(Circulation. 2001;103:163.)
© 2001 American Heart Association, Inc.
AHA Scientific Statement |
Primary Prevention of Ischemic Stroke
A Statement for Healthcare Professionals From the Stroke Council of the American Heart Association
Key Words: AHA Scientific Statements • stroke • prevention • risk factors • arrhythmia • hypercholesterolemia • smoking
Stroke ranks as the third leading cause of death in the United States. It is now estimated that there are more than 700 000 incident strokes annually and 4.4 million stroke survivors.1 2 The economic burden of stroke was estimated by the American Heart Association to be $51 billion (direct and indirect costs) in 1999.3 Despite the advent of treatment of selected patients with acute ischemic stroke with tissue plasminogen activator and the promise of other experimental therapies, the best approach to reducing the burden of stroke remains prevention.4 5 High-risk or stroke-prone individuals can be identified and targeted for specific interventions.6 This is important because epidemiological data suggest a substantial leveling off of prior declines in stroke-related mortality and a possible increase in stroke incidence.7 8
The Stroke Council of the American Heart Association formed
an ad hoc writing group to provide a clear and concise overview of the
evidence regarding various established and potential stroke risk
factors. The writing group was chosen based on expertise in specific
subject areas, and it used literature review, reference to previously
published guidelines, and expert opinion to summarize existing evidence
and formulate recommendations (Table 1
).
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As given in Tables 2 through 4, risk factors or risk markers for a first
stroke were classified according to potential for modification
(nonmodifiable, modifiable, or potentially modifiable) and strength of
evidence (well documented, less well
documented).5 The tables give
the estimated prevalence, population attributable risk, relative risk,
and risk reduction with treatment for each factor when known.
Population attributable risk reflects the proportion of ischemic
strokes in the population that can be attributed to a particular risk
factor and is given by the formula 100x[prevalence(relative
risk-1)/prevalence(relative
risk-1)+1]).9
Well-documented modifiable risk factors
(Table 3) were considered as those with clear, supportive
epidemiological evidence in addition to evidence of risk reduction with
modification as documented by randomized trials. Less well-documented
or potentially modifiable risk factors were those with either less
clear epidemiological evidence or without evidence from randomized
trials demonstrating a reduction of stroke risk with modification. Gaps
in current knowledge are indicated by question marks in the
tables.
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Table 5 summarizes guideline or consensus statement
management recommendations where available. Other recommendations are
indicated in the text. Based primarily on an individual patient’s risk
assessment profile (the Framingham Heart Study risk
profile6 is an easy-to-use
and valuable tool for identifying persons at risk of stroke) and
overall medical condition, interventions involving appropriate
lifestyle behavior changes and surgical and pharmacological treatments
can be implemented to treat, control, or modify specific risk factors
with the goal of reducing the risk of a first stroke.
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Nonmodifiable Risk Factors
Although these factors are nonmodifiable, they
identify individuals at highest risk of stroke and those who may
benefit from rigorous prevention or treatment of modifiable risk
factors.5 (See
Table 2
.)
Age
The cumulative effects of aging on the cardiovascular
system and the progressive nature of stroke risk factors over a
prolonged period of time substantially increase stroke risk. The risk
of stroke doubles in each successive decade after 55 years of
age.8 10
Sex
Stroke is more prevalent in men than in
women.8 Overall, men also
have higher age-specific stroke incidence rates than
women.11 Exceptions are in
35- to 44-year-olds and in those over 85 years of age in whom women
have slightly greater age-specific incidence than
men.11 However,
stroke-related case-fatality rates are higher in women than men. In
1997, females accounted for 60.8% of stroke
fatalities.2 Overall, 1 in 6
women will die of stroke, compared with 1 in 25 who will die of breast
cancer.12 Circumstances such
as oral contraceptive use and pregnancy uniquely contribute to the risk
of stroke in
women.13 14 15
Race/Ethnicity
Blacks1 11 16
and some Hispanic
Americans16 17
have high stroke incidence and mortality rates compared with whites.
For example, in the Atherosclerosis Risk In Communities (ARIC) study,
blacks had a 38% greater incidence of strokes than
whites.18 Possible reasons
for the high incidence and mortality rate of strokes in blacks include
a higher prevalence of hypertension, obesity, and diabetes mellitus
within the black
population.19 20 21
However, a higher incidence of these other risk factors does not
explain all of the excess
risk.19 Epidemiological
studies have also shown an increase in stroke incidence among
self-identified Hispanic
populations.22 23 24
Chinese and Japanese populations generally have high stroke incidence
rates as
well.25
Family History
Both paternal and maternal history of stroke may be
associated with increased stroke
risk.26 27 This
increased risk could be mediated through a variety of mechanisms,
including genetic heritability of stroke risk factors, the inheritance
of susceptibility to the effects of such risk factors, familial sharing
of cultural/environmental and lifestyle factors, and the interaction
between genetic and environmental
factors.28 Studies with
twins provide strong data suggesting familial inheritance of stroke.
Concordance rates for strokes are markedly higher in monozygotic than
in dizygotic twins.29 There
is a nearly 5-fold increase in stroke prevalence among monozygotic
versus dizygotic
twins.30
Well-Documented Modifiable Risk Factors
Several well-documented modifiable risk factors for
stroke exist. (See
Table 3.)
