Approximately 795000 people in the United States have a stroke each year, 610000 of whom have had first attacks, resulting in 6.8 million stroke survivors >19 years of Stroke ranks as the fourth-leading cause of death in the Globally, over the past 4 decades, stroke inci- dence rates have fallen by 42% in high-income countries and increased by >100% in low- and middle-income countries.3 Stroke incidence rates in low- and middle-income countries now exceed those in high-income countries.3 Stroke is a leading cause of functional impairment. For patients who are 65 years of age, 6 months after stroke, 26% are dependent in their activities of daily living, and 46% have Abstract The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of stroke among individuals who have not previously experienced a stroke or transient ischemic attack. Evidence- based recommendations are included for the control of risk factors, interventional approaches to atherosclerotic disease of the cervicocephalic circulation, and antithrombotic treatments for preventing thrombotic and thromboembolic stroke. Further recommendations are provided for genetic and pharmacogenetic testing and for the prevention of stroke in a variety of other specific circumstances, including sickle cell disease and patent foramen ovale. (Stroke. 2014;45:3754-3832.) Key Words: AHA Scientific Statements atrial fibrillation diabetes mellitus hyperlipidemias hypertension intracranial aneurysm ischemia prevention and control smoking stroke Guidelines for the Primary Prevention of Stroke A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association The American Academy of Neurology affirms the value of these guidelines as an educational tool for neurologists. Endorsed by the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, and the Preventive Cardiovascular Nurses Association James F. Meschia, MD, FAHA, Chair; Cheryl Bushnell, MD, MHS, FAHA, Vice-Chair; Bernadette Boden-Albala, MPH, DrPH; Lynne T. Braun, PhD, CNP, FAHA; Dawn M. Bravata, MD; Seemant Chaturvedi, MD, FAHA; Mark A. Creager, MD, FAHA; Robert H. Eckel, MD, FAHA; Mitchell S.V. Elkind, MD, MS, FAAN, FAHA; Myriam Fornage, PhD, FAHA; Larry B. Goldstein, MD, FAHA; Steven M. Greenberg, MD, PhD, FAHA; Susanna E. Horvath, MD; Costantino Iadecola, MD; Edward C. Jauch, MD, MS, FAHA; Wesley S. Moore, MD, FAHA; John A. Wilson, MD; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on Hypertension TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on July 15, 2014. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The Executive Summary is available as an online-only Data Supplement with this article at http://stroke.ahajournals.org/lookup/suppl/ doi:10.1161/STR.0000000000000046/-/DC1. The American Heart Association requests that this document be cited as follows: Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM, Chaturvedi S, Creager MA, Eckel RH, Elkind MSV, Fornage M, Goldstein LB, Greenberg SM, Horvath SE, Iadecola C, Jauch EC, Moore WS, Wilson JA; on behalf of the American Heart Association Stroke Council, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Functional Genomics and Translational Biology, and Council on Hypertension. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754 3832. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. 2014 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STR.0000000000000046 AHA/ASA Guideline Meschia et al Guidelines for the Primary Prevention of Stroke 3755 Stroke changes the lives not only of those who experience a stroke but also of their family and other care- givers. A major stroke is viewed by more than half of those at risk as being worse than death.4 Despite the advent of reperfu- sion therapies for selected patients with acute ischemic stroke, effective prevention remains the best approach for reducing the burden of stroke.5 7 Primary prevention is particularly important because >76% of strokes are first events.1 Fortunately, there are enormous opportunities for preventing stroke. An international case-control study of 6000 individuals found that 10 potentially modifiable risk factors explained 90% of the risk of stroke.8 As detailed in the sections that follow, stroke-prone individuals can readily be identified and targeted for effective interventions. This guideline summarizes the evidence on established and emerging stroke risk factors and represents an update of the last American Heart Association (AHA) statement on this topic, published in 2011.9 Targets for stroke prevention have been reordered to align with the AHA s public health campaign for ideal cardiovascular health known as Life s Simple 7.10 As with the earlier document, the guideline addresses prevention of both hemorrhagic and ischemic stroke. The traditional definition of ischemic stroke as a clinical event is used in most instances out of necessity because of the design of most stroke prevention studies; however, where permitted by the evidence, the Writing Group has adopted the updated tissue-based definition of isch- emic stroke as infarction of central nervous system tissue.11 Differences in stroke risk among men and women are well recognized, and certain risk factors are specific to women s health (eg, oral contraceptives [OCs] and hormone replace- ment therapy). To increase awareness of these important issues and to provide sufficient coverage of the topic, theAHA has issued a guideline on the prevention of stroke in women.11a Key recommendations are summarized in the current docu- ment but not reiterated in full. Readers are encouraged to review the new guideline. The committee chair nominated Writing Group members on the basis of their previous work in relevant topic areas. The AHA Stroke Council s Scientific Statement Oversight Committee and the AHA s Manuscript Oversight Committee approved all Writing Group members. In consultation with 2 research librarians, we developed individual search strategies for each topic section and for each database to identify poten- tially relevant studies from the PubMed, Ovid MEDLINE, Ovid Cochrane Database of Systematic Reviews, and Ovid Central Register of Controlled Trials databases. The Internet Stroke Center/Clinical Trials Registry (http://www.strokecenter.org/ trials/) and National Guideline Clearinghouse (http://guideline. gov/) were also searched.Articles included were limited to those that were randomized, controlled trials; systematic reviews; meta-analyses; and in some cases, cohort studies. The database searches were also limited to articles with English-language citations, with human subjects, and published between January 1, 2009, and varying end dates, (between October 2, 2012, and December 6, 2012). Medical subject headings (MeSH) and key words, including stroke; ischemic attack, transient; cerebral infarction; cerebral hemorrhage; ischemia; and cerebrovascular disorders, in addition to select MeSH and key words on each topic, were used in the search strategy. The writers used sys- tematic literature reviews covering the time period since the last review published in 2011 to October 2012. They also reviewed contemporary published evidence-based guidelines, personal files, and published expert opinion to summarize existing evi- dence, to indicate gaps in current knowledge, and, when appro- priate, to formulate recommendations using standard AHA criteria (Tables 1 and 2). All members of the Writing Group had the opportunity to comment on the recommendations and approved the final version of this document. The guide- line underwent extensive peer review, including review by the Stroke Council Leadership and Scientific Statements Oversight Committees, before consideration and approval by the AHA Science Advisory and Coordinating Committee. Because of the diverse nature of the topics covered, it was not possible to pro- vide a systematic, uniform summary