2 - Stroke Risk Factors - an Overview
Editors: Norris, John W.; Hachinski, Vladimir
Title: Stroke Prevention, 1st Edition
Copyright 2001 Oxford University Press
> Table of Contents > I - Primary Prevention > 2 - Stroke Risk Factors: an Overview
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2
Stroke Risk Factors: an Overview
Ralph L. Sacco
Ranked as the second leading cause of death worldwide, stroke is far more often disabling than fatal and results in enormous costs measured both health care dollars and lost productivity. Approximately 730,000 people have a new or recurrent stroke each year, and there are over 4 million stroke survivors in the United States. The estimated cost of stroke-related health care is a staggering $20 to $40 billion measured in both health care dollars and lost productivity.1
Over the next three decades, public health impact of stroke is likely to increase. The proportion of the population over age 65 is expected to rapidly grow. The aging of the population and the changing race/ethnic composition certain nations could lead to an increased absolute number of strokes per year, resulting in greater incidence, mortality, morbidity, and cost.
In recent years great strides have been made in understanding the pathophysiology of ischemic stroke and in testing applying treatments for acute stroke aimed at reducing morbidity and mortality after stroke. However, the most effective way to reduce the burden of stroke is through prevention. Stroke risk factors have been elucidated, and clinical trials have indicated the benefits of treatments for persons with hypertension, atrial fibrillation, hypercholesterolemia, and asymptomatic carotid disease. Stroke prevention strategies can occur at multiple stages: in the healthy, stroke-free population (primary prevention): among those who have developed recognizable risk factors and may subclinical
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disease (late primary or early secondary prevention); and after the development of neurological symptoms of stroke or transient ischemic attack, TIA (late secondary or tertiary prevention). The process requires changes in national health policy directed at public health practices to promote healthy lifestyles, recognition of who is at increased risk stroke, and modification this risk whenever possible to prevent stroke.
Classification and Determination of Stroke Risk Factors
Every stroke prevention strategy begins with an understanding of stroke risk factors. A risk factor is any exposure that leads to an increase in the probability of stroke among those with the factor relative to those without factor. Some factors are not modifiable and may be better characterized as risk markers, while others are amenable to behavioral, medical, or surgical modification. Risk markers may include age, gender, race-ethnicity and heredity. Modifiable risk factors may include environmental or even genetic exposures that when modified, lead to reductions in the risk of stroke. Conditions such as hypertension and hyperlipidemia are good examples of factors that may have both environmental and genetic determinants, but where control of the condition can lead to a reduction in stroke risk.
Epidemiologic studies such as case control and cohort studies have identified stroke risk factors. In case control studies the odds of exposure to a specific condition are assessed in cases with stroke compared to controls without stroke. The potency of the risk factor is measured by odds ratio. Problems can be encountered because the exposure is usually measured after onset of disease, and selection biases lead to a collection of cases who do not adequately reflect all individuals with stroke and controls who are not representative of the general population. These problems can be improved by using population-based study designs in which all the cases of stroke within a specific area are included and controls are randomly derived from the same community. Methods to measure exposures that reflect the pre-disease status can help reduce problems of the retrospective design. Despite these limitations, case control studies can provide cost-effective insights into risk factors that are less prevalent.
In cohort studies, the risk or incidence of disease is determined among those with and without the factor of interest to calculate relative risk or rate. Moreover, the attributable risk, or etiologic fraction, can be readily calculated as is a measure of the proportion cases explained or attributed to exposure. Prospective cohorts usually require systematic, lengthy follow-up after a baseline assessment. Retrospective cohort studies circumvent this problem by identifying individuals who had some baseline measurements made years before the study was conceived and then determine who subsequently developed stroke. The clear advantage to cohort studies is the measurement of exposure pre-stroke
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and the ability to determine prevalence of the exposure in general population. However these studies are time consuming, expensive, and require large numbers of subjects.
Experimental epidemiologic studies, such as the randomized, controlled clinical trial, are the mainstay of demonstrating that modification of a risk factor can lead to a reduction in stroke risk. The population at risk usually has already been selected, with the risk factor based on inclusion and exclusion criteria. Subjects are randomly assigned to an intervention or not and then followed for the occurrence of a specific outcome, such as stroke. Randomization is used to help ensure that the groups are balanced for known and unknown factors that could increase the risk of stroke and serve as confounders. While these studies can also be expensive and require large numbers of patients, they are essential to the development of evidence-based guidelines for stroke prevention.
