These include disturbance of cortical excitability, cortical spreading depression, meningeal inflam- mation, and activation of the trigeminovascular system.603 However, factors contributing to the increased risk of stroke with migraine remain elusive. Clinical-epidemiological stud- ies have suggested several mechanisms. In 1 prospective study of patients <55 years of age, hypercoagulable states were more frequent in the migraine than the nonmigraine Multivariate analy- sis showed that migraine without aura was associated with a 2.88-fold increased risk for hypercoagulable diagnosis (95% CI, 1.14 7.28), but in the group with brain infarcts who were <50 years of age, only migraine with aura was independently associated with hypercoagulable states (OR, 6.81; 95% CI, The Stoke Prevention in Young Women Study (SPYW) reported a 50% increased risk of ischemic stroke in those with probable migraine and visual aura (OR, 1.5; Interrelationships among the ACE dele- tion/insertion (D/I) polymorphism (rs1799752), migraine, and CVD, including ischemic stroke, were investigated in the WHS cohort.606 The increased risk for CVD among migraineurs with aura was apparent only for carriers of the DD (RR, 2.10; 95% CI, 1.22 3.59; P=0.007) and DI (RR, 2.31; 95% CI, 1.52 3.51) genotypes, suggesting that the DD/ DI genotype may play a role in, or at least be a marker for, this However, because of the small num- bers, further studies are warranted. Perhaps the most heavily investigated potential mecha- nistic link between migraine and stroke is the association of migraine and PFO. Initial studies found that PFOs are more common in young patients with cryptogenic stroke and those particularly migraine with aura.608 The speculated relationship between PFO and migraine includes microemboli that flow through the PFO, causing brain isch- emia and thereby triggering migraine.609 The Migraine Intervention with STARFlex Technology (MIST) trial, a randomized, double-blind, sham-controlled trial, showed no benefit of PFO closure on the cessation of migraine headaches There is much controversy concerning the results of this trial,611 and it was not designed to evaluate the primary prevention of stroke in patients with migraines with aura. Furthermore, recent studies have found a lack of association between migraine and PFO in a large population-based study among elderly indi- in a hospital-based case-control study,613 and in a placing some doubt on whether PFO has a causal role in migraines. In terms of primary prevention of stroke in patients with migraine, aspirin reduced risk of ischemic stroke (RR, 0.76; 95% CI, 0.63 0.93) but not other clinical atherothrombotic end points in the WHS group.615 In subgroup analyses, the pro- tective effect of aspirin on ischemic stroke was similar among women with or without migraines.615 However, women with migraine with aura on aspirin had an increased risk of MI (RR, 3.72; 95% CI, 1.39 9.95), primarily women with history of smoking or hypertension.615 The clinical significance of this increased risk for this subgroup is unclear because of small numbers. Migraine: Summary and Gaps Migraine headache, particularly migraine with aura, appears to be associated with stroke in women <55 years of age, but the mechanisms linking these 2 conditions remain unclear. The stroke risk of migraine in men appears to be less estab- lished. Randomized trial evidence that migraine prophylaxis decreases stroke risk is lacking. The significance of deep white matter lesions and other infarct-like lesions seen on MRI in patients with migraine remains unclear. No proven primary prevention strategy exists for patients with migraine. Closure of PFO for treatment of migraine and for primary or second- ary stroke prevention remains controversial, with no data from well-controlled studies showing benefit. Migraine: Recommendations 1. Smoking cessation should be strongly recommended in women with migraine headaches with aura (Class I; Level of Evidence B). 2. Alternatives to OCs, especially those containing estrogen, might be considered in women with active migraine headaches with aura (Class IIb; Level of Evidence B). 3. Treatments to reduce migraine frequency might be reasonable to reduce the risk of stroke (Class IIb; Level of Evidence C). 4. Closure of PFO is not indicated for preventing stroke in patients with migraine (Class III; Level of Evidence B). Metabolic Syndrome TheNationalCholesterolEducationProgram(AdultTreatment Panel III) originally defined metabolic syndrome as the pres- ence of 3 of the following: (1) abdominal obesity as deter- mined by waist circumference >102 cm (>40 in) for men and >88 cm (>35 in) for women; (2) triglycerides 150 mg/dL; (3) HDL cholesterol <40 mg/dL for men and <50 mg/dL for women; (4) BP 130/ 85 mmHg; and (5) fasting glucose A modified criterion for fasting glucose was published in 2004.617 The International Diabetes Foundation (IDF) then modified the definition by requiring inclusion of a waist circumference >88 cm for men and >80 cm in women plus 2 of the other National Cholesterol Education Program Adult Treatment Panel III criteria.618 In 2009, a harmonized definition was proposed wherein an identical set of thresholds was used for all components except waist circumference, an area in which further evidence for the relationship to CVD events was felt to be required.619 In the interim, the Harmonized Definition Work Group suggested that national or regional cut points for waist circumference should be used. Thus, because the waist circumference and risk for CVD and diabetes melli- tus vary around the world, the National Cholesterol Education Program Adult Treatment Panel III, IDF, and harmonized def- initions all make a provision for an ethnic/racial/geographic modification of waist circumference.620 Obesity and sedentary lifestyle, in addition to other genetic or acquired factors, seem to interact to produce the metabolic syndrome.621 Screening for the syndrome requires no more than a routine physical examination and routine blood tests.622 Obesity, discussed separately, is an important component of the metabolic syndrome and is associated with major health risk factors (such as diabetes mellitus, hypertension, and dys- lipidemia), poor health status, and, when extreme, lower life The visceral adiposity characteristic of the metabolic syndrome is associated with insulin resistance, inflammation, diabetes mellitus, and other metabolic and Visceral adipocytes provoke insulin resistance by promoting extensive lipolysis and release of fatty acids into the splanchnic circulation. Leptin, plasmin- ogen activator inhibitor-1, tumor necrosis factor- , and other proinflammatory cytokines, in addition to reduced production and release of adiponectin by adipocytes, have all been impli- cated in this pathophysiological process.626 The metabolic syndrome is highly prevalent in the United Applying the harmonized definition of the meta- bolic syndrome to data from the National Health and Nutrition Examination (2003 through 2006) in up to 3461 participants 20 years of age with a waist circumference threshold of 102 cm for men and 88 cm for women, the age-adjusted prevalence of metabolic syndrome was 34.3% among all adults, 36.1% among men, and 32.4% among women.627 With the use of race- or ethnicity-specific IDF criteria for waist circumference, the age-adjusted prevalence was 38.5% for all participants, 41.9% for men, and 35.0% for women. Prevalence increased with age, with the highest prevalence in subjects between 60 to 69 years of age. Prevalence was lower among black men than white or Mexican American men and lower among white women than among black or Mexican American women. Mostly attributable to the obligatory use of a lower waist circumference for the IDF, the IDF definition led to higher estimates of prevalence in all demographic groups, especially among MexicanAmerican men. Hyperinsulinemia/insulin resistance