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A. Overview navigator

  1. Carotid stenosis and cerebral artery dissection cause cerebrovascular disease
  2. Carotid Stenosis
    1. Narrowing of the carotid arteries
    2. Most of this narrowing is due to atherosclerotic plaque deposition
    3. The hemodynamic and metabolic factors involved in carotid disease and other vascular disease are related but not identical
    4. Vertebrobasilar disease is less common but can present with similar symptoms [1]
    5. Vertebrobasilar disease often associated with sight, balance, focusing problems [1]
  3. Carotid Stenosis and Stroke Risk
    1. Severe (>70%) stenosis is a major risk factor for transient and completed strokes
    2. Annual risk of stroke increases with increasing stenosis [5]
    3. Less severe (<50%) carotid stenosis is found in ~15% of patients with strokes
    4. Stenoses which compromise cerebral blood flow are a significant risk for stroke
    5. 20-45% of strokes in territory of ipsilateral carotid stenosis are not due to stenosis [14]
    6. Surgical endarterectomy of symptomatic carotid stenosis reduces stroke risk
    7. Medical therapies which reduce stenosis and stroke risk are now available
  4. Asymptomatic Carotid Stenoses [5]
    1. Stenoses 60-99% are associated with 3.2% annual risk of stroke
    2. Stenoses <60% associated with a 1.6% annual risk of stroke
    3. 45% of strokes in patients with 60-99% stenoses due to lacunes or cardioembolism
    4. Therefore, the use of endarterectomy in asymptomatic stenoses is of questionable value
  5. Carotid Stenosis and Cognitive Function [15]
    1. Brain hypoperfusion may lead to ischemic injury
    2. Brain left hemisphere is usually involved in cognitive function
    3. High grade stenosis of Left, but not Right, internal carotid artery associated with ~6X increased risk for cognitive deficits and 2.X risk of congnitive decline
  6. Mild to moderate alcohol consumption reduces ischemic stroke risk 20-50% [27,32]
  7. Event Rates for Acute Vascular Diseases [17]
    1. Prospective study in 91,106 persons in Oxfordshire UK 2002-05
    2. 2024 acute vascular events occurred in 1657 individuals
    3. Cerebrovascular disease 45% / 918: 618 strokes, 300 TIAs
    4. Coronary vascular 42% / 856: 159 ST-elevation MI, 316 non-ST MI, 281 USA, 163 SCD
    5. Peripheral vascular (PVD) 9% / 188: 43 aortic, 53 embolic visceral and limb ischemia, 92 critical limb ischemia
    6. 62 unclassifiable deaths
    7. Relative incidence of cerebrovascular compared with coronary events ~1.2
    8. Steep rise in event rates with age in all categories

B. Risk Factors for Carotid Stenosis navigator

  1. Carotid Stenosis
    1. Usually considered significant with >50-70% on ipsilateral side
    2. ACE gene polymorphisms do not correlate with stenosis [36]
  2. Hypertension (HTN)
    1. Hemorrhagic stroke
    2. Small vessel disease
    3. Acceleration of atherosclerosis
    4. Systolic HTN may be most important contributor in carotid stenosis
  3. Smoking
    1. Mild associated increase in carotid stenosis
    2. Probably synergistic with cholesterol and hypertension to increase atherosclerosis
  4. Hypercholesterolemia
    1. Especially with aortic atherosclerosis [2]
    2. LDL cholesterol, triglycerides and ApoB, ApoC3, ApoE correlate with progression
    3. High HDL cholesterol did not appear to be protective for carotid stenosis
  5. Coronary and/or Peripheral Vascular Disease
  6. Diabetes
  7. Resistance to activated protein C
  8. Vasculitis
  9. Sickle Cell Anemia [13]
  10. Age - increasing risk with increasing age
  11. Sedentary lifestyle with poor cardiorespiratory fitness [11]
  12. Moya Moya Disease