Nonmodifiable Risk Markers
Four nonmodifiable factors are generally considered to increase a person's risk of stroke. They include age, sex, race/ethnicity, and heredity.
Age and Sex
Age is one of the strongest determinants of stroke (Table 2.1). Stroke incidence rises with age, nearly doubling every decade after age 55, and the majority of strokes occur in persons older than 65.1 Most of the future predicted increase in the number of strokes occurring each year is largely due to the aging populations.
Stroke incidence is greater for men than women, with rates about 25% to 30% greater for men.2 In Sweden, Italy, and Taiwan, stroke incidence was 66%, 35%, and 16% greater in men than women, respectively.3,4,5 Women, however, have a greater life expectancy; hence, the prevalence of stroke in a population is usually greater among women. Differential incidence rates by sex vary stroke
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subtype, with rates among men greater for cerebral infarction, rates men and women similar for intracerebral hemorrhage, and rates among women greater subarachnoid hemorrhage.2,6 Some issues in stroke prevention are specific to women, such as oral contraceptives and postmenopausal estrogen use.
TABLE 2.1. Nonmodifiable Risk Markers for Incident Ischemic Stroke | |||||||||||||||
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Race/Ethnicity
Despite a decline in stroke mortality all race and sex groups, the relative difference between races in stroke mortality has remained fairly uniform, with nearly a two-fold increased stroke mortality in blacks compared to whites.7 Few studies, however, have had enough of a race/ethnic mixture to compare stroke incidence in multiethnic groups the same region. Various studies have found that blacks had a greater incidence and prevalence of stroke than whites comparable age, sex, and residence.8,9,10,11,12,13,14 In the National Health Nutrition Survey, the relative risk of stroke for blacks was higher than whites, even after adjustment for age, hypertension, and diabetes.15 In northern Manhattan, the overall age-adjusted one-year stroke incidence rate for blacks was 2.4 times that of whites in a population-based stroke incidence study among white, black, and Hispanic residents.16
By contrast with blacks, Hispanics have rarely been identified separately in epidemiologic studies of stroke. In northern Manhattan, Hispanics, predominately from the Dominican Republic, had an overall age-adjusted one-year stroke incidence rate 2 times that of whites.16 Finally, in other studies, Asians, particularly Chinese and Japanese, have exceedingly high stroke incidence rates that seem to be decreased among those who have migrated to Hawaii and California.17
The explanation for the increased mortality from stroke in African Americans, Hispanics, and Asians continues to be investigated. One explanation is that increased mortality is directly related to increased incidence. However, others have shown that different groups have a unique burden of stroke risk factors after controlling for differences in socioeconomic status and other demographic variables.18 One way to look at differential burdens in stroke risk is to calculate the attributable risk of the risk factor. The ability to identify differences in risk factor profiles across racial/ethnic groups will allow more targeted and better justified therapeutic or preventative interventions.
Heredity
The hereditability, or genetic risk, of cerebrovascular disease has been under-emphasized. Stroke is predominantly a complex disease, influenced by both genetic and environmental factors. Although there are more than 50 monogenic disorders associated with stroke, most are rare and account for a small percentage of stroke cases. Stroke is likely caused by several different genes whose individual
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effects are determined by certain environmental triggers in a complex geneenvironmental interaction causal model. Studies in different populations have demonstrated familial aggregation of stroke. Twin studies have found a significantly greater concordance of stroke in monozygotic than dizygotic twins.19 Cohort studies in different populations have demonstrated an association between parental stroke death and an increased risk of stroke in offspring.20 Variations the incidence of ischemic stroke in racial groups support the notion a genetic component.21 Relatives of people with ischemic stroke often share the same risk factors, making it difficult to separate genetic factors from shared environment.