of the magnitude of the effect associated with each of the recommendations. As with all therapeutic recommendations, patient preferences must be considered. Risk factors, which directly increase disease prob- ability and if absent or removed reduce disease probability, or risk markers, which are attributes or exposures associated with increased probability of disease but are not necessarily of a first stroke, were classified according to their potential for modification.7 Although this distinction is some- what subjective, risk factors considered both well documented and modifiable were those with clear, supportive epidemiolog- ical evidence and evidence of risk reduction when modified in the context of randomized clinical trials. Less well-docu- mented or potentially modifiable risk factors were those either with less clear epidemiological evidence or without evidence from randomized clinical trials demonstrating a reduction of stroke risk when modified. Assessing the Risk of First Stroke It may be helpful for healthcare providers and patients to be able to estimate risk for a first stroke for an individual patient. Patients prefer being told their own individual risk through the use of a global risk assessment tool, although it has only a small effect on preferences for reducing risk and no effect on patient beliefs or behavior compared with standard risk As detailed in other sections, numerous individual factors can contribute to stroke risk. The levels of evidence supporting a causal relationship among several of these factors and stroke vary, and specific or proven treat- ments for some may be lacking. Although most risk factors have an independent effect, there may be important interac- tions between individual factors that need to be considered in predicting overall risk or choosing an appropriate risk modifi- cation program. Risk assessment tools taking into account the effect of multiple risk factors have been used in community stroke screening programs and in some guideline statements to select certain treatments for primary stroke prevention.14,15 Some of the goals of such risk assessment tools are to identify people at elevated risk who might be unaware of their risk, to assess risk in the presence of >1 condition, to measure an individual s risk that can be tracked and lowered by appropri- ate modifications, to estimate risk for selecting treatments or stratification in clinical trials, and to guide appropriate use of further diagnostic testing. Although stroke risk assessment tools exist, the complexi- ties of the interactions of risk factors and the effects of certain risk factors stratified by age, sex, race/ethnicity, and geography are incompletely captured by available global risk assessment tools. 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 sex 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.16 Independent stroke predictors include age, systolic blood pressure (SBP), hypertension, diabetes mellitus, current smoking, established cardiovascular disease (CVD; myocardial infarction [MI], angina or coronary insuffi- ciency, congestive heart failure, and intermittent claudication), atrial fibrillation (AF), and left ventricular hypertrophy on ECG. Additional refinements include a measure of carotid intima-media thickness (IMT); however, these refinements result in only a small improvement in 10-year risk predic- tion of first-time MI or stroke that is unlikely to be of clinical FSP scores can be calculated to estimate sex-spe- cific, 10-year cumulative stroke risk. The initial FSP has been updated to account for the use of antihypertensive therapy and the risk of stroke and stroke or death among individuals with Despite its widespread use, the validity of the FSP among individuals of different age ranges or belonging to different race/ethnic groups has been inadequately studied. The FSP has been applied to ethnic minorities in the United Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Meschia et al Guidelines for the Primary Prevention of Stroke 3757 Kingdom and found to vary across groups, but the suitability of the scale to predict outcomes has not been fully established.20 Alternative prediction models have been developed using other cohorts and different sets of stroke risk factors. Retaining most of the Framingham covariates, one alternative stroke risk scoring system omits cigarette smoking and antihypertensive medication and adds time to walk 15 feet and serum creati- Another score is derived from a mixed cohort of stroke and stroke-free patients and includes history of stroke, marital status, blood pressure (BP) as a categorical variable, high-den- sity lipoprotein (HDL) cholesterol, impaired expiratory flow, physical disability, and a depression score.22 Several studies have generated risk assessment tools for use in patients with AF (see Atrial Fibrillation). Risk models have also been developed for other populations. For example, a stroke prediction model derived for use in Chinese adults in Taiwan included age, sex, SBP, diastolic BP (DBP), family history of stroke, AF, and dia- betes mellitus and was found to have a discriminative capacity similar to or better than those of other available stroke models.23 The model, however, has not been independently validated. Recent guideline statements from the AHA/American StrokeAssociation have emphasized the importance of includ- ing both stroke and coronary heart disease events as outcomes in risk prediction instruments intended for primary preven- The AHA/American College of Cardiology (ACC) CV Risk Calculator is available online for use in estimating risk at http://my.americanheart.org/cvriskcalculator. Assessing the Risk of First Stroke: Summary and Gaps An ideal stroke risk assessment tool that is simple, is widely applicable and accepted, and takes into account the effects of multiple risk factors does not exist. Each available tool has limi- tations. Newer risk factors for stroke such as obstructive sleep apnea, not collected in older studies, need to be considered.25 Risk assessment tools should be used with care because they do not include all the factors that contribute to disease risk.25 Some potential for harm exists from unnecessary application of interventions that may result from inappropriate use of risk assessment tools or from the use of poorly adjudicated tools. The utility of the FSP or other stroke risk assessment scales as a way of improving the effectiveness of primary stroke prevention is not well studied. Research is needed to validate risk assessment tools across age, sex, and race/ethnic groups; to evaluate whether any of the more recently identified risk factors add to the predic- tive accuracy of existing scales; and to determine whether the use of these scales improves primary stroke prevention. Assessing the Risk of First Stroke: Recommendations 1. The use of a risk assessment tool such as the AHA/ ACC CV Risk Calculator (http://my.americanheart. org/cvriskcalculator) is reasonable because these tools can help identify individuals who could benefit from therapeutic interventions and who may not be treated on the basis of any single risk factor. These calculators are useful to alert clinicians and patients of possible risk, but basing treatment decisions on the results needs to be considered in the context of the overall risk profile of the patient (Class IIa; Level of Evidence B). Generally Nonmodifiable Risk Factors and Risk Assessment Age The cumulative effects of aging on the cardiovascular sys- tem and the progressive nature of stroke risk factors over a prolonged period substantially increase the risk of ischemic stroke and intracerebral hemorrhage (ICH). An analysis of data from 8 European countries found that the combined risk of fatal and nonfatal stroke increased by 9%/y in men and The incidence of ICH increases with