C. Pathophysiology navigator

  1. Atherosclerotic plaque deposition in carotid vessels causes stenosis
    1. These changes refer to specific histopathological abnormalities found in vessels
    2. The abnormalities, or "plaques" include cellular and cholesterol-rich components
    3. Plaques form in subendothelial region of arteries and even arterioles
    4. Plaques restrict blood flow and provide a potential surface for clot formation
    5. Restriction of cerebral blood flow >60-70% often causes chronic symptoms
    6. Plaque rupture with thrombus formation is the major cause of acute stroke
  2. Factors Implicated in Perpetuating Atherogenesis
    1. High levels of specific cholesterol types, particularly Apolipoproteins and LDL
    2. Mechanical stresses and shear including high vascular (blood) pressure also key role
    3. Increased plasma homocysteine levels
    4. Hyperglycemia - likely due to glycatation of biomolecules
    5. Tobacco smoke - may activate certain inflammatory cells
    6. Autoimmune disease - anticardiolipin and antiendothelial antibodies, vasculitis
    7. Possible infectious initiators including CMV, chlamydia, other agents
    8. Reduction in effective anti-coagulant levels may cause irritation to vessel walls
    9. Combinations of these factors are likely synergistic
    10. Once initiated, atherogenesis progresses in setting of "low level" stimuli
  3. Components of Plaques
    1. Major component is oxidized low density lipoprotein (LDL cholesterol)
    2. Macrophages, often called "foamy histiocytes" when found in plaque region
    3. Platelet products and fibrin
    4. Fibroblasts and collagen- similar to wound helaing responses
    5. Smooth muscle cells proliferate in the "neointima" that forms in the plaque region
    6. Inflammatory cytokines, even without lymphocytes, can stimulate neointimal growth
    7. Many of the pathways could be similar to those in wound healing responses
    8. Chronic plaque formation with fibrosis leads mainly to stenotic lesions
    9. Fresh plaques are unstable and predisposed to rupture
  4. Cerebral Blood Flow (CBF)
    1. The brain is highly sensitive to CBF
    2. CBF is driven by cerebral perfusion pressure (CPP) and cerebral blood resistance (CBR)
    3. By Ohm's Law, CBF = CPP/CBR
    4. With normal CPP, CBF is closely matched to cerebral metabolic demands (Stage 0 CBF)
    5. Therefore, the oxygen extraction fraction (OEF) in cerebral venous blood is normal
    6. Moderate reductions in CPP due to stenosis have little effect on CBF
    7. This is because vasodilation occurs, and CBR drops, maintaining CBF (Stage I CBF)
    8. In Stage I with vasodilation, cerebral blood volume (CBV) increases (this is measurable)
    9. With further reductions in CPP (stenosis), vasodilation can no longer compensate
    10. Therefore, OEF increases and brain function is maintained (Stage II)
    11. Stage II CBF is a 6-7 fold risk factor for subsequent ipsilateral and all strokes
  5. Plaque Rupture
    1. Plaque rupture is the most frequent cause of coronary thrombosis
    2. Likely that carotid plaque rupture and thrombus formation leads to many acute strokes
    3. Plaques which rupture typically have dense dense infiltrate of macrophages and some lymphocytes, with fibrous cap of acellular lipid mass
    4. Rupture of plaque surface leaves highly thrombogenic material exposed
    5. Exposed ruptured surface forms nidis for platelet aggregation and clot formation
    6. In addition, there is potential for downstream embolization of ruptured plaque material
    7. Elevated serum cholesterol and low HDL increase risk of plaque rupture
    8. Cigarette smoking increases platelet thrombogenicity
  6. Older plaques are more stable and show endothelial erosion (rather than rupture)
    1. Often asymptomatic leading mainly to stenotic lesions
    2. Older plaques probably contribute to large thrombus formation in ~25% of MIs
    3. Gradual increase in plaque size leads to symptoms of chronic cerebral ischemia
    4. These include light headedness, syncope, transient ischemic attacks
    5. Stable plaques are richer in macrophages, smooth muscle, lower in lipids, than unstable
  7. Cerebrovascular Disease and Dementia [50]
    1. Presence of Apo E4 genotype may be synergistic for vascular dementia
    2. Chronic hypertension (HTN) may increase risk of dementia
    3. Treatment of systolic HTN in elderly reduces dementia incidence
    4. HTN, atherosclerosis and diabetes can contribute to cognitive decline, particularly in the presence of Apo E4
    5. Silent brain infarctions on MRI at baseline are 2X risk for dementia [46]
  8. Factors which Reduce Carotid Stenosis
    1. Cholesterol reduction
    2. Anti-inflammatory agents - increasing evidence for efficacy of aspirin
    3. Elevated HDL Levels
    4. Nitric oxide production by endothelial cells inhibits plaque growth
    5. Vitamin E may inhibit plaque growth as well
    6. Increased folic acid reduces plasma homocysteine levels and may reduce stenosis

