DIFFERENT STROKES FOR DIFFERENT FOLKS
| STROKES AND SILENT STROKES —Jacob S. Elkins, MD, Assistant Professor, Department of Neurology, University
of California, San Francisco, School of Medicine
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| Introduction: traditional vascular risk factors for stroke include hypertension, diabetes, and tobacco use; lesions in white
matter around ventricles seen on magnetic resonance imaging (MRI) common and radiographically and pathologically
indistinguishable from strokes that produce dramatic clinical presentations; recent population-based studies help determine
incidence, causes, and complications
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| Cardiovascular Health Study: MRI performed on ≈4000 participants; 30% had infarcts on brain by age 70 yr, and
only 15% of group ever had symptoms of stroke or transient ischemic attack (TIA); similar findings in other studies; similar
ratio between silent infarcts and infarcts that produce symptoms of stroke (7-8:1); risk factors for developing infarcts
in brain—similar to those that produce stroke; advanced age; lack of exercise; high systolic blood pressure (BP);
markers of atherosclerosis (eg, ankle-arm index, creatinine, marker of microvascular disease); most silent infarcts occur
in periventricular (subcortical) area; atrial fibrillation risk factor for patients with cortically based infarcts
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| Consequences of asymptomatic infarcts: Rotterdam Study performed MRI at baseline and repeated after 3 yr, with
careful cognitive testing before and after; study found people declining on cognitive tests had new infarct on MRI in interval
between scans and had ≈2 times risk of developing clinically defined dementia; infarcts may be markers of subclinical
vascular injury and strong predictor of future cardiovascular events; in patients who had infarct on MRI associated
with leukoaraiosis (white matter disease), risk for stroke 4 times as high as people with normal MRI, and rates of death
significantly higher; infarcts “covert” rather than “silent”; no proven therapy to prevent silent stroke or covert infarct on
MRI
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| Stroke prevention for patients in prehypertensive range: lifestyle modification primary recommendation; target
BP uncertain in stroke patients; benefits of pharmacologic therapy for primary prevention uncertain; risk for stroke
increases linearly once BP reaches 120/80 mm Hg
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| BP management for secondary stroke prevention: Heart Outcomes Prevention Evaluation (HOPE) trial—
study of ramipril vs placebo in patients with multiple vascular risk factors; ≈50% had hypertension and ≈50% had BP in
prehypertensive range; relative risk reduction for stroke in people who received ramipril essentially same in hypertensive
and prehypertensive groups; Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial—benefits of
therapy (perindopril) did not appear different for hypertensive patients or patients with lower BP; most benefit seen in
people who received angiotensin-converting enzyme (ACE) inhibitor and thiazide diuretic together
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| Agents for prehypertensive patients: Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension
Study—compared losartan to atenolol; despite identical reductions in BP, losartan group had 25% reduction in stroke
risk; Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention
(MOSES) study—identical BP reduction in both groups; risk for stroke 25% lower in group that received angiotensin-
receptor blocker (ARB; eprosartan); no evidence that ARBs more effective than ACE inhibitors; start with ACE inhibitor
and use ARB for patients with tolerability problems; thiazides reasonable alternative for first-line therapy for stroke prevention
and appear particularly beneficial to black patients
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| Carotid stenosis: accounts for 15% to 20% of strokes; carotid endarterectomy gold standard for stroke prevention in patients
with symptomatic carotid stenosis (≥50%)
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| Asymptomatic carotid stenosis: Asymptomatic Carotid Atherosclerosis Study (ACAS)—stopped early because of
perceived benefits in surgical arm compared to medical arm; patients with 60% to 99% stenosis defined by carotid ultrasonography
(US); at 5 yr, risk for stroke 11% in medical arm vs 5% in surgical arm; study criticized for 1) lack of statistical
benefit when outcome disabling stroke; suggests minor strokes not producing disability-driving results; 2) surgical
complication rate of 2.3% (lowest complication rate in any endarterectomy trial); 3) less benefit to women than to men;
Asymptomatic Carotid Surgery trial—nearly identical to ACAS; surgical complication rate 3.0%; at 5-yr follow-up,
results same as those of ACAS, but with similar benefit in women and men; benefit similar in all degrees of stenosis; less
benefit in patients >75 yr of age; guidelines for treating asymptomatic carotid disease—for patients 40 to 75 yr of age,
endarterectomy provides benefit in stroke reduction (5-yr stroke rate reduced by 50%; number needed to treat [NNT] to
prevent 1 stroke ≈14); surgical complication rate should be <3.0%; reasonable to consider 5-yr life expectancy of patient