age from <45 years to >85 years, and the incidence rates did not decrease between 1980 and 2006.27 Disturbing trends have been observed in the risk of stroke in younger individuals. In Greater Cincinnati/Northern Kentucky, the mean age of stroke decreased from 71.2 years in 1993 to 1994 to 69.2 years in 2005 because of an increase in the proportion of stroke in Table 2. Definition of Classes and Levels of Evidence Used in AHA/ASA Recommendations Class I Conditions for which there is evidence for and/or general agreement that the procedure or treatment is useful and effective. Class II Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy of a procedure or treatment. Class IIa The weight of evidence or opinion is in favor of the procedure or treatment. Class IIb Usefulness/efficacy is less well established by evidence or opinion. Class III Conditions for which there is evidence and/or general agreement that the procedure or treatment is not useful/ effective and in some cases may be harmful. Therapeutic recommendations Level of Evidence A Data derived from multiple randomized clinical trials or meta-analyses Level of Evidence B Data derived from a single randomized trial or nonrandomized studies Level of Evidence C Consensus opinion of experts, case studies, or standard of care Diagnostic recommendations Level of Evidence A Data derived from multiple prospective cohort studies using a reference standard applied by a masked evaluator Level of Evidence B Data derived from a single grade A study or one or more case-control studies, or studies using a reference standard applied by an unmasked evaluator Level of Evidence C Consensus opinion of experts AHA/ASA indicates American Heart Association/American Stroke Association individuals between 20 to 54 years of age.28 The Nationwide Inpatient Sample showed that the rates of stroke hospitaliza- tion increased for individuals between 25 and 34 years of age and between 35 and 44 years of age from 1998 to 2007.29 Stroke occurring at younger ages has the potential to cause greater lifetime impairment and disability. The Framingham Heart Study estimated the lifetime risk of stroke to be 1 in 6 or more for middle-aged adults.30 Low Birth Weight Low birth weight has been associated in several populations with risk of stroke in later life. Stroke mortality rates among adults in England and Wales are higher among people with lower birth weights.31 The mothers of these low-birth-weight babies were typically poor, were malnourished, had poor overall health, and were generally socially disadvantaged.31 A similar study compared a group of South Carolina Medicaid beneficiaries <50 years of age who had stroke with population The odds of stroke was more than double for those with birth weights <2500 g compared with those weighing 4000 g (with a significant linear trend for intermedi- ate birth weights). A US nationally representative longitudinal study found an odds ratio (OR) of 2.16 (P<0.01) for low-birth- weight babies compared with normal-birth-weight babies for the risk of stroke, MI, or heart disease by 50 years of age.33 Differences in birth weight may reflect differences in birth- place, and these geographic differences may relate to differ- ences in stroke mortality.34 Whether the association of birth weight with stroke risk is causal remains to be clarified. Race/Ethnicity Epidemiological studies support racial and ethnic differences in the risk of stroke.35 and some Hispanic/Latino have a higher incidence of all stroke types and higher mortality rates compared with whites. This is particularly true for young and middle-aged blacks, who have a substan- tially higher risk of subarachnoid hemorrhage (SAH) and ICH than whites of the same age.36,37 In the Atherosclerosis Risk in Communities (ARIC) study, blacks had an incidence of all stroke types that was 38% (95% confidence interval [CI], 1.01 1.89) higher than that of whites.42 American Indians have an incidence rate for stroke of 679 per 100000 person-years, which is high relative to non-Hispanic whites.43 It remains unclear whether these racial differences are genetic, environmental, or an interac- tion between the two. Possible reasons for the higher incidence and mortality rates of stroke in blacks include a higher prevalence of prehypertension, hypertension, obesity, and diabetes melli- A higher prevalence of these risk factors, however, may not explain all of the excess risk.50 Several studies have suggested that race/ethnic differences may be the result of social determi- nants, including neighborhood characteristics,51 53 language, access to and use of health care,35 Genetic Factors A meta-analysis of cohort studies showed that a positive family history of stroke increases the risk of stroke by 30% (OR, 1.3; The Framingham study showed that a documented parental history of stroke before 65 years of age was associated with a 3-fold increase in the risk of stroke in The odds of both monozygotic twins having strokes is 1.65-fold higher than for dizygotic twins.55 Stroke heritabil- ity estimates vary with age, sex, and stroke subtype.57,58 Younger stroke patients are more likely to have a first-degree relative with Women with stroke are more likely than men to have a parental history of stroke.58 Recent estimates of heritability using genome-wide common variant single-nucleotide polymorphism (SNP) data show similar heritability for cardioembolic (32.6%) and large-vessel disease (40.3%) but lower heritability for small- vessel disease (16.1%).59 These estimates, however, do not con- sider the potential contribution of rare variants. Genetic influences on stroke risk can be considered on the basis of their influence on individual risk factors, the genet- ics of common stroke types, and uncommon or rare familial causes of stroke. Many of the established and emerging risk factors that are described in the sections that follow such as arterial hypertension, diabetes mellitus, and hyperlipidemia have both genetic and environmental or behavioral compo- Genome-wide association studies have identified common genetic variants for these risk factors. Studies that assess the effect of the cumulative burden of risk alleles of stroke risk factors, as measured by a so-called genetic risk score, are beginning to emerge. For example, the burden of risk alleles for elevated BP was associated with a modest but significant increase in risk for ICH (OR, 1.11; 95% CI, 1.02 1.21; P=0.01) in 1025 cases and 1247 controls of European Whether a genetic risk score will provide clini- cally useful information beyond that afforded by clinical risk factors remains uncertain. Arguably, estimating genetic risk remains crude because only a few loci influencing stroke risk factors or stroke susceptibility have been identified. Common variants on chromosome 9p21 adjacent to the tumor suppressor genes CDKN2A and CDKN2B, which were initially found to be associated with MI,64 66 have also been associated with large-artery ischemic stroke.67 Common vari- ants on 4q25 and 16q22, adjacent to genes involved in cardiac development (PITX2 and ZFHX3, respectively), which were initially found to be associated with AF,68,69 were subsequently associated with ischemic stroke, particularly cardioembolic Although tests are commercially available for the 9p21, 4q25, and 16q22 risk loci, studies have yet to prove that altering preventive therapies on the basis of genotypes leads to improved patient outcomes. Genome-wide association studies have identified novel genetic variants influencing risk of stroke. A meta-analysis of genome-wide association studies from prospective cohorts identified a locus on 12p13 near the NINJ2 gene associated with incident ischemic stroke,71 but large case-control studies have not replicated this finding.72,73 This inconsistency may be because of a possible effect of this locus on