D. Evaluation navigator

  1. Introduction [43]
    1. Assessed by noninvasive B-mode ultrasonography on distal carotid arteries
    2. Evaluate carotid arterial intima-media thickness
    3. Increased carotid intima-media thickness is a risk factor for heart attack, stroke [48]
  2. Presence of carotid bruits probably not helpful
    1. Sensitivity for carotid disease probably ~50%
    2. Does not help with degree of stenosis
  3. Intra-Arterial Angiography is gold standard
    1. Costly and invasive
    2. Risk of stroke from procedure ~1%
    3. Required prior to endarterectomy procedure
    4. Dye load may compromise renal function
    5. Non-invasive imaging is generally preferred and nearly as accurate for >70% stenosis [9]
  4. Duplex (B-Mode) Ultrasonography (DUS) [35,43]
    1. DUS with doppler flow determinations
    2. Accurate in determining >70% carotid artery stenosis
    3. Rapid assessment, relatively low price, non-invasive
    4. Repeated ultrasound exams add nothing to risk assessment or prognosis
    5. Therefore, once the initial exam is done, patient is fully risk stratified
    6. Cannot examine smaller intracranial vessels
    7. DUS is not as sensitive as contrast enhanced MRA (see below) or CT angiography [9]
  5. Magnetic Resonance Angiography (MRA) [16]
    1. Good carotid assessment, especially internal carotid
    2. Able to visualize posterior and smaller intracranial vessels
    3. MRA is accurate for detecting stenoses of 70-99% in recently symptomatic patients
    4. Contrast enhanced MRA more sensitive (94%) and specific (93%) than DUS [9]
  6. Overall, non-invasive tests have 86% sensitivity, 98% specificity for 100% occlusion
  7. Combination MRA and DUS have 96% sensitivity and 80% specificity for stenosis [8]

