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Who is at risk of stroke ? Stroke and Aging
Elderly Risk doubles each decade after 55
Hypertensives For adults > 65 yo, risk of death from
Diabetics stroke = 7 x that of the general
Cardiac Patients (afib, MI, CAD) population
2/3 of strokes occur in people over 65
Major factor in dementia (occurring in
40% of Americans over age 80)
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Nonmodifiable Risk Factors Genetic Causes of Stroke
Age Referral for genetic counseling may be
Race considered for patients with rare genetic
Sex causes of stroke (Class IIb, Level of
Evidence C).
Low birth weight
There remain insufficient data to
Family history of stroke/TIA recommend genetic screening for the
prevention of a first stroke.
Modifiable, Well-Documented
Risk Factors Hypertension
Hypertension Dyslipidemia Regular screening for hypertension (at least
every 2 years in adults and more frequently in
Cigarette Diet
minority populations and the elderly) and
Smoking Obesity appropriate management (Class I, Level of
Diabetes Physical Inactivity Evidence A), including dietary changes,
Carotid Disease lifestyle modification, and pharmacological
Postmenopausal therapy as summarized in JNC-7, are
Atrial fibrillation Hormone Therapy recommended.
Sickle Cell
Disease
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Atrial Fibrillation-1 Atrial Fibrillation-2
Anticoagulation of patients with AF and Warfarin (INR 2.0 to 3.0) is
valvular heart disease (particularly those with
mechanical heart valves) is recommended. recommended for high-risk (>4% annual
(Class I). risk of stroke) patients (and many
Antithrombotic therapy is recommended to moderate-risk patients based on patient
prevent stroke in patients with non-valvular
atrial fibrillation based on assessment of their preferences) with atrial fibrillation who
absolute stroke risk, estimated bleeding risk have no clinically significant
and considering patient preferences and
access to high quality anticoagulation contraindications to oral anticoagulants
monitoring (Class I, Level of Evidence A). (Class I, Level of Evidence A).
VA-HIT
Cumulative Incidence of Stroke by Asymptomatic Carotid Stenosis-
Treatment Group 1
It is recommended that patients with
asymptomatic carotid artery stenosis be
screened for other treatable causes of stroke
and that intensive therapy of all identified
stroke risk factors be pursued (Class I, Level
of Evidence C).
The use of aspirin is recommended unless
contraindicated (Class I, Level of Evidence
B).
Bloomfield Rubins, H. et al. Circulation 2001;103:2828-2833
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Asymptomatic Carotid Stenosis-2 Asymptomatic Carotid Stenosis-3
Prophylactic carotid endarterectomy is Carotid angioplasty–stenting might be a
recommended in highly selected patients with reasonable alternative to endarterectomy in
high-grade asymptomatic carotid stenosis asymptomatic patients at high risk for the
performed by surgeons with <3% surgical procedure (Class IIb, Level of
morbidity/mortality (Class I, Level of Evidence Evidence B)
A). Given the reported periprocedural and overall
Patient selection should be guided by an 1-year event rates, it remains uncertain
assessment of comorbid conditions and life whether this group of patients should have
expectancy. either carotid endarterectomy or carotid
angioplasty–stenting.
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Physical Activity Obesity
Increased physical activity is recommended Obesity is classified by body mass
because it is associated with a reduction in the risk index (BMI) > 30 kg/m2
of stroke (Class I, Level of Evidence B).
Waist-hip ratio >0.86 in women and
Exercise guidelines as recommended by the
Centers for Disease Control and Prevention and
>0.93 in men correlates with a 3-fold
the National Institutes of Health of regular increased risk of stroke1
exercise (30 min or more of moderate-intensity Weight reduction is recommended
activity daily) as part of a healthy lifestyle are because it lowers blood pressure (Class
reasonable (Class IIa, Level of Evidence B). I, Level of Evidence A).
Aspirin-1 Aspirin-2
Aspirin is not recommended for the The use of aspirin is recommended for
prevention of a first stroke in men (Class III, cardiovascular (including but not
Level of Evidence A). specific to stroke) prophylaxis among
Aspirin can be useful for prevention of a first persons whose risk is sufficiently high
stroke among women whose risk is
for the benefits to outweigh the risks
sufficiently high for the benefits to outweigh
the risks associated with treatment (Class IIa, associated with treatment (a 10-year
Level of Evidence B). risk of cardiovascular events of 6% to
10%) (Class I, Level of Evidence A).