is an important marker of the metabolic syndrome; however, results concerning a relationship between glucose intolerance and stroke risk In 18990 men and women who were screened for entry into the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial from 21 different countries, 8000 subjects were normoglyce- mic, 8427 had impaired fasting glucose or impaired glucose tolerance, and 2563 had newly diagnosed type 2 diabetes mel- Among all subjects, an 18-mg/dL increase in fasting plasma glucose or a 45-mg/dL increase in the 2-hour glucose after an oral glucose tolerance test was associated with an increase in cardiovascular events, including stroke or death (HR, 1.17; 95% CI, 1.13 1.22). The relationships between other individual components of the metabolic syndrome and stroke risk, including elevated BP, are reviewed in other sec- tions of this guideline. The metabolic syndrome is a predictor of CVD and vascular death; however, this risk does not appear to be any larger than the sum of the components of the syndrome.626,641 A similar lack of greater predictability is true for the metabolic syndrome and This lack of relationship may be because of sample size or a small number of stroke events. The National Health and Nutrition Examination Survey, among 10357 subjects,643 the prevalence of metabolic syndrome was higher in people with self-reported history of stroke (43.5%) than in those with no history of stroke or myocardial infarct (22.8%; P 0.001). The metabolic syndrome was independently associated with stroke history in all ethnic groups and in both sexes (OR, 2.16; 95% CI, 0.48 3.16). The association between metabolic syndrome and stroke has been confirmed in other populations, including those enriched with elderly subjects, and the frequency of the meta- bolic syndrome was notably higher in patients with a history of but also in Korean patients with The adjusted RRs for ischemic stroke asso- ciated with the metabolic syndrome in prospective studies has ranged between 2.10 and 2.47, and an HR as high as 5.15 has This predictive capacity does not appear to be influenced by the definition used for the metabolic syndrome and showed no significant variation across sex, age, or ethnic groups. Yet, in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, the 642 subjects with the metabolic syndrome and a previous stroke or TIA did not experience an increased risk of stroke.654 Although many stud- ies have used >1 definition of the metabolic syndrome to assess the risk for stroke, the harmonized definition may prove to be superior in establishing the relationship.655,656 There are essentially no trial data that have addressed the effects of treatment on cardiovascular morbidity and mortal- ity in patients with the metabolic syndrome. In the JUPITER Trial, 17802 healthy men and women with LDL cholesterol levels <130 mg/dL and hs-CRP levels 2.0 mg/L were ran- domized to receive rosuvastatin 20 mg daily or placebo and followed up for the occurrence of the combined primary end point of MI, stroke, arterial revascularization, hospitalization for unstable angina, or death resulting from cardiovascular The rates were reduced by a hazard ratio of 0.56 (95% CI, 0.46 0.69) for the primary end point, 0.46 (95% CI, 0.30 0.70) for MI, and 0.52 (95% CI, 0.34 0.79) for stroke. Patients with or without the metabolic syndrome had similar reductions in CVD events. The TNT study included 10001 patients with clinically evident coronary heart disease.658 Treating to an LDL cholesterol substantially <100 mg/dL Meschia et al Guidelines for the Primary Prevention of Stroke 3789 with a high dose of a high-potency statin reduced both stroke and cardiovascular events by an additional 20% to 25% com- pared with a lower dose. Of these subjects, 5584 patients with the metabolic syndrome were randomly assigned to high- or As expected, the higher dose led to greater reductions in LDL cholesterol (73 versus 99 mg/dL at 3 months). Regardless of treatment assignment, more patients with the metabolic syndrome (11.3%) had a major cardio- vascular event than those without the metabolic syndrome follow-up of 4.9 years, major cardiovascular events occurred in 13% patients receiving the low-dose statin compared with 9.5% receiving the higher dose (HR, 0.71; 95% CI, 0.61 0.84; P<0.0001), and cardiovascular events were reduced by 26% (HR, 0.74; 95% CI, 0.59 0.93; P=0.011). Metabolic Syndrome: Summary and Gaps Individual components of the metabolic syndrome are associ- ated with an increased risk of ischemic stroke and should be treated as appropriate. The specific risk of stroke in people with the metabolic syndrome appears to be higher but remains uncertain, as is the effect of treatment of the syndrome. Metabolic Syndrome: Recommendations 1. Management of individual components of the meta- bolic syndrome is recommended, including lifestyle measures (ie, exercise, appropriate weight loss, proper diet) and pharmacotherapy (ie, medications for BP lowering, lipid lowering, glycemic control, and antiplatelet therapy), as endorsed in other sections of this guideline. (Refer to relevant sections for Class and Levels of Evidence for each recommendation.) Alcohol Consumption The National Institute on Alcohol Abuse and Alcoholism defines heavy drinking for a man as >4 drinks in any single day or >14 drinks per week and defines heavy drinking for a woman as >3 drinks any single day and >7 drinks per week.660 A standard drink is defined as 12 fl oz of regular beer, 5 fl oz of table wine, or a 1.5 fl oz shot of 80-proof spirits. Heavy alcohol consumption can lead to multiple medical compli- cations, including stroke. Heavy alcohol consumption is a risk factor for all types of stroke.661 665 Most studies suggest a J-shaped association between alcohol consumption and the risk of total and ischemic stroke, with a protective effect in light (<151 g/wk) or moderate (151 to 300 g/wk) drinkers and an elevated risk with heavy (>300 g/wk) alcohol consump- In contrast, a linear association exists between alcohol consumption and the risk of ICH.330,334,677,678 In a pro- spective cohort study of 540 patients with spontaneous ICH,679 heavy alcohol intake was associated with ICH at a young age (median age, 60 versus 74 years in nonabusers; P<0.001). Light-to-moderate alcohol consumption is associated with higher levels of HDL cholesterol,680,681 reduced plate- lower fibrinogen concentrations,684 and increased insulin sensitivity and glucose metabolism.685,686 Heavy alcohol consumption can result in hypertension,687 693 hypercoagulability, reduced cerebral blood flow,694 and an increased risk of AF.662,668,695 698 Studies show an increased risk for stroke in hypertensive patients who consume alco- hol, as well as poor BP control in heavy drinkers with hypertension. A study of 43685 men from the Health Professionals Follow-Up Study and 71243 women from the Nurses Health Study showed that alcohol intake had a J-shaped associa- tion for risk of stroke.667 A lower risk for stroke was found in women who were light drinkers, but women who drank 30 g alcohol per day had a 40% increased risk for stroke (RR, 1.41; 95% CI, 1.07 1.88 for ischemic stroke; RR, 1.40; 95% CI, 0.86 2.28 for ICH). There was a similar but nonsig- nificant pattern for men. In the WHS,699 alcohol consumption was not associated with risk for stroke, even for 10.5 drinks per week. However, a recent meta-analysis showed a higher mortality risk for women compared with men who drank >3 drinks per day.700 A prospective study of Chinese men701 supports the associa- tion between heavy alcohol and risk for stroke.A 22% increase in stroke occurred for those consuming at least 21 drinks per week, whereas consumption of 1 to 6 drinks per week was associated with the lowest risk. In a meta-analysis of 35 obser- consumption of 60 g alcohol per day was associated with a 64% increased risk for all stroke (RR, 1.64; 95% CI, 1.39 1.93), a 