The FIELD study assessed the effect of fenofibrate on car- diovascular events in 9795 subjects 50 to 75 years of age with type 2 diabetes mellitus who were not taking a statin therapy at study entry.319 The study population included 2131 people with and 7664 people without previous CVD. Over 5 years, 5.9% of patients (n=288) on placebo and 5.2% (n=256) on fenofibrate had a coronary event (P=0.16). There was a 24% MI. There was no effect on stroke with fenofibrate. A higher rate of statin therapy initiation occurred in patients allocated to placebo, which might have masked a treatment effect. The ACCORD trial randomized 5518 patients with type 2 diabetes mellitus who were being treated with open-label simvastatin to double-blind treatment with fenofibrate or placebo.177 There was no effect of added fenofibrate on the primary outcome (first occurrence of nonfatal MI, nonfatal stroke, or death from cardiovascular causes [HR, 0.92; 95% CI, 0.79 1.08; P=0.32]) and no effect on any secondary outcome, including stroke (HR, 1.05; 95% CI, 0.71 1.56; P=0.80). A recent meta-analysis examining the effects of fibrates on stroke in 37791 patients included some patients with diabetes Overall, fibrate therapy was not associated with a significant reduction on the risk of stroke (RR, 1.02; 95% CI, 0.90 1.16; P=0.78). However, a subgroup analysis suggested that fibrate therapy reduced fatal stroke (RR, 0.49; 95% CI, 0.26 0.93; P=0.03) in patients with diabetes mellitus, CVD, or stroke. Diabetes Mellitus, Aspirin, and Stroke The benefit of aspirin in the primary prevention of cardiovascu- lar events, including stroke in patients with diabetes mellitus, remains unclear. A recent study at 163 institutions throughout Japan enrolled 2539 patients with type 2 diabetes mellitus and no history of atherosclerotic vascular disease.321 Patients were assigned to receive low-dose aspirin (81 or 100 mg/d) or no aspirin. Over 4.37 years, a total of 154 atherosclerotic vascu- lar events occurred (68 in the aspirin group [13.6 per 1000 person-years] and 86 in the nonaspirin group [17.0 per 1000 single fatal stroke occurred in the aspirin group, but 5 strokes occurred in the nonaspirin group; thus, the study was insuf- ficiently powered to detect an effect on stroke. Severallargeprimarypreventiontrialshaveincludedsubgroup analyses of patients with diabetes mellitus. The Antithrombotic Trialists Collaboration meta-analysis of 287 randomized trials reported effects of antiplatelet therapy (mainly aspirin) versus There was a nonsignificant 7% reduction in serious vascular events, including stroke, in the subgroup of 5126 patients with diabetes mellitus. A meta-analysis covering the interval between 1950 and 2011 included 7 studies in patients with diabetes mellitus without previous CVD and helps to shed new light on this controversial A total of 11618 participants were included in the anal- ysis. The overall relative risk for major cardiovascular events was 0.91 (95% CI, 0.82 1.00), but an effect on stroke incidence was not found (RR, 0.84; 95% CI, 0.64 1.11). Because hyper- glycemia reduces platelet sensitivity to aspirin,324 an important consideration in patients with diabetes mellitus is aspirin dose. In another meta-analysis, there was no evidence that aspirin dose explained the lack of an aspirin effect on cardiovascular and stroke mortality in patients with diabetes mellitus.325 However, the systematic review identified an important gap in random- ized, controlled trials for using anywhere between 101 to 325 mg aspirin daily in patients with diabetes mellitus. Diabetes: Summary and Gaps A comprehensive program that includes tight control of hyper- tension with ACEI or ARB treatment reduces the risk of stroke in people with diabetes mellitus. Glycemic control reduces microvascular complications, but there remains no evidence that improved glycemic control reduces the risk of incident stroke. Adequately powered studies show that treatment of patients with diabetes mellitus with a statin decreases the risk of a first stroke. Although a subgroup analysis of VA-HIT suggests that gemfi- brozil reduces stroke in men with diabetes mellitus and dyslip- idemia, a fibrate effect was not seen in FIELD, and ACCORD found no benefit of adding fenofibrate to statin. However, the subgroup analysis from fibrate trials suggests a benefit of fibrates in patients with diabetes mellitus and a BMI >30 kg/m2 . Diabetes: Recommendations 1. Control of BP in accordance with an AHA/ACC/ to a target of <140/90 mmHg is rec- ommended in patients with type 1 or type 2 diabetes mellitus (Class I; Level of Evidence A). 2. Treatment of adults with diabetes mellitus with a statin, especially those with additional risk factors, is recommended to lower the risk of first stroke (Class I; Level of Evidence A). 3. The usefulness of aspirin for primary stroke prevention for patients with diabetes mellitus but low 10-year risk of CVD is unclear (Class IIb; Level of Evidence B). 4. Adding a fibrate to a statin in people with diabetes mellitus is not useful for decreasing stroke risk (Class III; Level of Evidence B). Cigarette Smoking Virtually every multivariable assessment of stroke risk factors and the Honolulu Heart Study327 ) has identified cigarette smoking as a potent risk factor for ischemic stroke, associated with an approximate doubling of risk. Data from studies largely conducted in older age groups also pro- vide evidence of a dose-response relationship, and this has been extended to young women from an ethnically diverse cohort.328 Smoking is also associated with a 2- to 4-fold increased risk for The data for ICH (apart from SAH), however, are inconsistent. A multicenter case-control study found an adjusted for ICH, and analyses from the Physicians Health Study332 also found such an association, but other studies, including a pooled analysis of the ARIC and CHS cohorts, found no relationship between smoking and ICH risk.135,334 336 A meta-analysis of 32 studies estimated the RR for ischemic stroke to be 1.9 (95% CI, 1.7 2.2) for smokers versus nonsmokers, the RR for SAH to be 2.9 (95% CI, 2.5 3.5), and the RR for ICH to be 0.74 (95% CI, 0.56 0.98).335 The annual number of stroke deaths attributed to smoking in the United States is estimated to