Hypertension
Hypertension is a major risk factor for both cerebral
infarction and intracerebral
hemorrhage.31 The incidence
of stroke increases in proportion to both systolic and diastolic blood
pressures. This relationship is "direct, continuous, and apparently
independent."32 Blood
pressure, particularly systolic blood pressure, increases with
age.33 Elevated systolic
pressure, with or without an accompanying elevation in diastolic
pressure, has been shown to increase stroke risk. Isolated systolic
hypertension is an important risk factor for stroke in the elderly
(systolic blood pressure >160 mm Hg and diastolic blood pressure <90
mm Hg).34
There has been compelling evidence for more than 30 years that the control of high blood pressure contributes to the prevention of stroke as well as to the prevention or reduction of other target-organ damage, including congestive heart failure and renal failure.35 36 A meta-analysis of 18 long-term randomized trials found that both ß-blocker therapy (relative risk 0.71; 95% CI 0.59 to 0.86) and treatment with high-dose diuretics (relative risk 0.49; 95% CI 0.39 to 0.62) were effective in preventing stroke.37 In the past 10 years, the importance of controlling isolated systolic hypertension to prevent stroke in the elderly has been underscored in clinical trials.38 For example, in the Syst-Eur Trial, 4695 patients with isolated systolic hypertension were randomized to active treatment (nitrendipine and possibly enalapril or hydrochlorothiazide to lower systolic blood pressure 20 mm Hg) or to placebo.38 The trial was stopped when stroke reduction reached 42% in the actively treated group. The Systolic Hypertension in the Elderly Program (SHEP) trial demonstrated a 36% reduction in the incidence of total stroke with antihypertensive treatment (chlorthalidone or atenolol).39 Despite extensive education efforts, a significant proportion of the population has undiagnosed or inadequately treated hypertension.34 40 41 This is particularly true in high-risk race/ethnic groups.42
Recommendation
Regular screening for hypertension (at least every 2
years in adults) and appropriate management, as summarized in the sixth
report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure, are recommended
(Table 5).34
(Level of Evidence I, Grade A)
Smoking
Active (current) cigarette smoking has been long
recognized as a major risk factor for stroke. Pathophysiological
effects of smoking are multifactorial, affecting both the systemic
vasculature and blood rheology. Smoking causes reduced blood vessel
distensibility and compliance by leading to increased arterial wall
stiffness.43 Smoking is also
associated with increased fibrinogen levels, increased platelet
aggregation, decreased high-density lipoprotein (HDL) cholesterol
levels, and increased
hematocrit.44
A meta-analysis of 22 studies indicates an approximate
doubling of the relative risk of cerebral infarction among smokers
versus nonsmokers.45 A
prospective estimate of a 1.8-fold increase in stroke risk associated
with smoking (after control for other stroke risk factors) from the
Framingham Heart Study confirms this substantial increase in
risk.46 Currently, 25% of
adults are active smokers.47
Therefore, 
18% of strokes are attributable to active cigarette
smoking. This estimated population attributable risk is only slightly
higher than the estimated 12% population attributable risk associated
with active smoking in the Rochester, Minn,
population.9
To the extent that former smoking may also place individuals at increased risk of stroke, efforts to prevent the initiation of smoking are important to the primary prevention of stroke. The relative risk of stroke among former smokers (compared with nonsmokers) was 1.34 in the Nurses’ Health Study48 and 1.26 in the Physicians’ Health Study.49 Currently, the Centers for Disease Control and Prevention estimate that 23% of the adult population are former smokers,47 implying a population attributable risk for former smoking of 6%. However, the stroke risk associated with former smoking has been shown to substantially decrease with increasing time since cessation. As such, in the Physicians’ Health and Nurses’ Health studies, the 6% population attributable risk estimate is a function of the distribution of time since quitting. The Framingham Heart Study found stroke risk to be at the level of nonsmokers at 5 years from cessation.50 A second study reported that stroke risks disappeared from 2 to 4 years after smoking cessation and that the benefits of cessation were independent of the age at starting and the number of cigarettes smoked per day.48 Wannamethee et al51 concluded that smoking cessation is associated with a considerable and rapid benefit in decreased risk of stroke, particularly in light smokers (<20 cigarettes/d). However, switching to pipe or cigar smoking confers little benefit, emphasizing the need for complete cessation of smoking.51
Avoidance of exposure to environmental tobacco smoke may also play a role in the primary prevention of stroke. Nearly 90% of nonsmokers have been shown to have detectable levels of serum cotinine, assumed to be present through exposure to environmental tobacco smoke.52 Because of the high population prevalence of exposure, even a small increase in the relative risk of stroke associated with exposure to environmental tobacco smoke may have a substantial population attributable risk. However, the increase in relative risk may not be small. It has been suggested that exposure to environmental tobacco smoke increases the risk for coronary events from 20% to 70%. An estimated 62 000 coronary heart disease deaths in 1985 were attributable to exposure to environmental tobacco smoke.52
Because atherosclerosis can lead to both stroke and coronary heart disease, it is reasonable to suspect environmental tobacco smoke as a cause for some strokes. After adjusting for potential confounders (age, sex, history of hypertension, heart disease, and diabetes), Bonita and colleagues53 found a 1.82-fold increase (95% CI 1.34 to 2.49) in the risk of stroke among nonsmokers and long-term ex-smokers exposed to environmental tobacco smoke. The risk was significant in both men and women. An increase of 1.82 is surprisingly large; however, even a more modest 1.20-fold increase in relative risk (the lower limit of the estimated effect on coronary heart disease) is associated with an estimated population attributable risk of 12% (based on a 67.5% population exposure, calculated as 90% prevalence of exposure in the 75% of the nonsmoking population).
In summary, these data suggest that the population attributable risk associated with all forms of exposure to cigarette smoke is substantial, with current smoking contributing to approximately half of the stroke events (population attributable risk of 18% for current smoking, 6% for former smoking, and 12% for exposure to environmental tobacco smoke).
Recommendation
Smoking cessation for all current smokers is
recommended
(Table 5).34
(Level of Evidence III, Grade C; note that the evidence level reflects
a lack of prospective randomized trials of smokers compared with
nonsmokers. However, the data from cohort and epidemiological studies
are consistent and overwhelming.)
Diabetes, Hyperinsulinemia, and Insulin
Resistance
Insulin-dependent diabetics have both an increased
susceptibility to atherosclerosis and an increased prevalence of
atherogenic risk factors, notably hypertension, obesity, and abnormal
blood lipids. A constellation of metabolic risk factors, termed
syndrome X, has also been identified in some type 2
diabetics.54 55
The main characteristics of syndrome X are hyperinsulinemia and insulin
resistance. These result in the secondary features of the syndrome,
including hyperglycemia, increased very-low-density lipoprotein
cholesterol, decreased HDL cholesterol, and hypertension.
Case-control studies of stroke patients and prospective epidemiological studies have confirmed an independent effect of diabetes on ischemic stroke, with an increased relative risk in diabetics ranging from 1.8- to nearly 6-fold. In the United States, from 1976 to 1980, a history of stroke was 2.5 to 4 times more common in diabetics than in persons with normal glucose tolerance. Among Hawaiian Japanese men in the Honolulu Heart Program, those with diabetes had twice the risk of thromboembolic stroke as nondiabetics, an increase in risk that was independent of other factors.56 In the Framingham Heart Study, although the impact of diabetes was greatest on peripheral arterial disease with intermittent claudication, for which the relative risk was increased 4-fold, coronary and cerebral artery territories were also affected. For brain infarction, the impact of glucose intolerance was greater in women than men, reaching significance as an independent contributor only in older women. Overall, persons with glucose intolerance have double the risk of brain infarction compared with nondiabetics.57
High blood pressure is common in patients with type 2
diabetes, with a prevalence of 40% to 60% in adults. The combination
of hyperglycemia and hypertension has long been believed to increase
the frequency of diabetic complications, including stroke. Several
recent trials examining stroke and other cardiovascular outcomes
compared the benefit of tight control of blood glucose and blood
pressure in type 2 diabetics with less stringent
management.58 For combined
fatal and nonfatal stroke, tight blood pressure control (mean blood
pressure achieved 144/82 mm Hg) resulted in a convincing 44% relative
risk reduction compared with more liberal control (mean blood pressure
achieved 154/87 mm Hg).59
This 44% benefit in stroke risk reduction is above and beyond the
20% risk reduction with antihypertensive treatment found in
diabetics in SHEP.60
However, improved glycemic control did not produce a significant
reduction in stroke incidence over 9 years of
follow-up.61
The conclusion reached from these studies and in a recent
review is that tight control of hypertension in diabetics significantly
reduces stroke incidence.62
Current measures to achieve tight glycemic control are less effective
for stroke prevention. Nevertheless, intensive therapy to achieve tight
control of hyperglycemia with 3 doses per day of insulin in patients
with recent-onset insulin-dependent (type 1) diabetes mellitus was
shown to reduce microvascular complications, nephropathy, and
retinopathy, as well as peripheral
neuropathy.59
The report of the Heart Outcomes Prevention Evaluation (HOPE) study represents an exciting development in prevention of cardiovascular disease. In this placebo-controlled, randomized clinical trial, the addition of the angiotensin-converting enzyme (ACE) ramipril was compared with the current medical regimen of high-risk patients. The substudy of 3577 diabetic patients (of a total population of 9541 participants in the HOPE study) showed a reduction of the primary combined outcome of myocardial infarction, stroke, and cardiovascular death by 25% (95% CI 12% to 36%, P=0.0004) and a reduction of stroke by 33% (95% CI 10% to 50%, P=0.0074).63 This benefit was present even after adjustment for the minor decrease in blood pressure in the ramipril group. There was also a reduction in diabetic complications (overt nephropathy, dialysis, or need for laser therapy).