The familial effect is thought to represent indirect genetic influences that likely operate through well-documented risk factors such as hypertension, diabetes mellitus, cardiac diseases, and abnormal lipid states. Each of these risk factors is itself under genetic influence that may or may not interact with environmental factors, and this observation argues against the notion that any single gene is a sufficient or necessary cause of stroke. Knowledge about these possible indirect genetic causes of stroke is incomplete. Potential genetic stroke risk factors include apolipoprotein E and lipoprotein a, as well as genetic markers of thrombosis, such as factor V Leiden, and fibrinogen. 22
The identification of genetic determinants for stroke would allow early identification of persons with increased risk of stroke through genetic screening. At present, genetic screening is not available for atherosclerosis or stroke. In the future it may be possible to alter genes with molecular biological techniques and modify the risk of stroke. Prior to these advances, detection a genetic factor could also lead to more intensive environmental risk factor modification.
Modifiable Risk Factors
Major reductions in stroke morbidity and mortality are more likely to arise from identification and control of modifiable factors in the stroke-prone individual. Modifiable stroke risk factors include hypertension, cardiac disease (particularly atrial fibrillation), diabetes, dyslipidemia, cigarette use, alcohol abuse, physical inactivity, diet, asymptomatic carotid stenosis, and transient ischemic attacks (Table 2.2).
Hypertension
After age, hypertension is the most powerful stroke risk factor. It is prevalent in both men and women and is of even greater significance in African Americans. The risk of stroke rises proportionately with increasing blood pressure. Isolated systolic hypertension is increasingly prevalent with age and increases the risk of stroke by 2 to 4 times, even after controlling for age and diastolic blood pressure.2
TABLE 2.2. Estimated Relative Risk, Prevalence, and Identification of Important Modifiable Risk Factors for Ischemic Stroke. The Prevalence of the Factor in the General Population Varies by Age, Sex, Race/Ethnicity, and Definition of the High Risk Factor | ||||||||||||||||||||||||||||||||
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Reduction of both systolic and diastolic blood pressure in hypertensives sub stantially reduces stroke risk. A large multicenter hypertension detection and follow-up program trial, comparing standardized stepped care with routine care, showed a 35% reduction in total strokes and a 44% fatal strokes over a five-year period.23 Reduction of isolated systolic hypertension to < 140 mm Hg in elderly individuals is clearly beneficial.24,25,26 The Syst-Eur trial demonstrated that treatment of older patients with isolated systolic hypertension led to a 42% reduction in stroke risk with no significant decline overall mortality.27 Meta-analyses of prospective randomized controlled trials indicated that a decrease in diastolic blood pressure of 5 to 6 mm Hg reduced the risk for stroke by 42%, with similar magnitudes of risk reduction for men, women, and subjects of all ages.28,29
Current guidelines for treatment of hypertension have been published by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.30 Definitions of hypertension have been broadened to include individuals who were once considered borderline hypertensive. Because the attributable stroke risk for hypertension (proportion of strokes explained by hypertension) ranges from 35% to 50% depending on age, even a slight improvement in the control of hypertension could translate into a substantial reduction
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in stroke frequency.31 The National Stroke Association recommends that to help decrease the risk for a first stroke, three following things should be done: (1) blood pressure should be controlled in patients with hypertension who are most likely to develop stroke, (2) physicians should check the blood pressure of all their patients at every visit, and (3) patients with hypertension should monitor their blood pressure at home.32
Cardiac Diseases
Various cardiac conditions have been clearly associated with an increase in the risk of ischemic stroke (Table 2.3). Because certain stroke risk factors, like hypertension, may also be determinants of cardiac disease, some cardiac conditions may be viewed as intervening events in the causal chain for stroke. Cardiac factors that have been documented independently to increase the risk of stroke include atrial fibrillation, valvular heart disease, myocardial infarction, coronary artery disease, congestive heart failure, and electrocardiographic evidence of left ventricular hypertrophy. Improved cardiac imaging has led to the increased detection of potential stroke risk factors, such as mitral annular calcification, patent foramen ovale (PFO), aortic arch atherosclerotic disease, atrial septal aneurysms, spontaneous echo contrast (a smoke-like appearance in the left cardiac chambers visualized on transesophageal echocardiography), and valvular strands.
Nonvalvular atrial fibrillation (AF) is a potent predictor of stroke, causing a nearly fivefold increase in the relative risk of stroke.33 It has been estimated that AF affects more than 2 million Americans and becomes more frequent with age, ranking as the leading cardiac arrhythmia in elderly. For each advancing
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decade of age, the incidence of AF nearly doubles. The overall prevalence is approximately 1%, but the prevalence among those older than 65 years is close to 6%. Therefore, the attributable risk of stroke from AF increases significantly with age, approaching that of hypertension among those 80 to 89 years old.