be between 21400 (with- out adjustment for potential confounding factors) and 17800 (after adjustment), which suggests that smoking contributes to From data available from the National Health Interview Survey and death certificate data for 2000 through 2004, the Centers for Disease Control and Prevention estimated that smoking resulted in an annual average of 61616 stroke deaths among men and 97681 stroke deaths among women.338 Cigarette smoking may potentiate the effects of other stroke risk factors, including SBP339 For example, a synergistic effect exists between the use of OCs and smoking on the risk of cerebral infarction. With nonsmoking, non-OC users serving as the reference group, the odds of cerebral infarc- tion were 1.3 times greater (95% CI, 0.7 2.1) for women who smoked but did not use OCs, 2.1 times greater (95% CI, 1.0 4.5) for nonsmoking OC users, and 7.2 times greater (95% CI, 3.2 16.1) for OC users who smoked.340 There was also a syn- ergistic effect of smoking and OC use on hemorrhagic stroke risk. With nonsmoking, non-OC users as the reference group, the odds of hemorrhagic stroke were 1.6 times greater (95% CI, 1.2 2.0) for women who smoked but did not use OCs, 1.5 times greater (95% CI, 1.1 2.1) for nonsmoking OC users, and 3.7 times greater (95% CI, 2.4 5.7) for OC users who smoked.341 Exposure to environmental tobacco smoke (also referred to as passive or second-hand smoke) is an established risk factor for heart disease.342,343 Exposure to environmental tobacco smoke may also be a risk factor for stroke, with a risk approaching the doubling found for active smoking,344 349 although 1 study found no association.350 Because the dose of exposure to environmental tobacco smoke is substantially lower than for active smoking, the magnitude of the risk associated with environmental tobacco smoke is surpris- ing. This apparent lack of a dose-response relationship may be explained in part by physiological studies suggesting a tobacco smoke exposure threshold rather than a linear dose- Recent studies of the effects of smok- ing bans in communities have also shown that these bans are associated with a reduction in the risk of stroke. After Arizona enacted a statewide ban on smoking in most indoor public places. including workspaces, restaurants, and bars, there was a 14% reduction in strokes in counties that had not previously had a ban in place.352 A study of New York State did not find a reduction in strokes despite a decrease in risk of MI when it enacted a comprehensive smoking ban in enclosed work- spaces, restaurants, and construction sites.353 Smoking likely contributes to increased stroke risk through both short-term effects on the risk of thrombus generation in ath- erosclerotic arteries and long-term effects related to increased Smoking as little as a single cigarette increases heart rate, mean BP, and cardiac index and decreases arterial dis- Beyond the immediate effects of smoking, both active and passive exposure to cigarette smoke is associated with the development of atherosclerosis.357 In addition to placing indi- viduals at increased risk for both thrombotic and embolic stroke, cigarette smoking approximately triples the risk of cryptogenic stroke among individuals with a low atherosclerotic burden and no evidence of a cardiac source of emboli.358,359 Although the most effective preventive measures are to never smoke and to minimize exposure to environmental tobacco smoke, risk is reduced with smoking cessation. Smoking cessa- tion is associated with a rapid reduction in the risk of stroke and other cardiovascular events to a level that approaches, but does not reach, that of those who never smoked.354,360 362 Although sustained smoking cessation is difficult to achieve, effective behavioral and pharmacological treatments for nicotine dependence are available.363 365 Comprehensive reviews and recommendations for smoking cessation are pro- vided in the 2008 Surgeon General s report,363 the 2008 update from the Public Health Service,366 and the 2009 affirmation of these recommendations from the US Preventive Services Task The combination of counseling and medications is more effective than either therapy alone.367 With regard to specific pharmacotherapy, in a meta-anal- ysis current to January 2012, nicotine replacement therapy, bupropion, and varenicline were all superior to inert control medications, but varenicline was superior to each of the other active interventions in direct comparisons.368 Emerging evi- dence suggests that varenicline may be more cost-effective than nicotine replacement therapy.369 Cigarette Smoking: Summary and Gaps Cigarette smoking increases the risk of ischemic stroke and SAH, but the data on ICH are inconclusive. Epidemiological studies show a reduction in stroke risk with smoking cessation and with community-wide smoking bans. Although effective programs to facilitate smoking cessation exist, data show- ing that participation in these programs leads to a long-term reduction in stroke are lacking. Cigarette Smoking: Recommendations 1. 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). 2. Abstention from cigarette smoking is recommended for patients who have never smoked on the basis of epidemiological studies showing a consistent and overwhelming relationship between smoking and both ischemic stroke and SAH (Class I; Level of Evidence B). Meschia et al Guidelines for the Primary Prevention of Stroke 3773 3. Community-wide or statewide bans on smoking in public spaces are reasonable for reducing the risk of stroke and MI (Class IIa; Level of Evidence B). Atrial Fibrillation AF, even in the absence of cardiac valvular disease, is associ- ated with a 4- to 5-fold increased risk of ischemic stroke result- ing from embolism of stasis-induced thrombi forming in the left atrial appendage (LAA).370 About 2.3 million Americans have either sustained or paroxysmal AF.370 Embolism of appendage thrombi associated with AF accounts for 10% of all ischemic strokes and an even higher fraction in the very elderly in the United States.371 The absolute stroke rate aver- ages 3.5%/y for 70-year-old individuals with AF, but the risk varies 20-fold among patients, depending on age and other clinical features (see below).372,373 AF is also an