Download Causes of Stroke - MCE Conferences

Stroke, Part I An Evidence-Based Review
of Risk Factors and
Prevention
Laurence J. Kinsella, M.D., F.A.A.N.
Stroke:
Incidence and Cost in the United States
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795,000 new or recurrent
cases yearly
1 stroke every 40 seconds
#3 cause of death
$73 billion annual health cost
4,400,000 stroke survivors at
high risk for recurrence
75 yo M with multiple Large artery territory
infarctions, typical of cardiogenic embolus
AHA Heart and Stroke Statistics Update 2009. Available at
http://www.americanheart.org/downloadable/heart/1240250946756LS1982%20Heart%20and%20Stroke%20Update.042009.pdf
Cost of Stroke

20% institutionalized after 3 months
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15-30% permanently disabled
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$73 billion in direct and indirect costs
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Average lifetime cost of stroke in the U.S.
estimated to be $140,000.
Stroke 2011;42:517-583.
Causes of Stroke
85%
Infarction
30-60%
20%
Cerebrovascular Penetrating
atherosclerosis
artery
disease
(lacunes)
15%
Hemorrhage
- Intracerebral
- Subarachnoid
15-30%
Cardiogenic
Embolism
(higher < 50, > 80)
5%
Other,
unusual
causes
Well-Documented and
Modifiable Risk Factors
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Hypertension
exposure to cigarette
smoke
diabetes
atrial fibrillation and
certain
other cardiac
conditions
dyslipidemia
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Carotid artery
stenosis
Sickle cell disease
Postmenopausal
hormone therapy
Poor diet
physical inactivity
Obesity
body fat distribution
Stroke 2011;42:517-584
Less well-documented or
potentially modifiable
Risk Factors
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Metabolic syndrome
Excessive alcohol
consumption
Drug abuse
Sleep-disordered
breathing
Migraine
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Hyperhomocysteinemia
Elevated lipoprotein(a)
Use of oral
contraceptives
Hypercoagulability
Inflammation
Infection
Stroke 2011;42:517-584
Stroke risk varies by clinical setting
Risk Factor
AFIB, Low Risk
Amaurosis Fugax
Asx carotid > 60%
TIA
AFIB, High Risk
Prior Stroke
Sx carotid > 70%
Annual Risk
1%
2-3%
2-3%
5-6%
8%
6-10%
16%
Gorelick P. Arch Neurol 1995;52:347-354
Causes of Stroke:
Cerebrovascular Atherosclerosis
85%
Infarction
15%
Hemorrhage
- Intracerebral
- Subarachnoid
30-60%
20%
15-30%
5%
Cerebrovascular Penetrating artery Cardiogenic embolism Other,
atherosclerosis disease (lacunes)
unusual
causes
Vascular Territories of the Cerebral
Hemisphere
Circle of Willis:
Key Collateral Circulation
Antero-posterior
Axial
Carotid Ultrasound
Internal carotid
artery
Common carotid
artery
Critical Internal Carotid artery
stenosis
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Most frequent cause of
recurrent or crescendo TIAs
Mechanism is stenosis with
flow reduction
Ulcerated plaque with artery
to artery embolism
Causes of Stroke:
Penetrating Artery Disease
(Lacunes)
85%
Infarction
60%
Cerebrovascular
atherosclerosis
15%
Hemorrhage
- Intracerebral
- Subarachnoid
15%
Cardiogenic embolism
20%
Penetrating
artery
disease (lacunes)
5%
Other,
unusual
causes
Lacunar Stroke
Thalamic Lacune
Subcortical White matter
lacunes
Lacunar Infarction
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Vessels undergo lipohyalinosis
4 most common locations
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Internal capsule
Thalamus
Pons
Cerebellum
Lacunar Infarcts
(Small Subcortical Strokes):
Summary
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Diagnosis: Clinical syndrome (e.g., pure motor or
pure sensory) plus CT/MRI confirmation
Risk factor management: Hypertension, diabetes
Carotid stenosis: Present in only 10%
Rate of re-occurrence: High (10%/yr)
Antiplatelet agents probably effective
Causes of Stroke:
Cardiogenic Embolism
85%
Infarction
60%
Cerebrovascular
atherosclerosis
20%
Penetrating artery
disease (lacunes)
15%
15%
Cardiogenic
embolism*
Hemorrhage
- Intracerebral
- Subarachnoid
5%
Other,
unusual
causes
Cardiogenic Embolism
Acute MI
(15%)
Other,less
common sources
(10%)
Prosthetic
cardiac valves
(10%)
Rheumatic heart
disease
(10%)
Nonvalvular atrial
fibrillation
(45%)
Ventricular
aneurysm
(10%)
Atrial Fibrillation (AF)
Predisposes to Stroke
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Mean Onset Age 64, > 2 Million
People
35% Have Stroke During
Lifetime
5% /Yr Stroke Rate, 12% after
TIA
> 75,000 Strokes/Yr in U.S.