TABLE 2.3. Cardiac Risk Factors for Incident Ischemic Stroke | |||||||||||||||||||
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Clinical trials have demonstrated conclusive evidence of the efficacy oral anticoagulants for stroke prevention among individuals with nonvalvular atrial fibrillation.34 Aspirin may also have some efficacy among lower-risk groups or those who have relative contraindications to anticoagulants. Stroke prevention in atrial fibrillation (SPAF III) demonstrated that warfarin with an international normalized ratio (INR) of 2 3 was far superior to aspirin and mini-dose warfarin with an INR < 1.5 in the prevention of stroke among high-risk patients with nonvalvular atrial fibrillation.35 The recommendation from the fifth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy was that long-term oral warfarin therapy (INR 2.0 3.0, target 2.5) be used in patients with atrial fibrillation who are eligible for anticoagulants, except in patients less than 60 years of age who have no associated cardiovascular disease.36 It has been estimated that for every 1000 patients with nonvalvular atrial fibrillation treated with warfarin for one year, 35 thromboembolic events can be prevented at a cost of one major bleed.
Stroke risk nearly doubles in those with antecedent coronary artery disease, triples with left ventricular hypertrophy, and nearly quadruples in subjects with cardiac failure.33 Acute myocardial infarction has been associated with stroke. Even uncomplicated angina, non-Q wave infarction, and silent myocardial infarction were found to be stroke risk factors in the Framingham Study cohort. The attributable risk of stroke for coronary heart disease was approximately 12% and ranged from 2.3% to 6.0% for cardiac failure, depending on age.
Mitral stenosis, endocarditis, and prosthetic heart valves are some of the valvular diseases that can also increase the risk of stroke. After adjusting for other risk factors in the Framingham cohort, the presence of mitral annular calcification (MAC) was associated with a relative risk of stroke of 2.1.37 Mitral valve prolapse (MVP) has a high prevalence in the general population and has been reported to be more frequent in young patients with unexplained stroke compared to controls. However, more recent studies with more stringent diagnostic criteria for MVP have failed to demonstrate a convincing independent increase in stroke risk.38,39
Diabetes Mellitus
Diabetes is a determinant of atherosclerosis and microangiopathy the coronary, peripheral, and cerebral arteries. Death from cerebrovascular disease is greatly increased among subjects with elevated blood glucose values.40 Cohort studies have demonstrated an independent effect of diabetes on stroke risk after
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controlling for other risk factors, with relative risks ranging from 1.5 to 3.O.2,41,42,43 Some studies have shown conflicting data regarding the relative risk of stroke in diabetic women as compared with men. A Swedish study showed a 6-fold rise in the risk of stroke in diabetic males compared to a 13-fold females.44 In Rochester, Minn., diabetes was a significant risk factor for stroke among men, but not women.45 Both studies found that the impact of diabetes on stroke risk was greater in older women. Among Hawaiian men of Japanese descent in the Honolulu Heart Program, those with diabetes had twice the risk of thromboembolic stroke compared with those without diabetes, independent of other risk factors.46 In the Framingham study, at all ages of both men and women, the incidence of atherothrombotic infarction among diabetics was almost twice that of nondiabetics.47
In western Europe, insulin-dependent, or type 1, diabetes accounts for perhaps 10% 20% of all diabetic patients. Worldwide, there seems to be an extraordinary increase in type 2 diabetes, from an estimated 124 million at present to a predicted 221 million by the year 2010, with only 3% of all patients with type 1 diabetes.48 Based on preliminary data from the Northern Manhattan Stroke Study, the prevalence of diabetes may be as high as 22% and 20% among elderly blacks and Hispanics, respectively, and the corresponding attributable risks of stroke were 13% and 20%.49
Intensive treatment of both type 1 and type 2 diabetes, aimed at maintaining near normal levels of blood glucose, can substantially reduce the risk of microvascular complications such as retinopathy, nephropamy, and neuropathy, but it has not been conclusively shown to reduce macrovascular complications, including stroke.50,51,52 However, the UK Prospective Diabetes Study group reported that aggressive treatment of blood pressure (< 150/85 mm Hg) among type 2 diabetics helped significantly to reduce the risk of stroke by 44%.53 Recent guidelines for management of diabetes have been published by the American Diabetes Association and have lowered the target fasting blood glucose level to 126 mg/dl.54 The National Stroke Association (NSA) recommends rigorous comprehensive control of blood sugar levels for adherent patients with type 1 and type 2 diabetes mellitus to prevent microvascular complications.32
