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). A meta-analysis of 7 trials (11618 subjects) of the effects of aspirin in patients with diabetes mellitus found a treat- ment-associated 9% reduction in major cardiovascular events (RR, 0.91; 95% CI, 0.82 1.00) but found no significant reduc- tion in stroke (RR, 0.84; 95% CI, 0.64 1.11).323 Four additional meta-analyses also found no reduction in stroke with aspirin in subjects with diabetes mellitus.884 887 A focused, multisociety position paper on the primary prevention of cardiovascular events in people with diabetes mellitus considered these and other studies and recommended low-dose aspirin for adults with diabetes mellitus who have a 10-year cardiovascular risk >10% (men >50 years of age and women >60 years of age who have at least 1 additional major risk factor such as smoking, hypertension, dyslipid- emia, a family history of premature CVD, or albuminuria) and who are not at high risk of aspirin-related bleeding complica- It was further recommended that aspirin not be used for cardiovascular prevention among those with diabetes mel- litus at low risk and that aspirin might be considered for those at intermediate (10-year risk in the 5% 10% range) risk. Relatively few women were enrolled in the primary preven- tion trials that showed a benefit of aspirin in the prevention of coronary heart events but no reduction in stroke. The WHS randomized 39876 initially asymptomatic women 45 years of age to receive 100 mg aspirin on alternate days or placebo and followed them up for 10 years for a first major vascular event (nonfatal MI, nonfatal stroke, or cardiovascular death).889 Unlike data from earlier studies that included mainly men, this study found a nonsignificant 9% reduction (RR, 0.91; 95% CI, 0.80 1.03; P=0.13) for the combined primary end point among women but a 17% reduction in the risk of stroke (RR, reduction in the risk of ischemic stroke (RR, 0.76; 95% CI, 0.63 0.93; P=0.009) and a nonsignificant increase in the risk of hemorrhagic stroke (RR, 1.24; 95% CI, 0.82 1.87; P=0.31). The overall average stroke rates were 0.11%/y in aspirin- treated women and 0.13%/y in placebo-treated women (RR, 0.02%/y; number needed to treat, 5000). Gastrointestinal hem- orrhage requiring transfusion was more frequent in the aspirin gastrointestinal hemorrhage rates were 0.06%/y for aspirin and 0.05%/y for placebo (absolute risk increase, 0.01%/y; num- ber needed to harm, 10000). The most consistent benefit for aspirin was in women 65 years of age at study entry, among whom the risk of major cardiovascular events was reduced a 30% reduction in the risk of ischemic stroke (RR, 0.70; 95% CI, 0.49 1.00; P=0.05); however, there was only a trend in the reduction of the overall risk of all types of stroke (RR, 0.78; 95% CI, 0.57 1.08; P=0.13), likely related to an increase in the risk of brain hemorrhages. Subgroup analyses showed a reduc- tion in stroke for those women with a history of hypertension further post hoc subgroup WHS analysis found that the over- all effect of aspirin was not modified in women with migraine (with or without aura), but aspirin use was associated with an increased risk of MI in those with migraine with aura (RR, 3.72; 95% CI, 1.39 9.95), an unexpected finding that may have been attributable to chance.615 TheAHA evidence-based guide- lines for CVD prevention in women also endorse the use of aspirin in high-risk women, unless contraindicated, in women 65 years of age if BP is controlled and benefit for ischemic stroke and MI prevention outweighs the risk of gastrointesti- nal bleeding and hemorrhagic stroke, as well as in women <65 years of age when benefit for ischemic stroke prevention is likely to outweigh complications.890 There are several other subpopulations for whom aspirin might be helpful in reducing risk of stroke. Patients with a reduced ankle-brachial index are at higher risk of vascular events. One trial evaluated the benefit of aspirin in a screened general population cohort with a low ankle-brachial index.891 There was no benefit of aspirin in reducing the rate of fatal or nonfatal coronary events, stroke, or revascularization pro- cedures (HR, 1.03; 95% CI, 0.84 1.27). One meta-analysis evaluated cilostazol versus placebo in 3782, 1187, and 705 patients with peripheral artery disease, cerebrovascular dis- ease, and coronary stenting, respectively.892 The incidence of vascular events was lower in the cilostazol group com- pared with the placebo group (RR, 0.86; 95% CI, 0.74 0.99; P=0.038), including a lower incidence of cerebrovascular increase in serious bleeding complications (RR, 1.00; 95% CI, 0.66 1.51; P=0.996). The primary and secondary prevention populations were not analyzed separately; however, there was no statistical heterogeneity among the trials. In a subgroup analysis of the Hypertension Optimal Treatment (HOT) trial, subjects with renal failure (estimated ) had a reduction in stroke risk with aspirin (HR, 0.21; 95% CI, 0.06 0.75).893 In addition, total mortality was reduced by half (HR, 0.51; 95% CI, 0.27 0.94) and cardiovascular mortality by 64% (HR, 0.36; 95% CI, 0.14 0.90). These results, however, were based on a post hoc analysis. Given the small number of participants with stage 4 or 5 chronic kidney disease (estimated glomerular fil- ) in the HOT trial, the RRs and benefits of aspirin in this population are not known. Antiplatelet Agents and Aspirin: Summary and Gaps Previous guideline statements endorse the use of aspirin for cardiac but not stroke prophylaxis among asymptomatic men whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment.876 These recommenda- tions were based on a reduction of coronary events in men and reduction of stroke in women. There remains little evidence (aside from cilostazol in those with peripheral artery disease) supporting the use of antiplate- let therapy other than aspirin and cilostazol for primary stroke prevention because of the lack of relevant trials. Antiplatelet Agents and Aspirin: Recommendations: 1. The use of aspirin for cardiovascular (including but not specific to stroke) prophylaxis is reasonable for people whose risk is sufficiently high (10-year risk >10%) for the benefits to outweigh the risks associ- ated with treatment. A cardiovascular risk calcula- tor to assist in estimating 10-year risk can be found online at http://my.americanheart.org/cvriskcalcula- tor (Class IIa; Level of Evidence A). 