69% increase for ischemic stroke (RR, 1.69; 95% CI, 1.34 2.15), and more than doubling for hemor- rhagic stroke (RR, 2.18; 95% CI, 1.48 3.20). Consumption of <12 g/d was associated with a reduced risk of total (RR, 0.67 0.96) stroke, with consumption of 12 to 24 g/d associ- ated with a lower risk of ischemic stroke (RR, 0.72; 95% CI, 0.57 0.91). A systematic review of triggers of ischemic stroke showed a significant association between ischemic stroke and alcohol abuse of >40 to 60 g within the preceding 24 hours (OR, 2.66; 95% CI, 1.54 4.61) or >150 g within the previous Alcohol Consumption: Summary and Gaps In observational studies, light to moderate alcohol consump- tion is associated with reduced risk of total and ischemic stroke, whereas heavier alcohol consumption increases stroke risk. Prospective, randomized, clinical trials showing that reduction of heavy alcohol consumption reduces risk or that light alcohol consumption is beneficial are lacking and are ethically untenable because it is well established that alcohol dependence is a major health problem. Alcohol Consumption: Recommendations 1. Reduction or elimination of alcohol consumption in heavy drinkers through established screening and counseling strategies as described in the 2004 US Preventive Services Task Force update is recom- (Class I; Level of Evidence A). 2. For individuals who choose to drink alcohol, con- sumption of 2 drinks per day for men and 1 drink per day for nonpregnant women might be reason- (Class IIb; Level of Evidence B). Drug Abuse Drug addiction is often a chronic, relapsing condition asso- ciated with societal and health-related problems.706 Drugs of abuse, including khat, cocaine, amphetamines, 3,4-methyl- enedioxy-N-methylamphetamine (also known as MDMA or ecstasy), and heroin, are associated with an increased risk Use of these drugs can produce acute severe BP elevations, cerebral vasospasm, vasculitis, embolization resulting from infective endocarditis, endothelial dysfunc- tion, hemostatic and hematological abnormalities resulting in increased blood viscosity and platelet aggregation, and In a recent Middle Eastern cohort study of patients with acute coronary syndrome,717 khat chewing was preva- lent and was associated with an increased risk of stroke and death. Cathinone, the major ingredient of the khat plant, has sympathomimetic and central nervous system stimulating effects. The literature also includes case series of stroke asso- ciated with cannabis use; however, the mechanism remains In a prospective study of 48 young patients with ischemic stroke, 21% had multifocal intracranial stenosis associated with cannabis use.720 Information about stroke-related drug abuse is limited mainly to epidemiological studies of urban populations. There is an increase in the risk of both ischemic and hem- In a cross-sectional study of hospital- amphetamine abuse was associated with ICH (adjusted OR, 4.95; 95% CI, 3.24 7.55) but not with ischemic stroke; cocaine abuse was associated with ICH (OR, 2.33; 95% CI, 1.74 3.11) and ischemic stroke (OR, 2.03; 95% CI, 1.48 2.79). Amphetamine abuse was associated with a higher risk of fatal ICH (OR, 2.63; 95% CI, 1.07 6.50). In a retro- spective analysis of patients with ICH, patients with cocaine- associated ICH had worse functional outcomes and an almost 3-fold greater risk of death during the acute hospitalization than patients with cocaine-negative ICH.727 Long-term treatment strategies, including medication, psychological counseling, and community-based programs, are effective in the management of drug dependency.706,728 According to the US Preventive Services Task Force, there is insufficient evidence to assess the balance of benefits and harms of screening adolescents, adults, and pregnant women for illicit drug use. Although standardized questionnaires to screen individuals for drug use/misuse have been shown to be valid and reliable, there is insufficient evidence to assess the clinical utility of these instruments when applied widely in primary care settings.729 Drug Abuse: Summary and Gaps Several drugs of abuse are associated with ischemic and hem- orrhagic stroke. There are no controlled trials demonstrating a reduction in stroke risk with abstinence. Drug Abuse: Recommendation 1. Referral to an appropriate therapeutic program is reasonable for patients who abuse drugs that have been associated with stroke, including cocaine, khat, and amphetamines (Class IIa; Level of Evidence C). Sleep-Disordered Breathing Approximately 4% of adults in the United States have sleep The diagnosis of sleep apnea is based on the apnea-hypopnea index (AHI), which describes the number of respiratory events (cessations or reductions in air flow) observed during sleep. Sleep apnea is defined as present if the AHI is 5 events per hour, and an increasing AHI indicates Several longitudinal studies have identified sleep apnea as an independent risk factor for stroke. The first prospective data demonstrating an association between sleep apnea and stroke risk came from the Wisconsin Sleep Cohort Study.732 This cohort included 1189 subjects followed up for 4 years. There was a 3-fold increase in the risk of stroke (OR, 3.09; 95% CI, 0.74 12.81) for subjects with an AHI 20 events per hour. The Sleep Heart Health Study followed up 5422 adults who were 40 years of age without a history of stroke but with untreated sleep apnea for a median of 8.7 years.733 The unadjusted stroke risk associated with sleep apnea was somewhat higher in men than in women; the OR for ischemic stroke per 10 years was 2.26 (95% CI, 1.45 3.52) for men and 1.65 (95% CI, 1.45 3.52) for women. After adjustment for age, BMI, race, smoking, SBP, antihypertensive medica- tions, and diabetes mellitus, sleep apnea was associated with stroke risk in men but not women. Among men, there was a progressive increase in ischemic stroke risk with increasing sleep apnea severity: AHI 9.5 to 19.1 events per hour, adjusted OR, 1.86 (95% CI, 0.70 4.95); AHI >19.1 events per hour, adjusted OR, 2.86 (95% CI, 1.10 7.39). A meta-analysis of 5 prospective studies that included 8435 participants identified an OR for incident stroke risk of 2.24 (95% CI, 1.57 3.19).734 This meta-analysis also found that increased stroke risk is associated with increasing sleep apnea severity with an OR of 1.35 (95% CI, 1.25 1.45) for every 10-unit increase in AHI. A study of 50 men with sleep apnea and 15 obese male control subjects found that silent brain infarctions on MRI were more common among patients with moderate to severe sleep apnea than among control subjects or patients with mild sleep apnea Although alternative therapeutic strategies exist, the main- stay of sleep apnea treatment is continuous positive airway pressure (CPAP), which improves a variety of clinical out- comes (eg, daytime sleepiness).730,736 No randomized trial has evaluated the effectiveness of CPAP on primary stroke preven- tion. The existing longitudinal cohort data indicate that CPAP treatment is associated with a reduction in cardiovascular risk among patients with sleep apnea compared with patients who are not treated with CPAP even after adjustment for vascular risk factors and that this finding is most robust for patients with the most severe sleep apnea.737 739 For example, a study of 264 healthy subjects, 403 untreated patients with sleep apnea, and 372 patients with CPAP treatment for 10 years739 had a combined vascular event end point that included fatal or non- fatal stroke or MI or acute coronary syndrome requiring car- diac intervention. In this cohort, severe untreated sleep apnea was associated with a 3-fold increased risk of vascular events (adjusted OR, 2.87; 95% CI, 1.17 7.51 for cardiovascular death; OR, 3.17; 95% CI, 1.12 7.52 for nonfatal cardiovascu- lar events), but patients with treated sleep apnea had vascular Meschia et al Guidelines for the Primary Prevention of Stroke 3791 event risks