doi: 10.1161/01.STR.0000223048.70103.F1
(Circulation. 2006;113:e873-e923.)
© 2006 American Heart Association, Inc.
AHA/ASA Guideline |
Primary Prevention of Ischemic Stroke
A Guideline From the American Heart Association/American Stroke Association Stroke Council: Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline.
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Abstract |
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 Top Abstract IntroductionAssessing the Risk of...Nonmodifiable Risk FactorsWell-Documented and Modifiable...Less Well-Documented or...Summary of RecommendationsReferences |
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Background and Purpose— This guideline provides an overview of the evidence on various established and potential stroke risk factors and provides recommendations for the reduction of stroke risk.
Methods— Writing group members were nominated by the committee chair on the basis of each writer’s previous work in relevant topic areas and were approved by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee. The writers used systematic literature reviews (covering the time period since the last review published in 2001 up to January 2005), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations based on standard American Heart Association criteria. All members of the writing group had numerous opportunities to comment in writing on the recommendations and approved the final version of this document. The guideline underwent extensive peer review before consideration and approval by the AHA Science Advisory and Coordinating Committee.
Results— Schemes for assessing a person’s risk of a first stroke were evaluated. Risk factors or risk markers for a first stroke were classified according to their potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented or less well documented). Nonmodifiable risk factors include age, sex, low birth weight, race/ethnicity, and genetic factors. Well-documented and modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, atrial fibrillation and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, alcohol abuse, drug abuse, oral contraceptive use, sleep-disordered breathing, migraine headache, hyperhomocysteinemia, elevated lipoprotein(a), elevated lipoprotein-associated phospholipase, hypercoagulability, inflammation, and infection. Data on the use of aspirin for primary stroke prevention are reviewed.
Conclusion— Extensive evidence is available identifying a variety of specific factors that increase the risk of a first stroke and providing strategies for reducing that risk.
Key Words: AHA Scientific Statements • stroke • risk factors • primary prevention
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Introduction |
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TopAbstractIntroductionAssessing the Risk of...Nonmodifiable Risk FactorsWell-Documented and Modifiable...Less Well-Documented or...Summary of RecommendationsReferences |
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Stroke remains a major healthcare problem. Its human and economic toll is staggering. It is estimated that there are >700 000 incident strokes in the United States each year, resulting in >160 000 deaths annually, with 4.8 million stroke survivors alive today.1 Although there was a 60% decline in stroke mortality over the 29-year period between 1968 and 1996, the rate of decline began to slow in the 1990s and has plateaued in several regions of the country.2 Despite an overall 3.4% fall in per capita stroke-related mortality between 1991 and 2001, the actual number of stroke deaths rose by 7.7%.1 Stroke ranks as the country’s third leading cause of death.1 Stroke incidence may be increasing.3 From 1988 to 1997, the age-adjusted stroke hospitalization rate grew 18.6% (from 560 to 664 per 100 000), while total stroke hospitalizations increased 38.6% (from 592 811 to 821 760 annually).4 In 2004, the cost of stroke was estimated at $53.6 billion (direct and indirect costs), with a mean lifetime cost estimated at $140 048.1
Stroke is also a leading cause of functional impairments, with 20% of survivors requiring institutional care after 3 months and 15% to 30% being permanently disabled.1 Stroke is a life-changing event that affects not only the person who may be disabled, but the entire family and other caregivers as well. Utility analyses show that a major stroke is viewed by more than half of those at risk as being worse than death.5 Despite the advent of treatment of selected patients with acute ischemic stroke with intravenous tissue-type plasminogen activator and the promise of other acute therapies, effective prevention remains the best treatment for reducing the burden of stroke.6–8 Primary prevention is particularly important because >70% of strokes are first events.1 The age-specific incidence of major stroke in Oxfordshire, UK, has fallen by 40% over the past 20 years in association with an increased use of preventive treatments and general reductions in risk factors.9 As discussed in the sections that follow, high-risk or stroke-prone individuals can now be identified and targeted for specific interventions.
This guideline provides an overview of the evidence on various established and potential stroke risk factors and represents a complete revision of the last statement on this topic (published in 2001).10 This guideline largely focuses on an individual patient–oriented approach to stroke prevention. This is in contrast to a population-based approach in which "... the entire distribution of risk factors in the population is shifted to lower levels through population-wide interventions," which is reflected in the AHA Guide for Improving Cardiovascular Health at the Community Level.11
The writing group consisted of experts with special interests in primary prevention representing disciplines including several medicial specialties, epidemiology, and the neurosciences. Writing group members were nominated by the committee chair on the basis of each individual’s previous work in relevant topic areas and were approved by the American Heart Association Stroke Council’s Scientific Statement Oversight Committee. The writers used systematic literature reviews (covering the time period since the last review published in 2001 up to January 2005), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and when appropriate, formulate recommendations based on standard American Heart Association criteria (Table 1, Figure). Because of the diverse nature of the topics, it was not possible to provide a systematic, uniform summary of the magnitude of the effect associated with each of the recommendations. Patient preferences need to be considered, as with all recommendations. All members of the writing group had numerous opportunities to comment in writing on the recommendations and approved the final version of this document. The guideline underwent extensive peer review before consideration and approval by the AHA Science Advisory and Coordinating Committee.
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As given in Tables 2, 3, and 4
, risk factors or risk markers for a first stroke were classified according to their potential for modification (nonmodifiable, modifiable, or potentially modifiable) and strength of evidence (well documented, less well documented).7 Although this classification system is somewhat subjective, well-documented and 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 (Table 4) were those with either less clear epidemio-logical evidence or without evidence from randomized trials demonstrating a reduction of stroke risk with modification. The tables give the estimated prevalence, population-attributable risk (ie, the proportion of ischemic stroke in the population that can be attributed to a particular risk factor, given by the formula 100*{[Prevalence (Relative Risk–1)] / [Prevalence (Relative Risk–1)+1]}),12 relative risk, and risk reduction with treatment for each factor when known. Gaps in current knowledge are indicated by question marks in the tables. It should also be noted that precise estimates of attributable risk for factors such as hormone replacement therapy are not available because of variation in the estimates of risk and changes in prevalence. Other tables summarize guideline or consensus statement management recommendations as available. Other recommendations are indicated in the text and tables.
