Learning Objectives

Advanced Therapeutics „ See Handout

STROKE

Susan C. Fagan, Pharm.D.,BCPS

University of Georgia College of Pharmacy

Outline Importance of Stroke

„ Introduction to Stroke „ 3rd leading cause of death in U.S. – may
„ Primary Prevention be increasing !
„ Pathophysiology of cerebral ischemia „ 700,000 cases annually
„ Secondary Prevention „ Leading cause of adult disability in U.S.
„ Acute Treatment „ Cost >$53 billion annually

Stroke Mortality Types of Stroke

90
80
„ Hemorrhagic (SAH, ICH, SDH)
70 „ Ischemic (atherothombotic vs.
60
50
cardioembolic) – 80% of all strokes are
40 ischemic
30
20
10
0
WM BM WF BF

1997 death rates per 100,000 population

http://www.americanheart.org - accessed 9/2000

1
 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)

Risk Factors for Stroke

Neurology 1995;45(suppl 1):S10

Risk Factor Relative Risk Prevalence Primary Prevention of Ischemic Stroke

Atrial fibrillation 5.6 – 17.6 1% A Guideline from the American Heart Association/ American
Stroke Association Stroke Council
Hypertension 4.0 – 5.0 25-40 %
Larry B. Goldstein, Chair; Robert Adams, Mark J. ALberts, Lawrence J. Appel,
Cardiac Disease 2.0 – 4.0 10 – 20 % Lawrence M. Brass, Cheryl D. Bushness, Antonio Culebras, Thomas J.
DeGraba, Philip B. Gorelick, John R. Guyton, Robert G. Hart, George Howard,
Diabetes 1.5 – 3.0 4–8% Margaret Kelly-Hayes, JV (Ian) Nixon, Ralph L. Sacco
Cigarettes 1.5 – 2.9 20 – 40 %
Alcohol abuse 1.0 – 4.0 5 – 30 %
Hyperlipidemia 1.0 – 2.0 6 – 50 %

Stroke 2006;37:1583 - 1633

AHA Classes and Levels of Evidence Assessing the Risk of a

„ Class I Agreement the treatment is useful and effective First Stroke
„ Class II Conflicting evidence and/or a divergence of opinion about the
usefulness/efficacy of a treatment. „ Each patient should have an assessment of
„ Class IIa Weight of evidence is in favor of the treatment. his or her stroke risk (Class I, Level of
„ Class IIb Usefulness/efficacy is less well established by evidence
Evidence A)
„ Class III Evidence and/or general agreement that the treatment is not „ Risk assessment tools such as the
useful/effective and in some cases may be harmful.
Framingham Stroke Profile should be
„ Levels of Evidence considered as they can help identify
„ A: Data derived from multiple randomized trials.
„ B: Data derived from a single randomized trial or individuals who could benefit from therapeutic
nonrandomized studies. interventions and who may not be treated
„ C: Consensus opinion of experts.
based on any 1 risk factor (Class IIa, Level of
Evidence B).

2
 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

Cigarette Smoking Diabetes

„ Abstention from cigarette smoking and smoking
cessation for current smokers are recommended
(Class I, Level of Evidence B).
„ Avoidance of environmental tobacco smoke for
stroke prevention should also be considered
(Class IIa, Level of Evidence C).
„ The use of counseling, nicotine products, and
oral smoking cessation medications should be
considered (Class IIa, Level of Evidence B).
„ It is recommended that hypertension be
tightly controlled in both type 1 and type 2
diabetes (the JNC 7 recommendation of
<130/80 mmHg in diabetics is endorsed) as
part of a comprehensive risk-reduction
program (Class I, Level of Evidence A).
„ Treatment of adult diabetics, especially those
with additional risk factors, with a statin to
lower the risk of a first stroke is
recommended (Class I, Level of Evidence A).

3
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).

Relationship Between Stroke and

Atrial Fibrillation-3 LDL-C Reduction

Amarenco P et al. Stroke 2004;35:2902-2909.

Hylek EM. NEJM 2003;349;1019-1026.