independent predictor of increased mortality.374 Paroxysmal AF increases stroke risk similar to sustained AF.375 There is an important opportunity for primary stroke pre- vention in patients with AF because the dysrhythmia is diag- nosed before stroke in many patients. However, a substantial minority of AF-related stroke occurs in patients without a prior diagnosis of the condition. Studies of active screening of patients >65 years of age for AF in primary care settings show that pulse assessment by trained personnel increases the detection of undiagnosed AF.376,377 Systematic pulse assess- ment during routine clinic visits followed by 12-lead ECG in those with an irregular pulse resulted in a 60% increase in the detection of AF.376 Risk Stratification in Patients With AF Once the diagnosis of AF is established, the next step is to estimate an individual s risks for cardioembolic stroke and for hemorrhagic complications of antithrombotic therapy. For estimating risk of AF-related cardioembolic stroke, more than a dozen risk stratification schemes have been proposed on the basis of various combinations of clinical and echocar- The widely used CHADS2 scheme (Table 3) yields a score of 0 to 6, with 1 point each given for congestive heart failure, hypertension, age 75 years, and diabetes mellitus and with 2 points given for prior stroke or transient ischemic attack (TIA).378 This scheme has been tested in multiple independent cohorts of AF patients, with 0 points corresponding to low risk (0.5% and 2 points indicating high risk (1.9%/y 7.6%/y).373 The -VASc scheme (Table 3) modifies CHADS2 by add- ing an age category (1 point for age 65 to 74 years, 2 points for age 75 years) and adding 1 point each for diagnosis of vas- cular disease (such as peripheral artery disease, MI, or aortic plaque) and for female sex. The main advantage of the more -VASc scheme for primary stroke pre- vention is improved stratification of individuals estimated to be at low to moderate risk using CHADS2 (scores of 0 to 1). A study of 45576 such patients found combined stroke and thromboembolism rates per 100 person-years ranging from -VASc of 0 to 1.79, respectively, resulting in significantly improved prediction.383 Instruments have also been proposed for stratifying risk of bleeding associated with warfarin treatment for AF. In the HAS-BLED scheme (Table 3), 1 point is assigned each for hypertension, abnormal renal or liver function, past stroke, past bleeding history or predisposition, labile INR (ie, poor time in therapeutic range), older age (age >65 years), and use of certain drugs (concomitant antiplatelet or nonsteroidal anti- inflammatory agent use, alcohol abuse).381 In a validation anal- ysis of data from 2293 subjects randomized to idraparinux or vitamin K antagonist therapy, the HAS-BLED score was mod- erately predictive (HAS-BLED >2: HR, 1.9 for clinically rele- vant bleeding; HR, 2.4 for major bleeding).382 The ATRIA Risk derived its point scheme from the Anticoagulation and Risk Factors in Atrial Fibrillation study, assigning 3 points for anemia or severe renal disease (estimated glomerular filtra- tion rate <30 mL/min or dialysis dependent), 2 for age 75 years, and 1 for any prior hemorrhage diagnosis or hyperten- sion. Subjects in a validation cohort were successfully divided into groups at low (ATRIA score of 0 to 3, <1%/y) and high (ATRIA score of 5 to 10, >5%/y) risk for major hemorrhage. Table 3. Stroke Risk Stratification Schemes for Patients With Atrial Fibrillation Scoring system Congestive heart failure 1 point Diabetes mellitus 1 point Risk scores range: 0 6 points Levels of risk for thromboembolic stroke Low risk for stroke=0 points Moderate risk=1 point High risk 2 points Scoring system Congestive heart failure 1 point Diabetes mellitus 1 point Vascular disease (eg, peripheral artery disease, myocardial infarction, aortic plaque) 1 point Female sex 1 point Risk scores range: 0 9 points Levels of risk for thromboembolic stroke Low risk=0 points Moderate risk=1 point High risk 2 points ACCP treatment guidelines based on estimated risk for thromboembolic Low risk: no therapy Moderate risk: OAC High risk: OAC Abnormal renal function 1 point Abnormal liver function 1 point Prior stroke 1 point Prior major bleeding or bleeding INR in therapeutic range <60% of time 1 point Use of antiplatelet or nonsteroidal Excessive alcohol use 1 point Risk scores range: 0 9 points Score >2 associated with clinically relevant and major bleeding.382 ACCP indicates American College of Chest Physicians; INR, international normalized ratio; OAC, oral anticoagulation; and TIA, transient ischemic attack. Most of these analyses stratifying risk of future bleeding have not focused on intracranial hemorrhages, the category of major bleeding with the greatest long-term effect on quality of life. Another limitation of prediction scales for hemorrhage is that several of their components such as age and hypertension are also risks for cardioembolic stroke. Selecting Treatment to Reduce Stroke Risk in Patients With AF Adjusted-dose warfarin has generally been the treatment of choice for patients at high risk for cardioembolic stroke and acceptably low risk of hemorrhagic complications, particu- larly intracranial hemorrhage. Treatment with adjusted-dose warfarin (target INR, 2 to 3) robustly protects against stroke (RR reduction, 64%; 95% CI, 49 74), virtually eliminating the excess risk of ischemic stroke associated with AF if the intensity of anticoagulation is adequate and reducing all-cause In addition, anticoagu- lation reduces stroke severity and poststroke mortality.386 388 Compared with aspirin, adjusted-dose warfarin reduces stroke Three newer oral anticoagulants have been approved in the United States for stroke prevention in patients with nonvalvu- lar AF: the direct thrombin inhibitor dabigatran (dosed at 150 mg twice daily in patients with creatinine clearance 30 mL/ min) and the direct factor Xa inhibitors rivaroxaban (20 mg once daily for patients with creatinine clearance 50 mL/min) and apixaban (5 mg twice daily for patients with no more than 1 of the following characteristics: age 80 years, serum creati- nine 1.5 mg/dL, or body weight 60 kg). Clinical trial data and other information for these