(patient must survive certain number of years on medical management before risks of medical therapy surpass surgical
risks)
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| Carotid stenting: Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE)
trial—aimed to prove stenting not worse than endarterectomy; comprised patients at high surgical risk (age
>80 yr or with known severe cardiac or pulmonary disease); findings do not apply to average patient with carotid stenosis
(endarterectomy gold standard for average patient with carotid stenosis until more data available)
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| Symptomatic carotid disease: study found people with left-sided carotid stenosis had 2.5 times greater risk for cognitive
decline than people without carotid stenosis; no cognitive decline in patients with right-sided carotid stenosis; suggests
asymptomatic carotid disease may lead to subclinical injury in brain and cognitive decline
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| Stroke classification: 1) large-artery atherosclerosis (stenosis >50% on vascular imaging studies); 2) cardioembolic;
risk factors on transesophageal echocardiography (TEE) or telemetry; 3) lacunar; defined by clinical presentation, subcortical
location, and small size of infarct; 4) cryptogenic; etiology unknown; 5) stroke from other defined causes (eg,
vasculitis, hypercoagulability)
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| Choosing antithrombotic agent after stroke: Warfarin-Aspirin Recurrent Stroke Study (WARSS)—patients
with history of ischemic stroke with no carotid stenosis and no identified cardioembolic source randomized to warfarin
or aspirin; international normalized ratio ≈2; stroke recurrence rates ≈17% in both arms; no difference in stroke subtypes;
substudies—1) antiphospholipid antibodies present in ≈20% of patients, but did not predict recurrent stroke
risk; no evidence that giving warfarin better than giving aspirin; 2) TEE performed in 630 patients after stroke; patent
foramen ovale (PFO) found in 33% of cases; no evidence that PFO risk factor for recurrent stroke; rate of stroke higher
in patients without PFO; literature suggests certain characteristics of PFO increase risk (eg, size of PFO, associated
atrial septal aneurysm); no sign that patients with PFO who received warfarin did better than those who received aspirin
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 | Intracranial atherosclerosis: Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial—patients
with stroke and intracranial atherosclerosis >50% defined by cerebral angiography randomized to warfarin or aspirin; after
2-yr follow-up, no difference between patients who received warfarin and those who received aspirin; more deaths and
more major hemorrhages in warfarin group; intracranial stenting—can result in successful angiographic outcomes; complication
rate varies (≈5% acceptable); may improve natural history; generally reserved for hemodynamically significant lesions
with recurrent symptoms; remains investigational; no evidence that average patient with intracranial atherosclerosis
after stroke should be referred for procedure
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| Summary: warfarin no longer recommended over aspirin for cryptogenic stroke, PFO, stroke with antiphospholipid antibodies,
or intracranial atherosclerosis; aspirin failure marker of high risk for recurrent stroke; no evidence that patients
who received warfarin did better than patients who continued aspirin therapy; data primarily applicable to older patients
with typical stroke and should not be generalized to patients <50 yr of age with risk of having other medical condition
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| Newer antiplatelet agents compared to aspirin: Clopidogrel versus Aspirin in Patients at Risk of Ischaemic
Events (CAPRIE) study—benefits of clopidogrel (Plavix) over aspirin modest; relative risk reduction in combined
cardiovascular outcome 8.7%; absolute risk reduction 0.5%; NNT with clopidogrel to prevent 1 outcome event ≈200;
benefits of clopidogrel appeared smaller in patients with prior stroke; safety of clopidogrel comparable to aspirin;
Management of Atherothrombosis With Clopidogrel in High-Risk Patients study (MATCH)—combination of clopidogrel
and aspirin did not give additional benefit of stroke prevention, compared to clopidogrel alone, and risk for
major bleeding substantially higher; dipyridamole and aspirin (Aggrenox)—European Stroke Prevention trial
showed reduced stroke risk of 23%, compared to aspirin alone; some concerns about inconsistencies; no effect on risk
for death; concerns about effects on coronary disease (in subsequent analyses, benefits appeared same with or without
coronary disease); similar safety profile to aspirin, but incidence of headache during first 2 days high; major trial comparing
clopidogrel to Aggrenox in progress
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| Current guidelines on antiplatelet medications: aspirin, clopidogrel, or Aggrenox acceptable first-line agents for noncardioembolic
stroke; aspirin should not be routinely added to clopidogrel for stroke prevention; for patients who have stroke while on
aspirin, increasing aspirin dose does not appear to provide additional benefit (reasonable to try other agents)
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| Summary: aggressive risk factor reduction essential; lower BP, lower cholesterol, and better glucose control associated
