
y
Blood dissects longitudinally spreading
distally and proximally
y
Tear of intima permits clots to enter
lumen
y
Expansion of intramural hemorrhage
narrows lumen causing stasis, activation
of platelets, and the coagulation cascade
y
Main dissection plane can lie between
the media and adventitia creating a
pseudoaneurysm
y
Rupture through adventitia into the
intracranial circulation causes
subarachnoid hemorrhage
– Frequent in young patients
– May be spontaneous or traumatic (neck manipulation,
hyperextension, lifting)
– More commonly detected in extracranial arteries
– Location includes mostly regions where the arteries are
mobile and not anchored
y Anterior circulation: cervical portion of the ICA
y Posterior circulation: segments of the vertebral arteries
(V1 and V3)
Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34
Arterial Dissections:
Treatment
y 2003 Cochrane Database review1
– Poor quality studies comparing ASA to warfarin
– ASA is likely to be effective and safer than warfarin
– Further studies are needed
y Due to the pathophysiology (red thrombi) most
experts recommend anticoagulants
y Annual risk of stroke recurrence in carotid
dissection is low (0.3% per year)2
1. Lyrer P, Engelter S. Cochrane Database Syst Rev. 2003;(3):CD000255
2. Touzé E et al. Neurology. 2003;61(10):1347
Adapted with permission from Caplan LR. Nat Clin Pract Neurol. 2008;4(1):34
AHA/ASA 2006 Guideline Recommendations
for Antithrombotic Therapy
in Cerebral Artery Dissection
1. For patients with extracranial arterial dissection, use
of warfarin for 3 to 6 months or use of antiplatelet
agents is reasonable (Class IIa, LOE B)
2 Beyond 3 to 6 months,
2.
months long-term
long term antiplatelet therapy
is reasonable. Anticoagulant therapy beyond 3 to 6
months may be considered among patients with
recurrent ischemic events
(Class IIb, LOE
C)
Sacco RL et al. Stroke. 2006;37(2):577
Secondary Stroke Prevention:
Aortic Arch Atheroma
y Prevalence and severity of aortic arch
atheroma (AAA) increases with age1
y 90% of the cases are stable and AAA
progresses slowly over time
Stroke Management in
Patients With Aortic Arch Atheroma
y Unclear if AAA is a source of emboli or a
marker of an increased risk of
atherosclerotic disease
y Risk of stroke is higher in patients with
complicated AAAs (ie, >5 mm in
thickness, ulcerated plaque, and mobile)2
Type of AAA
Odds Ratio of Stroke
Simple
2.3
Complex
7.1
1. Molina CA et al. Cerbrovasc Dis. 2007;24(suppl 1):84
2. Adapted with permission from Jones EF et al. Stroke. 1995;26(2):218
15
Carotid Angioplasty and Stenting:
Summary of Key Studies I
AAA Treatment
y
y New York University Atheroma Group1
y
y
– Statin therapy was protective against embolic events
Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators
(SAPPHIRE)1,2
Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S)3
Stent-Supported Percutaneous Angioplasty of the Carotid Artery Versus Endarterectomy (SPACE)4
– No protective effect with warfarin or antiplatelet agents
y Antiplatelet therapy is usually used in patients with
stroke or TIA
Hypotheses
y N
No d
definitive
fi iti study
t d h
has d
determined
t
i d if warfarin
f i iis superior
i
to antiplatelet agents for treatment of AAA
Degree
g
of stenosis (%)
SAPPHIRE
EVA-3S
SPACE
CAS is not inferior to CEA for
high-risk patients
CAS is not inferior to CEA for
symptomatic carotid stenosis
CAS is not inferior to CEA for
symptomatic carotid stenosis
334
527
1200
>50 symptomatic
y p
or
>80 asymptomatic
60 99 symptomatic
60–99
t
ti
≥50 symptomatic
t
ti
Death, stroke, or MI within
30 days after procedure or
death/ipsilateral stroke between
30 days and 1 year
Composite of stroke or death
within 30 days posttreatment
Ipsilateral stroke (ischemic or
hemorrhagic) or death within
30 days postprocedure
Patients (n)
y Aortic Arch Related Cerebral Hazard Trial (ARCH) is comparing
clopidogrel + ASA vs oral anticoagulation in preventing brain
infarction, brain hemorrhage, MI, peripheral embolism, and
vascular death2
Primary end point
Primary outcome (CEA
vs CAS) (%)
Early termination
20.1 vs 12.2*
3.9 vs 9.6
6.34 vs 6.84**
Slow recruitment
Safety and futility reasons
No further funding
*P=.004 for noninferiority; **P=.09 for noninferiority; CAS = carotid artery stenting