30% of all strokes > 80 years old
Gorelick P. Arch Neurol 1995;52:347-354
.
Stroke: Other, Unusual Causes
85%
Infarction
60%
Cerebrovascular
atherosclerosis
15%
Hemorrhage
- Intracerebral
- Subarachnoid
20%
15%
Penetrating artery Cardiogenic embolism
disease (lacunes)
*Dissection, migraine, oral contraceptive use in smokers,
meningovascular syphilis, cocaine and amphetamine use,
associated with prothrombotic states (e.g., sickle cell anemia)
5%
Other,
unusual
causes
Hemorrhagic Stroke
85%
Infarction
60%
Cerebrovascular
atherosclerosis
20%
Penetrating artery
disease (lacunes)
15%
15%
Cardiogenic
embolism
Hemorrhage
- Intracerebral
- Subarachnoid
5%
Other,
unusual
causes
Subdural hematoma
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Not considered a stroke, but may have focal signs from mass
effect
Obvious right SDH with mass effect
Subtle SDH in 75 yo M
with confusion, myoclonus after
falling at home s/p trimalleolar fracture repair
Hypertensive Intracerebral Hemorrhage
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Same locations as lacunes
 Thalamus, basal ganglia,
pons, cerebellum
Lipohyalinosis, microaneurysms
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Amyloid angiopathy may have
similar appearance
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Prognosis dependent on volume
of blood and Glasgow Coma
Scale
Intraventricular blood - poor
prognostic sign
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Ritter MA, Droste DW, et al. Role of cerebral amyloid angiopathy in
intracerebral hemorrhage in hypertensive patients.
Neurology. 2005;64:1233–7.
Clarke JL. Neurocrit Care. 2004;1:53-60.
Lobar Hemorrhages
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Present in frontal, parietal, temporal lobes
Rarely due to HTN
Consider hemorrhagic embolic infarction
tumor
AVM
amyloid
septic embolus
57 yo Hunter with sudden
onset headache, minimal left
hand weakness.
Qureshi AI, Tuhrim S, et al. Spontaneous intracerebral hemorrhage.
N Engl J Med.2001;344:1450–60
Subarachnoid Hemorrhage
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30,000 per year
80% due to aneurysm
20% non-aneurysmal
(venous rupture?)
1% of all ED
headaches
Guidelines for the Management of Aneurysmal
Subarachnoid Hemorrhage.
http://stroke.ahajournals.org/cgi/content/full/40/3/9
94. Stroke. 2009;40:994-1025.
Risk Factor Modification is critical
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>77% of all strokes are first time events without a
warning TIA
Risk factor control for hypertension, diabetes,
smoking, hyperlipidemia, etc.
Antiplatelet agents for cerebrovascular disease.
Anticoagulation for atrial fibrillation and other
selected heart diseases.
Endarterectomy vs stenting for high-grade
symptomatic carotid stenosis
Cumulative Stroke Rate per 100 Population
Reduction in Stroke in SHEP
36% reduction in stroke (p = 0.003)
Placebo
Active Treatment
0
12
24
months
36
48
60
JAMA. 1991 Jun 26;265(24):3255-64
Therapeutic Goals for Antihypertensive
Rx
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Condition
Pre-Hypertension
Uncomplicated
Diabetic or Kidney Dz
African-American
Goal BP
120/80-129/89
140/90
130/80
135/85
JNC VII, Hypertension 2003
Stroke reduction published in
the large statin trials
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Trial
GREACE
4S
CARE
ASCOT-LLA
HPS
LIPID
ALHAT-LLA
% reduction
47
37
31
27
25
19
9
Guidelines for Cholesterol
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With CHD or symptomatic athero, target goal is
LDL < 100 mg/dl, < 70 for high risk patients
(DM, smoking)
Patients with TIA or stroke with normal cholesterol
levels will benefit from statin therapy
Low HDL may be treated with gemfibrozil or
niacin
Sacco RL, et al. Guidelines for prevention of stroke. Stroke
2006;37:577-617.
Statins and ACEI in Secondary
Stroke Prevention
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SPARCL trial
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80 mg atorvastatin in 4731 pts after TIA or stroke
LDL 73 mg/dl in Tx, 129 mg/dl in placebo
11.2 vs. 13.1% had fatal/non-fatal stroke (p < .03)
20% RRR for all major cardiac events
Increased hemorrhages in those with prior ICH
Dagenais
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Metanalysis of 3 clinical trials of ACE inhibitors (ACEI)
29,805 patients
Reduced all cause mortality 7.8 vs 8.9% placebo
Amerenco P. SPARCL: high dose atorvastatin after stroke or transient
ischemic attack. NEJM 2006;355:613-615.