with lower risk for recurrent stroke; true lower limits and goals of therapy not yet established; antiplatelet agents, rather
than warfarin, mainstay of antithrombotic selection; always determine whether patient has atrial fibrillation or carotid
stenosis; efforts to prevent stroke may be key to preventing cognitive decline in elderly
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| POSTSTROKE CARE —Robert J. Adams, MD, Regents Professor of Neurology, Medical College of Georgia School of
Medicine, Augusta
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| Acute stroke care: evaluate cause and prevent recurrence; modify and treat risk factors; prevent medical complications;
educate patient and family; insure proper rehabilitation; limited role for acute anticoagulation therapy, even in stroke
cases thought to be related to cardiac disease; unfractionated or low molecular weight heparin—useful when patient
presents with mild acute ischemic stroke without hemorrhagic conversion; starting sooner better, but acceptable to wait
few days
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| Mechanisms of stroke: mechanism identified in ≈65% of cases, uncertain in ≈35% of cases; cardiogenic embolism—
atrial fibrillation; artificial heart valves; indication for long-term anticoagulation therapy; anticoagulation therapy not advocated
for atherosclerotic cerebrovascular disease (eg, carotid lesion); great vessel (eg, carotid) disease; intracranial disease
(more common in Asians and blacks); transcardiac embolus from deep venous system if right-to-left shunt present;
PFO on echocardiography not always cause of stroke
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| Diagnostic testing: no guidelines on complete stroke work-up; carotid endarterectomy—determine whether indicated;
duplex US common way to screen carotid arteries; magnetic resonance angiography (MRA) and computed tomography
(CT) angiography useful for follow-up or to confirm lumen reduction; recommendations for surgery based on reduction in
lumen diameter; greater risk with greater stenosis; ≥70% stenosis symptomatic; be more selective for surgery in patients
with stenosis of 50% (surgery less effective, especially in women; exceptions include high surgical risk); be more selective
in patients at intermediate risk; carotid angioplasty with or without stenting—option for high-risk patients when carotid
endarterectomy too risky; electrocardiography (ECG)—essential; provides information on atrial fibrillation and unsuspected
cardiac disease (eg, myocardial infarction [MI]; consult cardiologist); echocardiography—standard; transthoracic
echocardiography can lead to shorter long-term anticoagulation therapy; TEE more expensive, somewhat invasive, and reserved
primarily for younger (≤50 yr of age) stroke patients; TEE can reveal data about conditions with high risk for embolism,
PFO, and atrial septal aneurysm; no clear data that patients with severe aortic arch atheroma (≥4 mm) require different
management from someone with less severe (2-3 mm) disease (lipids should be managed more aggressively); conditions
with strong anticoagulation trial data include atrial fibrillation, prosthetic valves, and mitral stenosis; not all patients with
ejection fraction <25% should be on anticoagulation therapy (more data required); mitral valve prolapse and PFO not clear
indications for anticoagulation therapy; Holter monitoring—optional unless patient history unusual or suggests high likelihood
(eg, syncope, palpitations, intermittent atrial fibrillation); MRI—can be helpful; diffusion-weighted imaging (DWI)
detects early brain ischemia and useful for TIA or when diagnosis ambiguous; can show several spots in different arterial
circulations; look for intracranial stenosis; MRA and/or transcranial Doppler (TCD) US can be useful; lipid profile—
essential; performed within first 24 hr; management typically based on low-density lipoprotein (LDL); many believe most
ischemic stroke patients should be treated unless LDL <100 mg/dL; recommended that all ischemic stroke patients be on
statin therapy, but no class I data available; assess risk factors and select statin therapy if patient has carotid or large-artery
disease
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| Coagulopathy: laboratory studies (eg, prothrombin time [PT], partial thromboplastin time [PTT]) not routinely indicated;
homocysteine—no clear data that treating homocysteine improves outcome; high homocysteine risk factor for
heart disease and stroke, but no evidence that lowering with B vitamins beneficial; check in patients with unexplained
vascular disease and strong family history; look at platelet count; checking hemoglobin A1c recommended for patients
with diabetes; if patient does not have specific indications for warfarin, good trial data suggest warfarin does not offer
significant advantages over aspirin, but offers more risk; aspirin as initial antiplatelet therapy 50 to 325 mg daily; combination
of aspirin and dipyridamole or clopidogrel acceptable
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Educational Objectives
| The goal of this program is to educate the listener about stroke risk factors and management. After hearing and assimilating
this program, the participant will be better able to:
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| 1. Review trial data about secondary stroke prevention and blood pressure (BP) management.