2. Aspirin (81 mg daily or 100 mg every other day) can be useful for the prevention of a first stroke among women, including those with diabetes mellitus, whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment (Class IIa; Level of Evidence B). stroke in people with chronic kidney disease (ie, esti- ) (Class IIb; Level of Evidence C). This recommenda- tion does not apply to severe kidney disease (stage 4 or 5; estimated glomerular filtration rate <30 mL/ ). 4. Cilostazol may be reasonable for the prevention of a first stroke in people with peripheral arterial disease (Class IIb; Level of Evidence B). 5. Aspirin is not useful for preventing a first stroke in low-risk individuals (Class III; Level of Evidence A). 6. Aspirin is not useful for preventing a first stroke in people with diabetes mellitus in the absence of other high-risk conditions (Class III; Level of Evidence A). 7. Aspirin is not useful for preventing a first stroke in people with diabetes mellitus and asymptomatic peripheral artery disease (defined as asymptomatic in the presence of an ankle brachial index 0.99) (Class III; Level of Evidence B). 8. The use of aspirin for other specific situations (eg, AF, carotid artery stenosis) is discussed in the relevant sections of this statement. 9. As a result of a lack of relevant clinical trials, anti- platelet regimens other than aspirin and cilostazol are not recommended for the prevention of a first stroke (Class III; Level of Evidence C). Primary Prevention in the Emergency Department Emergency departments (EDs) in the United States are the default safety net for millions of Americans,894 yet at a time when more and moreAmericans use EDs for emergency and primary care, the By definition, EDs provide immediate access to healthcare providers trained in emergency care and allow access to advanced tech- nologies and medical specialists for patients with diverse medi- cal conditions. EDs are equipped to evaluate and manage acute life-threatening illness yet are increasingly called on to provide services typically associated with primary care. For many patients who use the ED for the majority of their healthcare services, the ED may serve as an important location to provide health promo- tion and disease prevention services, including stroke. In addition to addressing the primary reason for the ED visit, the ED encounter may serve to reinforce healthy living, to per- form primary disease identification and prevention, to provide early disease detection (secondary prevention), to encourage and facilitate compliance with disease management, and to refer patients to primary care providers for continued management of existing disease (tertiary prevention).896,897 With the growing num- bers ofAmericans using the ED for primary care, especially socio- economically at-risk populations, the ED may present a unique opportunity to reduce cerebrovascular disease and CVD.898 Enthusiasm to use the ED as a site for initiating primary and secondary preventative services, however, must be tempered by the higher cost of providing care in this setting and per- formance pressures on the ED personnel to decrease length of stay, rates of patients who leave without treatment, overall wait times, and resource use.896,899 Although the list of potentially modifiable stroke risk factors as reviewed in this guideline is extensive, not all are amenable to assessment and initiation of preventive strategies in the ED.896 Aside from resource avail- ability, to effectively initiate primary preventive strategies, ED personnel must know the risk factors for various diseases, in this case stroke; must understand the appropriate diagnostic evaluations and definitions for the risk factors; must be aware of recommendations for appropriate interventions; and must be able to arrange primary care follow-up to assess the effect of initiated preventive interventions. Adding delivery of primary care and primary prevention to the growing list of mandated interventions delivered in the ED setting will require engaging and enabling already largely receptive ED professionals.900 ED visits serve as opportunities to screen and potentially treat patients with asymptomatic hypertension. The prevalence of asymptomatic hypertension in patients presenting to the ED may be as high as 1 in 20.901 Although patients are asymptom- atic, many have target-organ injury; an ED cohort of blacks with elevated BP in the ED found that 90% had subclinical hyper- tensive heart disease.902 In ED patients with newly identified hypertension or chronically untreated hypertension, performing screening tests in the ED for target-organ damage and tests for identifiable causes of hypertension in selected patents is appro- priate. Most asymptomatic patients will not require acute BP reduction or long-term antihypertensive medication initiation in the ED. For most newly diagnosed hypertensive patients, the ED encounter can serve as a means of arranging appropriate referral Meschia et al Guidelines for the Primary