Dagenais GR, et al. ACE inhibitors in stable vascular disease without LV
dysfunction or CHF. Lancet 2006;368:581-588.
Vitamins and Stroke - Does
Homocysteine Suppression work?
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Homocysteine lowering with folic acid,
pyridoxine (B6), and cobalamin (B12)
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Reduced average by 2.5 µmol/liter
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No difference in vascular events despite
significant lowering of homocysteine
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Same results as VISP 2004 trial - no effect
The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators.
N Engl J Med 2006; 354:1567-77.
Aspirin - what dose and when?
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30 - 1200 mg qd has shown statistical benefit.
(25% RRR)
Not as effective after TIA (13% RRR)
325 mg paralyzes all platelets immediately when
chewed and swallowed, therefore this is ideal in
acute settings (TIA and Stroke)
81 mg is appropriate as “maintenance therapy” may reduce bleeding risk
8th ACCP Guidelines. Chest 2008
http://chestjournal.chestpubs.org/content/133/6_suppl
Combination ASA and
Clopidogrel
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MATCH trial shows increased risk of
hemorrhage with combination.
ASA-clopidogrel arm dropped from the ProFESS
trial
Combination not recommended for the
secondary prevention of stroke due to
hemorrhage risk
J Am Coll Cardiol 2011 Feb 22; 57:1002.
Diener et al, Lancet 2004.
Combination of ASA and
Clopidogrel in AFIB
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Low dose ASA 75-160 mg daily vs
ASA plus clopidogrel 75 mg daily
No reduction seen in vascular outcomes
Stroke, MI, vascular death rates unaffected
Found to be more effective at stroke reduction
than ASA alone for AFIB in patients who are
poor candidates for anticoagulation
Bhatt DL, et al. N Engl J Med 2006;354.
 ACTIVE-A,NEJM 2009;360:2066-2078
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Problems with Clopidogrel?
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Requires P450 2C19 metabolism
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2-3% are deficient in the enzyme, therefore no
antiplatelet effect
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2C19 Inhibited by proton pump inhibitors
(omeprazole, etc), reducing efficacy of
clopidogrel
Frere C et al, Effect of cytochrome P450 polymorphisms on platelet reactivity
after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol
2008; 101:1088-93
Gilard M et al. Influence of omeprazole on the antiplatelet action of
clopidogrel associated with aspirin: the randomized, double-blind OCLA
(Omeprazole Clopidogrel Aspirin) Study. J Am Coll Cardiol 2008: 51:256-60.
Dipyridamole and ASA 2
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ESPRIT
1363 pts randomized to ASA 30-325 mg alone,
1376 ASA with dipyridamole 200 mg bid
w/in 6 mos of TIA or stroke
Primary outcome - death, stroke, MI or bleeding
at 3.5 yrs
ARR 1% per year
NNT 100 pts to prevent outcome per year,
20 @ 5 yrs
ESPRIT study group. Lancet 2006;367:1665-73
ASA-dipyridamole vs Clopidogrel
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PROFESS trial
Combination pill no better than clopidogrel
in preventing recurrent stroke.
No neuroprotective effect seen for
dipyridamole (Persantine®) or telmisartan
(Micardis®)
Sacco RL, et al. Aspirin and extended-release dipyridamole versus
clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-51.
Antiplatelets and AFIB
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Warfarin reduces stroke by 64% and ASA 26%
50% of patients with Afib are not treated with
warfarin- risk of bleeding, fall risk, etc.
ASA + Clopidogrel demonstrated additional 28%
reduction in stroke and MI, but increased
hemorrhages over ASA alone (2%/yr)
ASA + Clopidogrel is an option for warfarin
intolerant patients with afib, with risks
Active-A. Effect of clopidogrel added to aspirin in patients with atrial fibrillation.
N Engl J Med. 2009 May 14;360(20):2066-78
When to use Coumadin in Afib
CHADS2 score
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CHF - any history
HTN - prior history
Age > 75
Diabetes
Secondary prevention after
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1
1
1
1
2
systemic embolization
Go AS, et al. JAMA 2003;290:2685
Gage BF, et al. JAMA 2001;285:2864.
When to use Warfarin in afib
CHADS2
score
Event rate/yr
No warfarin
0.49
NNT
0
Event rate/yr
Warfarin
0.25
1
0.72
1.52
125*
2
1.27
2.50
81*
3
2.20
5.27
33*
4
2.35
6.02
27*
5-6
4.60
6.88
44*
*consider warfarin therapy
417
Go AS, et al. JAMA 2003;290:2685
Gage BF, et al. JAMA 2001;285:2864.