stroke mortality,74 a synthetic association from rare variants not well represented in the subsequent replication studies, or a false-positive asso- ciation. Recent meta-analyses of large case-control studies have identified novel genetic associations with specific stroke subtypes, suggesting that risk factor profiles and pathologi- cal mechanisms may differ across subtypes. Two loci have been associated with large-vessel stroke in individuals of European ancestry: a locus on 6p21.175 and a locus on 7q21 Meschia et al Guidelines for the Primary Prevention of Stroke 3759 near the HDAC9 gene, encoding a protein involved in histone A variant in the PRKCH gene encoding a protein kinase has been associated with small-vessel stroke The genetic variants described to date account for only a small proportion of stroke risk. Even combined, their predictive value is likely to be low. Personalizing medicine through genetic testing has the potential to improve the safety of primary prevention pharma- cotherapies. For example, genetic variability in cytochrome (VKORC1), and rare missense mutations in the factor IX pro- peptide affect sensitivity of patients to vitamin K antagonists. This has led to testing of various genotype-guided dosing protocols. A 12-week randomized trial of 455 patients treated with warfarin showed significantly more time in therapeutic range for the international normalized ratio (INR) for patients assigned to the genotype-guided dosing regimen versus stan- A 4-week ran- domized trial of 1015 patients treated with warfarin showed no significant difference in the time in therapeutic range for the A 12-week randomized trial of 548 patients treated with acenocoumarol or phencou- mon showed no significant difference in the time in therapeu- tic range for the INR (61.6% versus 60.2%; P=0.52).81 A genome-wide association study of individuals taking 80 mg simvastatin identified common variants on SLCO1B1 that are associated with myopathy.82 This may prove useful in screening for patients being considered for simvastatin therapy, although randomized validation studies demonstrat- ing the clinical and cost-effectiveness of its use are lacking. Several monogenic disorders are associated with stroke. Although rare, their effect on the individual patient is substan- tial because individuals carrying a mutation are likely to develop stroke or other clinical characteristics of disease. Thus, iden- tification of the underlying gene for these disorders is impor- tant for diagnosis, counseling, and patient management. With the exception of sickle cell disease (SCD; discussed below), no treatment based specifically on genetic factors has yet been shown to reduce incident stroke. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopa- thy is characterized by subcortical infarcts, dementia, migraine headaches, and white matter changes that are readily apparent on brain magnetic resonance imaging (MRI).83 Cerebral autoso- mal-dominant arteriopathy with subcortical infarcts and leuko- encephalopathy is caused by any one of a series of mutations in Genetic testing for NOTCH3 mutations is available. Retinal vasculopathy with cerebral leukodystrophy is caused by mutation in the TREX1 gene, a DNA exonuclease involved in the response to oxidative DNA damage.85 Mutations in the COL4A1 gene can cause leukoaraiosis and microbleeds and can present with ischemic or hemorrhagic stroke or as the hereditary angiopathy with nephropathy, aneurysm, and muscle Fabry disease is a rare inherited disorder that can also lead to ischemic stroke. It is caused by lysosomal -galactosidaseA deficiency, which causes a progressive accumulation of globo- triaosylceramide and related glycosphingolipids.88 Deposition affects mostly small vessels in the brain and other organs, although involvement of the larger vessels has been reported. Enzyme replacement therapy appears to improve cerebral ves- sel function. Two prospective, randomized studies using human recombinant lysosomal -galactosidase A found a reduction in microvascular deposits and reduced plasma levels of globotri- These studies had short follow-up periods, and no reduction in stroke incidence was found. Agalsidase- and agalsidase- given at the same dose of 0.2 mg/kg have similar short-term effects in reducing left ventricular mass.85,92 Many coagulopathies are inherited as autosomal-dominant These disorders, including protein C and S deficien- cies, the factor V Leiden mutation, and various other factor deficiencies, can lead to an increased risk of cerebral venous As discussed below, there has not been a strong association between several of these disorders and arterial events such as MI and ischemic stroke.98,99 Some apparently acquired coagulopathies such as the presence of a lupus anticoagulant or anticardiolipin antibody (aCL) can be familial in 10% of cases.100,101 Inherited disorders of various clotting factors (ie, factors V, VII, X, XI, and XIII) are auto- somal-recessive traits and can lead to cerebral hemorrhage in infancy and childhood.102 Arterial dissections, moyamoya syndrome, and fibromuscular dysplasia have a familial com- Intracranial aneurysms are a feature of certain mendelian disorders, including autosomal-dominant polycystic kidney disease and Ehlers-Danlos type IV syndrome (so-called vas- cular Ehlers-Danlos). Intracranial aneurysms occur in 8% of individuals with autosomal-dominant polycystic kidney disease and 7% with cervical fibromuscular dysplasia.105,106 Ehlers-Danlos type IV is associated with dissection of verte- bral and carotid arteries, carotid-cavernous fistulas, and intra- Loss-of-function mutations in KRIT1, malcavernin, and PDCD10 genes cause cerebral cavernous malformation syn- Mutations in can cause inherited cerebral amyloid angiopathy syndromes.109 Genetic Factors: Summary and Gaps The cause of ischemic stroke remains unclear in as many as 35% of patients. The use of DNA sequence information, in conjunction with other omics (eg, transcriptomics, epig- enomics) and clinical information to refine stroke origin, although promising, has not yet proven useful for guiding preventive therapy. Genetic factors could arguably be clas- sified as potentially modifiable, but because specific gene therapy is not presently available for most conditions, genetic factors have been classified as nonmodifiable. It should be recognized that treatments are available for some, such as Fabry disease and SCD. Genetic Factors: Recommendations 1. Obtaining a family history can be useful in identify- ing people who may have increased stroke risk (Class IIa; Level of Evidence A). 2. Referral for genetic counseling may be considered for patients with rare genetic causes of stroke (Class IIb; Level of Evidence C). 3. Treatment of Fabry disease with enzyme replacement therapy might be considered, but has not been shown to reduce the risk of stroke, and its effectiveness is unknown (Class IIb; Level of Evidence C). 4. Noninvasive screening for unruptured intracranial aneurysms in patients with 2 first-degree relatives with SAH or intracranial aneurysms might be rea- sonable (Class IIb; Level of Evidence C).110 5. Noninvasive screening may be considered for unrup- tured intracranial aneurysms in patients with auto- somal-dominant polycystic kidney disease and 1 relatives with autosomal-dominant polycystic kidney disease and SAH or 1 relatives with autosomal- dominant polycystic kidney disease and intracranial aneurysm (Class IIb; Level of Evidence C). 6. Noninvasive screening for unruptured intracranial aneurysms in patients with cervical fibromuscu- lar dysplasia may be considered (Class IIb; Level of Evidence C). 7. Pharmacogenetic dosing of vitamin K antagonists may be considered when therapy is initiated (Class IIb; Level of Evidence C). 