that were similar to those of patients with mild untreated sleep apnea and healthy subjects. A cardiovascular end-point benefit was observed with CPAP treatment among 364 patients receiving CPAP compared with 85 untreated The adjusted HR was 0.34 (95% CI, 0.20 0.58) for CPAP treatment. Although no randomized, controlled trials have been pub- lished on primary prevention, several randomized, controlled trials and cohort studies have evaluated the effectiveness of CPAP among patients with stroke and TIA (These data are reviewed in detail in the AHA secondary stroke prevention Among these secondary prevention studies, the one with the longest follow-up studied 189 patients after stroke with sleep apnea for 7 years, finding that patients who did not use CPAP had a much higher recurrent stroke rate than patients who used CPAP (32% versus 14%; P=0.021) and a higher adjusted incidence of nonfatal vascular events (HR, The number needed to treat to prevent 1 new vascular event was 4.9 patients (95% CI, 2 19). Adherence to CPAP can be measured directly by CPAP machines in hours per night used and proportion of nights used. The reported CPAP adherence has varied considerably across studies and across populations, with mixed data about differ- ences in adherence related to differences in CPAP mode (eg, autotitrating versus fixed pressure) or humidification use.742 746 Cognitive-behavioral interventions appear to improve CPAP Several studies have sought to identify predic- tors of CPAP adherence, and results have varied across stud- ies. In general, however, patients who are most symptomatic (eg, excessive daytime sleepiness) are most likely to adhere to treatment in the long term.745 A CPAP use study among 1155 patients with sleep apnea found that 68% were continuing to use the CPAP after 5 years of follow-up.748 Patients with sleep apnea often have concomitant stroke risk factors, including hypertension, AF, diabetes mellitus, obesity, and hyperlipidemia, and several studies have dem- onstrated the importance of adjusting for these factors when examining the relationship between sleep apnea and risk of Given the robust relationship between sleep apnea numerous studies have specifically examined the degree to which CPAP treatment is associated with improvements in BP. Several meta-analyses suggest that the difference in SBP that can be expected with CPAP ranges from a decrease of 1.4 to 7.2 mmHg,736,752 754 with most of the estimates closer to the lower end of this range. Despite being highly prevalent, as many as 70% to 80% of patients with sleep apnea are neither diagnosed nor treated.755 The American Academy of Sleep Medicine730 advocates screening high-risk patients for symptoms of sleep apnea. High-risk populations include those with risk factors for stroke (eg, AF, refractory hypertension) and patients with stroke. The recommended screening includes a sleep his- tory (eg, snoring, witnessed apneas, daytime sleepiness), an evaluation of conditions that may occur as a consequence of sleep apnea (eg, motor vehicle accidents, stroke), and physi- cal examination (eg, BMI 35 kg/m2 , neck circumference >17 in for men or 16 in for women). The Epworth Sleepiness and Berlin Questionnaire757 are tools for screening for sleep apnea. However, most clinical screening tests miss a significant proportion of patients.758 Patients who are con- sidered to be high risk on the basis of this screening should be referred for polysomnography.730 Sleep-Disordered Breathing: Summary and Gaps Sleep apnea independently contributes to risk of stroke, and increasing sleep apnea severity is associated with increas- ing risk. No prospective, randomized trial has evaluated the effectiveness of sleep apnea treatment for primary stroke prevention. Sleep-Disordered Breathing: Recommendations 1. Because of its association with stroke risk, screening for sleep apnea through a detailed history, includ- ing structured questionnaires such as the Epworth Sleepiness Scale and Berlin Questionnaire, physical examination, and, if indicated, polysomnography may be considered (Class IIb; Level of Evidence C). 2. Treatment of sleep apnea to reduce the risk of stroke may be reasonable, although its effectiveness for pri- mary prevention of stroke is unknown (Class IIb; Level of Evidence C). Hyperhomocysteinemia Homocysteine is an amino acid derived from the metabolism of the essential amino acid methionine. Increased plasma lev- els of homocysteine are often a consequence of reduced enzy- matic activity in its metabolic pathways. This may be caused by genetic defects in the enzymes involved in homocysteine metabolism such as deficiencies of cystathionine -synthase and methylenetetrahydrofolate reductase (MTHFR), involved in the transsulfuration and remethylation pathways, respec- tively, or by a thermolabile variant of MTHFR that results from a point mutation in which cytosine is replaced by thymidine at position 677 (MTHFR C677T).759 Hyperhomocysteinemia also is caused by nutritional deficiencies of pyridoxine (vita- ), a cofactor of cystathionine -synthase, and of folic acid and cobalamin (vitamin B12 ), cofactors of MTHFR.760 Decreased renal clearance of homocysteine in patients with chronic renal failure may contribute to hyperhomocysteinemia. Elevated levels of plasma homocysteine are associated with 2- to 3-fold increased risk for atherosclerotic vascu- lar disease, including stroke.761 767 Carotid IMT and carotid artery stenosis are increased in people with elevated homo- In the Study of Health Assessment and Risk in Ethnic Groups (SHARE), a cross-sectional study of South Asian Chinese and white Canadians, plasma homocys- teine >11.7 mol/L, but not MTHFR C677T, was associated with increased carotid IMT.771 Several recent investigations found that the relationship between homocysteine levels and carotid IMT was eliminated after adjustment for other cardiovascular risk factors or renal function.772,773 One meta- analysis of epidemiological studies found a 19% (95% CI, 5 31) reduction in odds of stroke per 25% lower homo- cysteine concentration after adjustment for smoking, SBP, Another meta-analysis found that for each 5- mol/L increase in homocysteine, the odds of stroke increased by 59% (95% CI, 29 96), and for each 3- mol/L decrease in homocysteine, the odds of stroke decreased by A further line of evidence support- ing a causal role for homocysteine in a stroke is a meta-anal- ysis of 29 studies comparing the MTHFR C677T genotype between 4454 stroke patients and 7586 control subjects. This mendelian randomization approach found increased stroke in those with the TT genotype (OR for stroke, 1.26; 95% CI, 1.11 1.43) without significant between-study heterogeneity or evidence of publication bias.776 The B complex vitamins pyridoxine (B6 ), cobalamin (B12 ), and folic acid lower homocysteine levels. Folic acid intake is associated with reduced risk of ischemic stroke in some epide- miological studies but not in others.777 780 In a clinical trial of healthy adults without diabetes mellitus and CVD, B complex vitamin supplementation compared with placebo decreased carotid IMT in the group of participants whose baseline plasma homocysteine was 9.1 mol/L but not in those whose homo- cysteine levels were lower.781 A meta-analysis of 10 random- ized trials of folic acid similarly found that treatment decreased IMT but with substantial heterogeneity resulting from larger effects at higher baseline IMTs or with greater reductions in A substudy of the Vitamins to Prevent Stroke (VITATOPS) trial, however, reported that B complex vitamins did not slow the progression of carotid IMT.783 Most trials of patients with established atherosclerotic vas- cular disease have found no benefit of homocysteine lower- ing by B complex vitamin therapy on clinical cardiovascular end points. In the Vitamin Intervention for Stroke Prevention (VISP) trial, therapy with high doses of vitamin B6 , vitamin , and folic acid did not affect the risk of recurrent isch- emic stroke compared with a low-dose formulation of these B complex vitamins. In 2 Norwegian trials, 1 trial of patients with MI and the other of patients with coronary artery disease or aortic stenosis, B complex vitamins did not reduce mortal- ity or cardiovascular events, including stroke.784,785 Similarly, in the Women s Antioxidant and Folic Acid Cardiovascular Study (WAFACS), these B complex vitamins did not alter the risk of stroke in women with established CVD or 3 risk fac- Most recently, the VITATOPS trial,787 in which 8164 subjects with recent stroke or TIA were randomized to vitamin , vitamin B12 , and folic acid versus placebo and followed up for a median of 3.4 years, found no effect of B vitamin supple- mentation on risk of stroke (HR, 0.92; 95% CI, 0.81 1.06). Interestingly, a post hoc analysis restricted to the 1463 sub- jects in VITATOPS not taking antiplatelet medication788 found a reduced risk of stroke in the B vitamin group (HR, 0.6; 95% CI, 0.50 0.95) and a significant interaction between anti- platelet use and assignment to B vitamins. It remains unclear whether the effectiveness of B vitamin treatment within the no-antiplatelet subgroup represents biological modification of the effects of homocysteine by antiplatelet drugs, intergroup differences between patients on and off antiplatelet therapy (such as the greater proportion of patients with hemorrhagic or cardioembolic strokes among those not taking antiplatelets), or a spurious result of secondary analysis. A meta-analysis of folic acid supplementation in 26 randomized, controlled tri- found no effect on the risk of CVD (RR, 0.98; 95% CI, 0.95 1.02) but a trend toward reduced stroke risk (RR, 0.93; 95% CI, 0.86 1.00). A some- what stronger reduction in stroke (RR, 0.89; 95% CI, 0.79 0.99) was noted in a different subgroup analysis790 restricted to 35325 participants who did not have stroke as a qualifying event for inclusion in the trial. The effect of folic acid therapy has also been studied in patients with chronic renal disease and hyperhomocystein- emia, but the results of these studies are inconsistent.791 793 In the Atherosclerosis and Folic Acid Supplementation Trial, a placebo-controlled study of 315 patients with chronic renal failure, folic acid supplementation did not reduce the compos- ite risk of cardiovascular events, with fewer treated patients having strokes (RR reduction, 0.55; 95% CI, 0.01 0.80).793,794 Similarly, in the HOPE 2 study of patients with established vascular disease or diabetes mellitus, combination therapy with vitamin B6 , vitamin B12 , and folic acid lowered plasma homocysteine levels; did not affect the composite end point of cardiovascular death, MI, or stroke; but did reduce the risk A sub- sequent exploratory analysis found no heterogeneity in the effect on stroke based on whether or not the subjects had a prior history of stroke or TIA (P for interaction=0.88).796 Hyperhomocysteinemia: Summary and Gaps Hyperhomocysteinemia is associated with an increased risk of stroke. Trials that have examined the effect of homocys- teine-lowering therapy with B complex vitamins on the risk of stroke are inconsistent. Stroke reduction generally was found in trials in which the duration of treatment exceeded 3 years, the decrease in plasma homocysteine concentration was >20%, the region where patients were recruited did not fortify diet with folate, and the participants had no prior history of stroke. Better understanding of the mechanisms through which homocysteine causes atherosclerosis may enable identification of more targeted and effective therapies to reduce the risk of stroke in patients with elevated homo- cysteine levels. Hyperhomocysteinemia: Recommendation 1. The use of the B complex vitamins, cobalamin (B12 ), ), and folic acid might be considered for the prevention of ischemic stroke in patients with hyperhomocysteinemia, but its effectiveness is not well established (Class IIb; Level of Evidence B). Elevated Lp(a) Lp(a) is an LDL particle in which apolipoprotein B-100 is covalently linked to the glycoprotein apoprotein(a). The structure and chemical properties of this lipoprotein particle are similar to those of LDL. Lp(a) contributes to athero- genesis in experimental models797 and is associated with an increased risk for coronary artery disease.798,799 Apoprotein(a) also has structural homology to plasminogen but does not possess its enzymatic activity. Thus, it may inhibit fibrino- lysis, binding to the catalytic complex of plasminogen, tis- sue plasminogen activator, and fibrin, thereby contributing Meschia et al Guidelines for the Primary Prevention of Stroke 3793 Some, but not all, population-based epidemiological stud- ies have found that Lp(a) is associated with an increased risk In the Physicians Health Study, which com- prised primarily healthy, white, middle-aged men, there was no association between baseline plasma concentration of Lp(a) and future risk of stroke.804 In the CHS, the risk of stroke was increased 3-fold (RR, 3.00; 95% CI, 1.59 5.65) in older men whose Lp(a) levels were in the highest quintile compared with men with levels in the lowest quintile but not older women.801 In the ARIC study, the incidence of ischemic stroke was sig- nificantly increased in individuals with higher Lp(a) levels after adjustment for age, sex, and CVD risk factors, and this associa- tion was stronger in blacks than in whites. Compared with those with Lp(a) <10 mg/dL, the incidence of ischemic stroke was 2.12-fold greater (RR, 2.12; 95% CI, 1.48 3.03) in blacks with Lp(a) >30 mg/dL. In whites, it was 1.65-fold greater (RR 1.65; Several studies have found Lp(a) level to be associated with the severity of carotid artery stenosis and One study found that Lp(a) levels were higher in patients with strokes related to large-vessel atherothrombotic disease than in patients with lacunar strokes.808 A meta-analysis of 31 studies comprising 56010 subjects found that Lp(a) was higher in stroke patients and that incident stroke was 22% (RR, 1.22; 95% CI, 1.04 1.43) more frequent in patients in the high- est compared with the lowest tertile of Lp(a).809 A recent study assessing the value of emerging circulating lipid markers such as Lp(a) for the prediction of first cardio- vascular events showed that the addition of information on Lp(a) to that on conventional risk factors such as total and HDL cholesterol slightly improved the prediction of cardio- vascular events and would reclassify 4% of individuals to a 20% predicted risk of having a cardiovascular event within 10 years and therefore needing statin treatment according to Adult Treatment Panel III guidelines.810 A meta-analysis of observational studies reported an asso- ciation of elevated Lp(a) with first childhood arterial ischemic More recently, ele- vated Lp(a) was also associated with recurrent arterial isch- emic stroke in children.812 Niacin decreases Lp(a) levels.813 In a meta-analysis of sec- ondary prevention trials including a total of 9959 subjects, niacin treatment yielded relative odds reductions of 34% of any CVD event (P=0.007).173 However, no significant effect of niacin on stroke was observed. Lp(a): Summary and Gaps Elevated Lp(a) is associated with a higher risk of stroke. Although niacin lowers Lp(a), randomized trials have not showed that niacin supplementation lowers the risk of stroke. Elevated Lp(a): Recommendations 1. The use of niacin, which lowers Lp(a), might be reasonable for the prevention of ischemic stroke in patients with high Lp(a), but its effectiveness is not well established (Class IIb; Level of Evidence B). 