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Patient Presentation and
Summary Diagnosis
All individuals should have their risk of
stroke assessed
All modifiable risk factors should be
aggressively treated
Individuals with non-modifiable risk
factors should be aggressively studied
for the identification and treatment of
modifiable risk factors
Cerebrovascular Disease:
Pathophysiology
Pathogenesis
Hemorrhagic Stroke (17%) Ischemic Stroke (83%)
Large Artery
Intracerebral (20%)
Hemorrhage (59%)
Embolism
(20%)
Subarachnoid
Hemorrhage (41%)
Cryptogenic (30%)
Lacunar (25%)
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Platelet Cascade in
Vascular Disease: A Generalized Thrombus Formation
and Progressive Process 1 Adhesion
Unstable
angina ACS
MI von Willebrand
Platelets
Ischemic Factor/GP lb bind
stroke/TIA Collagen
GP la/lla bind 2 Activation
Critical leg Lipid
core
ischemia
Thrombin
Cardiovascul ADP
ardeath
Atherosclerosis Thrombosis 5 HT
TXA2
3 Aggregation
Activated
GP llb/llla Fibrinogen
Stable angina
Intermittent claudication
Handin RI. Harrison’s Principles of Internal Medicine.
Vol 1. 14th ed. NY, NY: McGraw-Hill; 1998:339-345.
Adapted from Stary HC et al. Circulation.
Circulation. 1995;92:1355-
1995;92:1355-1374 and Fuster V. Vasc Med.
Med. 1998;3:231-
1998;3:231-239. Schafer AI. Am J Med. 1996;101:199-209.
A cascade of biochemical
Acute ischemic stroke events
Occlusion of an artery in the brain Reduction in oxygen
Ischemic Ischemic
can lead to the development of an core penumbra These events cause neuronal and energy substrates
ischemic core and penumbra1 injury and death1
Membrane
The ischemic core is the area where blood flow Excessive concentrations of glutamate depolarization
is reduced by <15% of normal, affecting the are neurotoxic, and a large body of
territory distal to the site of the occlusion1 evidence now implicates the toxicity NMDA/AMPA
There are three major classes of prooxidant Mitochondrial There is evidence that free radicals and
peroxynitrate can cause cell damage1
Free radicals
enzymes1:
disruption
NADPH oxidase
activation
even delayed treatment with free-radical injury and leakage
Myeloperoxidase and monoamine oxidase
MMP Phospholipase scavengers can be effective in Endothelial
Dysregulation of
cellular processes
activation activation experimental focal cerebral ischemia2 damage
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Mitochondria are damaged by Open transition pores release
free radicals additional substances
The transmembrane potential of Calcium flows into the
mitochondria is altered intracellular space
Free-radical–mediated disruption of Increased levels of intracellular calcium
the mitochondria affects the inner lead to the generation of reactive oxygen
membrane and causes oxidation of species, such as hydroxyl, superoxide,
proteins that mediate electron transport, and peroxynitrate radicals1-3
H+ extrusion, and ATP production1
A large conductance pore in the inner
Release of cytochrome C from membrane, when open, can allow the
mitrochondria to the cytosol triggers passage of ions, molecules, and Calcium and
subsequent DNA fragmentation2 mitochondrial proteins4 cytochrome C release
Nitric oxide and oxidative stress are linked Free radical increase Free radical increase
to DNA damage and activation of poly(ADP-
ribose) polymerase, a nuclear enzyme that Neuron Cell Death
facilitates DNA repair and regulates transcription3
References: 1. Schild L, Reiser G. Oxidative stress is involved in the
permeabilization of the inner membrane of brain mitochondria exposed to hypoxia/reoxygenation and low References: 1. Bright, R, Mochly-Rosen D. The role of protein kinase C in cerebral ischemic and
micromolar Ca2+. FEBS J. 2005;272(14):3593-601. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology reperfusion injury. Stroke. 2005;36(12):2781-90. 2. Lipton P. Ischemic cell death in brain neurons.
of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22(9):391-7. 3. Lo EH, Dalkara T, Physiol Rev. 1999;79(4):1431-568.
Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4(5):399-415.
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Guidelines for Prevention of Stroke in Patients with
Ischemic Stroke or Transient Ischemic Attack
From the Stroke Council of the AHA Transient Ischemic Attacks
Guidelines now recognize TIA as an
Ralph L. Sacco, Chair; Robert Adams, Vice-Chair important harbinger of stroke
Greg Albers, Mark J. Alberts, Oscar Benavente, Karen >10% 90-day risk of stroke after TIA
Furie, Larry B. Goldstein, Philip Gorelick, Jonathan Prevention recommendations for
Halperin, Robert Harbaugh, S. Claiborne Johnston,
patients with ischemic stroke are now
Irene Katzan, Margaret Kelly-Hayes, Edgar J.
