Stroke Prevention

Frank Rubino, M.D.
Frank Rubino, M.D. is a Consultant in the Department of Neurology at Mayo
Clinic Jacksonville and a Professor, Mayo Graduate School of Medicine.

Introduction

Despite decline in stroke mortality, stroke incidence has not substantially declined, and as a matter of fact may be increasing since the mid-1980's. The figure that is usually given for the estimated incidence is 500,000 or more cases per year; however, recent studies estimate that the incidence of first ever and recurrent stroke is approximately 730,000 per year. Stroke remains the leading cause of serious long-term adult disability in the United States, and the third leading cause of death following cardiovascular disease and cancer. Despite these figures, in a recent survey in an area where stroke is well-publicized (greater Cincinnati metropolitan area) only 57% of public respondents were able to name at least one stroke warning sign, and only 68% were able to name at least one stroke risk factor.1

Thus public education remains an important issue. Patients and families should at least know that by using the 911 emergency telephone system the patients will arrive at the hospital sooner. In addition, the National Stroke Association has stroke prevention guidelines available to patients (Table 1). Patients may get more information by contacting the National Stroke Association at 1-800-STROKES or access their site on the Worldwide Web at www.stroke.org. Education is also important for physicians, nurses, and paramedical personnel.

Table 1. Stroke Prevention Guidelines

The National Stroke Association Stroke Prevention Guidelines advise patients to:
  1. Know your blood pressure, have it checked at least once a year, and, if it is elevated, work with your doctor to keep it under control;
  2. Find out if you have atrial fibrillation, which encourages the formation of blood clots that could cause a stroke;
  3. If you smoke, stop;
  4. If you drink alcohol, do so in moderation;
  5. Find out if you have high cholesterol;
  6. If you have diabetes, follow your physician's recommendations to control the condition;
  7. Include exercise in your daily routine;
  8. Eat a low-salt, low-fat diet;
  9. Ask your physician if you have circulation problems that could increase the risk of stroke; and
  10. If you experience any stroke symptoms, including sudden weakness of the face or a limb, a blurring of vision, dizziness, or an intense headache, seek immediate medical attention.

A TIA (transient ischemic attack) is typically defined as an episode of focal loss of brain function (usually negative phenomena) attributed to cerebral ischemia lasting less than 24 hours (usually 10-15 minutes) and localized to a limited region of the brain (in carotid artery distribution or basilar vertebral distribution). (A negative phenomenon is a loss of function such as hemiparesis or loss of feeling; whereas a positive phenomenon is an overactivity of function such as tingling, visual sparkles, colors, or zigzag lines, or even tonic/clonic movements). The terms TIA and stroke should be used accurately but are often used loosely and glibly by physicians, paramedical personnel, and even patients (Table 2). There are many conditions that can mimic stroke with four conditions being especially prominent: unrecognized seizures with postictal deficits, systemic infections, brain tumor, and toxi-metabolic disturbances.2 In addition, there are two relatively common syndromes especially in elderly patients that mimic TIAs and have both positive and negative phenomena: late-life migraine accompaniments3 and transient focal symptoms associated with cerebral amyloid angiopathy.4 (Tables 3 and 4) Cerebral amyloid angiopathy is a disease of the elderly, and usually presents as a spontaneous intracerebral hemorrhage rather than as a transient focal neurological syndrome.

Table 2. The following symptoms transient or prolonged cannot be classified as TIAs:

Table 3. Transient Migraine Accompaniments (Late Life
Migrainous Accompaniments)

Table 4. Presentations of Cerebral Amyloid Angiopathy Without Lobar Hemorrhage
  • Altered states of consciousness or syncope
  • Dizziness, wooziness or giddiness
  • Impaired vision associated with alterations of consciousness
  • Amnesia alone, vertigo alone, diplopia alone, dysphagia alone, or dysarthria alone
  • Tonic clonic motor activity
  • March of motor or sensory deficits
  • Scintillating scotoma
The symptoms in these spells are often both positive and negative and are as follows:
  • Scintillations or other visual displays are the most common symptoms to appear followed by paresthesias, aphasia, dysarthria, and paralysis.
  • There is a "build-up" of these accompaniments, especially the visual display; that is, they start off slight or small and build up in size and in intensity.
  • There may be a "march" of the paresthesias; that is, they start off in one location and spread to other parts of the body.
  • There is often a progression from one accompaniment to another, often with a delay.
  • There tends to be many spells which are very similar and occur in a stereotype fashion.
  • Headache may or may not occur.
  • On the average, the episodes last about 15-25 minutes.
  • Characteristically the spells occur in mid-life and often occur in "flurries."
  • In general, the clinic course is usually benign.