agents were recently reviewed in an AHA/American Stroke Association science advisory390 and are briefly summarized here. The Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial391 randomized 18113 patients to dabi- gatran 150 mg or 110 mg twice daily or adjusted-dose war- farin (target INR, 2 to 3). The study enrolled patients with and without a history of prior stroke but with overall mod- erate to high risk of stroke (mean CHADS2 score, 2.1) and excluded patients who had stroke within 14 days (6 months for severe stroke), increased bleeding risk, creatinine clear- ance <30 mL/min, or active liver disease. The primary out- come of stroke or systemic embolism during the mean 2-year follow-up occurred at a rate of 1.7%/y in the warfarin (INR, 2 to 3) group compared with 1.11%/y in the 150 mg dabi- gatran group (RR=0.66 versus warfarin; 95% CI, 0.53 0.82; P<0.001 for superiority). Intracranial hemorrhage rates were strikingly lower with 150 mg dabigatran relative to adjusted- 0.27 0.60). However, the overall rates of major bleeding were not different between the groups (3.11%/y versus 3.36%/y; P=0.31), and gastrointestinal bleeding was more frequent 95% CI, 1.19 1.89). MI was also increased in the 150 mg although this difference was no longer sig- nificant when silent MIs or unstable angina, cardiac arrest, and cardiac death were included.391 Meta-analysis of 7 trials of dabigatran use for various indications has supported the possibility of a small but consistent increased risk of MI or acute coronary syndrome versus the risk observed in various control arms of these studies (OR, 1.33; 95% CI, 1.03 1.71; Finally, analyses of multiple patient subgroups, categorized by nationality,394 and the pres- ence or absence of prior TIA/stroke, have not found evidence for differences in the risk/benefit profile for dabigatran. In the subgroup of patients 75 years of age,396 mg was associated with increased gastrointestinal hemor- rhage relative to warfarin (OR, 1.79; 95% CI, 1.35 2.37) but reduced ICH (OR, 0.42; 95% CI, 0.25 0.70). The Rivaroxaban Versus Warfarin in Nonvalvular Atrial Fibrillation (ROCKETAF) Trial397 randomized 14264 patients with nonvalvular AF to rivaroxaban 20 mg/d or adjusted-dose warfarin (target INR, 2 to 3). A CHADS2 score of 2 was required, yielding a mean score for enrolled subjects of 3.5, which was higher than in the RE-LY and ARISTOTLE trials; more than half of the participants had a stroke, TIA, or sys- temic embolism before enrollment. Over a median follow-up of 707 days, the primary end point of ischemic and hemor- rhagic stroke and systemic embolism in patients as actually treated (the prespecified analysis plan for efficacy in this study) occurred in 1.7%/y in those receiving rivaroxaban and 2.2%/y in those on warfarin (HR, 0.79; 95% CI, 0.66 0.96; P<0.001 for noninferiority; analyzed by intention to treat, HR, for superiority). The primary safety end point of major or nonmajor bleeding occurred in 14.9% of patients per year in those receiving rivaroxaban and 14.5% in those on warfarin reduced on rivaroxaban relative to warfarin. Subsequent sub- group analysis of the 6796 subjects without previous stroke found rivaroxaban to have borderline superiority to warfarin in intention-to-treat analysis of efficacy (HR, 0.77; 95% CI, 0.58 1.01), supporting its use in primary prevention. Other subgroup analyses397 found no differences in the effec- tiveness of rivaroxaban according to age, sex, CHADS2 score, or the presence of moderate renal insufficiency399 (creatinine clearance, 30 to 49 mL/min; these subjects were randomized to rivaroxaban 15 rather than 20 mg/d). Important concerns have been raised about the interpretation of ROCKET AF, most notably the relatively poor management of warfarin (mean time in therapeutic range, 55%) and the relatively high number of outcomes (stroke or systemic embolism) beyond the 2-day monitoring period after drug cessation.400 Apixaban has been studied in 2 phase III trials. The Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed orAre Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial401 compared apixaban 5 mg twice daily with aspirin 81 to 324 mg daily in 5599 subjects with nonvalvular AF unsuitable for warfarin therapy. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation compared the same dose of apixaban with adjusted-dose warfarin (target INR, 2 to 3) among 18201 patients with nonvalvular AF. Subjects in each study had at least 1 additional risk factor for stroke (prior stroke or TIA, Meschia et al Guidelines for the Primary Prevention of Stroke 3775 age 75 years, hypertension, diabetes mellitus, heart failure, or peripheral artery disease). A reduced dose of apixaban 2.5 mg twice daily was used in both studies for subjects with at least 2 of the following: 80 years, body mass 60 kg, or serum creatinine 1.5 mg/dL. AVERROES was terminated after a mean follow-up of 1.1 years when an interim analy- sis found apixaban to be markedly superior to aspirin for the prevention of stroke or systemic embolism (1.6%/y versus 3.7%/y; HR, 0.45; 95% CI, 0.32 0.62) with similar rates of major bleeding (1.4%/y versus 1.2%/y). Germane to primary prevention, apixaban was also superior to aspirin in subjects without prior TIA or stroke (HR, 0.51; 95% CI, 0.35 0.74).403 Over a median 1.8 years of follow-up in ARISTOTLE, the primary outcome occurred in 1.27%/y in the apixaban group (analyzed as intention to treat) and 1.60%/y in the warfarin feriority; P=0.01 for superiority). Much of the difference between the groups could be attributed to a reduction in ICH in the apixaban group (0.24%/y versus 0.47%/y); the differ- ences in ischemic or uncertain type of stroke were minimal (0.97%/y versus 1.05%/y). Major bleeding events were simi- larly less frequent on apixaban (2.13%/y versus 3.09%/y; found a similar magnitude effect for primary prevention of stroke or systemic embolism in subjects without prior stroke or TIA the sharpest difference again in risk of ICH (0.29%/y versus analysis found consistent efficacy of apixaban in subjects with impaired renal function (estimated glomerular filtra- tion rate <80 mL/min) and significantly greater reduction in major bleeding among those with more advanced dysfunction (estimated glomerular filtration