Dyslipidemias
Abnormalities of serum lipids (triglyceride, cholesterol, low-density lipoprotein [LDL], and high-density lipoprotein [HDL]) are clear risk factors for atherosclerotic disease, particularly coronary disease. Recent studies have helped clarify the relationship between lipids and stroke risk. Studies using ultrasound technology have established that total cholesterol or LDL cholesterol is directly associated and HDL cholesterol is inversely associated with extracranial carotid atherosclerosis and intima-media plaque thickness.55,56,57,58,59 Case control studies have
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found the concentration of HDL to be lower in stroke cases, even after controlling for other stroke risk factors, and ischemic stroke mortality has been found to be related to lower HDL levels.60,61,62,63 Most prospective studies have found no association between serum cholesterol and cerebral infarction, while some have demonstrated a relationship.41,64 In the Multiple Risk Factor Intervention Trial, mortality from ischemic stroke was greater among men with high cholesterol.65 In the Honolulu Heart Program, there was a continuous and progressive increase in both coronary heart disease CHD and thromboembolic stroke rates with increasing levels of cholesterol, with a relative risk of 1.4 comparing the highest and lowest quartiles.64
Meta-analyses among prospective studies have found either no or only a minimally increased relative risk of stroke due to elevated total cholesterol.66,67 The absence of a consistent significant relationship between cholesterol and stroke may be partially explained by the recognition that there are multiple stroke subtypes that are not all attributed to atherosclerosis. Additionally, most prospective studies were done among younger populations and focused on cardiac outcomes, and lipoprotein fractions were not always evaluated separately from total cholesterol.
Clinical trials analyzing the efficacy of lipid-lowering strategies with statins have demonstrated impressive reductions in stroke risk in various high-risk populations with cardiac disease. In these studies, stroke was either a secondary endpoint or a nonspecified endpoint, determined based on post-hoc analyses.68 Meta-analyses of some these trials have found significant reductions in stroke risk, with a 29% reduced risk of stroke and a 22% reduction in overall mortality.69,70 Secondary prevention trials showed a 32% stroke risk reduction, and primary trials demonstrated a 20% reduction. Two large trials in which stroke was prespecified as a secondary endpoint have also shown significant reductions using pravastatin among subjects with coronary artery disease and normal to only modest elevations of cholesterol.71,72
Using serial carotid ultrasound measurements, some clinical trials have also demonstrated carotid plaque regression with statins.73,74,75,76,77 Thus, recent observational and clinical trial data provide mounting support for the role of lipoproteins as precursors of carotid atherosclerosis and ischemic stroke the benefits cholesterol lowering in stroke reduction. Individuals with cholesterol levels above 200 mg/dl and with cardiovascular risk factors should have a complete lipid analysis (total cholesterol, LDL, HDL, triglycerides) and most likely would benefit from cholesterol lowering regimens, including statins.78
Cigarette Smoking
Despite the clear evidence that cigarette smoking is an independent determinant of stroke and other diseases, it remains a major modifiable public health threat
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Stroke Risk Factors 27 in every nation.79 A wealth of data support the role smoking as an important and prevalent stroke risk factor. In case control studies, the effect of cigarette smoking remained significant after adjustment for other factors, and a dose-response relationship was apparent.80 Prospective studies have confirmed these findings in both men and women.81,82 The Honolulu Heart Study demonstrated that smoking was an independent predictor of ischemic stroke, with adjusted relative risks of 2.5 for men and 3.1 for women. A meta-analysis 32 studies found a summary relative risk of stroke for smokers of 1.5 (95% CI 1.4 1.6).83 The risk decreased with age, and a slightly increased risk was noted for women compared to men. Stroke risk was increased twofold in heavy smokers (more than 40 cigarettes per day) compared to light smokers (less than 10 cigarettes day). The stroke risk attributed to cigarette smoking was greatest for subarachnoid hemorrhage, intermediate for cerebral infarction, and lowest hemorrhage. Even the effects of passive cigarette smoking exposure have been found to increase the risk of progression of atherosclerosis.84
Cigarette smoking is an independent determinant of carotid artery plaque thickness and the strongest predictor of severe extracranial carotid artery atherosclerosis.85,86,87,88 Other biological mechanisms by which cigarettes may predispose to stroke include increased coagulability, blood viscosity, and fibrinogen levels; enhanced platelet aggregation; and elevated blood pressure.