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

4
Asymptomatic Carotid Stenosis-2
„ Prophylactic carotid endarterectomy is
recommended in highly selected patients with
high-grade asymptomatic carotid stenosis
performed by surgeons with <3%
morbidity/mortality (Class I, Level of Evidence
A).
„ Patient selection should be guided by an
assessment of comorbid conditions and life
expectancy.
Postmenopausal Hormone
Therapy
„ It is recommended that postmenopausal hormone
therapy (with estrogen with or without a progestin)
not be used for primary prevention of stroke (Class
III, Level of Evidence A).
„ The use of hormone replacement therapy for other
indications should be informed by the risk estimate
for vascular outcomes provided by the reviewed
clinical trials.
„ Clinical trials with selective estrogen receptor
modulators (tamoxifen and raloxifene) suggest that
overall stroke risk may be lower with raloxifene.
Rossouw et al. JAMA 2002;288(3):321-
Diet and Nutrition
„ A reduced intake of sodium and increased intake of
potassium is recommended to lower blood pressure
in persons with hypertension (Class I, Level of
Evidence A).
„ The DASH diet, which emphasizes fruit, vegetables,
and low-fat dairy products and is reduced in
saturated fat, also lowers blood pressure and is
recommended (Class I, Level of Evidence A).
„ A diet that is rich in fruits and vegetables may lower
the risk of stroke and my be considered (Class IIb,
Level of Evidence C).
Asymptomatic Carotid Stenosis-3
„ Carotid angioplasty–stenting might be a
reasonable alternative to endarterectomy in
asymptomatic patients at high risk for the
surgical procedure (Class IIb, Level of
Evidence B)
„ Given the reported periprocedural and overall
1-year event rates, it remains uncertain
whether this group of patients should have
either carotid endarterectomy or carotid
angioplasty–stenting.
Women’s Health Initiative
• 16,608 postmenopausal women, 50-
50-79 years,
with an intact uterus at baseline were recruited by
40 U.S. clinical centers for the period 1993-
1993-1998.
• Received conjugated equine estrogens, 0.625
mg/d, plus medroxyprogesterone acetate, 2.5 mg/d,
in 1 tablet (n = 8506) or placebo (n = 8102).
• After a mean of 5.2 years of follow-
follow-up, the trial
was stopped because of high rates of invasive
breast cancer and the global index statistic
supported risks exceeding benefits.
2002;288(3):321-33
Diet and Stroke
RR = 0.68
RR = 0.75
JAMA 1999;282:1233-1239
5
Physical Activity
„ Increased physical activity is recommended
because it is associated with a reduction in the risk
of stroke (Class I, Level of Evidence B).
„ Exercise guidelines as recommended by the
Centers for Disease Control and Prevention and
the National Institutes of Health of regular
exercise (30 min or more of moderate-intensity
activity daily) as part of a healthy lifestyle are
reasonable (Class IIa, Level of Evidence B).
Alcohol Abuse
„ Reduction of alcohol consumption in heavy
drinkers is endorsed
„ through established screening and counseling
methods, as outlined in the U.S. Preventive
Services Task Force Update 2004
„ No more than 2 drinks per day for men and 1
drink per day for non-pregnant women
„ best reflects the state of the science for alcohol
and stroke risk (Class IIb, Level of Evidence B).
Aspirin-1
„ Aspirin is not recommended for the
prevention of a first stroke in men (Class III,
Level of Evidence A).
„ Aspirin can be useful for prevention of a first
stroke among women whose risk is
sufficiently high for the benefits to outweigh
the risks associated with treatment (Class IIa,
Level of Evidence B).
Obesity
„ Obesity is classified by body mass
index (BMI) > 30 kg/m2
„ Waist-hip ratio >0.86 in women and
>0.93 in men correlates with a 3-fold
increased risk of stroke1
„ Weight reduction is recommended
because it lowers blood pressure (Class
I, Level of Evidence A).
Oral Contraceptives
„ The incremental risk of stroke associated with use of
low-dose oral contraceptives in women without
additional risk factors, if one exists, appears low
(Class III, Level of Evidence B).
„ It is suggested that oral contraceptives be
discouraged in women with additional risk factors
(e.g., cigarette smoking or prior thromboembolic
events) (Class III, Level of Evidence C).
„ For those who elect to assume the increased risk,
aggressive therapy of stroke risk factors may be
useful (Class IIb, Level of Evidence C).
Aspirin-2
„ The use of aspirin is recommended for
cardiovascular (including but not
specific to stroke) prophylaxis among
persons whose risk is sufficiently high
for the benefits to outweigh the risks
associated with treatment (a 10-year
risk of cardiovascular events of 6% to
10%) (Class I, Level of Evidence A).
6
 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