rate 50 mL/min).405 Because of the clustering of stroke observed after discontinuation of apixaban, a black box warning was required for this agent (as for rivaroxaban), indicating that coverage with another antico- agulant should be strongly considered at the time of cessation unless there is pathological bleeding. suggest that the newer oral anticoagu- lants can be cost-effective, particularly for patients at high risk of cardioembolism or hemorrhage. A Markov decision model using data from RE-LY, for example, found that dabigatran 150 mg twice daily provided 0.36 additional quality-adjusted life-years at a cost of $9000,407 representing an incremental cost-effectiveness ratio ($25000 per quality-adjusted life-year) that is within the range tolerated by many healthcare systems. These analyses are based on only a single trial of dabigatran, however, and similar evaluations have yet to be performed for rivaroxaban and apixaban. The cost-effectiveness of newer anticoagulants relative to adjusted-dose warfarin is predicted to be sensitive to the cost of the medications, the risk for cardio- embolism or hemorrhage (cost-effectiveness improving with increasing risk), and the quality of INR control on warfarin. There are many factors to consider in the selection of an anticoagulant for patients with nonvalvular AF. The newer agents offer clearly attractive features such as fixed dose, lack of required blood monitoring, absence of known interaction with the immune complexes associated with heparin-induced and fewer identified drug interactions than warfarin. Most notably, each appears to confer lower risk than adjusted-dose warfarin for ICH, arguably the strongest determinant of long-term safety for anticoagulation (Table 4). These agents also raise important concerns, however, including substantial cost to the healthcare system, renal clearance, short half-lives, general unavailability of a moni- toring test to ensure compliance, and lack of a specific agent to reverse their anticoagulant effects.412 Although a dabigatran dose of 75 mg twice daily was approved for patients with creatinine clearance of 15 to 30 mL/min, such subjects were in fact excluded from RE-LY and have not been extensively studied. The short half-lives of the newer anticoagulants raise the possibility of increased risk of cardioembolism if doses are missed, a concern heightened by the relatively large number of events in ROCKET AF occurring between 2 and 7 days after discontinuation of rivaroxaban.400 In assessments of the lack of reversing agent for the newer anticoagulants, it is important to consider that even warfarin-related ICH mortality rates are extremely high despite the availability of reversing agents.413 An analysis of ICH events occurring on dabigatran 150 mg twice daily and adjusted-dose warfarin in RE-LY found no difference in mortality (35% versus 36%) and, because of the lower overall risk of bleeding with dabigatran, significantly fewer deaths caused by ICH (13 versus 32; P<0.01). In studies of antiplatelet agents for nonvalvular AF, aspirin offers modest protection against stroke (RR reduction, 22%; No convincing data favor 1 dose of aspi- rin (50 325 mg daily) over another. Two randomized trials assessed the potential role of the combination of clopidogrel (75 mg daily) plus aspirin (75 100 mg daily) for prevent- ing stroke in patients with AF. The AF Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) investigators compared this combination antiplatelet regi- men with adjusted-dose warfarin (target INR, 2 to 3) in AF patients with 1 additional risk factor for stroke in ACTIVE W and found a reduction in stroke risk with warfarin compared with the dual antiplatelet regimen (RR reduction, 40%; 95% CI, 18 56; P=0.001) and no significant difference in risk of ACTIVE A compared the combination of clopidogrel and aspirin with aspirin alone in AF patients who were deemed unsuitable for warfarin anticoagulation and who had at least 1 additional risk factor for stroke ( 25% Table 4. Odds ratios of intracranial hemorrhage relative to warfarin with an INR of 2.0 to 3.0 Drug Dose(s) OR (95% CI) Reference twice daily Dabigatran 110 to 150 mg twice daily CI indicates confidence interval; INR, international normalized ratio; and OR, odds ratio. Adapted with permission from Chatterjee et al.411 Copyright 2013, American Medical Association. All rights reserved. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation. were deemed unsuitable because of concern for warfarin- Dual antiplatelet therapy resulted in a significant reduction in all strokes (including parenchy- mal ICH) over treatment with aspirin alone (RR reduction, 28%; 95% CI, 17 38; P=0.0002) but also resulted in a sig- nificant increase in major bleeding (RR increase, 57%; 95% CI, 29 92; P<0.001). Overall and in absolute terms, major vascular events (the study primary end point) were decreased 0.8%/y, but major hemorrhages increased 0.7%/y (RR for major vascular events and major hemorrhages, 0.97; 95% CI, 0.89 1.06; P=0.54). Disabling/fatal stroke, however, was decreased by dual antiplatelet therapy (RR reduction, 26%; 95% CI, 11 38; P=0.001). A post hoc analysis of randomized trial data that used relative weighting of events suggested a modest net benefit from the combination of aspirin and clopi- dogrel over aspirin alone.416 Recommendations for the selection of antithrombotic therapy for patients with nonvalvular AF have had to adjust for 2 emerging trends: a decreasing rate of stroke for any possibly related to improv- ing control of other stroke risk factors, and the appearance of the newer oral anticoagulants with a lower risk of ICH. These 2 trends tend to have opposing effects on the tipping point at which the benefits of anticoagulation outweigh its risks: A lower stroke risk argues for more limited use of antico- agulation, and safer agents argue for more extensive use.418 On the basis of the decreasing risk of AF-related stroke, the 2012 American College of Chest Physicians evidence-based suggested that patients with nonrheu- matic AF at low stroke risk (ie, CHADS2 =0) be treated with no therapy rather than any antithrombotic agent (American College of Chest Physicians grade 2B; ie, weak recommenda- tion, moderate evidence); for those