Prevention of Stroke 3799 to outpatient primary care, coupled with counseling on lifestyle modifications, although this is inconsistently performed.221,903 ED personnel can identify patients with a history of hyperten- sion but nonadherence to their medication regimen who need to resume their previous medications. ED screening for hyper- tension is feasible and cost-effective. Once hypertensive patients are identified, ED personnel can educate on and encourage healthy lifestyles to address their hypertension and the impor- tance of outpatient follow-up, in accordance with the current Joint National Committee 8 outpatient guidelines.219,896,904 The incidence of diabetes mellitus has more than doubled over the last 2 decades, and millions with the condition remain undiagnosed. On the basis of screening hemoglobin A1c and fasting plasma glucose, the National Health and Nutrition Examination Survey estimated the prevalence of undiagnosed diabetes mellitus in the US population to be 2.8%.905 Similar to hypertension, there is an even higher prevalence of undi- agnosed diabetes mellitus in the ED patient population.905 Although point-of-care glucose and hemoglobin A1c testing of ED patients may be feasible, it remains to be determined whether such screening is cost-effective.906 Unselected screen- ing by capillary blood glucose or hemoglobin A1c measure- ment is not currently recommended by emergency medicine societies or other healthcare agencies, but emergency physi- cians support improved recognition and referral for hyper- Patients with known diabetes mellitus commonly use EDs for acute care of complications related to diabetes mellitus, and many present with poor glycemic con- trol. These encounters provide another opportunity to encour- age medication compliance, dietary management, lifestyle modification, and outpatient follow-up. Despite decades of public health interventions, cigarette smoking remains a leading cause of preventable deaths in the United States, accounting for 1 of every 5 deaths each year.909 Recognizing this continuing problem, theAmerican College of Emergency Physicians recommends ED interventions aimed at smoking cessation.910 Numerous studies have demonstrated that the ED represents a promising site for smoking cessa- tion interventions through self-service kiosks and culturally appropriate literature, brief interventions, and referrals to out- With the high prevalence of smoking- related illnesses leading to ED visits, these episodes provide outstanding teachable moments to encourage cessation. The use of oral antithrombotic agents for the prevention of stroke in patients with nonvalvular AF remains a corner- stone of stroke prevention.390,913 The US National Hospital Ambulatory Medical Care Survey revealed an 88% increase in US ED visits for AF, and visits for AF are likely to increase.914 Despite ample evidence supporting anticoagulation in selected patients with AF, 12% to 34% of patients with AF presenting in the ED are eligible for warfarin but are either undertreated The ED represents an important location to identify patients with new-onset AF, to initiate anticoagula- tion depending on comorbidities, and to plan for the initial management. Similar to patients with known hypertension and diabetes mellitus, for patients with known AF, their ED encounters provide opportunities to promote behaviors to improve compliance with medication and to ensure access to Alcohol consumption is a major contributor to many ED visits. In response to the epidemic of alcohol-related inju- ries and illnesses, numerous ED-based interventions have The American College of Emergency Physicians developed a brief alcohol use intervention bro- chure that does not require significant resources to produce or distribute but, by itself, was found to be only marginally effective in the absence of referral for cessation counseling.920 More interactive ED interventions require more resources but are more likely to produce enduring benefits.921 Integrating health promotion into the curriculum of emergency medicine training programs will help overcome existing nihilism of many practicing emergency physicians related to the benefit of alcohol interventions.922 Nutrition, physical activity, and drug abuse are potential lifestyle targets for behavioral interventions aimed at pri- mary stroke prevention. Of these issues, only the feasibility and efficacy of substance abuse screening and intervention have been studied in the adult ED setting, although an obe- sity screening study in a pediatric ED was recently reported, with more than half of the children being overweight or Obesity contributes to medical conditions fre- quently seen in the ED and may complicate medical inter- ventions. Many physicians are reluctant to discuss issues related to a patient s weight, and patients are not always receptive to the discussion.924 No study has investigated the use of the ED as a site for nutritional and dietary counseling. Overall, although emergency physicians recognize the need for health promotion, few actually practice routine screening and counseling of emergency patients, and many are skepti- cal of the effect of ED health promotion.924 Aside from education on individual risk factors and overall healthy lifestyle promotion, the ED can serve as an effective location to educate patients about stroke signs and symptoms and the need to seek immediate medical attention. A pilot study of stroke education using educational videos was per- formed using printed stroke education materials and one-on- Compared with a control group that did not receive any intervention, the intervention group demon- strated better stroke awareness immediately after the program, but by 3 months