Adapted from Fisher CM. Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci. 1980;7:9-17, with permission.

Transient focal symptoms
  • Repetitive stereotype spells.
  • Unlike typical TIA symptoms that are maximal at onset, these transient spells consist of numbness, tingling, or weakness that spread over contiguous parts of the body in a period of minutes.
  • Subsequently lobar hemorrhage may occur in the region of the cortex that corresponds to the affected part of the body.
  • The continuous spread of symptoms is reminicient both of the "build-up" of migraine accompaniments and the "Jacksonian march" of a focal cortical seizure.
  • Catastrophic hemorrhage is not an inevitable corollary to the transient spells.

Rapidly progressive dementia

  • Dramatic progression to a severely impaired state within days or weeks.
  • Prominent white matter changes on MRI scan of the brain.

Adapted from Greenberg SM, et al. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology. 1993;43:2073-9, with permission.

Risk Factors

The risk factors of ischemic cerebral vascular disease are similar to the risk factors of ischemic cardiovascular disease and are well known by most physicians (Tables 5 and 6). There have been significant improvements in the management of some of these risk factors, especially atrial fibrillation and carotid artery disease, and yet control of many of the risk factors still remain suboptimal.5 Efforts for preventing stroke must be through both a combination of primary and secondary prevention. There are so-called nonmodifiable risk factors which include age, gender, race/ethnicity, and heredity. However, it is important to remember that patients with these nonmodifiable risk factors also have modifiable risk factors such as hypertension, diabetes, heart disease, smoking and drinking, hyperlipidemia, and lack of exercise. It has been estimated that almost 400,000 strokes could be prevented by successful treatment of hypertension, cigarette smoking, atrial fibrillation, and heavy alcohol consumption. The annual savings for a 50% reduction in stroke occurrence through control of hypertension and smoking could reach $8 billion.6

Table 5. Ischemic Cerebrovascular Risk Factor

Table 6. Cardiac Risk Factors

  • Age, gender, familial history, and race-ethnicity are markers of increased stroke risk.
  • The great majority of ischemic strokes occur in persons over age 65.
  • Men have a greater stroke incidence than women.
  • Women, however, outnumber men in most stroke studies due to greater life expectancy.
  • With age there is an exponential increase in the incidence of stroke.
  • Stroke mortality among African-Americans is double that of white Americans.
  • Modifiable risk factors include hypertension, cardiac disease, diabetes, hyperlipidemia, asymptomatic carotid stenosis, cigarette smoking, and alcohol abuse.
  • New risk factors such as hypercoagulable states and patent foramen ovale are the subject of ongoing investigations.
Proven cardiac risks
  • Atrial fibrillation
  • Mechanical valve
  • Dilated cardiomyopathy
  • Recent myocardial infarction
  • Intracardiac thrombus
  • Intracardiac mass

Putative cardiac risks

  • Sick sinus syndrome
  • Patent foramen ovale
  • Thoracic aorta atherosclerotic debris
  • Spontaneous echocontrast
  • Previous myocardial infarction (2-6 months prior)
  • Hypokinetic/akinetic left ventricular segment
  • Mitral annulus calcification

Multiple cerebral circulation territories — recurrent clinical symptoms consistent with localization in multiple territories of the carotid and basilar vertebral distribution strongly suggests a cardioembolic source.

Age

Age is the most important risk factor for all stroke types including ischemic stroke. For each successive ten years after age 55 the stroke rate more than doubles in both men and women.7 Stroke incidence rates are 1.25 times greater in men than women, but because women tend to live longer than men, more women die of stroke each year. African-Americans have an age-adjusted incidence rate of stroke of approximately 1.6 times that of whites in the United States, and Asians, especially Chinese and Japanese, have higher stroke incidence rates than whites in the United States and western Europe.