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Assessing the Risk of a First Stroke |
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TopAbstractIntroductionAssessing the Risk of...Nonmodifiable Risk FactorsWell-Documented and Modifiable...Less Well-Documented or...Summary of RecommendationsReferences |
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It is helpful for healthcare providers and the public to be able to estimate a person’s risk for a first stroke. As detailed in the sections that follow, numerous factors can contribute to a person’s stroke risk, and many individuals have >1 risk factor. Some of these risk factors are relatively less well documented, and specific or proven treatments may be lacking. Although most risk factors have an independent effect, there may be important interactions between individual factors that need to be considered in predicting overall risk or choosing an appropriate risk modification program. Risk-assessment tools have been used in community stroke screening programs and utilized in some guideline statements to select certain treatments for primary stroke prevention.13,14 Some of the goals of such risk-assessment tools are (1) to identify persons at elevated risk who might be unaware of their risk; (2) to assess risk in the presence of >1 condition; (3) to measure an individual’s risk that can be tracked and lowered by appropriate modifications; (4) to estimate a quantitative risk for selecting treatments or stratification in clinical trials; and (5) to guide appropriate use of further diagnostic testing.
Although stroke risk–assessment tools exist, the complexities of the interactions of risk factors and the effects of certain risk factors stratified by age, gender, race-ethnicity, and geography are incompletely captured by any available global risk-assessment tool. In addition, these tools tend to be focused and generally do not include the full range of possible contributing factors. Some risk-assessment tools are gender specific and give 1-, 5-, or 10-year stroke risk estimates. The Framingham Stroke Profile (FSP) uses a Cox proportional-hazards model with risk factors as covariates and points calculated according to the weight of the model coefficients.15 Independent stroke predictors include age, systolic blood pressure, hypertension, diabetes mellitus, current smoking, established cardiovascular disease (any one of myocardial infarction [MI], angina or coronary insufficiency, congestive heart failure, or intermittent claudication), atrial fibrillation, and left ventricular (LV) hypertrophy on ECG. Point values can be calculated that correspond to a gender-specific 10-year cumulative stroke risk. The FSP has been updated to account for the use of antihypertensive therapy and the risk of stroke and stroke or death among individuals with new-onset atrial fibrillation (Table 5).16,17 Despite its widespread use, the validity of the FSP among individuals of a different age range or belonging to racial-ethnic groups other than those in the Framingham cohort has not been adequately studied. The FSP has been applied to ethnic minorities in the United Kingdom and found to vary across groups, but the suitability of the scale to predict outcomes has not been well tested.18
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Alternative prediction models have been developed using other cohorts and utilizing different sets of stroke risk factors. Retaining most of the Framingham covariates, one alternative stroke risk scoring system omits cigarette smoking and antihypertensive medication but adds "time to walk 15 feet" and serum creatinine.19 Another score is derived from a mixed cohort of stroke and stroke-free patients and includes prior history of stroke, marital status, blood pressure as a categorical variable, high-density lipoprotein (HDL) cholesterol, impaired expiratory flow, physical disability, and a depression score.20 Several studies have generated risk-assessment tools for use in subjects with atrial fibrillation (see below).
Summary and Gaps
It is clear that an ideal stroke risk–assessment tool that is generally applicable, simple, and widely accepted does not exist. Each available tool has its own limitations. The impact of newer risk factors for stroke, not collected in older studies, needs to be considered.21 Risk-assessment tools should be used with care, as they do not include all the factors that contribute to future disease risk.22 The utility of the FSP (Table 5
) or other stroke risk–assessment scales as a way of improving the effectiveness of primary stroke prevention programs is not well studied. Research is needed to validate risk-assessment tools across age, gender, and racial-ethnic groups; evaluate whether any of the more recently identified risk factors add to the predictive accuracy of existing scales; and determine whether the use of these scales improves primary stroke prevention programs.
Recommendation
Each patient should have an assessment of his or her stroke risk (Class I, Level of Evidence A). The use of a risk-assessment tool such as the FSP should be considered as these tools can help identify individuals who could benefit from therapeutic interventions and who may not be treated on the basis of any 1 risk factor (Class IIa, Level of Evidence B).
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Nonmodifiable Risk Factors |
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Although these factors are not modifiable, they identify those who are at highest risk of stroke and who may benefit from rigorous prevention or treatment of modifiable risk factors (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 for each successive decade after age 55 years.3,23
Sex
Stroke is more prevalent in men than in women.3 Men also generally have higher age-specific stroke incidence rates than do women (based on age-specific rates calculated from strata defined by race/ethnicity).24 Exceptions are in 35- to 44-year-olds and in those >85 years of age—groups in which women have slightly greater age-specific stroke incidence than do men.24 Factors such as oral contraceptive (OC) use and pregnancy contribute to the increased risk of stroke in young women,25–27 and the earlier cardiac-related deaths of men with cardiovascular disease may contribute to the relatively greater risk of stroke in older women. Women accounted for 61.5% of US stroke deaths in 2002 (100 500 deaths among women were attributed to stroke versus 62 662 among men).1 Overall, 1 in 6 women die of stroke as compared with 1 in 25 who die of breast cancer.28 In 2002, age-adjusted stroke mortality rates were 53.4/100 000 among white women and 71.8/100 000 among black women, versus rates of 54.2 and 81.7/100 000 among white and black men, respectively.1
Low Birth Weight
Stroke mortality rates among adults in England and Wales are higher among persons who had lower birth weights.29 A similar study compared a group of South Carolina Medicaid beneficiaries <50 years of age who had stroke to population controls.30 The odds of stroke were more than double for those with birth weights <2500 g as compared with those weighing 
4000 g (with a significant linear trend for intermediate birth weights). Regional differences in birth weight may partially underlie geographic differences in stroke-related mortality. However, the reason for this relationship remains uncertain, and statistical association does not prove causality.