Patient Education Diagnostic Procedures

Warning signs
„ Sudden numbness, weakness, or „ Computed tomography (CT) scan
paralysis of the face, arm, or leg; „ Magnetic resonance (MRI)
usually on one side of the body „ Magnetic resonance angiography
„ Confusion, trouble speaking or
(MRA)
understanding
„ Carotid ultrasound
„ Sudden trouble seeing, blurred vision

„ Dizziness, loss of balance or loss of

coordination
„ Sudden, severe headache with no
known cause
Stroke Warning Signs. Mayo Foundation. Viewed at:
www.mayo.edu/cerebro/education/stroke_warning.signs.html
„ Ocular pneumoplethysmography (OPG)
„ Cerebral angiography (or
arteriography)
„ Transcranial Doppler ultrasonography
http://www.mayo.edu/cerebro/education/stroke_diagnosis.html, accessed 7/26/02

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%)

Albers GW, et al. Chest. 1998;114:683S-698S.

?
Rosamond WD, et al. Stroke. 1999;30:736-743.

7
 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

of glutamate in the pathogenesis of

receptors
„ The ischemic penumbra is the area where
neuronal death after ischemia2
blood flow is reduced to between 40% and
15% of normal. „ Elevations in intracellular calcium induced Glutamate release
and calcium influx
The fate of the penumbra is dependent upon by cerebral ischemia can produce Calcium

key events that determine life or death for

overload
Occlusion perturbations in intracellular signaling
cells in this region, since (clot or embolus) pathways that may contribute to
cells in this area are in danger but resultant neuronal injury or death2
not yet irreversibly damaged2 References: 1. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view.
References: 1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999; vol. 79;
1431-1568. 2. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Trends Neurosci. 1999;22(9):391-7. 2. Lee JM, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses
Nat Rev Neurosci. 2003;4(5):399-415. to ischemia. J Clin Invest. 2000;106(6):723-31.

Calcium overload leads to Free radicals can injure cells

free radical production and DNA
Free radicals are formed in the Mitochondrial disruption
ischemic core and penumbra Cell damage leads to cell death

„ There are three major classes of prooxidant Mitochondrial „ There is evidence that free radicals and
peroxynitrate can cause cell damage1
Free radicals
enzymes1:
disruption

„ Nitric oxide synthases „ The important role of oxygen free- MMP

Calcium Nitric Free radical DNA oxidative injury
activation
„ Cycloxygenases, xanthine
overload oxide formation
radicals in cell damage associated with
dehydrogenase, xanthine oxidase, and Protease stroke is underscored by the fact that Cell membrane

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

„ Ischemia and reperfusion induced oxidative

stress are accompanied by deterioration of „ In milder ischemic injury, cell death
brain mitochondria2 resembles apoptosis (cell suicide),
particularly within the ischemic
penumbra2 References: 1. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999;
References: 1. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab.
2001;21(1):2-14. 2. Schild L, Reiser G. Oxidative stress is involved in the permeabilization of the
inner membrane of brain mitochondria exposed to hypoxia/reoxygenation and low micromolar Ca2+. vol. 79; 1431-1568. 2. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke:
FEBS J. 2005;272(14):3593-601. an integrated view. Trends Neurosci. 1999;22(9):391-7.

8
 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

References: 1. Lo EH, Dalkara T, Moskowitz MA. Mechanisms,

challenges and opportunities in stroke. Nat Rev Neurosci. 2003;
4(5):399-415. 2. Dirnagl U, Iadecola C, Moskowitz MA.
References: 1. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. Pathobiology of ischaemic stroke: an integrated view. Trends
1999;22(9):391-7. 2. Sasaki C, Kitagawa H, Zhang WR, Warita H, Sakai K, Abe K. Temporal profile Neurosci. 1999;22(9):391-7. 3. Lipton P. Ischemic cell death in brain neurons. Physiological Reviews. Oct 1999; vol. 79; 1431-1568.
of cytochrome c and caspase-3 immunoreactivities and TUNEL staining after permanent 4. Ouyang YB, Kuroda S, Kristián T, Siesjö BK. Release of mitochondrial aspartate aminotransferase
(mAST) following transient focal cerebral ischemia suggests the opening of a mitochondrial permeability
middle cerebral artery occlusion in rats. Neurol Res. 2000;22(2):223-8. transition pore. Neurosci Res Commun. 1997;20:167–73.