Hypertension

Hypertension is the number one modifiable risk factor for all types of cerebrovascular disease including large-vessel atherosclerosis, small-vessel lipohyalinosis (lacunar infarct), white matter disease of the cerebrum and brain stem, and spontaneous intracerebral hemorrhage. The efficacy of antihypertensive treatment in preventing stroke is well established in all age groups. Regardless of age and gender, blood pressure levels in excess of 150/90 must be treated.8

Cardiac Disease

Atrial fibrillation is the most important cardiac risk factor for stroke and is estimated to cause almost half of all cardioem-bolic strokes. Other cardiac risk factors include valvular heart disease especially mitral stenosis, but mitral annular calcification is also another valve risk, coronary disease, congestive heart failure, and left ventricular hypertrophy. On the other hand, mitral valve prolapse uncomplicated by endocarditis or atrial fibrillation is a very low risk factor. Other possible risk factors seen on transesophageal echocardiogram (TEE) are valvular strands, spontaneous echo contrast, left atrial enlargement, patent foramen ovale (PFO), and atrial septal aneurysm.

Diabetes Mellitus

Diabetes is a risk factor for atherosclerosis in general as well as hyperlipidemia; diabetics have about four times greater risk of stroke than normal individuals. In addition, hyperglycemia may worsen an acute ischemic cerebral infarction.

Smoking

Cigarette smokers have greater than two times the risk for stroke than do nonsmokers. Cessation of smoking can lead to a prompt reduction of risk; within two to five years smokers who quit reduce their risk to that of nonsmokers. The risk of stroke for smokers is higher for women than for men; and the risk increases with the number of cigarettes smoked per day.9

Lipids

Lowering lipids decreases the risk of stroke, and treatment of hyperlipidemia has emerged as an important potential means for the primary prevention of stroke. It may be that the statin drugs play another role in stroke prevention other than lowering lipids since previous studies have not clearly demonstrated the relationship between serum cholesterol levels and the risk of stroke. Elderly patients may benefit from treatment with statins even though hypercholesterolemia is not an independent risk factor for cardiovascular disease beyond the age of 70 years.10

Alcohol

Moderate consumption of alcohol (one to two drinks per day) may reduce cardiovascular disease including ischemic stroke; however there appears to be a dose response relationship between moderate alcohol consumption and the risk of intracerebral and subarachnoid hemorrhage. Thus, alcohol should not be considered as a preventive agent for stroke.

Illicit Drug Use

Cocaine is the drug most associated with both ischemic and hemorrhagic stroke. Other drugs that may play a role include heroin, amphetamines, LSD, PCP, "T's and blues," and marijuana. In addition, over-the-counter drugs such as sympathomimetic decongestants, cold remedies, diet aids (phenylpropanolamine), ephedrine, and pseudoephedrine have been linked with hemorrhagic and less likely ischemic stroke.

Lifestyle Factors

There is a beneficial relationship between leisure time physical activity and stroke in all age groups and in both men and women. Leisure time physical activity is associated with reduced mortality even after genetic and other familial factors are taken into consideration. Any physical activity, light, moderate, or heavy, is a significant protective for ischemic stroke.11 Obesity is associated with elevated blood pressure, blood glucose, and lipids. Central obesity manifested by abdominal deposition of fat may be a more important risk than obesity involving the hips and thighs. Current national dietary guidelines recommend that total fat be limited to 30% of calories and saturated fat to 10%. A diet high in mono-unsaturated fats which do not increase cholesterol may protect both heart and brain.

Oral Contraceptives and Migraine

Oral contraceptives with higher dose formulation of estrogen (greater than 50 mcg) were found to increase the risk of stroke in certain subgroups of women including women over 35 years of age, cigarette smokers, women with hypertension, and women with a history of migraine headaches. Low-dose contraceptives with an estrogen content of less than 50 mcg do not appear to be risk factors for stroke. Also the absolute risk of stroke associated with migraine is very small.

Previous TIA or Stroke

TIA is a risk factor for both ischemic cerebral infarction and myocardial infarction. The average risk of stroke in patients with TIA is about 4% with recent onset TIA having a higher risk than remote TIA. The risk of recurrent stroke is greatest in the first 30 days following an initial stroke, ranging from 3 to 8 percent. The 5-year cumulative risk of recurrence is about 25% with long-term stroke recurrence rates ranging from 4-14% per year with aggregate annual estimates of 6.1% for minor stroke and 9.0% for major stroke. Morbidity after a recurrent stroke is greater than after the index stroke.