Race-Ethnicity
Racial and ethnic effects on disease risk can be difficult to consider separately. African Americans24,31 and some Hispanic Americans32,33 have higher stroke incidence and mortality rates as compared with European Americans. In the Atherosclerosis Risk In Communities (ARIC) Study, blacks had an incidence of stroke 38% higher than that of whites.34 Possible reasons for the higher incidence and mortality rate of strokes in blacks include a higher prevalence of hypertension, obesity, and diabetes within the black population.35,36 However, a higher incidence of these risk factors does not explain all of the excess risk.35 Epidemiological studies have shown an increase in stroke incidence among self-identified Hispanic racial-ethnic populations.24,37,38 Incidence rates are also relatively higher among some Asian groups.39
Genetic Factors
Both paternal and maternal history of stroke have been associated with an increased stroke risk.40,41 This increased risk could be mediated through a variety of mechanisms, including (1) genetic heritability of stroke risk factors, (2) the inheritance of susceptibility to the effects of such risk factors, (3) familial sharing of cultural/environmental and lifestyle factors, and (4) the interaction between genetic and environmental factors.42 Twin studies provide strong data suggesting familial inheritance of stroke risk. Concordance rates for stroke are markedly higher in monozygotic than in dizygotic twins,43 with a nearly 5-fold increase in stroke prevalence among monozygotic as compared with dizygotic twins.44
Genetic influences on stroke risk can be considered on the basis of individual risk factors, the genetics of common stroke types, and uncommon or rare familial stroke types. Many of the established and emerging risk factors that are described in the sections that follow, such as hypertension, diabetes, and hyperlipidemia, have both genetic and environmental/behavioral components.43,45,46 In some cases, elevations of blood homocysteine are due to 1 or more mutations in the methylene-tetrahydrofolate reductase gene.47–49 Many coagulopathies are inherited as autosomal dominant traits.50 These disorders, including protein C and S deficiencies, factor V Leiden mutations, and various other factor deficiencies, can lead to an increased risk of venous thrombosis.51–56 However, as discussed below, there has not been a strong association between several of these disorders and arterial events, such as MI and stroke.52,57,58 Some apparently acquired coagulopathies, such as the presence of a lupus anticoagulant or anticardiolipin antibody, can be familial in &10% of cases.59,60 Inherited disorders of various clotting factors (ie, factors V, VII, X, XI, and XIII) are autosomal recessive traits and can lead to cerebral hemorrhage in childhood or the neonatal period.50 Arterial dissections, moyamoya syndrome, and fibromuscular dysplasia have a genetic or familial component in 10% to 20% of cases.61,62
The DeCode genetics group (Iceland) has reported genetic linkage of phosphodiesterase 4D (chromosome 5q12) and 5-lipoxygenase activating protein (chromosome 13q12-13) to common forms of ischemic stroke.63,64 In both cases, there appears to be an association between several specific genetic haplotypes and stroke, although no pathogenic mutations have been identified.
Several rare genetic disorders have been associated with stroke. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by subcortical infarcts, dementia, and migraine headaches.65 CADASIL can be caused by any of a series of mutations in the Notch3 gene.65,66 Acetazolamide may reduce migraine headaches in patients with CADASIL67 (Class IIb, Level of Evidence C). Marfan syndrome (due to mutations in the fibrillin gene) and neurofibromatosis types I and II are associated with an increased risk of ischemic stroke. Gene-transfer therapy has been attempted to correct the genetic defect.68 Fabry disease is a rare inherited disorder that can lead to ischemic stroke. It is caused by lysosomal 
-galactosidase A deficiency, which causes the progressive accumulation of globotriaosylceramide and related glycosphingolipids.69 Deposition affects mostly small vessels in the brain and other organs, although involvement of the larger vessels has been reported. Two prospective randomized studies using human recombinant lysosomal -galactosidase A found a significant reduction in microvascular deposits as well as reduced plasma levels of globotriaosylceramide (Class I, Level of Evidence A).70–72 These studies had short follow-up periods, and no effects on stroke rates were found. Enzyme replacement therapy also appears to improve cerebral vessel function.73
Summary and Gaps
Genetic factors could arguably be classified as potentially modifiable, but because specific gene therapy is not presently available, these have been placed in the "nonmodifiable" section. It should be recognized that treatments are available for some of the factors that have a genetic predisposition or cause (such as Fabry disease), and as described in the sections that follow.
Recommendations
Referral for genetic counseling may be considered for patients with rare genetic causes of stroke (Class IIb, Level of Evidence C). There remain insufficient data to recommend genetic screening for the prevention of a first stroke.
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Well-Documented and Modifiable Risk Factors |
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TopAbstractIntroductionAssessing the Risk of...Nonmodifiable Risk FactorsWell-Documented and Modifiable...Less Well-Documented or...Summary of RecommendationsReferences |
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There are several well-documented risk factors for first ischemic stroke with clear data showing a reduction in stroke risk with treatment. An important risk factor for a first stroke that is not adequately reflected in the organizational scheme used in this guideline is the presence of atherosclerotic vascular disease in another vascular bed. Those with a history of cardiovascular disease (coronary heart disease, cardiac failure, or symptomatic peripheral arterial disease) have a significant increased risk of a first stroke as compared with those without such a history, after adjustment for other risk factors (relative risk [RR]=1.73, 95% confidence interval [CI] 1.68 to 1.78 for men; RR=1.55, 95% CI 1.17 to 2.07 for women; adjusted for age, blood pressure, LV hypertrophy, cigarette smoking, atrial fibrillation, and diabetes).16 Treatments used in the management of these other conditions (eg, platelet antiaggregants) may also reduce the risk of stroke. The risk factors for first stroke and the risk factors for cardiovascular disease overlap. The impact of management of these common risk factors is reviewed in the context of their specific impact on stroke throughout this statement but should also be considered in the context of global reduction of vascular disease.