after intervention, although statistically still more knowledgeable than the control group, test scores had declined, highlighting the need for reinforcement. The inter- vention did not affect rates of smoking or positive changes in diet and physical activity. The ED can be part of a broader sys- tem to educate and reinforce these key messages. Health care, in particular emergency care, is undergoing dramatic changes. The increasing demands for emergent and primary care will strain the capacity of many EDs to provide even basic emergency care to acutely ill patients. To effectively incorporate preventive services into routine ED practice, a care- ful review of feasibility and cost-effectiveness is required of each intervention, again assuming that sufficient resources are Effective primary, secondary, and tertiary stroke prevention can occur in EDs, but significant healthcare organi- zational changes are required.926 These changes must address current limitations of health promotion training for healthcare providers, program funding, resource availability, and opportu- nities for timely referral for longitudinal care. Primary Prevention in the ED: Summary and Gaps The ED may serve as an important location to provide health promotion and disease prevention services, especially during these unique teachable moments, through screening, brief inter- vention, and referral for treatment. This opportunity to identify risk factors for stroke and to begin primary prevention requires further study into resource use, efficacy, effectiveness, and cost. Primary Prevention in the ED: Recommendations 1. ED-based smoking cessation programs and interven- tions are recommended (Class I; Level of Evidence B). 2. Identification of AF and evaluation for anticoagula- tion in the ED are recommended (Class I; Level of Evidence B). 3. ED population screening for hypertension is reason- able (Class IIa; Level of Evidence C). 4. When a patient is identified as having a drug or alco- hol abuse problem, ED referral to an appropriate therapeutic program is reasonable (Class IIa; Level of Evidence C). 5. The effectiveness of screening, brief intervention, and referral for treatment of diabetes mellitus and life- style stroke risk factors (obesity, alcohol/substance abuse, sedentary lifestyle) in the ED setting is not established (Class IIb; Level of Evidence C). Strategies to Improve Preventive Vascular Health Services Evidence-based guidelines are useful only if the recommen- dations translate into clinical practice. Primary vascular pre- vention approaches are underused in general practice.1,927 For example, in the United States, 6% of adults have undiag- nosed hypertension, and although the number of patients with BP treated to recommended targets has improved from 27% stantial gaps in quality remain.224,928 Opportunities to improve preventive services exist across the range of vascular risk fac- In the United States, vascular health varies substantially across the 50 states, but overall, only 3% of the adult popula- tion has ideal vascular health defined across 7 domains: hyper- tension, hyperlipidemia, smoking, BMI, diabetes mellitus, physical activity, and consumption of fruits and vegetables.929 Although preventive vascular services are a core activity of primary care physicians, specialists also have the opportunity and responsibility to identify stroke risk factors, to ensure that patients receive recommended treatments, and to encourage adherence to therapeutic interventions.930 Strategies to help cli- nicians implement guideline recommendations are often aimed at changing physician behavior related to risk factor preven- A combination of techniques is usually necessary to improve stroke preventive care, including physician education, audit and feedback of quality data, and use of checklists.931 939 Some strategies to improve stroke prevention care, although relatively costly, are more consistently effective, including electronic medical records; computer-based clinical reminder systems; and tailored, multifaceted programs.940 944 Other strate- gies focus on changing the organization or context in which the care is delivered, including delegation of preventive services to nonphysician staff (eg, nurses or pharmacists), the use of group visits, or the implementation of clinics devoted to screening and Quality improvement efforts that include activities that focus on the system, the provider, and the patient, as well as the coordination of services across these domains, are often the most effective.949 Studies examining the effectiveness of stroke education programs have generally iden- tified a modest effect on patient knowledge, risk perception, or However, studies have demonstrated the effectiveness of tailored patient self-management programs to improve vascular risk factor control.950,951 Integrated healthcare systems that have focused on improving the quality of vascu- lar prevention have demonstrated improvements in a variety of stroke risk factors at the facility or system level.952,953 Achieving sustained improvements in the quality of vascular prevention care at the system level may require multidimensional interven- tions, including implementation of electronic medical record systems, ongoing performance measurement, change in the cul- ture, and alignment of economic incentives.953,954 Stroke preven- tion services are most cost-effective for populations at increased risk (eg, patients >50 years of age).955 Preventive Health Services: Summary and Gaps Although stroke risk factor quality of care is improving, sub- stantial gaps in primary stroke prevention care exist. The existing literature includes prospective trials and observa- tional cohorts that demonstrate