2. The clinical benefit of using Lp(a) in stroke risk pre- diction is not well established (Class IIb; Level of Evidence B). Hypercoagulability The acquired and hereditary hypercoagulable states (thrombo- philias) are associated with venous thrombosis, but a relation- ship with arterial cerebral infarction is based largely on case series or case-control studies. Of these, the presence of aPLs, generally an acquired condition, is most strongly associated with arterial thrombosis. aCL (more prevalent but less spe- cific) and lupus anticoagulant (less prevalent but more spe- cific) are most frequently used to detect aPLs. Retrospective and prospective studies suggested an association between aCL and first ischemic stroke.814,815 From limited, often uncon- trolled data that include predominantly patients with SLE and potentially other vascular risk factors that are poorly detailed, asymptomatic patients with aPL are estimated to have a 0% to Acquired Hypercoagulable State: Relationship to Ischemic Stroke Case-control studies of aPL in young stroke patients have uni- formly demonstrated an association, as have most studies of unselected stroke populations. However, this is not the case for case-control studies among older adults with ischemic stroke. The Sneddon syndrome was formerly thought to be a manifes- tation of aPL syndrome, but it may be present in patients with or without aPLs,817 and the risk of ischemic stroke is increased only in those patients with increased aPLs. Several prospective cohort studies have assessed the rela- tionship between aPL and ischemic stroke. Stored frozen plasma from the Physicians Health Study was used to deter- mine whether aCL was a risk factor for ischemic stroke and venous thrombosis in healthy adult men.818 This was a nested, case-control study in a prospective cohort with 60.2 months of follow-up. At entry into the study, 68% of 22071 partici- pants submitted plasma samples. A control was matched by age, smoking history, and length of follow-up to each of the 100 patients with ischemic stroke and the 90 patients with deep vein thrombosis or pulmonary embolus. The aCL titers were higher in cases with deep vein thrombosis or pulmonary embolus than in matched controls (P=0.01). People with aCL titers above the 95th percentile had an RR for developing deep vein thrombosis or pulmonary embolus of 5.3 (95% CI, 1.55 18.3; P=0.01). Although an aCL level above the 95th percen- tile was an important risk factor for deep vein thrombosis or pulmonary embolus, there was no effect on stroke (an RR of 2 for ischemic stroke could not, however, be excluded because of low power). The Honolulu Heart Study was a nested case-control study examining aCL as a risk factor for ischemic stroke and MI.819 The study used stored frozen sera obtained from subjects in the Honolulu Heart Program who were followed for up to 20 years. aCL ( 2 GPI] dependent) was tested in 259 men who developed ischemic stroke, 374 men who developed MI, and a control group of 1360 men who remained free of both conditions. aCL was significantly associated with both incident ischemic stroke and MI. Men with a positive aCL had higher risk of stroke relative to men with negative CI, 1.0 2.3] at 20 years). These data suggest that aCL is an important predictor of future stroke and MI in men. The Framingham Offspring Cohort Study, a longitudinal observational study, used an ELISA to measure aCL from stored frozen sera. This study found an association between aCL titers and ischemic stroke or TIA, but only in women.820 Overall, although elevated aCL titers may be commonly found in isch- emic stroke patients, the strength of the association between elevated aCL titers and stroke origin or risk is uncertain. The shortcoming of many studies evaluating aCL in stroke patients such as the Framingham Offspring Cohort study has been the use of the aCL ELISA, a test with low sensitivity. The assay for anti- 2 GPI antibodies, a cofactor for antiphospho- lipid binding, may be more specific for thrombosis, including stroke and MI.819,821 Only a few studies have investigated 2 GPI in the absence of SLE. 819,821,822 Because most studies involved patients with SLE, lupus anticoagulant, or aCL, it is difficult to establish the value of anti- 2 GPI as an independent risk factor. Therefore, the clinical significance of these antibodies requires A prospective, observational study was performed to establish the incidence of first-time thromboem- bolic events in subjects with a high-risk aPL profile (positive lupus anticoagulant, positive aCL, and positive 2 The incidence of first thromboembolus was 5.3% annually com- pared with an annual rate of 1.9% in a study from the same group looking at subjects with only a single positive aPL test.824 Forty percent of thromboembolic events were stroke or TIA, and aspirin did not affect the incidence. Acquired Hypercoagulable State: Treatment for Primary Prevention of Stroke Adequately powered, controlled studies evaluating treatment of elevated aCL to prevent a first stroke are not available. In a subgroup analysis of the Physicians Health Study,818 aspirin every other day did not protect against venous throm- boembolism in 40- to 84-year-old men with moderate to high aCL titers. There is an ongoing primary prevention trial of warfarin therapy (INR, 2.0 2.5) to decrease thromboembolic events in patients with lupus and aPL.825 The Antiphospholipid Antibody Acetylsalicylic Acid (APLASA) study was a small, multicenter, double-blind, pla- cebo-controlled trial for the primary prevention of thrombosis in asymptomatic patients who were persistently aPL positive that compared low-dose aspirin (81 mg/d; n=48) with placebo (n=50) over an average follow-up of 2.30 0.95 years.816 The rates of acute thrombosis were 2.75 per 100 patient-years for the aspirin-treated subjects and 0 per 100 patient-years for placebo- sample size was relatively small; thus, the study insufficiently powered. A parallel and separate observational study published within the APLASA study816 found no reduction in the rate of first thrombotic events with low-dose (81 mg/d) aspirin over placebo in persistently aPL-positive asymptomatic individuals. These individuals also appeared to have a low overall annual incidence rate of acute thrombosis and often developed vascular events in the setting of additional thrombotic risk factors. Inherited Hypercoagulable State: Relationship to Ischemic Stroke Inherited hypercoagulable states that have been associated with stroke include fibrinogen level, the -chain 455 G/A fibrinogen, factor VIII levels, factor XIII Val34Leu, von Willebrand factor small polymorphism in intron 2, tissue-type plasminogen activator 7351 C/T, thrombotic thrombocyto- penic purpura, and heparin-induced thrombocytopenia.826 The majority of case-control studies have not found an association between arterial stroke and other hereditary hypercoagulable states such as factor V Leiden or prothrombin 20210 muta- tions or deficiencies of protein C, protein S, or antithrom- One study suggests that hypercoagulable states may be more frequent in stroke patients with PFO compared with those without PFO. That study found no difference in the prevalence of either the factor V Leiden mutation or the pro- thrombin 20210 mutation in patients with cryptogenic strokes compared with control subjects. The prevalence of the pro- 109) was higher in those with cryptogenic stroke and PFO versus those without PFO,827 suggesting a greater thrombotic risk in the setting of PFO than in either condition alone. The presumed stroke mechanism is paradoxical embolism related to venous rather than arterial thrombosis. Similarly, a familial cohort study found that the prothrombin 20210 mutation was a mild risk factor for venous thromboembolism but was not found to increase the risk of arterial thromboembolic events.828 Prothrombotic abnormalities have been identified in 20% to 50% of children with acute ischemic stroke and 33% to 99% of children with cerebral sinus venous thrombosis.829 In children with arterial ischemic stroke, emerging associations include an increased frequency of factor V Leiden mutation, elevated Lp(a), protein C