No randomized clinical trial has been performed to measure the benefits of cigarette smoking cessation. However, ample evidence exists from observational epidemiologic studies that smoking cessation leads to a reduction in stroke risk. The Nurses' Health Study and the Framingham Study both demonstrated that the risk of ischemic stroke is reduced to that nonsmokers after 2 years and 5 years, respectively.89,90 It has been estimated that if cigarette smoking could be eliminated in the United States, the number of strokes occurring each year could be reduced by 61,500 with a saving of 3.08 billion stroke-related health-care dollars.91 The NSA recommends the cessation of smoking as a stroke prevention measure, in accordance with guidelines by the Agency for Health Care Policy and Research that address various topics, including screening for tobacco use, advice to quit, interventions, smoking cessation pharmacotherapy, motivation quit, and preventing relapses.32,92
Alcohol Use
The role of alcohol as a stroke risk factor is controversial and differs by dose well as stroke subtype.93,94 Almost all studies have shown an increased risk of hemorrhagic stroke associated with increasing alcohol consumption in a dosedependent fashion.95 Those studies that have investigated alcohol as a risk factor for ischemic stroke have found conflicting results. In a case control study among 205 predominantly black patients in Chicago, no significant effect of alcohol on
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stroke risk was found when controlled for confounders.80 Other case control studies in New Haven,96 Winnipeg, Canada,97 London, U.K.,98 and Milan, Italy,99 similarly failed to find a significant association between alcohol and ischemic stroke. In northern Manhattan, a J-shaped relationship between alcohol and stroke was found, with an elevated stroke risk for heavy alcohol consumption and a protective effect in light to moderate drinkers (two or fewer drinks per day) when compared to nondrinkers (Figure 2.1).100 The methodological problems in the case control approach to study alcohol and stroke have been summarized by Camargo and others.94,98 For example, one investigation demonstrated that the odds ratio for stroke ranged from 0.73 (protective) to 1.93 (deleterious) depending upon whether controls were selected from a general hospital population, a population without potential alcohol-related diagnoses, or the community.98
Prospective cohort studies in predominantly white populations addressing the relationship of stroke to alcohol intake have found evidence of a protective effect of mild alcohol intake.101,102,103 The large Nurses' Health Study, which examined different stroke subtypes, found a protective effect of mild alcohol consumption (up to 1.2 drinks per day in women) for ischemic stroke.101 Other prospective cohort studies have failed to confirm this relationship.104 Several studies of Japanese subjects that looked specifically at ischemic stroke failed to show any protective effect of alcohol, suggesting that alcohol's effect as a stroke risk factor may vary by race/ethnicity.102,105
The various mechanisms through which alcohol may increase the risk of stroke include hypertension, hypercoagulable states, cardiac arrhythmias, and cerebral
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blood flow reductions. However, there is also evidence that light to moderate drinking can increase HDL-cholesterol, reduce the risk of coronary artery disease, and increase endogenous tissue plasminogen activator. The combination of deleterious and beneficial effects of alcohol is consistent with the observation a dose-dependent relationship between alcohol and stroke. Elimination of heavy drinking can undoubtedly reduce the incidence of stroke. Since some ingestion of alcohol, perhaps up to two drinks per day, may actually help reduce the risk of stroke, drinking in moderation should not be discouraged for most of the public.32
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FIGURE 2.1. Quadratic, or J-shaped, relationship between alcohol exposure and ischemic stroke risk from the Northern Manhattan Stroke Study. |
Physical Activity