the effectiveness of a vari- ety of approaches to delivering vascular prevention services. These studies have been designed to evaluate the effect of pri- mary prevention services on the control of risk factors such as hypertension, not on incident stroke rates. Quality improve- ment strategies that are multifaceted and tailored appear to be the most effective. Future research should identify the imple- mentation strategies that are associated with the greatest sus- tained improvements in preventing stroke. Preventive Health Services: Recommendation 1. It is reasonable to implement programs to systemati- cally identify and treat risk factors in all patients at risk for stroke (Class IIa; Level of Evidence A). Summary/Conclusions In this latest iteration of the guidelines, physicians and scientists should take pride in the advances that continue to be made in pre- venting stroke. Medications to control BP and lipids, anticoagu- lants for at-risk individuals with AF, revascularization, cigarette smoking cessation, diet, and exercise are among the interventions broadly applicable to the general public. With so many interven- tions, optimization of stroke prevention for individuals requires systems of care that identify risk factors as they emerge and that gain control of emerging risk factors safely, expeditiously, and cost-effectively. Access to care is necessary but not sufficient to guarantee optimal stroke prevention. Integration of inpatient and outpatient services and incentivizing efforts directed at prevent- ing stroke must also be considered. New recommendations and important revisions are summarized in Table 5. Meschia et al Guidelines for the Primary Prevention of Stroke 3801 Table 5. New and Revised Recommendations for 2014* Section 2014 Recommendation Description of Change from 2011 Assessing the risk of first stroke 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). Reworded to add AHA/ACC CV Risk Calculator and link Genetic factors 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). Slightly reworded; no change in class or level of evidence Screening for intracranial aneurysms in every carrier of autosomal-dominant polycystic kidney disease or Ehlers-Danlos type 4 mutations is not recommended (Class III; Level of Evidence C). Previous statement was worded with less specificity, referring to mendelian disorders associated with aneurysms Pharmacogenetic dosing of vitamin K antagonists may be considered when therapy is initiated (Class IIb; Level of Evidence C). Changed from Class III (is not recommended) to Class IIb (may be considered) Physical inactivity Healthy adults should perform at least moderate- to vigorous-intensity aerobic physical activity at least 40 min a day 3 to 4 d/wk (Class I; Level of Evidence B). Changed wording to match new AHA lifestyle guideline Dyslipidemia In addition to therapeutic lifestyle changes, treatment with an HMG coenzyme-A reductase inhibitor (statin) medication is recommended for primary prevention of ischemic stroke in patients estimated to have a high 10-y 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 (Class I; Level of Evidence A). Reworded to incorporate ACC/AHA guidelines (instead of NCEP); no change in class/LOE. Focusing on estimated cardiovascular risk as the determinant for initiating therapy is new. Niacin may be considered for patients with low high-density lipoprotein cholesterol or elevated lipoprotein(a), but its efficacy in preventing ischemic stroke in patients with these conditions is not established. Caution should be used with niacin because it increases the risk of myopathy (Class IIb; Level of Evidence B). Changed from LOE C to LOE B; the risk of myopathy is highlighted 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). Reworded from other to nonstatin (no change in class or LOE). Reference is no longer made to an low-density lipoprotein target for statin therapy because the decision to use moderate or intensive statin therapy depends on estimated risk of future cardiovascular events. Diet and nutrition A Mediterranean diet supplemented with nuts may be considered in lowering the risk of stroke (Class IIb; Level of Evidence B). New recommendation Hypertension Regular blood pressure screening and appropriate treatment of patients with hypertension, including lifestyle modification and pharmacological therapy, are recommended (Class I; Level of Evidence A). Annual blood pressure screening for high blood pressure and health-promoting lifestyle modification are recommended for patients with prehypertension (systolic blood pressure of 120 139 mmHg or diastolic blood pressure of 80 89 mmHg) (Class I; Level of Evidence A). New recommendations Successful reduction of blood pressure is more important in reducing stroke risk than the choice of a specific agent, and treatment should be individualized on the basis of other patient characteristics and medication tolerance (Class I; Level of Evidence A). New recommendation Self-measured blood pressure monitoring is recommended to improve blood pressure control (Class I; Level of Evidence A) New recommendation Obesity and body fat distribution Among overweight (body mass index=25 to 29 kg/m2 ) and obese (body mass index >30 kg/m2 ) individuals, weight reduction is recommended for lowering blood pressure (Class I; Level of Evidence A). Overweight and obesity have now been defined on the basis of body mass index (Continued) Obesity and body fat distribution cont'd Among overweight (body mass index=25 to 29 kg/m2 ) and obese (body mass index >30 kg/m2 ) individuals, weight reduction is recommended for reducing the risk of stroke (Class I; Level of Evidence B). Overweight and obesity have now been defined on the basis of