Dabigatran
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Direct thrombin inhibitor
110mg equally effective than warfarin at stroke
prevention with fewer hemorrhages
150mg superior to warfarin, similar hemorrhages
No drug interactions
No monitoring
expensive relative to warfarin
RELY Trial NEJM 2010
www.nejm.org/doi/full/10.1056/NEJMoa0905561
Stroke Prevention in AFIB 2011
Risk
Alternatives
lone AF < 65 yr
Recommendation
s
ASA 325 mg/d
low risk 65-75 yr
ASA 325 mg/d
-Warfarin INR 2-3
-ASA 81mg plus
clopidogrel 75mg
-Dabigatran 110mg
high risk or > 75 yr
Warfarin INR 2-3 -ASA plus
Or
clopidogrel if
Dabigatran 110mg warfarin is
Contraindicated
-Dabigatran 110mg
---
Active A Trial. NEJM 2009;360:2066-2078
www.nejm.org/doi/full/10.1056
Carotid Endarterectomy:
Symptomatic vs. Asymptomatic Carotid Stenosis
Stroke Rate (%/yr)
14
12
Medical Rx
10
Carotid Endarterectomy
8
6
4
2
0
Symptomatic
Carotid Stenosis
( > 70% )
Asymptomatic
Symptomatic
Carotid Stenosis
Carotid Stenosis
( > 60% )
( 50-69% )
Circulation. 2006;113:e409-e449.
Lancet. 2004 May 8;363(9420):1491-502.
Carotid Endarterectomy How soon after stroke/TIA?
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NASCET Data analysis
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For > 50% symptomatic stenosis
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NNT to prevent one ipsilateral stroke in 5 yrs:
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5 for those within 2 weeks of last ischemic event
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125 if randomized after 12 weeks.
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9 for men vs 36 for women
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5 for > 75 years
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18 for < 65 years
Rothwell PM. Lancet. 2004;363:915-24.
Steps to reduce Morbidity and
Mortality in Stroke
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Control fever and glucose
IV tPA within 4.5 hours of
onset - 30% increased chance
of little or no deficit at 3
months.
Aspirin 325 mg within 48 hrs 10/1000 reduction in deaths at
6 months
Admission to Stroke Unit - 40%
reduction in death
Don’t withdraw statins
Use an ACE inhibitor
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NPO and Swallowing eval
within 24 hrs - prevents
pneumonia, fever, prolonged
LOS, ?deaths
DVT prophylaxis - calf SCDs,
Subq Heparin
No BP Rx for < 200/120 for 48
hours (<185/110 w tPA)
80 mg Atorvastatin acutely
after TIA and Stroke, not
hemorrhage
Acute Stroke Treatment 2010
emedicine.medscape.com/article/1159752-treatment#Table4
Adams H et al. Stroke. 2007;38:1655-1711
Blanco M et al. Neurology. 2007 Aug 28;69(9):904-10
2011 Guidelines
Risk Factor Modification
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BP <140/90 or
BP <130/80 with DM,
renal disease
EtOH </=1 F, </=2 M
Statin use to maintain
LDL < 100 in low risk,
<100 in high risk pts
Warfarin for Afib or
ASA +/- clopidogrel
for poor risk Afib
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Population screening
for carotid dz not
recommended.
Consider CEA for
highly select pts with
Asx carotid stenosis
Stenting for Asx dz
not established
Stroke 2011;42:517–584.
Questions from the
Audience?
References
1. Guideline on the management of patients with extracranial carotid and
vertebral artery disease. J Am Coll Cardiol 2011 Feb 22; 57:1002.
2. Sacco RL, etal. Guidelines for prevention of stroke. Stroke
2006;37:577-617.
3. 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
Sep;126(3 Suppl):483S-512S.
4. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal
strokes by successful carotid endarterectomy in patients without recent
neurological symptoms: randomized controlled trial. Lancet. 2004 May
8;363(9420):1491-502.
5. NASCET: beneficial effect of carotid endarterectomy in symptomatic
patients with high grade stenosis. N Engl J Med 1991;325:445-453.
6. ACAS Study group: Endarterectomy for asymptomatic carotid stenosis.
JAMA 1995;273:1421-1428.
6. Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage.
http://stroke.ahajournals.org/cgi/content/full/40/3/994. Stroke.
2009;40:994-1025.
7. Diener H-C, et al. Aspirin and clopidogrel compared with clopidogrel
alone after recent ischaemic stroke or transient ischaemic attack in