8. Noninvasive screening for unruptured intracranial aneurysms in patients with no more than 1 relative with SAH or intracranial aneurysms is not recom- mended (Class III; Level of Evidence C). 9. Screening for intracranial aneurysms in every car- rier of autosomal-dominant polycystic kidney disease or Ehlers-Danlos type IV mutations is not recom- mended (Class III; Level of Evidence C). 10. Genetic screening of the general population for the prevention of a first stroke is not recommended (Class III; Level of Evidence C). 11. Genetic screening to determine risk for myopathy is not recommended when initiation of statin therapy is being considered (Class III; Level of Evidence C). Well-Documented and Modifiable Risk Factors Physical Inactivity Physical inactivity is associated with numerous adverse health effects, including an increased risk of total mortality, cardio- vascular morbidity and mortality, and stroke. The 2008 physi- cal activity guidelines for Americans provide an extensive review and conclude that physically active men and women generally have a 25% to 30% lower risk of stroke or mortality than the least active.111 Two meta-analyses of physical activ- ity reached the same conclusion.112,113 The benefits appear to occur from a variety of activities, including leisure-time phys- ical activity, occupational activity, and walking. Overall, the relationship between activity and stroke is not influenced by age or sex, but some data suggest linkages between these fac- tors and activity levels.114 116 The relationship between the amount or intensity of physi- cal activity and stroke risk remains unsettled and includes the possibility of a sex interaction. One study suggested an increas- ing benefit with greater intensity in women (median relative risk [RR], 0.82 for all strokes for moderate-intensity versus no or light activity; RR, 0.72 for high-intensity versus no or light activity). In men, there was no apparent benefit of higher intensity (median RR, 0.65 for moderate intensity versus no or light activity; RR, 0.72 for high intensity versus no or light In contrast, the prospective Northern Manhattan Study (NOMAS) suggested that moderate- to high-intensity physical activity was protective against risk of ischemic stroke in men (hazard ratio [HR], 0.37; 95% CI, 0.18 0.78) but not Increased physical activity has also been associated with a lower prevalence of Vigorous physical activity, regardless of sex, was associated with a decreased incidence of stroke in the National Runners Health Study.119 The protective effect of physical activity may be partly mediated through its role in reducing BP120 and controlling other risk factors for CVD,121,122 including diabetes melli- and excess body weight. Physical activity also reduces plasma fibrinogen and platelet activity and elevates plasma tissue plasminogen activator activity and HDL cholesterol Physical activity may also exert positive health effects by increasing circulating anti-inflammatory cytokines, including interleukin-1 receptor antagonist and interleukin-10, and modulating immune function in addi- A large and generally consistent body of evidence from prospective, observational studies indicates that routine physi- cal activity prevents stroke. The 2008 physical activity guide- lines for Americans recommend that adults should engage in 150 min/wk of moderate-intensity (eg, fast walking) or 75 min/wk of vigorous-intensity aerobic physical activity (eg, running) or an equivalent combination of moderate- and vigorous-intensity aerobic activity. These guidelines also note that some physical activity is better than none and that adults who participate in any amount of physical activity gain some The 2013 AHA/ACC guideline on lifestyle to reduce cardiovascular risk encourages moderate to vigorous aerobic physical activity for at least 40 minutes at a time to be done at least 3 to 4 d/wk for the purpose of reducing BP and improving lipid profile.127 Physical Inactivity: Summary and Gaps A sedentary lifestyle is associated with several adverse health effects, including an increased risk of stroke. Indeed, the global vascular risk prediction scale including the addition of physical activity, waist circumference, and alcohol consump- tion improved prediction of 10-year event rates in multiethnic communities compared with traditional Framingham vari- Clinical trials documenting a reduction in risk of a first or recurrent stroke with regular physical activity have not been conducted. Evidence from observational studies is suf- ficiently strong to make recommendations for routine physical activity to prevent stroke.127 Physical Inactivity: Recommendations 1. Physical activity is recommended because it is associ- ated with a reduction in the risk of stroke (Class I; Level of Evidence B). 2. Healthy adults should perform at least moderate- to vigorous-intensity aerobic physical activity at least 40 (Class I; Level of Evidence B). Meschia et al Guidelines for the Primary Prevention of Stroke 3761 Dyslipidemia Total Cholesterol Most studies have found high total cholesterol to be a risk factor for ischemic stroke. In the Multiple Risk Factor Intervention Trial (MRFIT), comprising >350 000 men, the RR of death resulting from nonhemorrhagic stroke increased progressively with each higher level of cholesterol.129 In the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) study, which included >28 000 cigarette-smoking men, the risk of cerebral infarction was increased among those with total cholesterol levels of 7 mmol/L ( 271 mg/ In the Asia Pacific Cohort Studies Collaboration (APCSC), which included 352 033 individuals, there was a 25% (95% CI, 13 40) increase in ischemic stroke rates for every 1-mmol/L (38.7-mg/dL) increase in total choles- In the Women s Pooling Project, which included 24 343 US women <55 years of age with no previous CVD, and in the Women s Health Study (WHS), a prospective cohort study of 27 937 US women 45 years of age, higher cholesterol levels were also associated with increased risk of ischemic stroke.132,133 In other studies, the association between cholesterol and stroke was less clear. In the ARIC study, including 14 175 middle-aged men and women free of clinical CVD, the relationships between lipid values and incident ischemic stroke were weak.134 Most studies have found an inverse relationship between cholesterol levels and risk of hemorrhagic stroke. In MRFIT, the risk of death resulting from ICH was increased 3-fold in men with total cholesterol concentrations <4.14 mmol/L (160 mg/dL) compared with higher levels.129 In a pooled cohort analysis of the ARIC study and the Cardiovascular Health Study (CHS), lower levels of low-density lipopro- tein (LDL) cholesterol were inversely associated with incident intracranial hemorrhage.135 In the APCSC, there was a 20% (95% CI, 8 30) decreased risk of hemorrhagic stroke for every 1-mmol/L (38.7-mg/dL) increase in total Similar findings were reported in the Ibaraki Prefectural Health Study, in which the age- and sex-adjusted risk of death from parenchymal hemorrhagic stroke in peo- ple with LDL cholesterol of 140 mg/dL was about half of that in people with LDL cholesterol <80 mg/dL (OR, 0.45; The Kaiser Permanente Medical Care Program reported that serum cholesterol <178 mg/dL increased the risk of ICH among men 65 years (RR, 2.7; In a Japanese nested case-control study, patients with intraparenchymal hemorrhage had lower cho- lesterol levels than control subjects.138 In contrast, in the Korean Medical Insurance Corporation Study of 115 000 men, low serum cholesterol was not an independent risk factor for ICH.139 Overall, epidemiological studies sug- gest competing stroke risk related to total cholesterol lev- els in the general population: low levels of total cholesterol increasing risk of ICH and high levels of total cholesterol increasing risk of ischemic stroke. Given the complex relationship