body mass index, and the recommendation has been upgraded from IIa to I Diabetes mellitus Control of blood pressure in accordance with an AHA/ACC/CDC advisory to a target of <140/90 mmHg is recommended in patients with type 1 or type 2 diabetes mellitus (Class I; Level of Evidence A). Reworded to reference AHA/ACC/ CDC advisory The usefulness of aspirin for primary stroke prevention for patients with diabetes mellitus but low 10-y risk of cardiovascular disease is unclear (Class IIb; Level of Evidence B). Deleted the phrase however, administering aspirin may be reasonable Cigarette smoking Counseling in combination with drug therapy using nicotine replacement, bupropion, or varenicline is recommended for active smokers to assist in quitting smoking (Class I; Level of Evidence A). Reworded and LOE changed from B to A Community-wide or statewide bans on smoking in public spaces are reasonable for reducing the risk of stroke and myocardial infarction (Class IIa; Level of Evidence B). New recommendation Atrial fibrillation For patients with valvular atrial fibrillation at high risk for stroke, defined as a CHA2 - VASc score of 2, and acceptably low risk for hemorrhagic complications, chronic oral anticoagulant therapy with warfarin at a target INR of 2.0 to 3.0 is recommended (Class I; Level of Evidence A). New recommendation For patients with nonvalvular atrial fibrillation, a CHA2 -VASc score of 2, and acceptably low risk for hemorrhagic complications, oral anticoagulants are recommended (Class I). Options include warfarin (INR, 2.0 to 3.0) (Level of Evidence A), dabigatran (Level of Evidence B), apixaban (Level of Evidence B), and rivaroxaban (Level of Evidence B). The selection of antithrombotic agent should be individualized on the basis of patient risk factors (particularly risk for intracranial hemorrhage), cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time INR is in therapeutic range for patients taking warfarin. New recommendation For patients with nonvalvular atrial fibrillation and CHA2 -VASc score of 0, it is reasonable to omit antithrombotic therapy (Class IIa; Level of Evidence B). New recommendation For patients with nonvalvular atrial fibrillation, a CHA2 -VASc score of 1, and acceptably low risk for hemorrhagic complication, no antithrombotic therapy, anticoagulant therapy, or aspirin therapy may be considered (Class IIb; Level of Evidence C). The selection of antithrombotic agent should be individualized on the basis of patient risk factors (particularly risk for intracranial hemorrhage), cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time INR is in therapeutic range for patients taking warfarin. New recommendation Closure of the left atrial appendage may be considered for high-risk patients with atrial fibrillation who are deemed unsuitable for anticoagulation if performed at a center with low rates of periprocedural complications and the patient can tolerate the risk of at least 45 d of postprocedural anticoagulation (Class IIb; Level of Evidence B). New recommendation Other cardiac conditions Anticoagulation is indicated in patients with mitral stenosis and a prior embolic event, even in sinus rhythm (Class I; Level of Evidence B). New recommendation Anticoagulation is indicated in patients with mitral stenosis and left atrial thrombus (Class I; Level of Evidence B). New recommendation Warfarin (target INR, 2.0 3.0) and low-dose aspirin are indicated after aortic valve replacement with bileaflet mechanical or current-generation, single-tilting-disk prostheses in patients with no risk factors* (Class I; Level of Evidence B); warfarin (target INR, 2.5 3.5) and low- dose aspirin are indicated in patients with mechanical aortic valve replacement and risk factors* (Class I; Level of Evidence B); and warfarin (target INR, 2.5 3.5) and low-dose aspirin are indicated after mitral valve replacement with any mechanical valve (Class I; Level of Evidence B). New recommendations Surgical excision is recommended for treatment of atrial myxomas (Class I; Level of Evidence C). New recommendation Table 5. Continued Section 2014 Recommendation Description of Change from 2011 (Continued) Meschia et al Guidelines for the Primary Prevention of Stroke 3803 Other cardiac conditions cont'd Surgical intervention is recommended for symptomatic fibroelastomas and for fibroelastomas that are >1 cm or appear mobile, even if asymptomatic (Class I; Level of Evidence C) New recommendation Aspirin is reasonable after aortic or mitral valve replacement with a bioprosthesis (Class IIa; Level of Evidence C). New recommendation It is reasonable to give warfarin to achieve an INR of 2.0 3.0 during the first 3 mo after aortic or mitral valve replacement with a bioprosthesis (Class IIa; Level of Evidence C). New recommendation Anticoagulants or antiplatelet agents are reasonable for patients with heart failure who do not have atrial fibrillation or a previous thromboembolic event (Class IIa; Level of Evidence A). New recommendation Vitamin K antagonist therapy is reasonable for patients with ST-segment elevation myocardial infarction and asymptomatic left ventricular mural thrombi (Class IIa; Level of Evidence C). The level of evidence has been downgraded from A to C, but the recommendation grade is the same Anticoagulation may be considered for asymptomatic patients with severe mitral stenosis and left atrial dimension 55 mm by echocardiography (Class IIb; Level of Evidence B). New recommendation Anticoagulation may be considered for patients with severe mitral stenosis, an enlarged left atrium, and spontaneous contrast on echocardiography (Class IIb; Level of Evidence C). New recommendation Anticoagulant therapy may be considered for patients with ST-segment