These new reports provide long-sought evidence for stroke prevention in diabetics. Control of hypertension in diabetics and treatment of high-risk diabetic patients with the ACE inhibitor ramipril prevent stroke.
Recommendations
Careful control of hypertension in both type 1 and type
2 diabetics is recommended. (Level of Evidence I, Grade A) Glycemic
control is recommended to reduce microvascular complications
(Table 5).64 65
Asymptomatic Carotid Stenosis
In the Cardiovascular Health Study, carotid stenoses
>50% were detected in 7% of the men and 5% of the women 65 years
of age.66 Similarly,
stenoses of 50% were detected in 7% of women and 9% of men aged 66
to 93 years in the Framingham
cohort.67 Therefore, it
seems likely between 7% and 10% of men and between 5% and 7% of
women above age 65 have carotid stenoses >50%.
Several studies have attempted to identify subgroups of patients with asymptomatic carotid artery stenosis who may be at particularly elevated risk of stroke. The Toronto Asymptomatic Cervical Bruit Study followed a cohort of 500 patients for a mean of 23 months.68 Overall, cerebral ischemic events (transient ischemic attack [TIA] or stroke) were more frequent in patients with severe (>75%) carotid artery stenosis, progressing carotid artery stenosis, or heart disease and in men. A total of 8 patients (1.6%) had an unheralded stroke; however, only 2 (0.4%) were ipsilateral to a high-grade extracranial carotid artery stenosis as demonstrated by Doppler ultrasonography. In another study, 38 asymptomatic patients with >90% stenosis of the internal carotid artery were followed up for a mean period of 48 months.69 Each year, 1.7% of the patients had an unheralded ipsilateral stroke. More recently, the NASCET (North American Symptomatic Carotid Endarterectomy Trial) investigators have retrospectively reviewed their data regarding the risk of stroke in the territory of an asymptomatic carotid artery stenosis contralateral to the side of the symptomatic vessel.70 71 The annual risk of stroke was 3.2% (over 5 years of observation) in patients with 60% to 99% stenosis. The average annual risk of ipsilateral stroke increased from 3.0% for those with 60% to 74% stenosis to 3.7% for those with 75% to 94% stenosis and decreased to 2.9% for those with 95% to 99% stenosis, with a rate of 1.9% for those with complete occlusion. Overall, 45% of ipsilateral strokes in patients with asymptomatic stenosis contralateral to a symptomatic stenosis may be attributable to lacunes or cardioembolism, underscoring the need to fully evaluate these patients for other treatable causes of stroke.
Taken together, these and other observational studies
suggest that the rate of unheralded stroke ipsilateral to a
hemodynamically significant extracranial carotid artery stenosis is
1% to 2% annually. This represents a significant factor on a
population basis. Some studies suggest that the rate of stroke may be
higher in those patients with progressing stenosis than in those with
stable disease and higher in those with more severe stenosis. As with
asymptomatic carotid bruit, an asymptomatic stenosis of the carotid
artery is an important indicator of concomitant ischemic cardiac
disease.68 69 72
There have been 4 published randomized controlled trials that were designed to address the benefit of carotid endarterectomy in patients with asymptomatic carotid artery stenosis. The CASANOVA (Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin) study was inconclusive.73 The Mayo Clinic Asymptomatic Carotid Endarterectomy (MACE) study included 71 randomized and 87 nonrandomized patients.74 Surgically treated patients were not given aspirin. There were no major strokes or deaths in either group. However, the study was stopped because myocardial infarction occurred in 26% of those in the surgical arm (no aspirin) versus 9% of those in the aspirin-treated medical arm (P=0.002), reflecting the high incidence of concomitant coronary artery disease in patients with asymptomatic carotid artery stenosis.
The Veterans Affairs Cooperative Study of carotid endarterectomy for patients with asymptomatic carotid artery stenosis included 444 men followed up for a mean of 48 months.75 Two hundred eleven patients received best medical therapy plus carotid endarterectomy, and 233 received medical therapy alone (including 650 mg of aspirin twice daily). Patients had >50% stenosis of the extracranial carotid artery demonstrated by angiography. Combined perioperative and angiographic risk was 4.7%. There was a 38% risk reduction for the combined end points of ipsilateral TIA, transient monocular blindness, and stroke over 2 years (P<0.001). Although the rate of fatal and nonfatal stroke was reduced in the surgical group (4.7% versus 9.4%, or 1.2% per year versus 2.4% per year), the difference was not significant (P=0.08). However, the study was not powered to detect differences in outcome subgroups.
The Asymptomatic Carotid Atherosclerosis Study (ACAS) was a randomized trial investigating the efficacy of carotid endarterectomy in patients with asymptomatic high-grade (>60% diameter reduction) carotid artery stenosis.76 Patients (n=1662) were randomized to surgery plus medical therapy (n=828) or to medical therapy without carotid endarterectomy (n=834). There was a 1.2% risk of angiography-related complications among the 424 patients undergoing postrandomization angiograms and a 2.3% aggregate perioperative stroke risk. The study was halted after a median follow-up of 2.7 years (4465 patient-years) because a significant benefit of surgery was found. The aggregate rate of ipsilateral stroke, any perioperative stroke, or death in surgically treated patients was estimated at 5% over 5 years; in medically treated patients, the corresponding rate was 11% (53% risk reduction, 2% per year event rate reduced to 1% per year; P=0.004). There was no relationship between benefit and the degree of carotid artery stenosis. Women did not benefit (17% nonsignificant risk reduction in women [95% CI -0.96 to 0.65] versus 66% risk reduction in men [95% CI 0.36 to 0.82]), a difference ascribed to a higher rate of perioperative complications in women (3.6% versus 1.7%). Other studies have also noted an increased risk of perioperative complications after endarterectomy in asymptomatic women compared with men.77 However, as with the Veterans Affairs trial, the study was not powered to detect differences among subgroups of patients.