between total choles- terol and stroke, it is noteworthy that there appears to be no positive association between total cholesterol and stroke HDL Cholesterol Some epidemiological studies have shown an inverse rela- tionship between HDL cholesterol and risk of stroke,141 145 whereas others have not.134 The Emerging Risk Factors Collaboration performed a meta-analysis involving individual records on 302430 people without vascular disease from 68 long-term prospective studies.146 Collectively, there were 2.79 million person-years of follow-up. The aggregated data set included 2534 ischemic strokes, 513 hemorrhagic strokes, and 2536 unclassified strokes. The analysis adjusted for risk fac- tors other than lipid levels and corrected for regression dilu- tion. The adjusted HRs were 0.93 (95% CI, 0.84 1.02) for ischemic stroke, 1.09 (95% CI, 0.92 1.29) for hemorrhagic stroke, and 0.87 (95% CI, 0.80 0.94) for unclassified stroke. There was modest heterogeneity among studies of ischemic =27%). The absence of an association between HDL and ischemic stroke and between HDL and hemorrhagic stroke contrast with the clear inverse association between HDL cholesterol and coronary heart disease observed in the same meta-analysis. Triglycerides Epidemiological studies that have evaluated the relationship between triglycerides and ischemic stroke have been inconsis- tent, in part because some have used fasting and others used nonfasting levels. Fasting triglyceride levels were not associ- ated with ischemic stroke in ARIC.134 Triglycerides did not predict the risk of ischemic stroke among healthy men enrolled in the Physicians Health Study.147 Similarly, in the Oslo study of healthy men, triglycerides were not related to the risk of In contrast, a meta-analysis of prospective studies conducted in the Asia-Pacific region found a 50% increased risk of ischemic stroke among those in the highest quintile of fasting triglycerides compared with those in the lowest The Copenhagen City Heart Study, a prospective, population-based cohort study comprising 14000 people, found that elevated nonfasting triglyceride levels increased the risk of ischemic stroke in both men and women. After multivariate adjustment, there was a 15% (95% CI, 9 22) increase in the risk of ischemic stroke for each 89-mg/dL increase in nonfasting triglycerides. HRs for ischemic stroke among men and women with the highest ( 443 mg/dL) com- pared with the lowest (<89 mg/dL) nonfasting triglyceride respectively. The 10-year risks of ischemic stroke were 16.7% and 12.2%, respectively, in men and women 55 years of age with triglyceride levels of 443 mg/dL.150 Similarly, the WHS found that in models adjusted for total and HDL cholesterol and measures of insulin resistance, nonfasting triglycerides, but not fasting triglycerides, were associated with cardiovas- cular events, including ischemic stroke.151 A meta-analysis of 64 randomized clinical trials that tested lipid-modifying drugs found an adjusted RR of stroke of 1.05 (95% CI, 1.03 1.07) for each 10-mg/dL increase in baseline triglycerides, although fasting status is not specified.152 In the Emerging Risk Factors Collaboration meta-analysis, triglyceride levels were not asso- ciated with either ischemic or hemorrhagic stroke risk, and determination of fasting status did not appear to change the lack of association.146 Treatment of Dyslipidemia Treatment with statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduces the risk of stroke in patients with or at high risk for atherosclerosis.153,154 One meta-analysis of 26 trials that included >90000 patients found that statins reduced the risk of all strokes by 21% (95% CI, 15 27).153 Baseline mean LDL cholesterol in the studies ranged from 124 to 188 mg/dL and averaged 149 mg/dL. The risk of all strokes was estimated to decrease by 15.6% (95% CI, 6.7 23.6) for each 10% reduction in LDL cholesterol. Another meta-anal- ysis of randomized trials of statins in combination with other preventive strategies that included 165792 individuals showed that each 1-mmol/L (39-mg/dL) decrease in LDL cholesterol reduction in stroke.155 Several meta-analyses also found that beneficial effects are greater with greater lipid lowering. One meta-analysis of 7 randomized, controlled trials of primary and secondary prevention reported that more intensive statin therapy that achieved an LDL cholesterol of 55 to 80 mg/dL resulted in a lower risk of stroke than less intensive therapy that achieved an LDL cholesterol of 81 to 135 mg/dL (OR, Another meta-analysis of 10 randomized, controlled trials of patients with atherosclerosis and coronary artery disease reported a significant reduction in the composite of fatal and nonfatal strokes with higher versus lower statin doses (RR, 0.86; 95% CI, 0.77 0.96).157 A meta-analysis of 22 trials involving 134537 patients assessed the association of LDL cholesterol lowering with a statin and major cardiovascular events, including stroke, according to risk categories ranging from <5% to >30% 5-year risk of a major cardiovascular event.158 The risk of major vas- cular events was lowered by 21% (95% CI, 23 29) for each 39-mg/dL reduction in LDL cholesterol. For every 39-mg/dL reduction in LDL, there was a 24% (95% CI, 5 39) reduction in the risk of stroke in participants with an estimated 5-year risk of major vascular events <10%, which was similar to the rela- tionship seen in higher-risk categories. Similarly, another meta- analysis, which included 14 trials reporting stroke outcomes in patients with an estimated 10-year risk of cardiovascular events of <20%, found that the RR of stroke was significantly lower among statin recipients than among control subjects (RR, In addition, in Justification for the Use of statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), statin treatment reduced the inci- dence of fatal and nonfatal stroke compared with placebo (HR, 0.52; 95% CI, 0.34 0.79) in healthy men and women with LDL cholesterol levels <130 mg/dL and high-sensitivity C-reactive protein (hs-CRP) levels 2.0 mg/L.160 Concerns about lowering of LDL cholesterol by statin therapy increasing the risk of hemorrhagic stroke are not sup- ported. One meta-analysis of 31 trials comparing statin ther- apy with a control reported that statin therapy decreased total stroke (OR, 0.84; 95% CI, 0.78 0.91) and found no difference in the incidence of ICH (OR, 1.08; 95% CI, 0.88 1.32).161 These findings are consistent with another meta-analysis that included 23 randomized trials and found that statins were not associated with an increased risk of ICH (RR, 1.10; 95% CI, The intensity of cholesterol lowering did not correlate with risk of ICH. The beneficial effect of statins on ischemic stroke is most likely related to their capacity to reduce progression or to induce regression of atherosclerosis. Meta-analyses of statin trials found that statin therapy slows the progression of carotid IMT and that the magnitude of LDL cholesterol reduction correlates inversely with the progression of carotid IMT.153,163 Moreover, beneficial effects on carotid IMT are greater with higher-intensity statin therapy.164 166 In addition, plaque char- acteristics appear to improve with statin therapy. One study using high-resolution MRI reported that intensive lipid ther- apy depleted carotid plaque lipid,167 and another found that high-dose atorvastatin reduced carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide Statins should be prescribed in accordance with the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. 