The cardiovascular benefits of physical activity have been emphasized by numerous organizations, including the Center for Disease Control, National Institutes of Health, and the American Heart Assocation, based on accumulating data regarding the beneficial effects of physical activity in reducing risk of heart disease and premature death.106 Previous studies have evaluated the association between physical activity and the risk of stroke.107,108,109,110,111,112,113,114,115 The beneficial effects have been predominately described among white populations, more apparent for men than women, and generally described younger rather than older adults. The Honolulu Heart Program, which investigated older middle-aged men of Japanese ancestry, showed a protective effect of habitual physical activity from thromboembolic stroke only among the nonsmoking group.108 The Framingham Study demonstrated the benefits of combined leisure and work physical activities for men, but not for women.109 In the Oslo Study, among men aged 40 to 49, increased leisure physical activity was related to a reduced stroke incidence.110 For women 40 to 65 years old, the Nurses' Health Study showed an inverse association between level of physical activity and the incidence any stroke.114 In the Northern Manhattan Stroke Study, the benefits of leisure-time physical activity were noted for all age, sex, and race/ethnic subgroups.112 (Figure 2.2)
The optimal amount of exercise needed to prevent stroke is unclear, particularly for the elderly. Among subjects in a case control study West Birmingham, United Kingdom, who were free of cardiovascular disease, recent vigorous exercise was no more protective than walking.113 Among the older cohort of the Framingham Study, the strongest protection was detected in the medium tertile physical activity subgroup, with no benefit gained from additional activity.109 The protective effect of physical activity may be partly mediated through its role in controlling various risk factors such as hypertension, diabetes, and obesity. Other than control of risk factors, biological mechanisms such as increased HDL and reduced homocysteine level also may be responsible for the effect of physical activity.116,117
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FIGURE 2.2. Dose response relationship by intensity and duration of physical activity (matched by age, sex, race/ethnicity, and adjusted for HTN, DM, PVD, smoking, cardiac disease, obesity, heavy alcohol use, activities limited for medical reasons, education, and season of enrollment). |
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Physical activity is a modifiable behavior that deserves greater emphasis in stroke prevention campaigns. The 1994 Behavioral Risk Factor Surveillance Survey found that 60% of adults did not achieve the recommended amount of physical activity, and people with the lowest incomes less than 12th-grade education were more likely to be sedentary.1 Moreover, 70% to 80% of older women report levels less than the recommended amount of physical activity.118 Public health goals are to increase the percentage of people who engage in regular physical activity, and reduce the percentage of those who engage in no leisure-time physical activity, particularly among people aged 65 and older.119 Leisure-time physical activity could translate into a cost-effective means of decreasing the public health burden of stroke and other cardiovascular diseases among the rapidly aging population.32
Dietary Factors
While data have suggested that diet may play an important role as a stroke risk factor, few studies have been able to clarify this relationship because of the complex issues associated with dietary intake and nutritional status (Table 2.4). Early, large ecological studies suggested that excess fat intake associated with migration may lead to increased risk of both coronary heart disease and stroke.120 High daily dietary intake of fat is associated with obesity and may act as an independent
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risk factor or may affect other stroke risk factors, such as hypertension, diabetes, hyperlipidemia, and cardiac disease. Results from the Framingham Study, however, suggested conflicting findings, with an inverse association between dietary fat and ischemic stroke.121 Dietary sodium may also be associated with increased stroke risk. Specifically, increased sodium intake is involved with an increased risk of hypertension.122
TABLE 2.4. Dietary Factors Possibly Related to the Risk of Stroke | ||||||||||||||||||||||||||||||
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Another important dietary component is homocysteine. Case control studies have demonstrated an association between moderately elevated homocysteine and vascular disease, including stroke.123,124 Genetic and environmental causes of increased serum homocysteine have been implicated as a modifiable determinant of cardiovascular and cerebrovascular events.125-126 The Framingham Study found that deficiencies in folate, B-12 levels, and pyridoxine accounted for the majority of elevated homocysteine levels in the study cohort.127 Additionally, evidence from case control studies has suggested that increased dietary and supplemental intake of vitamin B-6 may decrease stroke risk.128 Large studies, such as the Vitamin in Stroke Protection Trial (VISP), are currently investigating the protective effects of vitamin B-6, B-12, and folate for recurrent stroke.