Kenton, Michael Marks, Lee H. Schwamm, Thomas
broadly applied to those with TIA
Tomsick Recognizes common etiologies and urgent
need for treatment
Stroke
troke 2006;
2006; 37:577-617
37:577-617
and ARBs are recommended as first-choice medications for Statins are recommended with target LDL-C of <100 mg/dL
patients with DM (Class I, Evidence A). and <70 mg/dL for the very high–risk (Class I, Evidence A).
Glucose control is recommended to near normoglycemic levels Those with no pre-existing indications for statins (nl chol levels,
to reduce microvascular complications (Class I, Evidence A) and no CHD, or no atherosclerosis), are reasonable to consider for
possibly macrovascular complications (Class IIb, Evidence B). statins to reduce the risk of vascular events (Class IIa,
Evidence B).
Hemoglobin A1c goal <7% (Class IIa, Evidence B).
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Symptomatic Carotid Endarterectomy
HPS: Conclusions for people with ASA 2006 Secondary Stroke Recs
cerebrovascular disease Ipsilateral severe (70% to 99%) carotid
Lowering LDL cholesterol by 1 mmol/L (40 mg/dL) reduces stenosis, CEA is recommended (Class I,
the 5-year risk of ischaemic stroke by about one-quarter, Evidence A).
with no apparent adverse effect on cerebral haemorrhage
Ipsilateral moderate (50% to 69%) carotid
Similar proportional reductions in stroke risk are seen with
stenosis, CEA is recommended depending age,
statin therapy irrespective of age, sex, lipid levels, blood
pressure, or use of other medications (including aspirin) gender, comorbidities, and the severity of
symptoms (Class I, Evidence A).
Statin therapy clearly reduces the risk of major vascular
events among people with pre-existing cerebrovascular
disease, irrespective of the presence of coronary disease Stenosis < 50%, there is no indication for CEA
(Class III, Evidence A).
Heart Protection Study Collaborative Group. Lancet 2002;360:7-22
For patients with ischemic stroke or TIA with
persistent or paroxysmal (intermittent) AF,
anticoagulation with adjusted-
adjusted-dose warfarin
adjusted-dose
For patients with noncardioembolic ischemic
(target INR 2.5, range 2.0 to 3.0) is
stroke or TIA, antiplatelet agents are
recommended (Class I, Evidence A).
recommended rather than oral anticoagulation
to reduce the risk of recurrent stroke and other
For patients unable to take oral anticoagulants, cardiovascular events (Class I, Evidence A).
aspirin 325 mg per day is recommended (Class
I Evidence A).
Albers GW, et al. Chest (2001);119:300S-320S.
1.13
ticlopidine HCl ADP phosphodiesterase
Hazard Ratio
20 P=0.25
P=0.25
Warfarin
The primary ADP
outcome occurred
10 in 17.8% of cAMP
Aspirin patients in the collagen
warfarin group and Activation thrombin
16.0% in the ASA TXA2
GP IIb/IIIa
group.
(fibrinogen COX
0
receptor)
0 90 180 270 360 450 540 630 720
TXA2
No. at Days After Randomization
aspirin
Risk
Warfarin 1103 1047 1013 998 972 956 939 924 885
Aspirin 1103 1057 1032 1004 984 974 951 932 900 ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.
Mohr JP et al. N Engl J Med. 2001;345:1444-1451. Schafer AI. Am J Med. 1996;101:199-209.
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Stroke Prevention - Non-cardioembolic Antiplatelet Therapy
ASA 2006 Recommendations ASA 2006 Recommendations
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Acute Treatment Steps in Acute Stroke Care
1) stabilize the patient
2) treat the stroke
3) prevent secondary injury
4) prevent recurrence
CEA, anticoagulation and/or antiplatelet
5) modify risk factors
6) educate patient and family
TIME IS BRAIN
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Neuroprotection Other Acute Strategies
Disappointing early clinical trials Antiinflammatory agents
Still agents in development Parenteral antiplatelet agents (GPIIBIIIA
Possible MOAs = GABA agonists, antagonists)
glutamate antagonists, ion channel
modulation, free radical scavengers
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Patient selection for
intervention
DWI / PWI mismatch may indicate a
“penumbral” area which might benefit
from reperfusion, neuroprotective or
antiinflammation therapies.
On the Horizon
Kondziolka D, Wechsler L, Goldstein S et al:
Transplantation of cultured human neuronal
cells for patients with stroke. Neurology
2000;55:565-569
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