deficiency, and aPL. The 2 most common genetic causes of thrombophilia are the factor V Leiden mutation and the G20210A mutation of Although their association with adult stroke is unclear, there is evidence of an association with ischemic stroke in children and young adults. A combination of mul- tiple case-control studies demonstrated an 4.3-fold increased incidence of factor V Leiden in children with acute ischemic A meta-analysis of the association of factorV Leiden with ischemic stroke in adults 50 years of age showed a fixed-effect OR of 2.00 for the mutation. This association was even stronger (OR, 2.73; 95% CI, 1.98 3.75) in those patients with cryptogenic stroke in whom there is an increased suspi- cion of hypercoagulability; however, the estimated effect car- ries the risk of inflation by case selection bias.831 A combined retrospective and prospective multicenter study of cerebral venous thrombosis found that a hypercoagulable state was the most common predisposing factor, followed by pregnancy, malignancy, and homocysteinemia.832 These coag- ulopathies may therefore predispose to venous thromboem- bolism, including cerebral venous sinus thrombosis, but may only rarely be associated with ischemic stroke. A systematic review assessed the risk of thrombosis associ- ated with thrombophilia in 3 high-risk groups: women using oral estrogen preparations, women during pregnancy, and patients undergoing major orthopedic surgery.833 This is rele- vant for the primary prevention of cerebral venous thrombosis and ischemic stroke from paradoxical cerebral embolism in the setting of a PFO. The effectiveness of prophylactic treat- ments in preventing venous thromboembolism in these groups and the relative cost-effectiveness of universal and selec- tive venous thromboembolism history based screening for Meschia et al Guidelines for the Primary Prevention of Stroke 3795 thrombophilia compared with no screening were evaluated. Selective screening based on prior venous thromboembolism history was more cost-effective than universal screening. Inherited Hypercoagulable State: Treatment for Primary Prevention of Stroke There is very little evidence to guide the management of asymptomatic people with thrombophilia. A systematic review of prospective observational studies indicated that most venous thromboembolic events occurred during periods of high risk such as surgery, trauma, or pregnancy.834 These studies and expert opinion suggest that antithrombotic pro- phylaxis during these periods would be likely to be effec- However, the effect of prophylaxis on the incidence of stroke or TIA in these subjects is not known. Hypercoagulability: Summary and Gaps Inherited and acquired hypercoagulable states are associated with venous thrombosis, but their association with arterial cerebral infarction is uncertain. Young women with isch- emic stroke have a higher prevalence of aPL. The majority of case-control studies have not found an association between acquired or hereditary hypercoagulable states and stroke in other patient populations. The relationship between the pres- ence of PFO and thrombophilia deserves further study because it may affect primary and secondary stroke prevention strate- gies. Large prospective studies should be undertaken to refine the risks and to establish the associations of thrombophilias with venous thromboembolism and first ischemic stroke. Although the pathogenic role of prothrombotic abnormalities in childhood and young adult ischemic stroke is increasingly becoming evident, the lack of any clinical trial data precludes definitive recommendations for screening or treatment. Hypercoagulability: Recommendations 1. The usefulness of genetic screening to detect inher- ited hypercoagulable states for the prevention of first stroke is not well established (Class IIb; Level of Evidence C). 2. The usefulness of specific treatments for primary stroke prevention in asymptomatic patients with a hereditary or acquired thrombophilia is not well established (Class IIb; Level of Evidence C). 3. Low-dose aspirin (81 mg/d) is not indicated for pri- mary stroke prevention in individuals who are persis- tently aPL positive (Class III; Level of Evidence B). Inflammation and Infection Inflammation affects the initiation, growth, and stability of Furthermore, inflammation has pro- thrombotic effects and plays a role in major stroke risk fac- tors such as AF, which could increase the risk of stroke.836 Nevertheless, the value of assessing inflammation in assessing risk to optimize the primary prevention of stroke remains contro- versial. A number of serum markers of inflammation, including fibrinogen, serum amyloid A, lipoprotein-associated phospholi- pase A2, and interleukin-6, have been proposed as risk mark- ers. Several studies suggest a relationship between hs-CRP and lipoprotein-associated phospholipase A2 and stroke risk.837-840 In addition to numerous epidemiological studies and random- ized, clinical trials with coronary disease end points, several epidemiological studies have identified associations between hs- CRP and stroke, including the Physician s Health Study, 841 the and the Framingham Heart Study.843 The RRs between the highest tertiles/quartiles and the lowest tertile/quartiles range from 1.5 to 2.0. The association persists after adjustment for multiple risk factors. However, hs-CRP is also associated with similar increases in mortality from several cancers and lung indicating that its association with cardiovascular risk is not specific. On the basis of multiple prospective studies, hs-CRP was recommended for measurement limited to people with moderate risk for coronary disease (10% to 20% 10-year risk using the Framingham Risk Score) as an adjunct to global risk assessment to help guide the aggressiveness of risk factor Recent evidence indicates that elevated plasma levels of YKL-40, a product of lipid-laden macrophages, are associated with an increased risk of ischemic stroke indepen- dently of hs-CRP levels.845 The JUPITER study, a randomized trial of a statin versus placebo, was performed in people free of CVD with otherwise normal LDL cholesterol levels ( 130 mg/ dL) but with hs-CRP levels >2 mg/dL. The trial found a reduc- tion in cardiovascular end points, including stroke (RR, 0.52; The study design did not include similarly treated subjects with lower lev- els of hs-CRP. No data are available to determine the potential effects of other treatments such as aspirin in this population. Monitoring of hs-CRP has not been evaluated in randomized trials to determine whether it is useful in adjusting statin dose in patients who might be considered for treatment, nor has its cost-effectiveness for population screening been assessed. This is also true of the other markers of inflammation. Another way to evaluate the role of inflammation as a risk factor for stroke is to examine the incidence of vascular dis- ease in people with systemic chronic inflammatory diseases such as rheumatoid arthritis (RA) and SLE. A large number of prospective cohort studies have identified increased risks for CVD (including stroke) in people with RA, with ORs consis- tently in the range of 1.4 to 2.0 compared with people without At least 50% of premature deaths in patients with RA have been attributed to CVDs.851 Excess risk was especially apparent in 35- to 55-year-old women with RA.846 This asso- ciation remained after adjustment for other cardiovascular risk factors. Furthermore, data from the Danish Nationwide Cohort Study indicate that RA increases the rates of bothAF (incidence rate ratio, 1.42) and stroke (1.32),852 but a causal relationship between AF and stroke in RA has not been established. Patients with SLE had very elevated RRs for CVD in the 2- to 52-fold Although stroke rates were not assessed, several stud- ies have identified higher prevalence rates of atherosclerotic plaques in the carotid arteries in RA or SLE patients