In general hypertension, transient ischemic attack, cigarette smoking, ischemic heart disease, atrial fibrillation, diabetes, and mitral valve disease are risk factors significantly associated with an increased risk of ischemic stroke.12 One of the most important measures for prevention of stroke is risk factor management. The outcome of a patient with a treated stroke may never be as good as that of someone in whom a stroke is prevented.9

Emerging And Potential Risk Factors

Although the above risk factors are seen singly or multiply in the majority of ischemic strokes, there are still about 20-30% of cases in which these traditional factors are not seen. There is ongoing research looking at several new and emerging risk factors.13

Patent Foramen Ovale (PFO)

The patent foramen ovale may serve as a passage way for paradoxical emboli from the venous to the arterial circulation through a right to left shunt. The diagnosis of paradoxical embolus is made when a PFO is discovered and there is no other alternative stroke mechanism identified even though an identified venous source may be lacking. Venous ultrasound studies of the legs are often negative in this situation, but an MR venogram of the pelvis might pick up a deep venous thrombosis. Size of the PFO opening and degree of functional shunting are important factors; in addition the coexistence of an atrial septal aneurysm appears to potentiate the PFO risk. Options for treatment include antiplatelet treatment, anticoagulant therapy, and surgical closure of the foramen.

Proximal Aortic Atherosclerosis

Atheroma in the ascending aorta and aortic arch may serve as potential source of cerebral emboli. The emboli may emerge spontaneously or intraoperatively during coronary artery bypass surgery. However, the optimal management of proximal aortic atherosclerosis remains uncertain.

Antiphospholipid Antibodies

The antiphospholipid antibody syndrome is one of venous and arterial thrombosis, thrombocytopenia, and fetal loss. One-half of the patients with this syndrome have it as a primary disease and the other half have it as a secondary disease with lupus or lupus-like disease. The IgG class of antibodies is the one most strongly associated with clinical disease. There is a spectrum of neurological diseases associated with this syndrome, but especially cerebral infarction. Treatment of antiphospholipid antibody syndrome is high intensity anticoagulation with a target International Normalized Ratio (INR) of 3.0-4.0.

Protein C, Protein S, and Antithrombin III

Deficiencies in natural anticoagulants (Protein C, Protein S, Antithrombin III) are an uncommon cause of stroke and more often produce venous rather than arterial thrombosis. Resistance to activated Protein C is a newly identified and common cause of a hypercoagulable state. Again, this seems to be more important in the genesis of cerebral venous thrombosis rather than arterial occlusions.

Homocysteine

Hyperhomocysteinemia is a risk factor for atherosclerosis in the coronary, cerebral, and peripheral vasculature. Nutritional deficiencies in folate, vitamin B12, and vitamin B6 required for homocysteine metabolism may promote
hyperhomo-cysteinemia.14 High plasma homocysteine levels and low levels of folate and B6 are associated with extracranial carotid artery stenosis in the elderly.15 Another study showed that hyperhomocysteinemia caused changes mainly in the small penetrating vessels of the cerebrum.16 At any rate, fol-ate supplements in the range of 1 to 2 mg per day are sufficient to reduce or normalize high homocysteine levels even if the elevation is not due to inadequate folate consumption. Therefore, it seems prudent to have stroke prone patients on multivitamins rather than measuring homocysteine serum levels.

Leukocytes and Acute Infections

The leukocyte may play a role in ischemic vascular disease by adhering to the intracellular adhesive molecule-1 (ICAM-1) receptor located on the endothelial cell and then releasing damaging cytokines. Acute infectious illnesses are more frequent in patients presenting with ischemic stroke. Recent infections may be related to concentrations of anti-inflammatory cytokines, Protein C, and tPA (tissue plasminogen activator). TPA is the primary mediator of intravascular fibrinolysis and tPA antigen may be a risk factor for ischemic stroke in men.

Other Hemostatic Factors

Thrombocytosis, sickle-cell anemia, polycythemia, and increased or decreased hematocrit have all been implicated as risk factors for stroke.