Recommendations
Persons with evidence of noncerebrovascular atherosclerotic vascular disease (coronary heart disease, cardiac failure, or symptomatic peripheral arterial disease) are at increased risk for a first stroke. Treatments used in the management of these other conditions (eg, platelet antiaggregants) and as recommended in other sections of this guideline can reduce the risk of stroke (Class and Level of Evidence as indicated in the relevant sections).
Hypertension
Hypertension (Table 3) affects at least 65 million persons in the United States and is a major risk factor for both cerebral infarction and intracerebral hemorrhage.74,75 The relationship between blood pressure and cardiovascular risk is "continuous, consistent, and independent of other risk factors."76 The higher the blood pressure, the greater the stroke risk.77 Blood pressure, particularly systolic blood pressure, increases with increasing age.78 The Framingham Study found that individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension.79 More than two thirds of persons >65 years of age are hypertensive.76
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.76 A meta-analysis of 18 long-term randomized trials found that both ß-blocker therapy (RR=0.71; 95% CI 0.59 to 0.86) and treatment with diuretics (RR=0.49; 95% CI 0.39 to 0.62) were effective in preventing stroke.80 Overall, antihypertensive therapy is associated with a 35% to 44% reduction in the incidence of stroke.81 In at least 1 study, there was no significant difference in the rates of stroke among groups of hypertensive persons (mean diastolic blood pressures between 100 and 115 mm Hg) who achieved mean diastolic blood pressures of 85.2, 83.2, or 81.1 mm Hg.82 Recent national guidelines recommend lowering blood pressure to <140/90 mm Hg (with lower targets in some subgroups, such as individuals with diabetes; see section on diabetes), and ongoing trials are exploring optimal lower general targets.76
Several categories of antihypertensive agents, including thiazide diuretics, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), ß-adrenergic receptor blockers, and calcium channel blockers, reduce cardiovascular risk, including the risk of stroke, in patients with hypertension.81,83–86 Blood pressure control can be achieved in most patients, but the majority require combination therapy with 2 antihypertensive agents.87,88 Direct comparisons among the various types of antihypertensives are limited. At least 1 study compared the effects of an angiotensin II type 1 receptor blocker with a ß-adrenergic receptor blocker in 9193 persons with essential hypertension (160 to 200/95 to 115 mm Hg) and electrocardiographically determined LV hypertrophy over 4 years.85 Blood pressure reductions were similar for each group. There was a 13% (RR=0.87; 95% CI 0.77 to 0.98) reduction in MI, stroke, or death among the ARB-treated patients as compared with those given a ß-adrenergic receptor blocker, which included a 25% (RR=0.75; 95% CI 0.63 to 0.89) reduction in fatal or nonfatal stroke. It remains unsettled whether specific classes of antihypertensive agents offer special protection against stroke in addition to their blood pressure–lowering effects in other settings.
Controlling isolated systolic hypertension (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg) in the elderly is also important. The Systolic Hypertension in Europe (Syst-Eur) Trial randomized 4695 patients with isolated systolic hypertension to active treatment with a calcium channel blocker or placebo and showed a 42% risk reduction in the actively treated group.89 The Systolic Hypertension in the Elderly Program (SHEP) Trial found a 36% reduction in the incidence of stroke with treatment with a thiazide diuretic with or without a ß-blocker.90
Despite the efficacy of antihypertensive therapy and the ease of diagnosis and monitoring, a significant proportion of the population has undiagnosed or inadequately treated hypertension.91 Only 70% of Americans with hypertension are aware that they have the condition; 60% are being treated and 34% are controlled (<140/90 mm Hg).76 Lack of diagnosis and inadequate treatment are particularly evident in minority populations and in the elderly.76,92 Because the risk of stroke increases progressively with increasing blood pressure and because a substantial number of individuals have a blood pressure level below current drug treatment thresholds, nondrug or lifestyle approaches have been recommended as a means to reduce the risk of stroke in nonhypertensive individuals.93
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) provides a comprehensive, evidence-based approach to the classification and treatment of hypertension.76 Although somewhat controversial, this recent revision classifies blood pressure into 4 groupings (Table 6). Treatment recommendations are based on this revised classification scheme (Table 6).
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Summary and Gaps
The benefit of hypertension treatment for primary prevention of stroke is clear. Choice of a specific regimen must be individualized, but reduction in blood pressure is generally more important than the specific agent used to achieve this goal. Hypertension remains undertreated in the community, and programs to improve treatment compliance need to be developed and supported.
Recommendations
Regular screening for hypertension (at least every 2 years in most adults and more frequently in minority populations and the elderly) and appropriate management (Class I, Level of Evidence A), including dietary changes, lifestyle modification, and pharmacological therapy as summarized in JNC 7,76 are recommended (Table 6).