It should be noted that the benefit of endarterectomy in the setting of asymptomatic carotid artery stenosis is highly dependent on surgical risk. Yet, most physicians are not aware of the complication rates of the surgeon to whom they refer patients for the operation.78 79
Recommendation
Endarterectomy may be considered in patients with
high-grade asymptomatic carotid stenosis performed by a surgeon with
<3% morbidity/mortality rate. (Level of Evidence I, Grade A) Careful
patient selection, guided by comorbid conditions, life expectancy, and
patient preference, as well as other individual factors, including sex,
and followed by a thorough discussion of the risks and benefits of the
procedure, is required. It is important that patients with asymptomatic
carotid artery stenosis be fully evaluated for other treatable causes
of stroke.
(See
Table 5.)
Atrial Fibrillation
Atrial fibrillation is a common arrhythmia and an
important risk factor for stroke, with established effective therapy
for stroke prevention. The annual risk of stroke in unselected patients
with nonvalvular atrial fibrillation is 3% to 5%, with the condition
responsible for 50% of thromboembolic
strokes.80 It is estimated
that approximately two thirds of the strokes that occur in patients
with atrial fibrillation are cardioembolic. The median age of patients
with atrial fibrillation is 75 years. The Framingham Heart Study noted
a dramatic increase in stroke risk associated with atrial fibrillation
with advancing age, from 1.5% for those 50 to 59 years of age to
23.5% for those 80 to 89 years of
age.81 In addition, atrial
fibrillation was associated with an OR for death of 1.5 (95% CI 1.2 to
1.8) in men and 1.9 (95% CI 1.5 to 2.2) in women after adjustment for
other risk factors.
Five placebo-controlled trials investigating the efficacy of warfarin in the primary prevention of thromboembolic stroke included the Copenhagen Atrial Fibrillation Aspirin and Anticoagulation (AFASAK) trial,82 Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF),83 Stroke Prevention in Atrial Fibrillation I (SPAF I),84 Veterans Affairs Stroke Prevention in Atrial Fibrillation trial (SPINAF),85 and the Canadian Atrial Fibrillation Anticoagulation (CAFA) trial.86 The efficacy of aspirin was studied in 2 of these trials (AFASAK and SPAF I). Combined analysis of these 5 trials showed that the relative risk of thromboembolic strokes for patients treated with warfarin was reduced by 68%.
An important observation arising from the randomized treatment trials is that there are a limited number of predictors of high stroke risk within the population of patients with atrial fibrillation. The predictors of high risk include advancing age, prior TIA or stroke, systolic hypertension (systolic blood pressure >160 mm Hg), a history of hypertension, impaired left ventricular function, diabetes mellitus, and women over the age of 75 years.87 Long-term oral anticoagulation of patients with these high-risk features reduces the risk of stroke by 68% based on results of the intention-to-treat analysis of the randomized trials and by as much as 80% when the on-treatment effect is noted.88
Recommendation
Antithrombotic therapy (warfarin or aspirin) should be
considered for patients with nonvalvular atrial fibrillation based on
an assessment of their risk of embolism and risk of bleeding
complications
(Tables 4 and 5).87
(Level of Evidence I, Grade A)
Other Cardiac Disease
Other types of cardiac disease that contribute a small
yet finite risk to thromboembolic stroke include dilated
cardiomyopathy, valvular heart disease (eg, mitral valve prolapse,
endocarditis, and prosthetic cardiac valves), and intracardiac
congenital defects (eg, patent foramen ovale, atrial septal
defect, and atrial septal aneurysm). Overall, an estimated 20% of
ischemic strokes are due to cardiogenic embolism. Potential cardiac
sources of emboli are associated with up to 40% of cryptogenic strokes
in some series involving the younger
population.89
The presence of cerebrovascular disease is strongly associated with the presence of symptomatic90 91 92 93 and asymptomatic94 95 96 97 98 cardiac disease. Conversely, based on the Framingham Heart Study, 8% of men and 11% of women will have a stroke within 6 years after acute myocardial infarction. In addition, myocardial infarction is associated with the development of atrial fibrillation and is a common source of cardiogenic emboli.81 However, acute myocardial infarction is infrequently associated with stroke, occurring in 0.8% of patients.99 100 101 The majority of these strokes (in 0.6% of patients) are ischemic.101
Perioperative stroke occurs in 1% to 7% of patients undergoing cardiac surgical procedures (predominantly coronary artery bypass procedures and open heart surgery). A history of prior neurological events, increasing age, diabetes, and atrial fibrillation have been identified as risk factors for early and delayed stroke after cardiac surgery.102 103 104 105 106 107 108 109 110 111 112 Other factors associated with perioperative stroke include duration of cardiopulmonary bypass and the presence of aortic atherosclerosis.113 114
Sickle Cell Disease
Sickle cell disease (SCD) is a genetic disorder with
autosomal dominant inheritance in which the abnormal gene product is an
altered ß-chain in the structure of hemoglobin. Although the clinical
manifestations are highly variable, typically SCD manifests early in
life as a severe hemolytic anemia punctuated by bouts of painful
episodes involving the extremities and bones ("vaso-occlusive
crises"), bacterial infections, and organ infarctions, including
stroke. In addition, there are systemic effects including impaired
growth and possibly cognitive developmental
retardation.115
Stroke prevention is most important for patients with
homozygous SS disease. The prevalence of stroke by age 20 in
these patients is at least
11%,116 and a substantial
number of patients also have "silent" strokes on brain
MRI.117 The highest stroke
rates occur in early childhood. Recent advances in detection of risk
with transcranial Doppler have made primary prevention of stroke a high
priority in children with
SCD.118 119 The
risk of stroke during childhood is 1% per year, but patients with
transcranial Doppler evidence of high cerebral blood flow velocity
rates (time-averaged mean velocity of 200 cm/s) have stroke rates in
excess of 10% per year.
A recently completed randomized trial (Stroke Prevention Trial in Sickle Cell Anemia; the STOP study) compared periodic blood transfusion with standard care in 130 children with SCD ranging in age from 2 to 16 years (mean 8 years).120 Blood transfusions were given an average of 14 times per year for >2 years in the treatment group, with a target reduction of Hb S from a baseline of 90% to 95% of total hemoglobin to <30%. The trial was halted 16 months early at the point at which 11 strokes had occurred in the standard-care arm compared with 1 stroke in the transfusion-treated group. The risk of stroke was reduced from 10% per year to <1%. Given these results, a Clinical Alert issued by the National Heart, Lung, and Blood Institute of the National Institutes of Health has recommended screening all children with SCD who have no history of stroke, with consideration of transfusion for those with 2 abnormal transcranial Doppler studies.
At present, the duration of transfusion needed has not been determined. Long-term transfusion is always associated with iron toxicity that must be treated with chelation.121 In the STOP study, there was no evidence of transfusion-related infection, but this and alloimmunization remains a transfusion risk.120 The role of other therapies such as bone marrow transplantation or hydroxyurea, which reduce the number of painful crises but have an uncertain effect on organ damage, including stroke, requires further study.122 123 The roles of anticoagulation and antiplatelet agents have not been evaluated. The use of methods other than transcranial Doppler, such as MRI or magnetic resonance angiography, to predict stroke sufficient to trigger prophylactic transfusion has not been well studied. There are no systematic data on prevention of stroke in adults with SCD, and improvements in care have increased expected longevity well beyond 40 years of age, making stroke in older SCD patients a more common clinical problem. Preventive therapies other than transfusion and the development of a prevention strategy in adults should be explored.