Atrial Fibrillation

Atrial fibrillation is the most common cardiac risk factor for ischemic stroke. The incidence of atrial fibrillation doubles with each successive decade of life above age 55; the median age of the atrial fibrillation population is 75-years old. The strokes associated with atrial fibrillation tend to be large and disabling with the embolus arising from the atrial fibrillation induced left atrial thrombus.17 There are associated factors which increase the risk of atrial fibrillation; these include age older than 75 years and female gender, hypertension, prior ischemic stroke, TIA, or systemic embolism, and diabetes. Echocardiographic risk factors included left atrial enlargement, left ventricular dysfunction, increased left ventricular mass, and mitral annular calcification.

Atrial fibrillation patients may be stratified into three levels of risk: 1) low (about 1%/year) for those without risk factors listed above; 2) moderate (about 3.5%/year) for those with a history of hypertension but no other risk factors; 3) high (about 8%/year) for those with risk factors listed above unless treated with anticoagulation.18 Patients younger than 65 with no risk factors (lone atrial fibrillation) have a low annual stroke rate of only 1% and therefore can be treated with aspirin. In patients with risk factors, warfarin therapy (INR between 2.0 and 3.0) dramatically reduces the risk of stroke. However, the risk of intracranial hemorrhage is increased in patients older than 75 years and in those anticoagulated with an INR above 3.0.

Carotid Endarterectomy

Before considering carotid endarterectomy for either a symptomatic or asymptomatic patient, the treating physician must know the skills of the surgeon including morbidity and mortality rates. The physician must also assess the patient's preoperative risks which include neurological, anatomical or angiographic, and medical risks (See Table 7).19 A recent multicenter study of preoperative risks for asymptomatic carotid artery stenosis showed that female sex, age 75 years or older, and a history of congestive heart failure were each associated with a higher risk of postoperative stroke or death. In addition, patients undergoing prophylactic endarterectomy for asymptomatic carotid artery stenosis in combination with coronary artery bypass graft surgery were at particularly high risk for postoperative complications.20 Therefore prophylactic carotid endarterectomy for asymptomatic carotid artery stenosis in patients undergoing coronary artery bypass surgery for symptomatic coronary artery disease is not recommended.21

Table 7. Risks of Carotid Endarterectomy

Neurologic risks
  • Recent stroke
  • Progressive ischemia
  • Frequent transient ischemic attacks
  • Multiple brain infarcts

Anatomical ("angiographic") risks

  • High carotid bifurcation (e.g., cervical spine - 2 level)
  • Very long stenosis (extending 3 cm distally into internal carotid artery or 5 cm proximally into common carotid artery
  • Thrombus in internal carotid artery
  • Severe contralateral internal carotid artery stenosis or occlusion
  • Intracranial tandem stenosis or occlusion

Medical Risks

  • Hypertension
  • Coronary artery disease (angina or recent myocardial infarct)
  • Other cardiac disease and congestive heart failure
  • Diabetes
  • Chronic lung disease
  • Smoking
  • Renal or hepatic disease
  • Cancer

Adapted from Caplan LR. A 79-year-old musician with asymptomatic carotid artery disease. JAMA 1995; 274:1383-9, with permission.

Symptomatic Carotid Artery Stenosis

Carotid artery stenosis has been defined as mild (less than 30%), moderate (30% to 69%), or severe (70% to 99%). Carotid endarterectomy is a proven treatment modality in patients with severe symptomatic (focal hemisphere or retinal symptoms) carotid artery stenosis; the perioperative complication rate must not exceed 6% to achieve this benefit. Symptomatic patients with mild stenosis should be treated medically and not surgically, and patients with symptomatic moderate stenosis are still being studied.22 Since the inaccuracy of carotid duplex ultrasonography has been noted in many large studies, patients with moderate stenosis measured by this method should have definite assessment by other imaging modalities before determination of therapy.23

Patients with symptomatic severe carotid stenosis and either contralateral carotid artery occlusion or intracranial stenosis have a doubled perioperative risk but still can benefit from endarterectomy. However, patients who have an identifiable intraluminal thrombus above the stenotic segment have a very high postoperative complication rate and therefore should be anticoagulated at least one month before proceeding with carotid endarterectomy.8