Cigarette Smoke
Virtually every multivariable assessment of stroke risk factors (eg, Framingham,15 Cardiovascular Health Study,94 and the Honolulu Heart Study95) has identified cigarette smoking as a potent risk factor for ischemic stroke (Table 3), associated with an approximate doubling of ischemic stroke risk (after adjustment for other risk factors). In addition, smoking has been clearly associated with a 2- to 4-fold increased risk for hemorrhagic stroke.96,97 A meta-analysis of 32 studies estimated the RR for ischemic stroke to be 1.9 (95% CI 1.7 to 2.2) for smokers versus nonsmokers and the RR for subarachnoid hemorrhage to be 2.9 (95% CI 2.5 to 3.5).98 The annual number of stroke deaths attributed to smoking in the United States has been estimated to be between 21 400 (without adjustment for potential confounding factors) and 17 800 (with adjustments), which suggests that smoking contributes to 12% to 14% of all stroke deaths.99 In 1989, these and other studies led the US Surgeon General to conclude that a definite relationship exists between smoking and both ischemic and hemorrhagic stroke, particularly at young ages.100,101
Cigarette smoking may also potentiate the effects of other stroke risk factors. For example, a synergistic effect exists between the use of OCs and smoking on the risk of cerebral infarction. With nonsmoking, non–OC-using women used as the reference group, the odds of cerebral infarction were 1.3 times greater (95% CI 0.7 to 2.1) for women who smoked but did not use OC, 2.1 times greater (95% CI 1.0 to 4.5) for nonsmoking OC users, but 7.2 times greater (95% CI 3.2 to 16.1) for OC users who smoked (note that the "expected" odds ratio [OR] in the absence of interaction for the smoking OC users would be &2.7).102 There was also a synergistic impact of smoking and OC use on hemorrhagic stroke risk. With nonsmoking, non–OC-using women used as the reference group, the odds of hemorrhagic stroke were 1.6 times greater (95% CI 1.2 to 2.0) for women who smoked but did not use OC, 1.5 times greater (95% CI 1.1 to 2.1) for nonsmoking OC users, but 3.7 times greater (95% CI 2.4 to 5.7) for OC users who smoked (note that the "expected" OR in the absence of interaction for the smoking OC users would be &2.4).103
There is growing acceptance that exposure to environmental tobacco smoke (passive cigarette smoke) is a risk factor for heart disease.104 Several studies suggest that environmental tobacco smoke is also a substantial risk factor for stroke, with a risk approaching the doubling found for active smoking.105,106 Because the dose of exposure to environmental tobacco smoke is substantially lower than for active smoking, the magnitude of the risk associated with environmental tobacco smoke seems surprising. This lack of an apparent dose–response relationship between the level of exposure and risk may in part be explained by physiological studies suggesting that there is a tobacco smoke exposure "threshold" rather than a linear dose–effect relationship.107
Smoking likely contributes to increased stroke risk through both acute effects on the risk of thrombus generation in narrowed arteries and chronic effects related to an increased burden of atherosclerosis.108 Smoking as little as a single cigarette increases heart rate, mean blood pressure, and cardiac index and decreases arterial distensibility.109,110 In addition to the immediate effects of smoking, both active and passive cigarette smoke are associated with the development of atherosclerosis.111 In addition to placing individuals at increased risk for both thrombotic and embolic stroke, cigarette smoking approximately triples the risk of cryptogenic stroke among individuals with low atherosclerotic burdens and no evidence of cardiac sources of emboli.112
Although the most effective preventive measures are to never smoke and to minimize exposure to environmental tobacco smoke, risk is reduced with smoking cessation. Smoking cessation is associated with a rapid reduction in the risk of stroke and other cardiovascular events to a level that approaches but does not reach that of those who never smoked.108,113,114
Sustained smoking cessation is difficult to achieve. However, effective behavioral and pharmacological treatments for nicotine dependence now exist.115,116 A combination of nicotine replacement therapy, social support, and skills training provides an effective approach for quitting.117 A comprehensive review of the public health impact of smoking is provided in the 2004 Surgeon General’s report.118
Summary and Gaps
Cigarette smoking is clearly associated with the risk of stroke. Epidemiological studies show a reduction in risk with smoking cessation over time. Although effective programs to facilitate smoking cessation exist, data showing that participation in these programs leads to a reduction in stroke are lacking.
Recommendations
Abstention from cigarette smoking and (for current smokers) smoking cessation are recommended (Table 7) (Class I, Level of Evidence B). Data from cohort and epidemiological studies are consistent and overwhelming. Avoidance of environmental tobacco smoke for stroke prevention should also be considered (Class IIa, Level of Evidence C). The use of counseling, nicotine replacement, and oral smoking-cessation medications has been found to be effective for smokers and should be considered (Class IIa, Level of Evidence B).
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Diabetes
Persons with type 2 diabetes have both an increased susceptibility to atherosclerosis and an increased prevalence of atherogenic risk factors, notably hypertension, obesity, and abnormal blood lipids. Since 1990, the prevalence of those diagnosed with diabetes rose 61%, with an increase of 8.2% from 2000 to 2001.1 In 2001, 11.1 million Americans had physician-diagnosed diabetes, and an estimated additional 5.1 million had undiagnosed disease.1
Case-control studies of stroke patients and prospective epidemiological studies have confirmed an independent effect of diabetes on ischemic stroke, with an increased RR in persons with diabetes ranging from 1.8-fold to nearly 6-fold (Table 3).119 Among Hawaiian Japanese men in the Honolulu Heart Program, those with diabetes had twice the risk of thromboembolic stroke as compared with those who did not have diabetes—an increase in risk that was independent of other factors.120 In the Framingham Heart Study, although the impact of diabetes was greatest on peripheral arterial disease with intermittent claudication, where the RR was increased 4-fold, coronary and cerebral artery territories were also affected.121 The impact of diabetes was greater in women than in men, reaching significance as an independent contributor in older women.121 In 2000, 1.1 million persons 35 years of age with diabetes reported being diagnosed with a stroke.1
Stroke risk can be reduced in patients with diabetes. A small randomized trial of multifactorial intensive interventions in patients with type 2 diabetes and microalbuminuria targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria with interventions including behavioral risk factor modification and the use of a statin, ACEI, ARB, or an antiplatelet drug as appropriate.122 After a mean of 7.8 years, the risk of cardiovascular events was reduced by nearly 50% (adjusted hazard ratio [HR]=0.47; 95% CI 0.22 to 0.74; P=0.01) with intensive treatment versus conventional therapy. First events included 3 nonfatal strokes, 4 nonfatal MIs, and 3 cardiovascular deaths in the 80 patients in the intensive arm versus 11 nonfatal strokes, 8 nonfatal MIs, and 1 cardiovascular death in the 80 patients in the control arm.