Reperfusion increases the Neuroprotection may

production of free radicals improve clinical outcomes
Reducing free-radical–mediated damage is one approach1,2

Neurons in the penumbra may Acute Ischemic Stroke

benefit from neuroprotection DNA oxidative
Ischemic Cascade Reperfusion Cascade
injury
before and after reperfusion Cytokines
(TNF, IL-1)
MMP Glutamate release
„ Reperfusion-induced oxidative stress is activation

accompanied by deterioration of brain Inflammatory

Free radicals NMDA/AMPA receptor activation
mitochondria1 cell activation

„ Mediators of inflammation, cytokines, such as Depolarization

Reperfusion
platelet-activating factor, interleukin-1
(IL-1), and tumor necrosis factor β, are produced Nitric
Calcium increase
by injured brain cells2 oxide

„ 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.

Treatment Secondary Prevention

„ Secondary Prevention „ After a stroke nine-fold risk of
„ Acute Treatment recurrence (40% at 5 years)
„ Event rate of up to 20%/ year (high risk
atrial fibrillation)

Sacco, Arch Int Med, 2000

9
 Guidelines for Prevention of Stroke in Patients with
Ischemic Stroke or Transient Ischemic Attack
From the Stroke Council of the AHA
Ralph L. Sacco, Chair; Robert Adams, Vice-Chair
Greg Albers, Mark J. Alberts, Oscar Benavente, Karen
Furie, Larry B. Goldstein, Philip Gorelick, Jonathan
Halperin, Robert Harbaugh, S. Claiborne Johnston,
Irene Katzan, Margaret Kelly-Hayes, Edgar J.
Kenton, Michael Marks, Lee H. Schwamm, Thomas
Tomsick
Stroke
troke 2006;
2006; 37:577-617
37:577-617
Components of Secondary Prevention
Blood pressure control
Diabetes management
Lipid management
Smoking cessation
Alcohol moderation
Weight reduction / Physical activity
Carotid Artery Interventions
Antiplatelet agents / anticoagulants
Statins
Diuretics +/- ACE inhibitors
Diabetes
ASA 2006 Secondary Stroke Recs
„ More rigorous control of HTN and dyslipidemia should be
considered in patients with DM.
„ BP targets of 130/80 mm Hg (Class IIa, Evidence B). ACEIs
and ARBs are recommended as first-choice medications for
patients with DM (Class I, Evidence A).
„ Glucose control is recommended to near normoglycemic levels
to reduce microvascular complications (Class I, Evidence A) and
possibly macrovascular complications (Class IIb, Evidence B).
„ Hemoglobin A1c goal <7% (Class IIa, Evidence B).
Transient Ischemic Attacks
„ Guidelines now recognize TIA as an
important harbinger of stroke
„ >10% 90-day risk of stroke after TIA
„ Prevention recommendations for
patients with ischemic stroke are now
broadly applied to those with TIA
„ Recognizes common etiologies and urgent
need for treatment
Blood Pressure Control
ASA 2006 Secondary Stroke Recs
„ Antihypertensives are recommended beyond the hyperacute
period (Class I, Evidence A).
„ Benefit for those with & w/o HTN (Class IIa, Evidence B)
„ Target BP level and reduction are uncertain, but normal BP
levels are <120/80 by JNC-7 (Class IIa, Evidence B).
„ Lifestyle modifications have been associated with BP reductions
and should be included (Class IIb, Evidence C).
„ Optimal drug regimen uncertain; data support diuretics and the
combination of diuretics and an ACEI (Class I, Evidence A).
Cholesterol Control
ASA 2006 Secondary Stroke Recs
„ Those with elevated chol, CHD, or evidence of an
atherosclerotic origin should be managed according to NCEP III
(Class I, Evidence A).
„ Statins are recommended with target LDL-C of <100 mg/dL
and <70 mg/dL for the very high–risk (Class I, Evidence A).
„ Those with no pre-existing indications for statins (nl chol levels,
no CHD, or no atherosclerosis), are reasonable to consider for
statins to reduce the risk of vascular events (Class IIa,
Evidence B).
10
 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

Atrial Fibrillation Stroke Prevention - Non-cardioembolic

ASA 2006 Recommendations ASA 2006 Recommendations

„
„ 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.

Warfarin-Aspirin for Recurrent Mechanisms of Action of

Stroke Study (WARSS) 30
Oral Antiplatelet Therapies
clopidogrel bisulfate ADP dipyridamole
Probability of Event (%)

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.