E. Long Term Treatment [49] navigator

  1. Morbidity associated with carotid stenosis
    1. Transient ischemic attacks (TIA)
    2. Full stroke (cerebrovascular accident, CVA)
    3. Light Headedness, Syncope
    4. Internal carotid artery stensosis presents with monocular blindness or TIA or stroke
    5. Transient monocular blindness carries a better prognosis than TIA [16]
    6. In asymptomatic patients, 60% of strokes occur in patients with stenosis <50% [35]
  2. Halting Disease Progression [24]
    1. Aggressive lipid lowering with statins (HMG-CoA reductase inhibitors)
    2. Blood pressure normalization
    3. Stop Smoking
    4. Weight Reduction
    5. Diabetes Mellitus - good control is key
    6. Cardiorespiratory fitness reduces progression of carotid atherosclerosis in men [11]
  3. Cholesterol Reduction
    1. Early trials showed no benefit of cholesterol reduction in reducing stroke
    2. The agents used in those trials likely had multiple actions with competing effects
    3. HMG CoA reductase inhibitors (statins) clearly reduce stroke risk and carotid stenoses
    4. Simvastatin (Zocor®) showed stroke reduction in the "4S" trial
    5. Atorvastatin (Lipitor®) 80mg po qd reduced recurrent stroke after TIA or stroke but no known CAD by 16%, and reduced major cardiovascular events 20% within 5 years [3]
    6. Atorvastatin 80mg qd reduced risk of stroke or any cerebrovascular event by ~25% versus atorvastatin 10mg qd (LDL-C averaged 77mg/dL and 101mg/dL respectively) [26]
    7. LDL Chol reduced to ~80mg/dL 40mg qd rosuvastatin (Crestor®) in low risk patients reduced carotid intima-media thickness over 1-2 years versus increase in placebo [4]
    8. Pravastatin (Pravachol®) reduces progression of atherosclerosis in carotid arteries
    9. Lovastatin reduces atherosclerotic plaque size in occluded carotids
    10. Cholesterol reduction for carotid disease did not affect cancer risk or overall mortality
  4. Aspirin (ASA) [28]
    1. Inhibition of platelet binding to endothelium
    2. 75mg qd showed 18% prevention of stroke / death (SALT study)
    3. 300mg qd showed ~15% prevention of stroke / death / MI (UK-TIA study)
    4. 1000-1300 mg qd 31-57% prevention of stroke / death in males (various studies)
    5. ASA 1300mg qd superior to warfarin INR 2.0-3.0 for secondary prevention in patients with symptomatic intracranial arterial stenosis [7]
    6. Recommended for patients who bleed on warfarin, TIA or minor stroke, history of MI
    7. ASA effective in patients with history of MI, regardless of sex (81-325mg/d)
    8. Overal risk reduction of 15% for low dose and 9% for high dose (>325mg/d) ASA
    9. Aspirin had no benefit compared with placebo in stroke prevention in asymptomatic patients with carotid bruits and >50% carotid stenosis [29]
    10. Dipyridamole (Persantine®) added to ASA (combination sold as Aggrenox®) modestly improves stroke prevention [53]
  5. Clopidogrel (Plavix®)
    1. Primary prevention of stroke in patients with atherosclerosis
    2. Irreversibly inhibts platelet aggregation
    3. Binds to ADP receptors (adenyl cyclase coupled) on platelet surface
    4. Clopidogrel is similar to ticlopidine in structure and efficacy without neutropenia [23]
    5. Rash and diarrhea are major side effects
  6. TASS (Ticlopidine - Aspirin Stroke Study) [25]
    1. Ticlopidine 250mg bid compared with aspirin 650mg bid in TASS
    2. Ticlopidine had 2% fewer non-fatal stroke or death from any cause (17% versus 19%)
    3. Ticlopidine had 3% fewer fatal and non-fatal strokes (10% versus 13%)
    4. Clopidogrel should be used in place of ticlopidine in all cases
  7. CAT Study
    1. Ticlopidine 250mg bid versus placebo in people with completed stroke
    2. Major endpoints included recurrent nonfatal stroke, nonfatal MI, vascular death
    3. Ticlopidine group showed 30% fewer episodes, equal male-female benefit
  8. Warfarin
    1. Warfarin shows benefit (INR 2.8-4.8) in decreasing risk for CVA in post-MI patients
    2. It also showed equal efficacy with ASA in decreasing risk for recurrent MI
    3. Warfarin is clearly more effective than ASA in preventing cardioembolic strokes
    4. May be used in non-cardioembolic strokes in addition to (low dose) ASA
    5. Strongly recommended in atrial fibrillation (especially in Rheumatic Heart Disease)
    6. In non-valvular atrial fibrillation, warfarin has 64% risk reduction compared to placebo, 40% reduction compared with ASA
    7. In patients with atrial fibrillation and cerebral ischemia, INR target is ~3 [31]
    8. In patients with metal valves, warfarin can be safely combined with low dose ASA
  9. Blood Pressure (BP) Normalization
    1. ACE inhibitors (ACE-I) are generally recommended first line
    2. Angiotensin II receptor blockers (ARB) likely as effective as ACE-I
    3. Losartan, an ARB, reduced CV morbidity, stroke and death more than atenolol (a ß-blocker), independent of BP control
    4. Perindopril, an ACE-I, reduced risk of recurrent stroke 28% or any CV event in patients with previous stroke [8]
    5. Thiazide diuretics (such as hydrocholorothiazide) are added if BP reduction not optimal
  10. Estrogens
    1. Estrogen alone is likely protective against stroke
    2. Generally should be considered in elderly patients to prevent osteoporosis and CAD
    3. Smoking reverses many of the protective effects of estrogen
    4. Progesterone may be antagonistic to estrogen's protective action
    5. Only low dose estrogens should be used in replacement therapy
  11. Lack of Association (either positive or negative) with Stroke
    1. Antioxidant vitamins ß-carotene and Vitamin C
    2. Oral Contraceptive Pills (OCP) - some combinations show increased stroke risk
    3. OCP should be taken by smokers as this combination greatly increases stroke risk
  12. Critical and symptomatic stenoses may be relieved with endarterectomy
  13. Acute Therapy for Stroke