The combination of hyperglycemia and hypertension has long been believed to increase the frequency of diabetic complications, including stroke. Several trials have compared the effect on stroke and other cardiovascular outcomes of tight control of blood glucose and blood pressure in type 2 diabetic patients versus less stringent management. For example, the UK Prospective Diabetes Study Group found that for combined fatal and nonfatal stroke, tight blood pressure control (mean blood pressure achieved 144/82 mm Hg) resulted in a 44% RR reduction as compared with more liberal control (mean blood pressure achieved 154/87 mm Hg).123 There was also a 20% risk reduction with antihypertensive treatment in diabetic subjects in the Systolic Hypertension in the Elderly Program.124 Although tight control of hypertension in diabetic individuals significantly reduces stroke incidence,125 improved glycemic control did not produce a significant reduction in stroke over 9 years of follow-up (although the use of oral hypoglycemic drugs, potentially working through other mechanisms, may reduce stroke risk).123 Nevertheless, intensive therapy to achieve tight control of hyperglycemia in patients with recent-onset insulin-dependent (type 1) diabetes mellitus was shown to reduce microvascular complications of the disease, such as nephropathy, retinopathy, and peripheral neuropathy.126
The Heart Outcomes Prevention Evaluation (HOPE) Study compared the addition of an ACEI to 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 MI, stroke, and cardiovascular death by 25% (95% CI 12 to 36; P=0.0004) and stroke by 33% (95% CI 10 to 50; P=0.0074) among diabetic patients with a previous cardiovascular event or an additional cardiovascular risk factor.127 Whether these benefits were a specific effect of the ACEI or were an effect of blood pressure lowering has been the subject of debate. Diabetic complications (overt nephropathy, dialysis, or need for laser therapy) were also reduced. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study compared the effects of an angiotensin II type 1 receptor blocker with a ß-adrenergic receptor blocker in 9193 persons with essential hypertension (160 to 200/95 to 115 mm Hg) and electrocardiographically determined LV hypertrophy over 4 years.85 Blood pressure reductions were similar for each group. The 2 regimens were compared among the subgroup of 1195 persons who also had diabetes in a prespecified analysis.128 There was a 24% reduction (RR=0.76; 95% CI 0.58 to 0.98) in major vascular events and a nonsignificant 21% reduction (RR=0.79; 95% CI 0.55 to 1.14) in stroke among those treated with the ARB.
Although secondary subgroup analyses of some studies did not find a benefit of statins in diabetic subjects,129,130 the Medical Research Council/British Heart Foundation Heart Protection Study (HPS) found that the addition of a statin to existing treatments in high-risk patients resulted in a 24% reduction (95% CI 19% to 28%) in the rate of major vascular events.131 A 22% reduction (95% CI 13% to 30%) in major vascular events (regardless of the presence of known coronary heart disease or cholesterol levels) and a 24% reduction (95% CI 6% to 39%; P=0.01) in strokes occurred among 5963 diabetic individuals treated with the statin in addition to best medical care.132 The Collaborative Atorvastatin Diabetes Study (CARDS) reported that in type 2 diabetic subjects with at least 1 additional risk factor (retinopathy, albuminuria, current smoking, or hypertension) and a low-density lipoprotein (LDL) cholesterol level <160 mg/dL but without a prior history of cardiovascular disease, treatment with a statin resulted in a 48% reduction (95% CI 11% to 69%) in stroke.133
Summary and Gaps
A comprehensive program that includes tight control of hypertension with ACEI or ARB treatment reduces the risk of stroke in persons with diabetes. Glycemic control reduces microvascular complications, but evidence showing a reduction in stroke risk with tight glycemic control is lacking. Adequately powered studies show that treatment of diabetic patients with a statin decreases their risk of a first stroke.
Recommendations
It is recommended that hypertension be tightly controlled in patients with either type 1 or type 2 diabetes (the JNC 7 recommendation of <130/80 mm Hg in diabetic patients is endorsed) as part of a comprehensive risk-reduction program (Table 6) (Class I, Level of Evidence A). Treatment of adults with diabetes, especially those with additional risk factors, with a statin to lower the risk of a first stroke is recommended (Class I, Level of Evidence A) (Table 7).134 Recommendations to consider treatment of diabetic patients with an ACEI or ARB76,134 are endorsed (Table 7).
Atrial Fibrillation
With or without atrial fibrillation, all patients with mechanical heart valves require anticoagulation, with the target level of anticoagulation varying according to the type and position of the valve and the presence of other risk factors (Class I).135 The rate of thromboembolism in patients with mechanical heart valves is 4.4 per 100 patient-years without antithrombotic therapy, 2.2 per 100 patient-years with antiplatelet drugs, and 1 per 100 patient-years with warfarin.136 Patients with paroxysmal or persistent atrial fibrillation and valvular heart disease such as mitral stenosis are at the highest risk for future embolic events and should also be anticoagulated (Class I).135
Atrial fibrillation alone is associated with a 3- to 4-fold increased risk of stroke after adjustment for other vascular risk factors (Table 3).137 For those without prior transient ischemic attack (TIA) or stroke, 2% to 4% per year have an ischemic stroke.138,139 About 60 000 strokes occur annually among the estimated 2.3 million Americans with this cardiac dysrhythmia, with the number of atrial fibrillation–related strokes anticipated to more than double in coming decades.140
The prevalence of atrial fibrillation increases with age. Atrial fibrillation affects &5% of those 70 years of age, and the mean age of atrial fibrillation patients is 75 years.137,140 Estimates of attributable risk reveal that about one quarter of strokes in the very elderly (80 years old) are due to atrial fibrillation.137 Atrial fibrillation is also associated with increased mortality after adjustment for other vascular risk factors.141 Strokes associated with atrial fibrillation are especially large and disabling. Importantly, rhythm control does not appear to reduce stroke rates,142 and as discussed below, antithrombotic therapies remain the mainstay for stroke prevention.