Dietary intake of fruits and vegetables may reduce the risk of stroke. These foods may contribute to stroke protection through antioxidant mechanisms or
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through elevation of potassium levels.129,130,131,132 Dietary antioxidants, including vitamin C, vitamin E, and beta-carotene, belong to a group of antioxidants called flavonoids that are found in fruits and vegetables. These scavengers of free radicals are thought to be associated with stroke risk reduction through the freeradical oxidation of LDL, which inhibits the formation atherosclerotic plaques.133 The large Western Electric cohort found a moderate decrease in stroke risk associated with a higher intake of both beta-carotene and vitamin C.134 Other dietary factors associated with a reduced risk of stroke include milk and calcium135 and fish oils.136,137
Extracranial Carotid Stenosis
Carotid stenosis has long been recognized as an important predictor of both TIA's and stroke. The occurrence of symptoms may be dependent on the severity and progression of the stenosis, the adequacy collateral circulation, character of the atherosclerotic plaque, and the propensity to form thrombus at the site of the stenosis. In the case of patients with symptomatic disease, the two-year risk of stroke is quite high, approaching 26% among medically treated patients with TIA or minor stroke and an ipsilateral carotid stenosis of >70%.138 For those with asymptomatic carotid artery disease, the annual stroke risk is lower and reported to be 1.3% in those with stenosis of 75% or less, and 3.3% with stenosis of more than 75%, with an ipsilateral stroke risk of 2.5%.139,140 The combined TIA and stroke risk was 10.5% per year in those with more than 75% carotid stenosis. The prevalence of asymptomatic carotid disease increases with age, occurring in 53.6% of subjects 65 to 94 years age.141
The efficacy of carotid endarterectomy in asymptomatic carotid stenosis has been evaluated in a few clinical trials, including the Asymptomatic Carotid Artery Surgery Study (ACAS).142 Patients eligible for ACAS were under age 80 with asymptomatic carotid stenosis greater than 60% and could not have any unstable cardiac disease. Overall, the 30-day ipsilateral stroke or death rate among surgically treated patients was only 2.3%. The trial found a five-year ipsilateral stroke risk of 10.5% among the medical group and 4.8% in the surgical group. There was a 55% risk reduction of ipsilateral stroke associated with carotid endarterectomy. The benefit for men was greater than women (risk reduction 69% vs. 16%). Given the right circumstances based on the degree of stenosis, other co-morbid conditions, and the expertise of the surgeon, endarterectomy may be beneficial in certain asymptomatic persons.
Transient Ischemic Attacks
TIAs are a strong predictor of subsequent stroke, with annual stroke risks of 1% to 15%. The first year following a TIA is associated with the greatest stroke risk.
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In hospital-referred patients, the average annual risk of stroke, myocardial infarction, or death was 7.5% after TIA.143 Amaurosis fugax, transient monocular blindness (TMB), had a better outcome than cerebral ischemic attacks, and stroke usually occurred in the same vascular territory as initial TIA. Recommendations for the treatment of TIA include identification the underlying etiology of the TIA, targeted risk factor prevention strategies, and the use of antithrombotic medications.144,145,146
Other Potential Stroke Risk Factors
Other potential stroke risk factors have been identified in some studies, but need confirmation and clarification through further epidemiologic investigations (Table 2.5).
New technology for the detection of polymorphisms has opened the field genetic risk factors for stroke. Included among the potential genetic markers lipids are lipoprotein apo E. Hematologic testing has also suggested that various markers of hypercoagulable states may be independent stroke risk factors, such as antiphospholipid antibodies, lupus anticoagulant, factor V Leiden, free protein S and protein C deficiencies. Other risk factors, such as the use of oral
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contraceptives and hormone replacement, are being investigated in large prospective studies. Finally, the interaction of these potential factors with known stroke risk factors needs to be investigated.
TABLE 2.5. Other Potential Stroke Risk Factors Under Further Epidemiologic Investigations | |
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Conclusion
The Prevention of First Stroke Guidelines outlines evidence that can be used by clinicians for the prevention of first stroke.32 These guidelines state that preventing persons from having first stroke will require a comprehensive multidisciplinary strategy to identify and manage major risk factors to promote adherence to preventive protocols. Based on the estimated prevalence of risk factors and their attributable risks for stroke in the United States, it is estimated that a significant percentage of strokes could be prevented through the control these modifiable stroke risk factors.147 Despite the wealth of data on the importance of stroke risk factors, control these conditions remains inadequate due to poor patient compliance and adherence to behavior modifications as well decreased detection and treatment by health care providers. Further reductions in the risk of stroke will require enhancements in our ability to detect, modify, and treat persons with risk factors.
References
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