11
Stroke Prevention - Non-cardioembolic Antiplatelet Therapy
ASA 2006 Recommendations ASA 2006 Recommendations

• Compared to aspirin alone,

alone, both the
„ Acceptable options for initial therapy combination of aspirin and extended-
extended -release
extended-release
(Class IIa,
IIa, Level of Evidence A). dipyridamole and clopidogrel are safe.
safe.
„
„ aspirin (50-
(50-325 mg qd)
(50-325 qd) • The combination of aspirin and extended-
extended-
„
„ the combination of aspirin and extended-
extended- release dipyridamole is suggested instead of
release dipyridamole (25/200 mg bid) aspirin alone.
alone. [Class IIa,
IIa, Level A]
„ clopidogrel (75 mg qd)
„ qd) • Clopidogrel is suggested instead of aspirin
alone based on direct comparison trials. [Class
IIb,
IIb, Level B
B]]

Secondary Stroke Prevention

ASA 2006 Recommendations
MATCH: Safety Outcomes
• The addition of aspirin to clopidogrel „ Excess life-threatening bleeding events
increases the risk of hemorrhage and is with combination versus clopidogrel
monotherapy:
not routinely recommended for stroke or
96 (2.6%) vs. 49 (1.3%); p<0.0001
TIA patients. [Class III, Level A]
„ Excess minor bleeds with combination
therapy versus clopidogrel alone:
• For patients allergic to aspirin,
aspirin,
120 (3.2%) vs. 39 (1.0%);
clopidogrel is recommended.
recommended. [Class IIa,
IIa,
p<0.0001
Level B] Diener H-C, et al. Lancet 2004;364:331-337

Level A recommendations Summary

„ Antihypertensive treatment
„ These guidelines provide
„ Glucose control to reduce microvascular
comprehensive and timely evidence-
complications of diabetes.
based recommendations.
„ Statins to reduce LDL to <100 or <70 for
high risk patients (sympt CHD or athero). „ There is an intent to fully update the
„ CEA for sympt. 50-99% guidelines every three years, with
„ NO CEA for <50% sympt stenosis. updates encouraged when pivotal
„ Warfarin at INR 2.5 for a. fib. (ASA if unable) studies are published.
„ Antiplatelet for noncardioembolic.
„ NO combination clopidogrel and ASA

12
 Acute Treatment
TIME IS BRAIN
Clinical Trials in Stroke
Kidwell; Stroke 2001;32:1349-1359
Clinical Trials in Stroke
„ 178 controlled clinical trials have been
done; 73,949 patients included
„ Only 3 met criteria for positive outcome
„ Changes over time include: number of
studies, inc. sample size and quality
and a reduction in time window
Kidwell; Stroke 2001;32:1349-1359
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
Clinical Trials in Stroke
Kidwell; Stroke 2001;32:1349-1359
Reperfusion Strategies
„ IV tPA within 3 hours of onset (< 5% of
patients currently receive it) increases
likelihood of return to normal by 30%.
„ IV Ancrod within 3 hours (not currently
available) similar efficacy to tPA
„ IA Prourokinase (not available) but
effective within 6 h in MCA occlusion.
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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

What about heparin? What about heparin?

„ Patients who are not candidates for thrombolytic
therapy
„ We do not recommend full-dose anticoagulation for
treatment of unselected patients with ischemic stroke.
(grade B2 evidence)
„ Clinicians may consider early anticoagulation for
treatment of acute cardioembolic and large-artery
ischemic strokes and for progressing stroke when the
presumed mechanism is ongoing thromboembolism
„“It seems quite extraordinary that clinicians
continue to use this treatment in the
absence of reliable data from randomized
trial evidence: a triumph of opinion over
evidence”
Peter Sandercock, DM, FRCPE;
Stroke 2001;32:579

Albers GW, et al. Chest 2001;119:300S-320S.

DWI – PWI MRI MISMATCH in a 73 yo

Functional Imaging-Guided with L hemiparesis
Pharmacotherapy

SPECT: single photon emission

computed tomography : CBF
From: Karonen et al.
Stroke 1999;30:
1583-1590
NMR/MRI: Nuclear magnetic
resonance / magnetic resonance
imaging: Diffusion and CBF

PET: Positron Emission

Tomography: CBV, CBF, CMRO2,
CMRG A = DWI, clearly smaller than B=PWI at 6 hours;
C=27 hours and D= 1 week after symptom onset

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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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