compared with control subjects.854 856 Patients with RA and SLE might be considered a subgroup at high risk for CVD worthy of enhanced risk factor measurement and control.857 Chronic infections such as periodontitis, chronic bronchitis, and infection with Helicobacter pylori, Chlamydia pneumoniae, or cytomegalovirus might promote atherosclerosis and increase the risk of stroke.858 There is evidence that the cumulative effect of multiple infections, or infectious burden, rather than single organisms, may be associated with risk of stroke and carotid Unfortunately, several randomized trials of antibiotic therapy have failed to find any benefit in the preven- tion of cardiovascular end points, including stroke.861,862 A final issue in the role of infection and inflammation in stroke relates to acute infectious diseases (such as influenza). Possible mechanisms include the induction of procoagulant acute-phase reactants (such as fibrinogen) or destabiliza- tion of atherosclerotic plaques. Hospitalization for infection appears to be a short-term risk factor for stroke,863 although it is unclear what, if any, management implications this has for patients. An increase in cardiovascular deaths has long been observed in association with influenza.864,865 A retrospec- tive study found that treatment with an antiviral agent within 2 days of an influenza diagnosis was associated with a 28% reduction (HR, 0.72; 95% CI, 0.62 0.82) in the risk of stroke or TIA over the ensuing 6 months.866 One case-control study867 of influenza vaccination demonstrate a reduced risk of stroke associated with vaccination. A pro- spective study in Taiwan found that influenza vaccination of people >65 years of age was associated with lower all-cause mortality, including a 65% reduction in stroke (HR, 0.35; 95% However, because of the risk of bias, ran- domized trials have been advocated.870 Although all people at increased risk of complications from influenza should receive influenza vaccinations on the basis of evidence including ran- domized trials, influenza vaccination is recommended by the AHA/ACC for the secondary prevention of CVD. There have been no recommendations for influenza vaccination in the primary prevention of stroke. No studies have identified any increase in the risk of stroke after influenza vaccinations.871 Inflammation and Infection: Recommendations 1. Patients with chronic inflammatory disease such as RA or SLE should be considered at increased risk of stroke (Class I; Level of Evidence B). 2. Annual influenza vaccination can be useful in lower- ing stroke risk in patients at risk of stroke (Class IIa; Level of Evidence B). 3. Measurement of inflammatory markers such as hs- CRP or lipoprotein-associated phospholipase A2 in patients without CVD may be considered to iden- tify patients who may be at increased risk of stroke, although their usefulness in routine clinical practice is not well established (Class IIb; Level of Evidence B). 4. Treatment of patients with hs-CRP >2.0 mg/dL with a statin to decrease stroke risk might be considered (Class IIb; Level of Evidence B). 5. Treatment with antibiotics for chronic infections as a means to prevent stroke is not recommended (Class III; Level of Evidence A). Antiplatelet Agents for Primary Prevention of Stroke Aspirin use is associated with an increased risk of gastrointes- tinal bleeding. For example, 1 observational study found that the overall hemorrhagic event incidence was 5.58 (95% CI, 5.39 5.77) per 1000 person-years for aspirin users compared nonusers (incidence rate ratio, 1.55; 95% CI, 1.48 1.63).872 A meta-analysis of 9 clinical trials including 50868 subjects found no overall benefit of aspirin for the primary preven- with no heterogeneity among trials.873 Similarly, a second meta-analysis of 9 trials with 100076 subjects found that aspirin reduced the risk of ischemic stroke (RR, 0.86; 95% CI, 0.75 0.98), but this benefit was offset by an increase in hemorrhagic stroke (RR, 1.36; 95% CI, 1.01 1.82), again with no heterogeneity among trials.874 A third meta-analysis had similar results (risk of stroke, 0.20%/y versus 0.21%/y, other stroke, 0.16%/y versus 0.18%/y, P=0.08, aspirin versus Taken together, these results reflect risk but no benefit of aspirin for the prevention of a first stroke in the general population. The US Preventive Services Task Force recommends aspirin at a dose of 75 mg/d to prevent MI (but not stroke) in men 45 to 79 years of age and to pre- vent stroke in women 55 to 79 years of age on the basis of their vascular risk and the chances of serious gastrointestinal The US Preventive Services Task Force further notes that the 10-year level of cardiovascular risk for which the benefit exceeds bleeding risk varies from 3% to 11%, depending on age and sex. The most recent AHA guideline for the primary prevention of CVD and stroke also recom- mends aspirin for primary cardiovascular prevention in those with a 10-year coronary heart risk 10%.877 There is no evi- dence that antiplatelet medications reduce the risk of stroke in the general population at low risk.878 880 Although stroke was not analyzed as a separate end point, lack of aspirin use was independently associated with a 16% higher risk of cardiovas- cular events (HR, 1.16; 95% CI, 1.03 1.31) among healthy male physicians 65 years of age.881 The benefit of aspirin for primary prevention of stroke is therefore limited to selected subgroups of patients. Several relevant trials further inform the use of aspirin and other antiplatelet agents for the preven- tion of a first stroke. The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial randomized 2539 patients with type 2 diabetes mellitus but without a history of atheroscle- rotic disease (including stroke) to either low-dose aspirin (81 or 100 mg/d) or no aspirin.321 The primary outcome was the occur- rence of atherosclerotic events (fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease). There was no effect of aspirin on the primary end point (HR, 0.80; 95% CI, 0.58 1.10; P=0.16) and no effect on cerebrovas- cular events (2.2% with aspirin versus 2.5% with no aspirin; HR, 0.84; 95% CI, 0.53 1.32; P=0.44). There was no difference in the combined rates of hemorrhagic stroke and severe gastro- intestinal bleeding. A subgroup analysis of the JPAD trial noted that aspirin therapy lowered the rate of cerebrovascular events in patients with diabetes mellitus with uncontrolled hyperten- sion (SBP 140 mmHg and/or DBP 90 mmHg) compared with those with controlled BP (HR, 1.64; 95% CI, 0.83 3.29), although the 95% CI includes the possibility of no benefit.882 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial was a randomized, double-blind, Meschia et al Guidelines for the Primary Prevention of Stroke 3797 placebo-controlled trial including 1276 adults with type 1 or 2 diabetes mellitus and an ankle-brachial index of 0.99 but no symptomatic CVD who were randomized in a 2-by-2 factorial design to 100 mg aspirin or placebo plus antioxidants or placebo The study had 2 primary end points: (1) death resulting from coronary heart disease or stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia and (2) death resulting from coronary heart disease or stroke. There was no interaction between aspirin and antioxidant. There was no effect of aspirin on the composite primary end points (HR, 0.98; 95% CI, 0.76 1.26; P=0.86) or on death resulting from coronary heart disease or stroke (HR, 1.23; 95% CI, 0.79 1.93; P=0.36). There was no effect of aspirin on fatal stroke (HR, in the risk of gastrointestinal hemorrhage (HR, 0.90; 95% CI, 0.53 1.52; P=0.69). The lack of increased bleeding risk with aspirin in those with diabetes mellitus was also found in the observational study cited above (incidence rate ratio for aspirin Diabetes mellitus was independently associated with an increased risk of major bleeding regardless of aspirin use (RR, 1.36; 95% CI, 1.28 1.44). 