1. Tunick PA et al. Am J Cardiol. 2002;90(12):1320
2. Aortic Arch Related Cerebral Hazard Trial (ARCH).
http://clinicaltrials.gov/ct2/show/NCT00235248. Accessed July 16, 2008
1. Yadav JS et al. N Engl J Med. 2004;351(15):1493; 2. Gurm HS et al. N Engl J
Med. 2008;358(15):1572; 3. Mas JL et al. N Engl J Med. 2006;355(16):1660;
4. SPACE Collaborative Group. Lancet. 2006;368(9543):1239
Treatment of LAICOD Based Upon
Key Clinical Trials
Carotid Angioplasty and Stenting:
Summary of Key Studies II
Study
Trial conclusion
High risk for CEA
Symptomatic
patients (%)
SAPPHIRE
EVA-3S
SPACE
CAS is not inferior to CEA for highrisk patients at 6 months, 1 year,
and 3 years
Rates of stroke or death at
1 month and 6 months are
lower in CEA
Trial failed to prove noninferiority
of CAS vs CEA
Required
Not required
Not required
29
100
100
ASA
Warfarin
22.1
21.8
EC-IC Bypass Study
Operator experience
CAS
Required periprocedural risk <6%
39% done by operators in
training
No prespecified experience in
CAS
CEA
Required periprocedural risk <6%
≥25 CEAs performed in prior
year before enrollment
≥25 CEAs performed
Stent type
2 stents
(same manufacturer)
5 stents
(different manufacturers)
3 stents
(different manufacturers)
Mandatory
(only 1 system)
Tried in 92%
(any of 7 systems)
Used in 27%
(any of 5 systems)
Protection device
Outcome (%)
WASID1
Ischemic stroke, brain hemorrhage, or death from vascular causes
(primary outcome)*
Group2
Is an EC
EC-IC
IC anastomosis better than medical treatment for symptomatic
LAICOD?**
NIH registry on use of WingspanTM stent for 70%–99% intracranial
stenosis3
Stroke or death within 30 days or stroke in the territory (1–6 months)
Restenosis (50% or more)
No
14
25
*Major hemorrhage occurred more frequently in warfarin vs ASA group (8.3% vs
3.2%; HR 0.40; 95% CI 0.18-0.84; P=.01)
**Carotid Occlusion Surgery Study (COSS) is ongoing and retesting the
hypothesis of benefit for EC-IC bypass
1.Yadav JS et al. N Engl J Med. 2004;351(15):1493; Gurm HS et al. N Engl J Med.
2008;358(15):1572; Mas JL et al. N Engl J Med. 2006;355(16):1660; 4. SPACE
Collaborative Group. Lancet. 2006;368(9543):1239
1. Chimowitz MI et al. N Engl J Med. 2005;352(13):1305
2. The EC/IC Bypass Study Group. N Engl J Med. 1985;313(19):1191
3. Zaidat OO et al. Neurology. 2008;70(17):1518
Secondary Stroke Prevention:
Other Specific Conditions
Condition
Recurrent Stroke Prevention in
Other Cerebrovascular Conditions
Comments
Hyperhomocysteinemia
• Hyperhomocysteinemia is associated with a 2x risk of stroke
• Vitamin Intervention for Stroke Prevention (VISP) study, reduction
of total homocysteine after nondisabling cerebral infarction had no
effect on vascular outcomes
• Are there subgroups who might receive benefit from multivitamin
therapy?