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| 2. Assess risks and benefits of treating patients with carotid disease.
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| 3. Choose an appropriate antithrombotic agent after stroke, based on clinical findings and trial data.
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| 4. Compare trial data on newer antiplatelet agents to aspirin for stroke prevention.
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| 5. Work up stroke patients, based on clinical findings and likely cause of stroke.
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Discussed on This Program
Aspirin (acetylsalicylic acid; ASA) (several trade names)
Atenolol [Tenormin] Clopidogrel bisulfate [Plavix] Dipyridamole and aspirin [Aggrenox]
Eprosartan mesylate [Teveten]
Heparin sodium injection Heparin sodium lock flush solution [Heparin Lock Flush, Hep-Lock, Hep-Lock U/P] Losartan
potassium [Cozaar]
Nitrendipine [Baypress] (investigational)
Perindopril erbumine [Aceon] Ramipril [Altace]
Warfarin sodium [Coumadin]
Suggested Reading
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering
Committee. Lancet 348:1329, 1996; Adams HP Jr et al: Classification of subtype of acute ischemic stroke. Definitions
for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24:35, 1993;
Adams HP Jr et al: Guidelines for the early management of patients with ischemic stroke: A scientific statement from
the Stroke Council of the American Stroke Association. Stroke 34:1056, 2003; Biller J et al: Guidelines for carotid endarterectomy:
a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart
Association. Stroke 29:554, 1998; Brainin M et al: Organization of stroke care: education, referral, emergency management
and imaging, stroke units and rehabilitation. European Stroke Initiative. Cerebrovasc Dis 17 Suppl 2:1, 2004; Coull
BM et al: Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development
Committee of the American Academy of Neurology and the American Stroke Association (a division of the American
Heart Association). Neurology 59:13, 2002; Diener HC et al: Management of atherothrombosis with clopidogrel in
high-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH): study design and baseline data.
Cerebrovasc Dis 17:253, 2004; Goldstein LB et al: Primary prevention of ischemic stroke: A statement for healthcare
professionals from the Stroke Council of the American Heart Association. Circulation 103:163, 2001; Levine SR et al:
Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291:576,
2004; Mohr JP et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J
Med 345:1444, 2001; Smith SC Jr et al: AHA/ACC Scientific Statement: AHA/ACC guidelines for preventing heart
attack and death in patients with atherosclerotic cardiovascular disease: 2001 update: A statement for healthcare professionals
from the American Heart Association and the American College of Cardiology. Circulation 104:1577, 2001; Tanne D
et al: Risk profile and prediction of long-term ischemic stroke mortality: a 21-year follow-up in the Israeli Ischemic Heart
Disease (IIHD) Project. Circulation 98:1365, 1998; Thomas DJ: Protected carotid artery stenting versus endarterectomy
in high-risk patients reflections from SAPPHIRE. Stroke 36:912, 2005; van Dijk EJ et al: C-reactive protein and cerebral
small-vessel disease: the Rotterdam Scan Study. Circulation 112:900, 2005; Vermeer SE et al: Prevalence and
risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke 33:21, 2002.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Adams has received research grants, has served as a consultant for, and/or is on the Speakers’ Bureau for Boehringer
Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Merck & Co., Novartis Pharmaceuticals Corp.,
Sanofi-Synthelabo, Inc., and Wyeth-Ayerst.
Dr. Elkins spoke in San Francisco, CA, at the Annual Review in Family Medicine, presented March 6-7, 2006, by the University
of California, San Francisco, School of Medicine. Dr. Adams was recorded at Kiawah Island, SC, on July 22, 2005,
at Seizures, Spells and Shakes: Neurology for the Non-Neurologist, presented by the Medical College of Georgia School
of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of
this program.
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