patients preferring anti- thrombotic treatment, aspirin rather than anticoagulation was recommended (grade 2B). These guidelines also favored oral anticoagulation rather than antiplatelet therapy for those at moderate risk (ie, CHADS2 =1; grade 2B) and for those at high risk (ie, CHADS2 2; American College of Chest Physicians grade 1B, ie strong recommendation, moderate evidence) and the use of dabigatran (the only approved newer anticoagulant when the guidelines were formulated) rather than warfarin as oral anticoagulant (grade 2B). For patients in these groups who select antiplatelet rather than anticoagulant therapy, the guidelines recommended combination aspirin plus clopido- grel rather than aspirin alone (grade 2B). Of these clinical sce- narios, the greatest uncertainty surrounds the management of patients at moderate risk (CHADS2 =1). A large cohort study did not find net clinical benefit of warfarin for AF patients with a CHADS2 score of 1,417 and a decision-analysis model predicted that anticoagulation would be beneficial in this group only when the lower risk of ICH associated with the newer agents was assumed.418 Most guidelines have not explicitly incorporated risk for anticoagulant-related hemorrhagic complications, largely because of the paucity of precise data on the risk of bleeding. Some of the risks for hemorrhage are also risks for cardio- embolism and thus do not necessarily argue against antico- agulation. Age >75 years, for example, is a factor favoring rather than opposing anticoagulation.377 One bleeding risk that appears sufficient to tip the balance away from anticoagula- tion in nonvalvular AF is a history of lobar ICH suggestive of cerebral amyloid angiopathy.419 Other risks for ICH such as certain genetic profiles or the presence of asymptomatic cerebral microbleeds on neuroimaging do not currently appear sufficient by themselves to outweigh the benefits of antico- agulation in patients at average risk of cardioembolism.420 For patients treated with adjusted-dose warfarin, the initial 3-month period is a particularly high-risk period for bleeding421 and requires especially close anticoagulation monitoring. ICH is the most devastating complication of anticoagulation, but the absolute increase in risk is small for INR 3.5.387 Treatment of hypertension in AF patients reduces the risk of both ICH and ischemic stroke and hence has dual benefits for antico- agulated patients with AF.422 424 A consensus statement on the delivery of optimal anticoagulant care (focusing primarily on warfarin) has been published.425 The combined use of warfa- rin with antiplatelet therapy increases the risk of intracranial and extracranial hemorrhage.426 Because adjusted-dose warfa- rin (target INR, 2 to 3) appears to offer protection against MI comparable to that provided by aspirin in AF patients,427 the addition of aspirin is not recommended for most patients with AF and stable coronary artery disease.428,429 There are meager data on the type and duration of optimal antiplatelet therapy when combined with warfarin in AF patients with recent coronary angioplasty and stenting.430,431 The combination of clopidogrel, aspirin, and warfarin has been suggested for at least 1 month after placement of bare metal coronary stents in patients with AF.432 Because drug-eluting stents require even more prolonged antiplatelet therapy, bare metal stents are gen- erally preferred for AF patients taking warfarin.433,434 A lower target INR of 2.0 to 2.5 has been recommended in patients requiring warfarin, aspirin, and clopidogrel after percutane- ous coronary intervention during the period of combined anti- platelet and anticoagulant therapy.435 Closure of the LAA has been evaluated as an alternative approach to stroke prevention in nonvalvular AF.436 In a trial of 707 subjects randomized 2:1 to percutaneous LAA closure with the WATCHMAN device (in which patients were treated with warfarin for at least 45 days after device placement, then aspirin plus clopidogrel from echocardiographically demon- strated closure of the LAA until 6 months after placement, then aspirin alone) versus adjusted-dose warfarin (target INR, 2 to 3), LAA closure was noninferior to warfarin for preventing the primary outcome of ischemic or hemorrhagic stroke, cardiac or unexplained death, or systemic embolism during the mean 18-month follow-up (RR, 0.62; 95% CI, 0.35 1.25; P<0.001 for noninferiority). Hemorrhagic stroke was less frequent in the LAA closure group (RR, 0.09; 95% CI, 0 0.45), but ischemic stroke was insignificantly more frequent (RR, 1.34; 95% CI, 0.60 4.29), in part because of procedure-related strokes (occurring in 5 of the 449 patients in whom LAA closure was attempted, including 2 with long- term residual deficits). At 1588 patient-years of follow-up, the rate of the primary efficacy end point of stroke, systemic embolism, and cardiovascular death was not inferior for the WATCHMAN device compared with warfarin.437 Although this approach appears promising, there are substantial reasons for proceeding cautiously with this treatment, including the Meschia et al Guidelines for the Primary Prevention of Stroke 3777 relatively modest power of the trial, the exclusion of subjects with firm contraindications to anticoagulation (who would otherwise appear to be ideal candidates for LAA closure), and the lack of comparison to the newer, potentially more effec- tive oral anticoagulants. Other potential nonpharmacological approaches such as therapeutic cardioversion and rhythm con- trol do not reduce stroke risk.438 Intervals of asymptomatic AF also persist after apparently successful radiofrequency abla- suggesting a persistent need for antithrombotic treat- ment after this procedure. Several randomized, clinical trials have consistently shown that rhythm control does not protect against stroke relative to rate control.438,440 442 For patients with AF of 48 hours or when duration is unknown, it is recommended that patients receive warfarin to an INR of 2.0 to 3.0 for 3 weeks before and 4 weeks after chemical or electrical cardioversion.443 Subgroup analyses of ROCKET AF444 sug- gest that protection from cardioembolism around the time of cardioversion appears to be comparable for warfarin and the novel oral