Inherited
thrombophilia
• Weak association between FVL, PTGM, MTHFR, APCR, and
stroke in adults; more clear in younger age groups
• No studies comparing antiplatelets to warfarin for secondary
prevention have been done
• Evaluate for alternative mechanism
Antiphospholipid
(APL) antibodies
• Associated with venous and arterial occlusive disease
• In Warfarin vs Aspirin Recurrent Stroke Study/Antiphospholipid
Antibodies and Stroke Study (WARSS/APASS) collaboration, the
risk of vascular occlusive events in patients with ischemic stroke
and APL was not different in patients treated with ASA or warfarin
Treatment and LOE
Daily vitamin B6, B12 and folate
(Class IIa, LOE B)
Antiplatelet or anticoagulants
(Class IIa, LOE C)
Anticoagulants if recurrent
thrombosis
(Class IIb, LOE C)
Antiplatelet
(Class IIa, LOE B)
Anticoagulants if APL syndrome with
occlusive disease in multiple organs,
miscarriages, and livedo reticularis
(Class IIa, LOE B)
APCR = activated protein C resistance; FVL = factor V Leiden; MTHFR =
methylenetetrahydrofolate reductase C677T mutation; PTGM = prothrombin
G20210A mutation
Sacco RL et al. Stroke. 2006;37(2):577
16
Secondary Stroke Prevention:
Other Specific Conditions
Condition
Cerebral venous
sinus thrombosis
Comments
• In Stroke Prevention Trial in Sickle Cell Anemia (STOP),
children with mean flow velocity ≥200 cm/sec at MCA
(measured noninvasively by TCD) were randomized to
exchange transfusion (goal: HbS <30%) or placebo
Sickle cell disease
• Annual stroke rate was 1% in children undergoing
transfusion and 10% in those not receiving transfusion
• Small studies suggested that hydroxyurea reduces the risk
of stroke recurrence
• High risk of moyamoya disease
Postmenopausal
hormone therapy
Treatment and LOE
Anticoagulants (even in the
presence of hemorrhagic
infarction)
(Class IIa, LOE B)
• Venous infarctions are frequently hemorrhagic
• More frequent in patients with hypercoagulable states
• Anticoagulant superior to placebo
• In Women's Estrogen for Stroke Trial (WEST) and Women’s
Health Initiative (WHI) studies, women assigned to hormonal
replacement had a higher risk of stroke compared with
placebo
Risk factor control and antiplatelet
agents
(Class IIa, LOE B)
Blood transfusion to reduce HbS
to <30%–50% of total Hb,
hydroxyurea, and bypass surgery
for advanced occlusive disease
(Class IIb, LOE C)
Appendix II
References
Postmenopausal hormone
therapy is not recommended
(Class III, LOE A)
HbS = sickle cell hemoglobin
Sacco RL et al. Stroke. 2006;37(2):577
Adams RJ. Big strokes in small persons. Arch Neurol. 2007;64(11):1567-1574.
Adams RJ, Albers G, Alberts MJ, et al. Update to the AHA/ASA recommendations for the prevention of
stroke in patients with stroke and transient ischemic attack. Stroke. 2008;39(5);1647-1652.
Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular
risk factors in outpatients with atherothrombosis. JAMA. 2006;295(2):180-189.
Caplan LR. Dissections of brain-supplying arteries. Nat Clin Pract Neurol. 2008;4(1):34-42.
Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus calcification—a window to diffuse
atherosclerosis of the vascular system. Atherosclerosis. 2001;155(1):1-8.
Cardiogenic brain embolism. The second report of the Cerebral Embolism Task Force. Arch Neurol.
1989;46(7):727-743.
Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for
ischemic stroke: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest.
2004;126(3 suppl):483S-512S.
Casas JP, Hingorani AD, Bautista LE, Sharma P. Meta-analysis of genetic studies in ischemic stroke: thirtytwo genes involving approximately 18,000 cases and 58,000 controls. Arch Neurol. 2004;61(11):1652-1661.
Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack—proposal for a new definition.
N Engl J Med. 2002;347(21):1713-1716.
Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with
nonvalvular atrial fibrillation: a randomized trial. JAMA. 2005;293(6):690-698.
American Heart Association. Heart Disease and Stroke Statistics—2008 Update. Dallas, Texas:
American Heart Association; 2008.
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal
women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA.
2004;291(14):1701-1712.
Assistance Publique-Hôpitaux de Paris; National Health and Medical Research Council, Australia;
sanofi-aventis; Bristol-Myers Squibb. Aortic Arch Related Cerebral Hazard Trial (ARCH).
http://clinicaltrials.gov/ct2/show/NCT00235248. Accessed July 22, 2008.
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic
intracranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316.
Coulshed N, Epstein EJ, McKendrick CS, Galloway RW, Walker E. Systemic embolism in mitral valve
disease. Br Heart J. 1970;32(1):26
1970;32(1):26-34.
34.
de Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecularweight heparin for cerebral sinus thrombosis. Stroke. 1999;30(3):484-488.
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