F. Carotid Endarterectomy and Stenting [18,24,49] navigator

  1. Surgical treatment of symptomatic and critical stenoses
    1. Only current methods for reduction or elimination of carotid stenosis
    2. Consider for symptomatic stenosis >50% through near (but not for total) occlusion
    3. Ideally, procedure should be done within 2 weeks of last ischemic event [41]
    4. Carotid artery stenting with an emboli-protection device is not inferior to carotid endarterectomy at 1- and 12- months [33,40] or at 3 year follow up [21]
    5. Carotid artery stenting with an emboli-protection device may be inferior to carotid endarterectomy in a separate 6-month study [34]
  2. Benefits versus risk of perioperative stroke have been studied very carefully
    1. Morbidity / Mortality ~2% of operations in most studies
    2. Only centers which perform at or better than this rate should continue this operation
    3. Mortality ~2.5% at low volume hospitals [44]
    4. In general, only symptomatic patients should be treated with endarterectomy [45]
    5. Efficacy greatest in men > women, age >75 years, and when done within 2 weeks of last ischemic event [41]
    6. Carotid angioplasty ± stenting had similar outcomes as endarterectomy at 30 days and 1 year in a met-analysis, though endarterectomy remains standard of care [33]
    7. Overall, few differences between endarterectomy and angioplasty stent [49]
  3. Efficacy clear for symptomatic lesions with >60-70% carotid stenosis [18,24]
    1. Highly beneficial for symptomatic lesions >70% stenosis to near-occlusion
    2. Decreased recurrent strokes and lowered functional impairment by ~70-90%
    3. Reduced stroke within 5 years ot operation in asymptomatic patients <75 years with >70% stenosis from 12% to 6% [19]
    4. Clearly beneficial for patients with non-disabling ischemic symptoms and stenoses >60% (60% American approximately equals 80% stenosis European, ECST) [45]
    5. Patients with >60% stenosis without symptoms will have a reduced 5-year risk of ipsilateral stroke with endarterectomy if perioperative mortality is <3% [20]
    6. In patients with <50% stenosis, endarterectomy in patients with a history of at least one CVA had no benefit at 4.5 [22] or 5 [47] years
    7. With symptomatic moderate carotid stenosis (50-69%), 5 year risk of ipsilateral stroke is 15.7% with endarterectomy, 22.2% with medical therapy [47]
    8. At 3 years, >28% of endarterectomy and 25% of carotid stenting high risk patients had major events showing non-inferiority of stenting [21]
    9. Patients >75 years with symptomatic stenosis >50% and no substantial comorbidities benefit from endarterectomy [30]
    10. Thus, for 50-69% stenosis, one patient benefit requires 15 endarterectomies [18,47]
    11. This improves to one benefit for 6 endarterectomies in patients >75 years [30]
  4. Cost Effectiveness
    1. About 130,000 endarterectomies are performed each year in the USA
    2. Screening for asymptomatic carotid stenosis >60% is not cost effective
    3. In this analysis, cost would be ~$120,000 per year of life saved
  5. Carotid Hyperperfusion Syndrome [39]
    1. Symptomatic disease is an uncommon complication of endarterectomy
    2. Typically occurs 5-8 days after surgery
    3. Headache, seizures, focal neurological signs, intracranial hemorrhage can occur
    4. Major problem is hyperperfusion causing brain edema, mainly in white matter
    5. Perfusion-weighted MRI scanning is likely best diagnostic method
    6. Diuretics, anti-seizure agents, and anti-hypertensives usually treat successfully
    7. Vascular homeostasis is eventually achieved in most patients
    8. Medications can usually be stopped