Recommendation
Children with SCD should be screened with transcranial
Doppler ultrasonography at 6-month intervals to determine their level
of stroke risk. Those at elevated risk should be considered for
transfusion therapy. (Level of Evidence I, Grade
A)
Hyperlipidemia
Abnormalities of serum lipids (triglycerides,
cholesterol, low-density lipoprotein [LDL], and HDL) have
traditionally been regarded as a risk factor for coronary artery
disease but not for cerebrovascular disease. However, recent studies
have helped clarify the relationship between lipids and stroke, as well
as showing that the risk of stroke and amount of carotid atheroma can
be reduced with cholesterol-lowering medications.
In a large meta-analysis of 45 prospective observational cohorts involving 450 000 individuals, no association was found between cholesterol and stroke rate.124 However, these epidemiological studies of the relationship between total cholesterol and stroke are confounded by reports of an inverse association between total cholesterol and cerebral hemorrhage, with a greater mortality from hemorrhagic stroke among those with serum cholesterol levels <160 mg/dL.125 126 127 In the studies included in the meta-analysis, most of the strokes were fatal, and there was not a clear differentiation between ischemic and hemorrhagic strokes.
For ischemic stroke, some studies have found a weak
association between serum cholesterol and an increasing risk of
cerebral infarction.128 For
example, the Multiple Risk Factor Intervention Trial demonstrated
increased mortality among men with high cholesterol
levels.129 The adjusted
risk ratio was 1.8 for those with serum cholesterol 240 to 279 mg/dL
and 2.6 for those with cholesterol levels 280 mg/dL. In the Honolulu
Heart Program, there was a continuous and progressive increase in both
coronary heart disease and thromboembolic stroke rates with increasing
levels of cholesterol. An inverse relationship between HDL and stroke
risk was demonstrated in both the Oxfordshire Community Study and the
Northern Manhattan Stroke
Study.130 131 132
More recent studies utilizing ultrasound technology have established an
association between lipid levels and extracranial carotid
atherosclerosis and intimal-media plaque
thickness.66 67 133 134 135
Older clinical trials did not confirm a reduction in stroke risk with the use of lipid-lowering therapies.136 However, more recent clinical trials using serial ultrasound measurements showed that reductions of elevations of LDL with ß-hydroxy-ß-methylglutaryl-CoA (HMG-CoA) reductase inhibitors ("statins") can modestly retard the progression of asymptomatic carotid atherosclerosis.67 137 138 139 140
Trials using these agents have demonstrated consistent benefits in reduction of stroke risk among individuals with coronary artery disease and elevated cholesterol levels, as well as among those with only mild to borderline elevations of cholesterol.141 142 143 144 145 146 For example, the Simvastatin Survival Study (4S) evaluated the effects of lowering cholesterol on 4444 patients with elevated total cholesterol levels and coronary heart disease.141 The simvastatin-treated group experienced 51% and 35% reductions in ischemic nonembolic stroke and TIAs, respectively. In 1998, the Food and Drug Administration (FDA) approved simvastatin to reduce the risk of first stroke or TIA in people with high total cholesterol and coronary heart disease. The West of Scotland Primary Prevention (WOSCOPS) trial found a nonsignificant 11% reduction in stroke in men with coronary heart disease and hypercholesterolemia who were treated with pravastatin.147 The Cholesterol And Recurrent Events (CARE) study investigated the efficacy of lowering cholesterol with pravastatin in 4159 patients who had suffered a heart attack in the previous 2 years and showed a reduction in stroke or TIA risk by 32%.148 Pravastatin was also approved by the FDA in 1998 for use in reducing risk of stroke or TIA in patients who have had a heart attack and have normal cholesterol levels (total cholesterol <240 mg/dL).
The benefits of statin agents in stroke prevention in patients with coronary heart disease have been supported by several meta-analyses.146 149 150 Exactly how statins provide stroke protection is uncertain. Although some of the stroke reduction may be due to lipoprotein alterations, statins may also act through mechanisms unrelated to their lipid-lowering properties, such as improved endothelial function, plaque stabilization, and antithrombotic, anti-inflammatory, and neuroprotective properties.151 152 153 154 155
Lipoprotein(a) [Lp(a)], an apolipoprotein homologous with plasminogen,156 is a known risk factor for the development of coronary heart disease.157 158 A study performed in Japan found that Lp(a) was also an independent risk factor for ischemic stroke, especially in young adults.159 However, a population-based prospective study in the United States found that Lp(a) was only a weak risk factor for cerebrovascular disease in men and was not a significant predictor of stroke risk in women.158 One case-control study revealed no relationship between Lp(a) concentrations and either stroke, TIA, or carotid atheromata in men,160 whereas a second found that serum Lp(a) levels were associated with stroke risk independent of other factors.161 There was no association between elevated Lp(a) levels and future stroke risk in a study in which patients with ischemic stroke were compared with matched controls.162
Recommendations
Management of patients with elevated cholesterol
according to National Cholesterol Education Program II guidelines is
recommended
(Table 5).34
Patients with known coronary heart disease and elevated LDL cholesterol
levels should be considered for treatment with a statin. (Level of
Evidence I, Grade A) Additional data are required to elucidate the role
of Lp(a) as an independent risk factor for
stroke.
Less Well-Documented or Potentially Modifiable Risk Factors
Less well-documented or potentially modifiable risk
factors are given in
Table 4.
Obesity
Obesity (defined as a body mass index [BMI] 30
kg/m2) predisposes to cardiovascular disease
in general and to stroke in particular. However, obesity prevalence
increases with advancing age, and obesity is associated with increased
blood pressure, blood sugar, and blood lipids. On the basis of these
associations alone, it is not surprising that obesity would be related
to an increased risk of stroke. However, several large studies suggest
abdominal obesity, rather than BMI or general obesity, is more closely
related to stroke risk. The age-adjusted relative risk of stroke was
2.33 in a comparison of the extreme quintiles of waist-hip ratios in
American men participating in the Health Professionals Follow-Up
Study.163
In women, obesity was associated with an increased risk of
ischemic stroke with increasing levels of BMI. The relative risk ranged
from 1.75 (95% CI 1.17 to 2.59) for BMI of 27 to 28.9
kg/m2, 1.90 (95% CI 1.28 to 2.82) for BMI
of 29 to 31.9 kg/m2, and 2.37 (95% CI, 1.60
to 3.50) for BMI of 32 kg/m2.
Weight gain after the age of 18 years was also related to ischemic
stroke, with increasing weight associated with increasing stroke
risk.164 Thus, recent
evidence supports abdominal obesity in men and obesity and weight gain
in women as independent risk factors for stroke.