169 These guidelines represent a dramatic shift away from specific LDL cholesterol targets. Instead, the guidelines call for esti- mating the 10-year risk for atherosclerotic CVD and, based on the estimated risk, prescribing a statin at low, moderate, or high intensity. The intensity of statin therapy depends on the drug and the dose. For example, lovastatin at 20 mg/d is con- sidered low-intensity therapy, and lovastatin at 40 mg/d is con- sidered moderate-intensity therapy. Atorvastatin at 10 mg/d is considered moderate-intensity therapy, and atorvastatin at 80 mg/d is considered high-intensity therapy. A cardiovascu- lar risk calculator to assist in estimating 10-year risk can be found online at http://my.americanheart.org/cvriskcalculator. Although the new guidelines shift focus away from specific lipid targets, values for total cholesterol and HDL are incor- porated into the cardiovascular risk calculator, along with age, sex, race, SBP, hypertension treatment, diabetes mellitus, and cigarette smoking. The benefits of lipid-modifying therapies other than statins on the risk of ischemic stroke are not established. A meta- analysis of 78 lipid-lowering trials involving 266973 patients reported that statins decreased the risk of total stroke (OR, 0.85; 95% CI, 0.78 0.92), whereas the benefits of other lipid- lowering interventions were not significant, including diet Reduction in the risk of stroke is proportional to the reduction in total and LDL cholesterol; each 1% reduction in total cholesterol is associated with a 0.8% reduction in the risk of stroke. Similarly, another meta-analysis of 64 randomized, controlled trials reported that treatment-related decreases in LDL cholesterol were associated with decreases in all strokes 7.2); however, there was no relationship between triglycerides Niacin increases HDL cholesterol and decreases plasma levels of lipoprotein(a) [Lp(a)]. The Coronary Drug Project found that treatment with niacin reduced mortality in men with prior MI.171 In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study of patients with established CVD, the addition of extended-release niacin to intensive simvastatin therapy did not reduce the risk of a composite of cardiovascular Meschia et al Guidelines for the Primary Prevention of Stroke 3763 events, which included ischemic stroke.172 In a meta-analysis of 11 studies comprising 9959 subjects, niacin use was associated with a significant reduction in cardiovascular events, including a composite of cardiac death, nonfatal MI, hospitalization for acute coronary syndrome, stroke, or revascularization procedure (OR, 0.66; 95% CI, 0.49 0.89). There was an association between niacin therapy and coronary heart disease event (OR, 0.75; 95% CI, 0.59 0.96) but not with the incidence of stroke (OR, 0.88; However, there are serious safety concerns about niacin therapy. The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2- THRIVE) trial involving 25693 patients at high risk for vascu- lar disease showed that extended-release niacin with laropiprant (a prostaglandin D2 signal blocker) caused a significant 4-fold increase in the risk of myopathy in patients taking simvastatin.174 Fibric acid derivatives such as gemfibrozil, fenofibrate, and bezafibrate lower triglyceride levels and increase HDL cho- lesterol. The Bezafibrate Infarction Prevention study, which included patients with prior MI or stable angina and HDL cho- lesterol 45 mg/dL, found that bezafibrate did not significantly decreaseeithertheriskofMIorsuddendeath(primaryendpoint) or stroke (secondary end point).175 The Veterans Administration HDL Intervention Trial of men with coronary artery disease and low HDL cholesterol found that gemfibrozil reduced the risk of all strokes, primarily ischemic strokes.176 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate neither decreased the composite primary end point of coronary heart disease death or nonfatal MI nor decreased the risk of stroke. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study of patients with type 2 diabetes mellitus, adding fenofibrate to simvastatin did not reduce fatal cardiovascular events, nonfatal MI, or nonfatal stroke compared with simvastatin alone.177 A meta-analysis of 18 trials found that fibrate therapy produced a 10% (95% CI, 0 18) relative reduc- tion in the risk for major cardiovascular but no benefit on the risk of stroke (RR reduction, 3%; 95% CI, 16 to 9).178 Ezetimibe lowers blood cholesterol by reducing intestinal absorption of cholesterol. In a study of familial hypercholesterol- emia, adding ezetimibe to simvastatin did not affect the progres- sion of carotid IMT more than simvastatin alone.179 In another trial of subjects receiving a statin, niacin led to greater reductions in mean carotid IMT than ezetimibe over 14 months (P=0.003).180 Counterintuitively, patients receiving ezetimibe who had greater reductions in the LDL cholesterol had an increase in the carotid The rate of major cardiovascular events was lower in those randomized to niacin (1% versus 5%; P=0.04). Stroke events were not reported. A clinical outcome trial comparing ezetimibe and simvastatin with simvastatin alone on cardiovascular outcomes is in progress.181 Ezetimibe has not been shown to decrease cardiovascular events or stroke. Dyslipidemia: Recommendations 1. In addition to therapeutic lifestyle changes, treat- ment with an HMG coenzyme-A reductase inhibitor (statin) medication is recommended for the primary prevention of ischemic stroke in patients estimated to have a high 10-year risk for cardiovascular events as recommended in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults 169 (Class I; Level of Evidence A). 2. Niacin may be considered for patients with low HDL cholesterol or elevated Lp(a), but its efficacy in pre- venting ischemic stroke in patients with these con- ditions is not established. Caution should be used with niacin because it increases the risk of myopathy (Class IIb; Level of Evidence B). 3. Fibric acid derivatives may be considered for patients with hypertriglyceridemia, but their efficacy in pre- venting ischemic stroke is not established (Class IIb; Level of Evidence C). 4. Treatment with nonstatin lipid-lowering therapies such as fibric acid derivatives, bile acid sequestrants, niacin, and ezetimibe may be considered in patients who cannot tolerate statins, but their efficacy in preventing stroke is not established (Class IIb; Level of Evidence C). Diet and Nutrition A large and diverse body of evidence has implicated several aspects of diet in the pathogenesis of high BP, the major modifi- able risk factor for ischemic stroke. A scientific statement from the AHA concluded that several aspects of diet lead to elevated Specifically, dietary risk factors that are causally related to elevated BP include excessive salt intake, low potassium intake, excessive weight, high alcohol consumption, and suboptimal dietary pattern. Blacks are especially sensitive to the BP-raising effects of high salt intake, low potassium intake, and suboptimal In this setting, dietary changes have the potential to sub- stantially reduce racial disparities in BP and stroke.182,183 Nutrition science is generally limited because random- ized trials involving long-term follow-up are challenging to conduct. Nutritional epidemiology faces challenges of mea- surement error, confounders, variable effects of food items, variable reference groups, interactions, and multiple testing.184 Keeping these limitations in mind, it is worth noting that sev- eral aspects of diet have been associated with stroke risk. A meta-analysis found a strong inverse relationship between servings of fruits and vegetables and subsequent stroke.185 Compared with individuals who consumed <3 servings per day, the RR of ischemic stroke was less in those who con- and in those who consumed >5 servings per day (RR, 0.72; 95% CI, 0.66 0.79). The dose-response relationship extends into the higher ranges of intake.186 Specifically, in analyses of the Nurses Health Study and the Health Professionals the RR of incident stroke was 0.69 (95% CI, 0.52 0.92) for people in the highest versus lowest quin- tile