Randomized clinical trials have firmly established the value of antithrombotic therapies for reducing the risk of stroke in patients with atrial fibrillation (Table 3). Risk is reduced by &60% with adjusted-dose warfarin and by &20% with aspirin.143 Adjusted-dose warfarin reduces stroke by &45% as compared with aspirin.139 Randomized trials have also been conducted comparing a direct thrombin inhibitor to high-quality adjusted-dose warfarin in persons with atrial fibrillation, but the US Food and Drug Administration has not approved its use.144,145
The absolute risk of stroke varies 20-fold among atrial fibrillation patients, according to age and associated vascular diseases. Several stroke risk–stratification schemes have been developed and validated.146–148 The 2001 American College of Cardiology (ACC)/AHA/European Society of Cardiology (ESC) guideline recommends anticoagulation for patients with atrial fibrillation who are >60 years of age and have a history of hypertension, diabetes, coronary artery disease (CAD), impaired LV systolic function, heart failure, or prior thromboembolism, and for all those with atrial fibrillation who are >75 years of age.149 However, this stratification scheme had not been prospectively validated (although the individual factors had been validated). Since publication of the 2001 ACC/AHA/ESC guideline, the so-called CHADS2 stratification scheme has been proposed and validated.146 (CHADS2 is an acronym for congestive heart failure, hypertension, age >75 years, diabetes mellitus, and prior stroke or TIA.) The CHADS2 score was derived from independent predictors of stroke risk in patients with nonvalvular atrial fibrillation (Table 8).146 The score gives 1 point each for congestive heart failure, hypertension, age 75 years, and diabetes mellitus and 2 points for prior stroke or TIA.146 The score was validated in a large cohort study and in clinical trials.138,147 Atrial fibrillation patients with low (&1%/year, CHADS2 score=0 to 1, about half of patients), moderate (2.5%/year, CHADS2 score=2, &25% of patients), and high (>5%/year, CHADS2 score 3, &25% of patients) stroke risk were reliably predicted.138 An apparent limitation of the CHADS2 scheme that applies to secondary prevention involves patients with prior stroke or TIA and no other risk factors. These rare patients score 2 on the CHADS2 scale (moderate risk), but in the validation study of the CHADS2 score, patients with prior stroke or TIA averaged 10.8 strokes per 100 patient-years.147 In the Stroke Prevention in Atrial Fibrillation (SPAF) 2012 aspirin analysis, the few patients with prior stroke or TIA without other risk factors (which included the CHADS2 risk factors except heart failure) had a stroke rate of 5.9%/year (95% CI 2 to 18).150 Therefore, patients with prior stroke or TIA in the setting of atrial fibrillation without additional risk factors should be considered at high risk for recurrence and should be treated with warfarin unless contraindicated. For patients with echocardiographic data, the SPAF III scheme has also been validated.147,148
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The threshold of absolute stroke risk warranting anticoagulation is importantly influenced by the estimated bleeding risk if anticoagulated, patient preferences, and access to high-quality anticoagulation monitoring. Risk stratification is the first step in the decision process (Table 8). Most patients with atrial fibrillation who are <75 years of age without prior stroke or TIA have a relatively low risk of stroke (1% to 2% per year) if given aspirin, and they do not benefit sufficiently from anticoagulation to warrant its use for primary stroke prevention.138,151,152 It is generally agreed that atrial fibrillation patients whose estimated stroke risk exceeds 4% per year should be anticoagulated in the absence of contraindications.153
Several studies have found that only about half of patients with atrial fibrillation who are candidates for anticoagulation receive warfarin.154–156 Anticoagulation is particularly under-used in elderly patients with atrial fibrillation.157 Although the attributable risk of stroke associated with atrial fibrillation increases with age,135 elderly (ie, 75 years of age) atrial fibrillation patients have about twice the risk of serious bleeding complications during anticoagulation as compared with younger patients.158 Nevertheless, anticoagulation is still warranted if their risk of ischemic stroke without warfarin is greater than their risk of bleeding.139 In addition to age, poorly controlled hypertension and concomitant aspirin or nonsteroidal antiinflammatory drug use confer higher bleeding risk during anticoagulation. Therefore, age per se is not a contraindication to the anticoagulation of high-risk atrial fibrillation patients.
The optimal target international normalized ratio (INR) for primary prevention of stroke in patients with nonvalvular atrial fibrillation appears to be 2.0 to 2.5.159 This range is too narrow for practical management, and a range of 2 to 3 is generally recommended for most atrial fibrillation patients.153,160 For primary prevention in the very elderly (for whom the lowest efficacious intensity of anticoagulation is particularly important to minimize bleeding), a target INR of 2 (target range 1.6 to 2.5) is recommended by some experts,153,159,161 although others favor a target range of 2 to 3 for atrial fibrillation patients of all ages.162
The importance of treatment of hypertension is discussed in a previous section. Hypertension is also an independent risk factor for stroke in atrial fibrillation patients (particularly those with systolic blood pressure >160 mm Hg). It is unclear whether sustained control of hypertension in atrial fibrillation patients reduces cardiogenic embolism. However, intracerebral bleeding, the most devastating complication of anticoagulation in the elderly, is exquisitely sensitive to blood pressure control.163 Control of hypertension in atrial fibrillation patients is therefore critically important, reducing both the risk of ischemic stroke and the risk of intracerebral hemorrhage complicating antithrombotic therapy.164
Summary and Gaps
Atrial fibrillation is an important, treatable stroke risk factor. Validated stroke risk–stratification schemes identify those at particularly low risk (<2% per year) who can be treated with aspirin. It should be noted that guideline statements from different groups may vary in their recommendations about risk stratification. Long-term anticoagulation importantly reduces stroke risk in those at higher risk and without contraindications to this treatment. The development of safer, easier-to-use oral anticoagulants might improve the risk-benefit ratio. Controversy remains about the optimal target level of anticoagulation in those at risk of increased bleeding. Many patients with atrial fibrillation, particularly those >75 years of age, who would benefit from anticoagulation do not receive this treatment.165
Recommendations
Anticoagulation of patients with atrial fibrillation who have valvular heart disease (particularly those with mechanical heart valves) is recommended (Class I, Level of Evidence A). Antithrombotic therapy (warfarin or aspirin) is recommended to prevent stroke in patients with nonvalvular atrial fibrillation according to assessment of their absolute stroke risk, estimated bleeding risk, patient preferences, and access to high-quality anticoagulation monitoring (Table 8) (Class I, Level of Evidence A). Warfarin (INR 2.0 to 3.0) is recommended for high-risk (>4% annual risk of stroke) patients (and most moderate-risk patients according to an assessment of bleeding risk) with atrial fibrillation who have no clinically significant contraindications to oral anticoagulants (Class I, Level of Evidence A).