elevation myocardial infarction and anterior apical akinesis or dyskinesis (Class IIb; Level of Evidence C). New recommendation Antithrombotic treatment and catheter-based closure are not recommended in patients with patent foramen ovale for primary prevention of stroke (Class III; Level of Evidence C). New recommendation Asymptomatic carotid stenosis Patients with asymptomatic carotid stenosis should be prescribed daily aspirin and a statin. Patients should also be screened for other treatable risk factors for stroke, and appropriate medical therapies and lifestyle changes should be instituted (Class I; Level of Evidence C). New recommendation. The use of aspirin and statin therapy was implied but not explicitly stated except in the perioperative and postoperative context in the prior guidelines. It is reasonable to consider performing carotid endarterectomy in asymptomatic patients who have >70% stenosis of the internal carotid artery if the risk of perioperative stroke, myocardial infarction, and death is low (<3%). However, its effectiveness compared with contemporary best medical management alone is not well established (Class IIa; Level of Evidence A). New recommendation It is reasonable to repeat duplex ultrasonography annually by a qualified technologist in a certified laboratory to assess the progression or regression of disease and response to therapeutic interventions in patients with atherosclerotic stenosis >50% (Class IIa; Level of Evidence C). New recommendation Prophylactic carotid angioplasty and stenting might be considered in highly selected patients with asymptomatic carotid stenosis (minimum, 60% by angiography, 70% by validated Doppler ultrasound), but its effectiveness compared with medical therapy alone in this situation is not well established (Class IIb; Level of Evidence B). New recommendation In asymptomatic patients at high risk of complications for carotid revascularization by either carotid endarterectomy or carotid angioplasty and stenting, the effectiveness of revascularization versus medical therapy alone is not well established (Class IIb; Level of Evidence B). New recommendation Sickle cell disease Transcranial Doppler screening for children with sickle cell disease is indicated starting at 2 y of age and continuing annually to 16 y of age (Class I; Level of Evidence B). Slightly reworded to include up to 16 y (no change in class or LOE) In children at high risk for stroke who are unable or unwilling to be treated with periodic red cell transfusion, it might be reasonable to consider hydroxyurea or bone marrow transplantation (Class IIb; Level of Evidence B). Changed from LOE C to LOE B Migraine Smoking cessation should be strongly recommended in women with migraine headaches with aura (Class I; Level of Evidence B). New recommendation Alternatives to oral contraceptives, especially those containing estrogen, might be considered in women with active migraine headaches with aura (Class IIb; Level of Evidence B). New recommendation Table 5. Continued Section 2014 Recommendation Description of Change from 2011 (Continued) As health professionals, we must ensure that progress in pre- venting stroke does not lead to complacency.We must acknowl- edge that several recommendations remain vague because of suboptimal clinical trial evidence or, even more concerning, may be out of date and therefore irrelevant. Diet and exercise are notoriously challenging to study with the same rigor as drugs or devices. It is easier to convince a patient to take a pill than to radically change his or her lifestyle. Nonetheless, we must expect the same standards of evidence for lifestyle interventions. Devices such as stents for carotid stenosis and occluders for PFO should be required to demonstrate favorable effects on patient-centered outcomes such as preventing stroke and not merely demonstrate favorable effects on surrogates such as expanding lumens or closing holes. The control groups of old that showed the benefits of CEA for asymptomatic stenosis would be seen as grossly undertreated medically by contemporary standards. It would be important to see if revas- cularization remains relevant in a modern context. Acknowledgments We thank medical librarians Ann Farrell at Mayo Clinic Rochester and Tara Brigham at Mayo Clinic Florida for assistance with a sys- tematic review of the medical literature. Migraine cont'd Closure of patent foramen ovale is not indicated for preventing stroke in patients with migraine (Class III; Level of Evidence B). New recommendation Drug abuse 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). Wording slightly revised to specifically list drugs associated with stroke Sleep-disordered breathing Because of its association with stroke risk, screening for sleep apnea through a detailed history, including 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). Wording slightly revised to include polysomnography and use of specific questionnaires. Recommendation class and LOE have been downgraded. Elevated lipoprotein(a) The clinical benefit of using lipoprotein(a) in stroke risk prediction is not well established (Class IIb; Level of Evidence B). New recommendation Inflammation and infection Treatment of patients with high-sensitivity C-reactive protein >2.0 mg/dL with a statin to decrease stroke risk might be considered (Class IIb; Level of Evidence B). The revised recommendation now defines elevated high-sensitivity C-reactive protein as >2.0 mg/ dL in the context of considering statin initiation Antiplatelet agents and aspirin The use of aspirin for cardiovascular (including but not specific to stroke) prophylaxis is reasonable for people whose risk is sufficiently high (10-y risk >10%) for the