Recommendation
Weight reduction in overweight persons is recommended
on the basis of the associated increase in comorbid conditions that can
lead to stroke. Reduction in stroke risk with weight loss has not been
established on the basis of existing prospective randomized studies.
(Level of Evidence IV, Grade C)
Physical Inactivity
Regular physical activity has well-established benefits
for reducing the risk of premature death and cardiovascular disease.
The beneficial effects of physical activity have also been documented
for
stroke.165 166 167 168 169 170 171 172 173
The Framingham Heart Study, Honolulu Heart Program, and Oslo Study have
shown the protective effect of physical activity for
men.166 167 168
For women, the Nurses’ Health Study and Copenhagen City Heart Study
demonstrated an inverse association between level of physical activity
and stroke
incidence.169 170
The protective effects of leisure-time physical activity have also been
found for blacks and Hispanics in the National Health and Nutrition
Examination Survey (NHANES) I Follow-Up Study and the Northern
Manhattan Stroke
Study.171 172
Dose-response relationships have sometimes been difficult to demonstrate, with no to deleterious effects of vigorous physical activity compared with lower levels of physical activity.167 173 174 In the Northern Manhattan Stroke Study, intensive forms of physical activity provided additional benefits compared with light-to-moderate activities. Additional protection was observed with increasing duration of exercise; however, the prevalence of such activities in the elderly was quite low.172 The protective effect of physical activity may be mediated in part through its role in controlling various known risk factors for stroke, such as hypertension,175 cardiovascular disease,176 diabetes,177 and body weight. Other biological mechanisms are also associated with physical activity, including reductions in plasma fibrinogen and platelet activity, as well as elevations in plasma tissue plasminogen activator activity and HDL concentrations.178 179 180 181
Currently available data support the benefits of physical activity. Guidelines endorsed by the Centers for Disease Control and Prevention and the National Institutes of Health recommend that Americans should exercise moderately for at least 30 minutes on most, and preferably all, days of the week.182 183 For stroke, the benefits are apparent even for light-to-moderate activities, such as walking, and the data support additional benefit from increasing the level and duration of one’s recreational activity. Physical activity is a modifiable behavior that requires greater emphasis in stroke prevention campaigns.
Recommendation
As per guidelines endorsed by the Centers for Disease
Control and Prevention and the National Institutes of Health, regular
exercise (30 minutes of moderate-intensity activity daily) is part of
a healthy lifestyle and helps to reduce comorbid conditions that may
lead to stroke
(Table 5).183
(Level of Evidence III, Grade C)
Poor Diet/Nutrition
Data regarding the effects of general nutritional
status on stroke risk are limited. There is no evidence that the use of
dietary vitamin E or C supplements or the use of specific carotenoids
substantially reduces the risk of
stroke.184 There may be a
protective relationship between stroke and consumption of fruits and
vegetables, especially cruciferous and green leafy vegetables and
citrus fruit and juice.185
An analysis of data from the Nurses’ Health Study and the Health
Professionals’ Follow-Up Study that included individuals free of
cardiovascular disease at baseline found that the relative risk of
stroke was 0.69 (95% CI 0.52 to 0.92) for persons in the highest
quintile of fruit and vegetable
intake.185 An increment of
1 serving per day was associated with a 6% lower risk of stroke.
However, it cannot be certain whether the effect was specifically due
to diet or a reflection of a generally more healthy lifestyle in these
individuals.
Recommendation
A healthy diet containing at least 5 daily servings of
fruits and vegetables may decrease the risk of stroke
(Table 5). (Level of Evidence III, Grade
C)
Alcohol Abuse
The effect of alcohol as a risk factor for ischemic
stroke is controversial and likely dose dependent. For hemorrhagic
stroke, cohort studies have shown that alcohol consumption has a direct
dose-dependent
effect.186 187 188
For cerebral infarction, chronic heavy drinking and acute intoxication
have been associated with an increased risk among young
adults.189 In older adults,
risk is increased among heavy-drinking men. No effect is present among
men and women after controlling for other confounding risk factors, and
there is a protective effect for moderate alcohol
consumption.186 187 190 191 192 193 194 195
Some studies have supported a J-shaped dose-response curve between alcohol intake and ischemic stroke risk, with protection for those drinking up to 2 drinks per day and an increased risk for those drinking >5 drinks per day compared with nondrinkers.196 197 198 The dose-response relationship between alcohol and stroke is consistent with the observed deleterious and beneficial effects of alcohol. The deleterious effects of alcohol for stroke may occur through various mechanisms, including increasing hypertension, hypercoagulable states, and cardiac arrhythmias and reducing cerebral blood flow. However, there is also evidence that light-to-moderate alcohol intake can reduce the risk of coronary artery disease, increase HDL cholesterol, and increase endogenous tissue plasminogen activator. Although it is difficult to consider recommending alcohol to those who are nondrinkers, elimination of heavy drinking and reduction to moderate levels of alcohol intake (no more than 2 drinks per day) for those who are currently drinking will probably do no harm and may reduce the incidence of stroke.
Recommendation
No more than 2 drinks per day for men and 1 drink per
day for nonpregnant women, as reflected in the US Preventive Services
Task Force report
(Table 5), is
recommended.64 (Level of
Evidence IV, Grade C)
Hyperhomocysteinemia
Although the definition of hyperhomocyst(e)inemia has
not been standardized across epidemiological studies, fasting plasma
levels of homocyst(e)ine between 5 and 15 µmol/L are generally
considered
normal,96 199 200
and levels 16 µmol/L are generally classified as indicating
hyperhomocyst(e)inemia (although the risk is likely
continuous).199 201
In the Framingham Heart Study original cohort (aged 67 to 96 years),
Selhub and colleagues202
found 19% had homocysteine concentrations >16.4 µmol/L.
Homocysteine concentrations increase with age, with men having higher
levels than women, especially at younger
ages.203 From NHANES III,
Selhub and colleagues204
recently identified population references for total homocysteine
concentrations. For men aged 40 to 59 years and those aged 60 years,
the prevalence of high homocyst(e)ine (defined as >11.4 µmol/L) is
28.6% and 43.2%, respectively. For women aged 40 to 59 years and
those aged 60 years, the prevalence of high homocyst(e)ine (defined
as >10.4 µmol/L) is 21.1% and 46.5%,
respectively.204
Numerous case-control studies have shown an association
between hyperhomocyst(e)inemia and stroke. Based on a change of 5
µmol/L in homocysteine level, a meta-analysis found a summary OR for
cerebrovascular disease of 1.5 (95% CI 1.3 to
1.9).205 From the NHANES
III data, the OR comparing the top quartile with the bottom 3 quartiles
is 2.25 (95% CI 1.59 to
3.18).206 In the Framingham
Study, the relative risk for stroke, comparing the lowest quartile with
the highest, was 1.82 (95% CI 1.14 to
2.91).207 Although the
association between plasma homocyst(e)ine and cerebrovascular risk is
biologically plausible, it is more consistently present in case-control
studies than in prospective studies, so further confirmatory evidence
is
required.199 207 208 209 210
The OR from NHANES III, when coupled with the prevalence estimates from Selhub et al,202 gives a population attributable risk of 26% for men aged 40 to 59 years, 35% for men aged >60 years, 21% for women aged 40 to 59 years, and 37% for women aged >60 years. These population attributable risk estimates must be interpreted with caution, because no data are available that would permit the estimation of population attributable risk after adjustment for other cerebrovascular risk factors that are positively correlated with homocyst(e)ine levels.