Other Cardiac Conditions
Other types of cardiac disease that can contribute to the risk of thromboembolic stroke include dilated cardiomyopathy, valvular heart disease (eg, mitral valve prolapse, endocarditis, prosthetic cardiac valves), and intracardiac congenital defects (eg, patent foramen ovale [PFO], atrial septal defect, atrial septal aneurysm). Potential cardiac sources of emboli are associated with up to 40% of cryptogenic strokes in some series involving the younger population.166 The presence of cerebrovascular disease is strongly associated with the presence of symptomatic167–169 and asymptomatic170–174 cardiac disease. In addition, MI is associated with the development of atrial fibrillation and is a source of cardiogenic emboli.141 Because of shared risk factors, patients with MI represent a group that is also at increased risk of stroke. Acute coronary syndromes are infrequently associated with stroke in the acute setting, occurring in 0.8% of patients.175–177 The majority of these strokes (0.6%) are ischemic.176
Although a detailed review of the management of cardiac conditions is beyond the scope of this guideline, several points will be highlighted. The incidence of stroke is inversely proportional to cardiac ejection fraction. Patients with MI who have an ejection fraction <29% have a RR of stroke of 1.86, as compared with patients who have an ejection fraction of >35% (P=0.01; an 18% increase in stroke risk for every 5% decline in ejection fraction).178 The use of warfarin for cardioembolic prophylaxis in patients with reduced LV ejection fraction in the setting of idiopathic cardiomyopathy remains controversial, and trials are in progress comparing warfarin with antiplatelet treatment.
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.179–190 Other factors associated with perioperative stroke include duration of cardiopulmonary bypass and the presence of aortic atherosclerosis.191,192 Studies proving the benefits of specific prophylactic procedures are lacking.
Summary and Gaps
In addition to atrial fibrillation, a variety of cardiac conditions have been associated with an increased risk of stroke. Data on the relative benefits and risks of specific prophylactic interventions are beyond the scope of this document.
Recommendations
Various AHA/ACC practice guidelines recommend strategies to reduce the risk of stroke in patients with a variety of cardiac conditions. These include the management of patients with valvular heart disease,136 unstable angina,193 chronic stable angina,194 and acute MI.195 Strategies to prevent postoperative neurological injury and stroke in patients undergoing surgical revascularization for atherosclerotic heart disease are discussed in detail in the recently published coronary artery bypass graft surgery guidelines.196 It is reasonable to prescribe warfarin to post–ST-segment–elevation MI patients with LV dysfunction with extensive regional wall-motion abnormalities (Class IIa, Level of Evidence A), and warfarin may be considered in patients with severe LV dysfunction, with or without congestive heart failure (Class IIb, Level of Evidence C).197
Dyslipidemia
Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke.198–201 Three prospective studies in men subsequently showed increases in ischemic stroke rates at higher levels of total cholesterol, particularly for levels above 240 to 270 mg/dL.199,200,202 The Asia Pacific Cohort Studies Collaboration, which included 352 033 individuals, found a 25% increase in ischemic stroke rates for every 1-mmol/L (38.7-mg/dL) increase in total cholesterol.203 The Eurostroke project (22 183 subjects, 34% female) found only a trend toward increased risk with 6% more cases of cerebral infarction for every 1-mmol/L increase in total cholesterol.204 The US Women’s Pooling Project (24 343 women at risk) found a 25% increased risk of fatal ischemic stroke for each 1-mmol/L increase in total cholesterol in women 30 to 54 years of age.205 Therefore, there does appear to be a clear relationship between dyslipidemia and the risk of ischemic stroke in both men and women (Table 3).
Only a few studies have analyzed the relationship between LDL cholesterol (the major component of total cholesterol) and ischemic stroke. No consistent association has been found, although the total number of subjects at risk in these studies is limited.206–208
The relationship between HDL cholesterol and ischemic stroke is best determined from prospective studies because tissue inflammation and caloric deficit can reduce HDL levels after stroke. The Copenhagen City Heart Study, including both sexes, found a 47% reduction of ischemic stroke events for every 1-mmol/L increase in HDL cholesterol.209 In 3 prospective population-based studies, men had significantly increased rates of ischemic stroke at low HDL cholesterol levels, especially levels <30 to 35 mg/dL.202,210,211 The Eurostroke project found fewer ischemic strokes in men with low HDL (nonsignificant trend) but more ischemic strokes in women with low HDL (marginally significant).204 Studies in Japan and the United States found trends toward higher ischemic stroke rates in women with low HDL.208,211 Thus, it appears that low HDL is a risk factor for ischemic stroke in men, but more data are needed to verify its effect in women.
Triglyceride levels vary considerably, making elevated levels difficult to evaluate as a risk factor for stroke. Elevated triglycerides are a component of the metabolic syndrome. Trends toward higher triglyceride levels in patients who subsequently experience ischemic stroke have been reported.206,209 In a study of 11 117 subjects with CAD, ischemic cerebrovascular events were significantly associated with high triglyceride and low HDL cholesterol levels.207
Carotid intima-media thickness, measured by B-mode ultrasound, is an atherosclerotic disease marker. Lipoprotein levels have been correlated with carotid intima-media thickness.212 In clinical trials, colestipol-niacin combination therapy, statin monotherapy, and statin-niacin combination therapy each retarded the progression of asymptomatic carotid atherosclerosis assessed by carotid intima-media thickness.213–217
HMG-CoA reductase inhibitors (statins) have received regulatory approval for the prevention of ischemic stroke in patients with CAD; the approval was based on consistent benefits in large randomized trials using these agents.27,83,214,218 Additional studies include the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which enrolled high-risk hypertensive subjects, and the Heart Protection Study, which enrolled high-risk subjects mostly with previous coronary events.129,219 In these studies, stroke rates were reduced 27% to 32% among subjects assigned to the statin as compared with placebo. Another statin trial including elderly people (70 years of age) found no effect on total stroke rate but did find a 25% reduction in TIAs. However, confidence intervals in this study were wide, so a beneficial effect on stroke cannot be excluded.220 Among a comparable number of elderly people in the Heart Protection Study, statin therapy reduced the rate of first strokes by 29%.