benefits to outweigh the risks associated with treatment. A cardiovascular risk calculator to assist in estimating 10-y risk can be found online at http://my.americanheart.org/cvriskcalculator (Class IIa; Level of Evidence A). Reworded to include cardiovascular risk calculator and link; changed from Class I to IIa Aspirin might be considered for the prevention of a first stroke in people with chronic kidney disease (ie, estimated glomerular filtration rate <45 mL min 1 ) (Class IIb; Level of Evidence C). This recommendation does not apply to severe kidney disease (stage 4 or 5; estimated glomerular filtration rate <30 mL min 1 ). New recommendation Cilostazol may be reasonable for the prevention of a first stroke in people with peripheral arterial disease (Class IIb; Level of Evidence B). New recommendation As a result of a lack of relevant clinical trials, antiplatelet regimens other than aspirin and cilostazol are not recommended for the prevention of a first stroke (Class III; Level of Evidence C). New recommendation ACC indicates American College of Cardiology; AHA, American Heart Association; CDC, Centers for Disease Control and Prevention; CV, cardiovascular; INR, international normalized ratio; LOE, level of evidence; and NCEP, National Cholesterol Education Program. *This table does not include recommendations that have been removed. Table 5. Continued Section 2014 Recommendation Description of Change from 2011 Meschia et al Guidelines for the Primary Prevention of Stroke 3805 Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/Advisory Board Other James F. Meschia Mayo Clinic NINDS None None None None None None Cheryl Bushnell Wake Forest University Baptist Medical Center World Federation of Neurology None None None None None None Bernadette Boden-Albala New York University, Global Institute of Public Health NIH None None None None None None Lynne T. Braun Rush University Medical Center NIH None None None None Nurse Practitioner Advisory Board*; UpToDate* None Dawn M. Bravata Department of Veteran Affairs Department of Veteran Affairs ; NIH/NHLBI None None None None None None Seemant Chaturvedi University of Miami Miller School of Medicine None None None None None Abbott Vascular*; Boehringer-Ingelheim*; Thornhill Research* W.L. Gore* None Mark A. Creager Brigham and Women s Hospital Medtronic ; NIH None None None None AstraZeneca ; Baxter Healthcare*; Merck (via TIMI Group)*; Novartis*; Takeda* None Robert H. Eckel University of Colorado at Denver None None None None None Amarin*; Amylin*; Genetech*; Janssen, Johnson & Johnson*; Lilly*; Novo Nordisk*; Regulus*; Sanofi-Aventis* None Mitchell S.V. Elkind Columbia University BMS/Sanofi ; diaDexus, Inc NIH None None Merck Organon (Nuvaring and stroke) ; Novartis (aliskiren and stroke)* None BMS-Pfizer Pharmaceutical Partnership*; Janssen*; Daiichi Sankyo*; Biogen IDEC* None Myriam Fornage University of Texas Health Science Center at Houston None None None None None None None Larry B. Goldstein Duke University None None Pfizer* None None Daiichi Sankyo* None Steven M. Greenberg Massachusetts General Hospital NIH/NINDS None None None None None None Susanna E. Horvath Columbia University None None None None None None None Costantino Iadecola Weill Cornell Medical College None None None None None None None Edward C. Jauch Medical University of South Carolina NIH/NINDS None None None None None None Wesley S. Moore University of California at Los Angeles None None None None None None None John A. Wilson Wake Forest School of Medicine None None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. Disclosures References 1. 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Sacco RL, Benjamin EJ, Broderick JP, Dyken M, Easton JD, Feinberg WM, Goldstein LB, Gorelick PB, Howard G, Kittner SJ, Manolio TA, Whisnant JP, Wolf PA. American Heart Association Prevention Conference, IV: prevention and rehabilitation of stroke: risk factors. Stroke. 1997;28:1507 1517. 8. O Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, Rangarajan S, Islam S, Pais P, McQueen MJ, Mondo C, Damasceno A, Lopez-Jaramillo P, Hankey GJ, Dans AL, Yusoff K, Truelsen T, Diener HC, Sacco RL, Ryglewicz D, CzlonkowskaA, Weimar C, Wang X,Yusuf S; INTERSTROKE Investigators. Risk factors for ischaemic and intrace- rebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112 123. 9. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA; on behalf of the American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:517 584. 10. Sacco RL. The new American Heart Association 2020 goal: achiev- ing ideal cardiovascular health. J Cardiovasc Med (Hagerstown). 2011;12:255 257. 11. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/Advisory Board Other Kevin M. Cockroft Penn State Hershey Medical Center None None None None None Covidien Neurovascular* None Karen L. Furie Rhode Island Hospital None None None None None None None David M Greer Yale University None None None None None None None Millie Hepburn-Smith NYU Langone Medical Center None None None None None American Association of NeuroScience Nurses (member of the Board of Directors)*; National Aphasia Association (Board of Directors)* None Steven J. Kittner University of Maryland 1U01NS069208 The Stroke Genetics Network (SiGN) Study is an NINDS-funded international consortium to study the genetics of ischemic stroke and ischemic stroke Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) is an NINDS-funded study of the risk factors for intracerebral hemorrhage occurrence and outcome* None None None None None None Tatjana Rundek University of Miami None None None None None None None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. 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