Folic acid, together with vitamins B6 and B12, has been shown to be effective in reducing elevated plasma homocyst(e)ine levels,211 but no randomized trials have as yet been completed to determine whether lowering elevated homocyst(e)ine levels will subsequently reduce stroke. Secondary prevention trials are in progress.199 212
Recommendations
An emphasis should be placed on meeting current
recommended daily amounts of folate (400 µg/d), vitamin
B6 (1.7 mg/d), and vitamin
B12 (2.4 µg/d) by intake of vegetables,
fruits, legumes, meats, fish, and fortified grains and cereals
(nonpregnant, nonlactating
individuals).201 Specific
recommendations regarding treatment of patients without cerebrovascular
or cardiovascular disease are deferred pending completion of ongoing
clinical trials. In the interim, given their safety and low cost, use
of folic acid and B vitamins may be considered for patients with known
elevated homocysteine levels. (Level of Evidence IV, Grade
C)
Drug Abuse
Illicit drug abuse, particularly involving the use of
amphetamines, "crack" cocaine, and heroin, has emerged as a serious
public health threat. Although the available data are derived primarily
from limited epidemiological studies focusing on minority populations
with low socioeconomic status, a consistent increase in the risk of
both ischemic and hemorrhagic stroke has been
demonstrated.213 214 215 216 217 218 219 220
Adjusting for other potential stroke risk factors, some studies have
found an 7-fold increase in stroke risk among drug
abusers.213 220
However, another study217
found no significant association between illicit drug abuse and stroke.
The pathogenesis of stroke in illicit drug abuse is likely
multifactorial, possibly involving sudden surges in blood pressure,
vasculitis, and hemostatic and hematologic abnormalities that can
result in increased blood viscosity and platelet
aggregation.221 222
Recommendation
History of illicit drug abuse should be sought
during routine medical evaluations and the patient referred for
appropriate counseling (US Preventive Services Task Force report;
Table 5).64
Hypercoagulability
Although the results of certain blood tests have
been associated with hypercoagulable states characterized by venous
thrombosis, many have not been clearly proven to be associated with
cerebrovascular arterial thrombosis. The presence of antiphospholipid
antibodies (aPL) has been shown in several case-control studies and one
prospective study to be associated with ischemic stroke. The 2 most
frequent tests used to detect aPL are anticardiolipin antibodies (more
prevalent, but less specific) and lupus anticoagulants (less prevalent,
but more specific).
Unfortunately, the definition of a significant positive result on testing for aPL has not been uniformly delineated. For example, the isotype of anticardiolipin antibody (IgG, IgM, or IgA) tested and the definition of a significantly elevated level varies among studies. As a result, it is difficult to give accurate prevalence data or risk of stroke associated with the presence of aPL. Although empirical treatments have been given for secondary stroke prevention in persons with aPL, evidence supporting the efficacy of this approach is limited.223 224 The Antiphospholipid Antibodies and Stroke Study (APASS) and Warfarin-Aspirin Recurrent Stroke Study (WARSS) results may help to shed light on the best treatment for secondary stroke prevention. However, further studies may then be needed to investigate primary prevention in persons with aPL.
Many case reports and case-control studies have been
published related to the association of other coagulation abnormalities
and stroke (eg, factor V Leiden, prothrombin 20210 mutation, protein C
deficiency, protein S deficiency, and antithrombin III deficiency;
Table 3). However, many have been poorly adjusted for other
stroke risk factors. More recent case-control and prospective studies
of these abnormalities have cast doubt on their importance as
independent risk factors for ischemic stroke. Therefore,
hypercoagulable states are presently difficult to categorize as targets
for primary stroke prevention.
Even if only a small increased risk of ischemic stroke exists with some of these hypercoagulable states, they may be important to consider in the overall risk profile of patients. Because some of the identified factors underlying hypercoagulable states are relatively common, these patients may also have other risk factors for stroke. These disorders may eventually be a target for more aggressive primary stroke prevention; however, further studies are needed to confirm whether these are indeed risk factors for stroke and whether populations who more frequently have these coagulation abnormalities should be targeted for testing and more aggressive primary prevention.
Recommendation
Specific recommendations regarding treatment of
patients without cerebrovascular or cardiovascular disease or a history
suggestive of a clinical coagulopathy are deferred pending further
study.
Hormone Replacement Therapy
The impact of postmenopausal hormone replacement
therapy on stroke risk appears to be neutral, but owing to a lack of
control studies, definitive conclusions cannot be reached. Since 1980,
there have been at least 18 studies published on this
subject.225 With the
exception of the Framingham Heart Study, none detected a large increase
in stroke risk, and several reported a slight (but often
nonsignificant) decrease in risk. The Framingham Heart Study found a
2.60-fold increase in the relative risk of atherothrombotic stroke
among women receiving hormone replacement therapy compared with
nonusers.226 In other
studies, the relative risk of stroke among hormone replacement therapy
users varied from 0.23 to 1.46, with the relative risk of fatal stroke
ranging from 0.30 to
1.40.170 192 227 228 229 230 231 232 233 234 235 236 237 238 239
A review indicated a neutral effect of postmenopausal hormone
replacement therapy, with a relative risk of
0.96.240 However, the
studies conducted to date have had methodological
limitations.225 These
limitations include nonspecific end points, lack of control for prior
hormone replacement use or specific regimens, a lack of sufficient
numbers of women from minority race-ethnic groups, and possible
confounding by a healthy-user
effect.225 The benefits and
risks in terms of stroke must also be balanced against other potential
effects of hormone replacement, including osteoporosis and breast
cancer. Further studies are required to clarify this important
issue.
Recommendation
The risk of stroke associated with hormone replacement
therapy appears low but requires further study. Until more data are
available, the use of hormone replacement therapy should be guided by
factors other than stroke risk.
Oral Contraceptive Use
Much of the perceived increased stroke risk associated
with the use of oral contraceptives is based on early studies with
high-dose preparations225
(ie, first-generation oral contraceptives containing 50 µg of
estradiol241 242 243 ).
The majority of studies of second-generation oral contraceptives
containing lower doses of estrogens did not find an increased risk of
stroke.242 243 244 245 246
However, one study did report an increased risk of stroke in women
using first-, second-, or third-generation oral
contraceptives.247 The
reasons for this discrepancy are not certain. In addition, women who
are cigarette smokers, are hypertensive, or have diabetes, migraine, or
prior thromboembolic events may be at increased stroke risk if they use
oral
contraceptives.248 249
A meta-analysis concluded that the risk of ischemic stroke is increased in oral contraceptive users but that the absolute increase in risk would be small because of the low stroke incidence in this population.250 The increase in risk was present even with the newer low-dose estrogen preparations. Methodological limitations limited definitive conclusions regarding the impact of additional risk factors such as hypertension and cigarette smoking in oral contraceptive users.