of fruit and vegetable intake. Median intake in the high- est quintile was 10.2 servings of fruits and vegetables in men and 9.2 in women. For each serving-per-day increase in fruit and vegetable intake, the risk of stroke was reduced by 6% (95% CI, 1 10). A subsequent analysis of the Nurses Health showed that increased intake of flavonoids, primarily from citrus fruits, was associated with a reduced risk of isch- emic stroke (RR, 0.81; 95% CI, 0.66 0.99; P=0.04). As high- lighted in the 2010 US Dietary Guidelines, most Americans obtain only 64% and 50% of the recommended daily con- sumption of vegetables and fruits, respectively.188 A randomized, controlled trial of the Mediterranean diet performed in 7447 individuals at high cardiovascular risk showed that those on an energy-unrestricted Mediterranean diet supplemented by nuts (walnuts, hazelnuts, and almonds) had a lower risk of stroke than people on a control diet (3.1 versus 5.9 strokes per 1000 person-years; P=0.003) and that those on an energy-unrestricted Mediterranean diet supple- mented by extra virgin olive oil had a lower risk of stroke than people on a control diet (4.1 strokes per 1000 person- In ecological studies,190 and meta- a higher level of sodium intake was associ- ated with an increased risk of stroke. In prospective studies, a higher level of potassium intake was also associated with a reduced risk of stroke.195 198 It should be emphasized that a plethora of methodological limitations, particularly dif- ficulties in estimating dietary electrolyte intake, hinder risk assessment and may lead to false-negative or even paradoxical results in observational studies. One trial tested the effects of replacing regular salt (sodium chloride) with a potassium-enriched salt in elderly Taiwanese In addition to increased overall survivorship and reduced costs, the potassium-enriched salt reduced the risk of mortality from cerebrovascular disease (RR, 0.50). This trial did not present follow-up BP measurements; hence, it is unclear whether BP reduction accounted for the beneficial effects of the intervention. In contrast, in the Women s Health Initiative, a low-fat diet that emphasized consumption of whole grains, fruits, and vegetables did not reduce stroke inci- dence; however, the intervention did not achieve a substantial increase in fruit and vegetable consumption (mean difference, only 1.1 servings per day) or decrease in BP (mean difference, <0.5 mmHg for both SBP and DBP).200 The effects of sodium and potassium on stroke risk are likely mediated through direct effects on BP and effects inde- pendent of BP.201 In clinical trials, particularly dose-response studies, the relationship between sodium intake and BP is direct and progressive, without an apparent threshold.202 204 Blacks, hypertensives, and middle-aged and older adults are especially sensitive to the BP-lowering effects of a reduced In other trials, an increased intake of potas- sium was shown to lower BP206 and to blunt the pressor effects Diets rich in fruits and vegetables, including those based on the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat), lower BP.208 As documented in a study by the Institute of Medicine,211 sodium intake remains high and potassium intake quite low in the United States. Other dietary factors may affect the risk of stroke, but the evidence is insufficient to make specific recommendations.182 In Asian countries, a low intake of animal protein, saturated fat, and cholesterol has been associated with a decreased risk but such relationships have been less apparent in A recent prospective study214 showed that higher intake of red meat was associated with a higher risk of stroke, but a higher intake of poultry was associated with a lower risk of stroke. Additionally, a meta-analysis of prospective studies concluded that intake of fresh, processed, and total red meat is associated with an increased risk of isch- Potentially, the source of dietary protein may affect stroke risk. In the absence of a clinical syndrome of a specific vitamin or nutrient deficiency, there is no conclusive evidence that vitamins or other supplements prevent incident stroke. Diet and Nutrition: Summary and Gaps From epidemiological studies and randomized trials, it is likely that diets low in sodium and rich in fruits and vegeta- bles, such as the Mediterranean and DASH-style diets, reduce stroke risk. Few randomized trials with clinical outcomes have been conducted. US Dietary Guidelines for Americans recom- mend a sodium intake of <2300 mg/d (100 mmol/d) for the general population. In blacks, individuals with hypertension, those with diabetes mellitus, those with chronic kidney dis- ease, and individuals 51 years of age, a sodium intake of The AHA recommends <1500 mg sodium per day.216 The ideal lower limit of dietary salt intake remains ill defined and may depend on comorbidi- ties such as diabetes mellitus and heart failure managed with US Dietary Guidelines for Americans recommend that potassium intake be at least 4700 mg/d (120 Diet and Nutrition: Recommendations 1. Reduced intake of sodium and increased intake of potassium as indicated in the US Dietary Guidelines for Americans are recommended to lower BP (Class I; Level of Evidence A). 2. A DASH-style diet, which emphasizes fruits, vegeta- bles, and low-fat dairy products and reduced satu- rated fat, is recommended to lower BP127,218 (Class I; Level of Evidence A). 3. A diet that is rich in fruits and vegetables and thereby high in potassium is beneficial and may lower the risk of stroke (Class I; Level of Evidence B). 4. A Mediterranean diet supplemented with nuts may be considered in lowering the risk of stroke (Class IIa; Level of Evidence B). Hypertension The Seventh Joint National Committee defined hypertension as SBP >140 mmHg and DBP >90 mmHg.219 The most recent panel appointed by the National Heart, Lung, and Blood Institute to review hypertension management guidelines was silent on the issue of defining hypertension but chose instead to focus on defining BP thresholds for initiating or modify- Hypertension is a major risk factor for both cerebral infarction and ICH. The relationship between BP and stroke risk is strong, continuous, graded, consistent, indepen- dent, predictive, and etiologically significant.221 Throughout the usual range of BPs, including the nonhypertensive range, the higher the BP is, the greater the risk of stroke.222 The prevalence of hypertension has plateaued over the past decade. On the basis of national survey data from 1999 Meschia et al Guidelines for the Primary Prevention of Stroke 3765 to 2000 and 2007 to 2008, the prevalence of hypertension in the United States remained stable at 29%.223,224 Hypertension control has also improved over the past 25 years, with control rates of 27.3% measured in 1988 to 1994 and 50.1% measured in 2007 to 2008. The improved control is likely attributable to heightened awareness and treatment. Awareness of hyperten- sion among US residents significantly increased from 69% in from 54% to 73% over the same period. Despite the improve- ments, however, rates of control were lower among Hispanics compared with whites and among those 18 to 39 years of age compared with older individuals. BP, particularly SBP, rises with increasing age in both chil- Individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hyperten- More than two thirds of people 65 years of age are Because the risk of stroke increases progressively with increasing BP and because many individuals have a BP level below current drug treatment thresholds,220 nondrug or life- style approaches are recommended as a means of reducing BP in nonhypertensive individuals with an elevated BP (ie, pre-hypertension: 120 to 139 mmHg SBP or 80 to 89 mmHg Pharmacological treatment of prehypertension appears to reduce the risk of stroke. 