G. Summary of Medical versus Surgical (Endarterectomy) Treatment [24]navigator

  1. Asymptomatic
    1. Stenosis <60% always treated medically
    2. Stenosis >60% stratified by surgical mortality risk >3% (go medical) or <3% (go surgical)
    3. Mortality Risk >3%: Age >79 years, unstable cardiac disease, no experienced surgeon
    4. Mortality Risk <3%: Age <79 years, stable cardiac disease, experienced surgeon
  2. Symptomatic
    1. Stenosis <50% always treated medically
    2. Stenosis >70% treated with endarterectomy
    3. Stenosis 50-70% is difficult decision; 60% often used as cutoff (surgery for >60%)
  3. Symptomatic 50-70% Stenosis
    1. Lower Risk of stroke: less severe stenosis, age <75, female, stroke >3 months earlier, visual symptoms only, no intracranial stenosis, microvascular ischemia
    2. Higher Risk of stroke: more severe stenosis, age >75, male, stroke <3 months earlier, hemispheric symptoms, intracranial stenosis, no microvascular ischemia
    3. In general, higher risk patients should undergo endarterectomy
  4. Carotid Stents
    1. Percutaneous carotid stent placement may be a safe alternative to endarterectomy [10]
    2. Use of emboli-protection device with stenting in severe disease is not inferior to carotid endarterectomy [40]
    3. No differences in overall outcomes compared with carotid endarterectomy in meta- analysis at 30 days and 1 year [33]
    4. In patients with symptomatic carotid stenosis of >60%, the rates of death and stroke at 1 and 6 months were lower with endarterectomy than with stenting [6]
  5. In type 2 diabetics, pioglitazone (Actos®) 150-45mg/d for 18 months reduced carotid intima-media thickness compared with glimepiride 1-4mg/d [42]

H. Carotid Artery Dissectionnavigator

  1. Relatively uncommon problem
  2. Risk Factors
    1. Usually related to trauma (progresses over days to weeks after trauma)
    2. Also occurs in persons with connective tissue disorders
    3. These include Marfan and Ehlers-Danlos Syndromes
    4. Other risk factors include hypertension and local infections
  3. Presentation
    1. Ischemic stroke (young persons) - may be due to direct occlusion or thromboembolism
    2. Unilateral head or neck pain
    3. Oculosympathetic palsy
    4. Tinnitus (pulsatile)
    5. Scalp tenderness
    6. Cranial nerve palsies (about 10%)
    7. Dysgeusia - unpleasant taste in the mouth
  4. Differential Diagnosis of Dysgeusia
    1. Drugs - clarithromycin, metronidazole, chemotherapies
    2. Carotid artery dissection
    3. Cranial neuropathies

I. Dissection of Carotid and Vertebral Arteries [1,51,52]navigator

  1. Uncommon cuase of cerebral ischemia and stroke
    1. Carotid artery dissections occur ~3/100,000 per year
    2. Vertebral artery dissections occur ~1/100,000 per year
  2. Peak in 5th decade of life
  3. Likely due to underlying structural defect in arterial wall
  4. Pain and ischemic manifestations are main effects
  5. Conventional angiography is the main diagnostic method
  6. MRA is also useful and are replacing conventional angiography

J. Hereditary Cerebral Arteriopathy (CADASIL) [37,38]navigator

  1. Cerebral autosomal dominant arteriopathy, subcortical infarcts and leukoencephalopathy
  2. Caused by mutations in the Notch3 gene, coding a large transmembrane receptor, chr 19
  3. May be responsible for significant portion of patients with "mutli-infarct" dementia
  4. Typically presents as early onset (mean 45 years) dementia with lacunar infarcts
  5. MRI changes precede symptoms
  6. Other symptoms include migraine, transient ischemic attacks, mood changes, dementia

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