Recommendation
The risk of stroke associated with use of low-dose oral
contraceptives in women without additional risk factors appears low.
Oral contraceptives should be avoided in women with additional risk
factors (eg, cigarette smoking or prior thromboembolic
events).
Inflammatory Processes
Atherosclerosis, the most common cause of stroke, is
now believed to be a disease of chronic inflammation. Its lesions
typically occur at branch points and bifurcations in large and
medium-sized elastic and muscular arteries. The extracranial internal
carotid artery and the vertebral artery (at its origin and just distal
to the posterior inferior cerebellar artery) are the cerebral vessels
most commonly affected.
Endothelial cells of normal postcapillary venules express P-selectin, intercellular adhesion molecule-1 (ICAM-1), and E-selectin when exposed to cytokines, peroxides, and other stimuli associated with hypoxic injury. Their appearance mediates leukocyte adhesion and trafficking. The adhesion receptors ICAM-1 and VCAM-1 (vascular cell adhesion molecule-1) are also expressed by endothelium at sites predisposed to atherosclerosis251 and continue to be expressed during the development of the atheroma. Shear stress and turbulence may contribute to adhesion receptor expression and may explain the localization of atherosclerotic plaques at vessel bifurcations.252 253 254
Monocytes and T cells bind to the expressed adhesion molecules, become activated, and secrete products such as cytokines and proteolytic enzymes that contribute to vessel damage. Markers of inflammation, such as leukocyte adhesion receptors255 and cytokines,256 as well as activated T cells and macrophages,257 are present in carotid endarterectomy specimens of recently symptomatic patients, which suggests that acute inflammatory responses may predispose to plaque destabilization and symptoms. Elevated levels of soluble leukocyte adhesion receptors have been associated with carotid artery atherosclerosis.258 259 260
Chronic infection may underlie atherosclerosis. Chlamydia pneumoniae, a Gram-negative obligate intracellular bacterium, has been identified in atherosclerotic carotid plaques261 262 263 264 265 and localizes to regions of altered plaque morphology.263 264 The fact that seropositivity to Chlamydia does not seem to correlate to carotid atherosclerosis, as measured by duplex ultrasonography,265 266 supports the notion that Chlamydia may participate in plaque progression and destabilization as opposed to initiation of atherosclerosis, which may be why there appears to be a relationship between serum antibody titers to C pneumoniae and stroke.267 268 269 270 The benefit of eradicating C pneumoniae from carotid plaques with antibiotic therapy remains unclear.271 Data linking infection with other pathogens, such as cytomegalovirus and herpes simplex virus, with atherosclerosis are not as robust as those for C pneumoniae.267 272
Several observational studies suggest that acute infection may be associated with ischemic stroke. C-reactive protein (CRP) and serum amyloid A, acute-phase reactants produced by the liver, are markers of systemic inflammation. CRP levels are increased in smokers273 274 and in apparently healthy men with vascular risk factors.274 There is a significant and positive association between plasma CRP levels and the risk of vascular events, including stroke.273 275 276
Data from prospective randomized clinical trials suggest that the efficacy of common preventive agents such as aspirin and HMG-CoA reductase inhibitors may be related, at least in part, to their anti-inflammatory effects. In the Physicians’ Health Study, aspirin significantly reduced the risk of vascular events only among men in the highest quartile of CRP levels,273 although the direct effect of aspirin on CRP is unclear.277 278 Pravastatin use, which was shown to decrease the risk of vascular events and stroke in the CARE trial, led to a significant decrease in CRP levels over the 5-year follow-up, whereas CRP levels increased in patients who received placebo. This effect of pravastatin appears to be independent of its effect on lowering LDL cholesterol.154 Whether CRP contributes to vascular disease or is merely a marker of vascular risk is unclear, but an inflammatory environment seems to predispose to the risk of stroke in experimental model studies.279
Recommendation
The currently available data do not provide sufficient
evidence to support a specific management
recommendation.
Management Strategies
Table 5 summarizes strategies for risk factor management
based on published guidelines and/or consensus statements. Details of
the various recommendations can be found in the original references.
Risk factors for which specific guidelines have not been previously
adopted have not been included in the
Table.280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330
Future Research
As can be readily appreciated by inspection of the tables and in the accompanying text, significant gaps exist in current knowledge of the impact of specific factors on stroke risk. Moreover, the possible impact of treatment of many of the potentially modifiable factors on subsequent stroke risk is uncertain. Whether the focus of management of specific risk factors should be modified in different race-ethnic groups requires further study. Additional study is also necessary to develop a fuller understanding of differences in risks between men and women. Despite recent advances in acute stroke management and promising new approaches to improving poststroke recovery, prevention remains the cornerstone of therapy for these devastating diseases.
Footnotes
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in September 2000. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0197. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or
This statement is being published simultaneously in the January 2001 issue of Stroke.
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R. B. Horenstein, D. E. Smith, and L. Mosca Cholesterol Predicts Stroke Mortality in the Women's Pooling Project Stroke, July 1, 2002; 33(7): 1863 - 1868. [Abstract] [Full Text] [PDF]
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P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
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 M L Bots THE EUROSTROKE PROJECT J Epidemiol Community Health, February 1, 2002; 56(90001): i1 - 1. [Full Text] [PDF]
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K. J. Greenlund, W. H. Giles, N. L. Keenan, J. B. Croft, G. A. Mensah, and S. L. Huston Physician Advice, Patient Actions, and Health-Related Quality of Life in Secondary Prevention of Stroke Through Diet and Exercise * The Physician's Role in Helping Patients to Increase Physical Activity and Improve Eating Habits Stroke, February 1, 2002; 33(2): 565 - 571. [Abstract] [Full Text] [PDF]
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P. A. Tunick and I. Kronzon Primary Prevention of Ischemic Stroke Circulation, September 11, 2001; 104 (11): e59 - e59. [Full Text] [PDF]
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L. Mosca, P. Collins, D. M. Herrington, M. E. Mendelsohn, R. C. Pasternak, R. M. Robertson, K. Schenck-Gustafsson, S. C. Smith Jr, K. A. Taubert, and N. K. Wenger Hormone Replacement Therapy and Cardiovascular Disease: A Statement for Healthcare Professionals From the American Heart Association Circulation, July 24, 2001; 104(4): 499 - 503. [Full Text] [PDF]
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 L. K. Massey Dairy Food Consumption, Blood Pressure and Stroke J. Nutr., July 1, 2001; 131(7): 1875 - 1878. [Abstract] [Full Text] [PDF]
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M. S.V. Elkind Implications of stroke prevention trials: Treatment of global risk Neurology, July 12, 2005; 65(1): 17 - 21. [Abstract] [Full Text] [PDF]
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