Asymptomatic Carotid Artery Stenosis

One needs to study the ACAS (The Asymptomatic Carotid Atherosclerosis Study) results before recommending carotid endarterectomy for asymptomatic patients. 24 First, no benefit was detected in reducing the risk of disabling strokes. Secondly, women did not seem to benefit since the perioperative complication rate of 3.6% was double that of men. Thirdly, it is known from prospective studies that the annual risk of stroke when stenosis is less than 75% to 80% is below 2%; this is a figure which cannot be improved upon by surgical therapy.8 The ACAS study reported surgical benefit in patients with greater than 60% stenosis, but the benefits are marginal. Carotid endarterectomy can only be recommended in properly selected asymptomatic patients with severe carotid stenosis (80% to 99%) when the angiogram and surgery can be performed with less than 3% combined stroke or death rate and the patients life expectancy is greater than three years.21

Antiplatelet And Anticoagulant Therapy

Antiplatelet drugs are most effective against white platelet-fibrin thromboemboli that form on irregular surfaces in fast moving arterial streams. Anticoagulants are effective against the formation and propagation of erythrocyte-fibrin red clots which tend to form in areas of slow blood flow such as dilated cardiac atria, ventricular aneurysms, distended leg veins, and tightly stenotic arteries.25 Aspirin is the primary drug utilized in secondary stroke prevention. There is still controversy about the dose, but 650 to 975 mg daily are recommended. If a patient is on low-dose aspirin (80 to 325 mg daily) and suffers an additional ischemic event, the dose of aspirin could be increased. If that fails, ticlopidine 250 mg bid or clopidogrel 75 mg daily may be substituted. Ticlopidine is somewhat more effective than aspirin, but the difference is modest. In addition, ticlopidine is expensive and has many side effects including 0.5% to 1% risk of neutropenia, 15% risk of gastrointestinal intolerance or rash, and a 10% increase in total serum cholesterol. Patients taking ticlopidine must have complete blood counts and platelet counts every two weeks for the first three months, and the drug must be discontinued if the neutrophil count falls below 1,200/mm3. Clopidogrel will probably replace ticlopidine because it appears not to be associated with bone marrow toxicity. However, clopidogrel is only slightly more effective than 325 mg of aspirin per day in preventing the combined endpoints of stroke, myocardial infarction, and vascular death in patients with an ischemic stroke.

Anticoagulants are of proven benefit in the following situations: 1) patients with atrial fibrillation, 2) patients with thrombi in the left ventricle, 3) patients with mechanical heart valves, and 4) patients with cerebral venous and sinus thrombosis. Anticoagulants are probably beneficial in patients with dissection of the carotid or vertebral arteries, and possibly beneficial in patients with the antiphospholipid syndrome.

In conclusion, the main tools for primary prevention of stroke are patient education, risk factor management, and carotid endarterectomy in very selected cases. The tools of secondary prevention are risk factor management, antiplatelet therapy, and anticoagulation therapy for cardioembolic disease, and carotid endarterectomy for high grade stenosis.

REFERENCES

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  3. Fisher CM. Late-life migraine accompaniments as a cause of unexplained transient ischemic attacks. Can J Neurol Sci. 1980; 7:9-17.
  4. Greenberg SM, Vonsattel JP, Stakes JW, et al. The clinical spectrum of cerebral amyloid angiopathy: presentations without lobar hemorrhage. Neurology. 1993; 43: 2073-2079.
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  13. Saver JL. Emerging risk factors for stroke: patent foramen ovale, proximal aortic atherosclerosis, antiphospholipid antibodies, and activated protein C resistance. J Stroke and Cerebrovasc Dis. 1997; 6:167-172.
  14. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998; 338:1042-1050.
  15. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995; 332:286-291.
  16. Evers S, Koch HG, Grotemeyer KH, et al. Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol. 1997; 54:1276-1282.
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  18. The SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators. Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III Study. JAMA. 1998; 279:1273-1277.
  19. Caplan LR. A 79-year-old musician with asymptomatic carotid artery disease. JAMA. 1995; 274:1383-1389.
  20. Goldstein LB, Samsa GP, Matchar DB, et al. Multicenter review of preoperative risk factors for endarterectomy for asymptomatic carotid artery stenosis. Stroke. 1998; 29:750-3.
  21. Cohen SN. Carotid endarterectomy for asymptomatic disease. J Stroke and Cerebrovasc Dis. 1997; 6:180-184.
  22. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991; 325:445-453.
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Jacksonville Medicine / November, 1998

 

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