anticoagulants. AF: Summary and Gaps AF is a prevalent, potent, and treatable risk factor for embolic stroke. Knowing which treatment offers the optimal balance of benefits and risks for a particular patient remains challeng- ing, however. Complicating the decision is that the field is rapidly changing, with ongoing changes in the epidemiology of AF-related stroke, improvements in the ability to predict risk of stroke and hemorrhage, and a growing armamentarium of effective therapies. This fluid environment has contributed to a proliferation of proposed guidelines, which can vary substantially. One clear goal is therefore to continue to collect sufficient data on risk stratification and treatment effects to strengthen the foundation for future recommendations. A key step toward this goal is head-to-head comparison of the newer anticoagu- lants with each other and with emerging alternatives such as LAA closure. Despite improving public awareness, anticoagulation for suitable AF patients remains underused, particularly among the very elderly. A potential benefit of the newer anticoagu- lants would be to improve use and compliance for appro- priate patients. Another step toward optimizing the use of anticoagulants is large-scale MRI studies of cerebral micro- bleeds to determine whether and when they should alter the decision to prescribe anticoagulants, especially in the elderly. Risk for future ICH may be particularly important in selecting one of the newer anticoagulants because the major advantage of these agents may be their reduced risk for this complication. AF: Recommendations 1. For patients with valvular AF at high risk for stroke, defined as a CHA2 -VASc score of 2 and accept- ably low risk for hemorrhagic complications, long- term oral anticoagulant therapy with warfarin at a target INR of 2.0 to 3.0 is recommended (Class I; Level of Evidence A). 2. For patients with nonvalvular AF, 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 hemor- rhage), cost, tolerability, patient preference, potential for drug interactions, and other clinical characteris- tics, including the time that the INR is in therapeutic range for patients taking warfarin. 3. Active screening for AF in the primary care setting in patients >65 years of age by pulse assessment fol- lowed by ECG as indicated can be useful (Class IIa; Level of Evidence B). 4. For patients with nonvalvular AF and CHA2 - VASc score of 0, it is reasonable to omit antithrom- botic therapy (Class IIa; Level of Evidence B). 5. For patients with nonvalvular AF, a CHA2 -VASc score of 1, and an acceptably low risk for hemor- rhagic complication, no antithrombotic therapy, anticoagulant therapy, or aspirin therapy may be considered (Class IIb; Level of Evidence C). The selec- tion of antithrombotic agent should be individual- ized 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 the time that the INR is in the therapeutic range for patients taking warfarin. 6. Closure of the LAA may be considered for high-risk patients with AF who are deemed unsuitable for anti- coagulation if performed at a center with low rates of periprocedural complications and the patient can tolerate the risk of at least 45 days of postprocedural anticoagulation (Class IIb; Level of Evidence B). Other Cardiac Conditions Cardiac conditions other than AF that are associated with an increased risk for stroke include acute MI; ischemic and nonischemic cardiomyopathy; valvular heart disease, includ- ing prosthetic valves and infective endocarditis; patent fora- men ovale (PFO) and atrial septal aneurysms (ASAs); cardiac tumors; and aortic atherosclerosis. Acute MI A meta-analysis of population-based studies published between 1970 and 2004 found that the risk of ischemic stroke after acute MI was 11.1 per 1000 (95% CI, 10.7 11.5) during Factors associated with increased stroke risk included advanced age, hypertension, diabetes mellitus, anterior MI, AF, and con- gestive heart failure. Importantly, the risk of embolic stroke is increased in patients with anterior MI and left ventricular thrombus. Contemporary studies have found that left ventric- ular thrombus affects 6% to 15% of patients with anterior MI and 27% with anterior MI and left ventricular ejection Systemic embolism occurs in 11% of patients with left ventricular thrombus.450 In the Warfarin, Aspirin Reinfarction Study, (WARIS II), warfarin, combined with aspirin or given alone, compared with aspirin alone reduced the risk of thromboembolic stroke but was associated with a greater risk of bleeding.451 A meta-analysis of 14 trials comprising 25307 patients with an acute coronary syndrome reported that aspirin plus warfarin, in which the achieved INR was 2.0 to 3.0, compared with aspirin alone reduced the risk of death, nonfatal MI, and nonfatal thromboembolic stroke but doubled the risk of major bleeding.452 A meta-analysis of 24542 patients in 10 randomized trials that evaluated the effi- cacy of warfarin after acute MI found a stroke incidence over 5 years of 2.4%. In this meta-analysis, warfarin decreased the risk of stroke (OR, 0.75; 95% CI, 0.63 0.89) but increased the risk of bleeding. The 2013 ACCF/AHA guideline for the management of ST-segment elevation MI (STEMI) states that anticoagulant therapy with a vitamin K antagonist is reason- able for patients with STEMI and asymptomatic left ventricu- lar mural thrombi (Class IIa; Level of Evidence C) and that anticoagulant therapy may be considered for patients with STEMI and anterior apical akinesis or dyskinesis (Class IIb; Level of Evidence C).453 Cardiomyopathy The incidence of stroke in patients with cardiomyopathy and The Warfarin/ Aspirin Study in Heart Failure (WASH) randomized patients with heart failure, reduced left ventricular systolic function, and no other indications for anticoagulant therapy to warfarin, aspirin, or no treatment.454 There was no difference between groups in the primary composite cardiovascular end point, which included stroke. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial randomized patients with heart failure, reduced left ventricular systolic function, and sinus rhythm to warfarin, clopidogrel, or aspirin. The study was terminated early because of slow enrollment. There was no difference in the composite primary end point of death, nonfatal MI, or nonfatal stroke, but warfarin was associated with fewer nonfatal strokes than aspirin or clopidogrel.455 The Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial randomized 2305 patients with reduced left ventricular ejection fraction and sinus rhythm to warfarin or aspirin and followed them up for up to 6 years.457 There was no difference in the primary composite outcome of ischemic stroke, ICH, or death resulting from any cause (HR, 0.93; 95% CI, 0.79 1.10), but there was a significant reduction in the rate of ischemic stroke with warfarin compared with aspi- rin (0.72 versus 1.36 events per 100 patient-years; HR, 0.52; 95% CI, 0.33 0.82). The rate of major hemorrhage, however, was greater in the warfarin than in the aspirin group. The 2009 ACCF/AHA guideline for the diagnosis and management of heart failure in adults states that the usefulness of anticoagula- tion is not well established in patients with heart failure who do not have AF or a previous thromboembolic event.458 The American College of Chest Physicians guidelines on anti- thrombotic therapy and prevention of thrombosis state that the usefulness of anticoagulation is not well established in patients with heart failure who do not have AF or a previous thromboembolic event (Class IIb; Level of Evidence B).458 Based on the more recent WARCEF trial,457 this recommenda- tion is upgraded in this document to state that anticoagulants or antiplatelet agents are reasonable for patients with heart failure who do not have AF or a previous thromboembolic event (Class IIa; Level of Evidence B). Valvular Heart Disease The risk of embolic stroke is increased in patients with rheu- matic mitral valve disease, even in the absence of AF, and in patients with prosthetic heart valves. Rheumatic carditis is the most common cause of mitral stenosis. Studies from the middle part of the last century found an annual incidence of systemic embolism among patients with rheumatic mitral valve disease of 1.5% to 4.7% (reviewed by Whitlock et al459 ). Thrombus and subsequent embolism may be more likely to occur in large left atria. The ACCF/AHA guidelines for the management of valvular heart disease recommend anticoag- ulation in patients with mitral stenosis and a prior embolic event, even in sinus rhythm (Class I; Level of Evidence B), and in patients with mitral stenosis with left atrial thrombus (Class I; Level of Evidence B).460 Reports on the association of embolic stroke with mitral valve prolapse have been inconsis- A population-based study of patients from Olmsted County, Minnesota, found an increased RR of stroke or TIA among patients with mitral valve prolapse who were initially in sinus rhythm (RR, 2.2; 95% CI, 1.5 3.2).464 Independent factors associated with stroke included older age, mitral valve thickening, and the development of AF. The ACCF/AHA guidelines for the management of valvular heart disease rec- ommend aspirin therapy for patients with mitral valve pro- lapse who experience TIAs (Class I; Level of Evidence C) and warfarin for these patients with a history of stroke and mitral regurgitation, AF, or left atrial thrombus (Class I; Level of The risk of stroke is also increased in patients with mitral annular calcification. There was an increased risk of stroke (RR, 2.1; 95% CI, 1.2 3.6) among participants in the Framingham study who had mitral annular calcification.465 Risk of stroke was associated with the severity of mitral annular calcification. Similarly, in the SHS, a cohort study of American Indians, stroke incidence was increased among those with mitral annular calcification (RR, 3.1; 95% CI, 1.8 In contrast, in the multiethnic NOMAS, mitral annular calcification was associated with an increased risk of MI and vascular death but not ischemic stroke.467 There is no evidence that anticoagulant therapy reduces the risk of stroke in patients with mitral annular calcification. Calcific aortic stenosis is an uncommon cause of embolic stroke, unless disrupted by val- vuloplasty, transcatheter aortic valve replacement, or open surgical aortic valve replacement.468 Prosthetic heart valves can serve as a source of thrombo- embolism. The risk of embolic stroke is greater in patients with mechanical valves than bioprosthetic valves. The annual incidence of thromboembolism in patients with bioprosthetic valves and sinus rhythm is 0.7% (reviewed by Bonow et al460 ). Among patients with bioprosthetic valves, the risk of embo- lism is greatest within the first 3 months after implantation and is higher with mitral than aortic bioprosthetic valves.469 ACCF/AHA guidelines for the management of patients with Meschia et al Guidelines for the Primary Prevention of Stroke 3779 valvular heart disease recommend aspirin after aortic or mitral valve replacement with a bioprosthesis in patients with no risk factors (ie, AF, previous thromboembolism, left ventricular dysfunction, and hypercoagulable condition) and warfarin (INR, 2.0 to 3.0) after aortic or mitral valve replacement with a bioprosthesis in patients with additional risk factors (Class I; Level of Evidence C). During the first 3 months after aortic or mitral valve replacement with a bioprosthesis, the guidelines indicate that it is reasonable to give warfarin to achieve an INR of 2.0 to 3.0 (Class IIa; Level of Evidence C). In the first 3 months after bioprosthetic valve implantation, aspirin is recommended for aortic valves; the combination of aspirin and clopidogrel is recommended if the aortic valve is transcatheter; and vitamin K antagonist therapy with a target INR of 2.5 is recommended for mitral valves. After 3 months, aspirin is recommended.459 A meta-analysis of 46 studies comprising 13088 patients who received mechanical mitral or aortic valve prostheses reported an incidence of valve thrombosis or embolism in the absence of antithrombotic therapy of 8.6 per 100 patient-years (95% CI, 7.0 10.4). Risk of embolism was lower in patients with tilting disk and bileaflet valves than in those with caged ball valves (no longer used).470 Antithrombotic therapy with a vitamin K antagonist reduced the risk of thromboembolic events to 1.8 per 100 patient-years (95% CI, 1.7 1.9). Even among anticoagu- lated patients, the risk of embolism is higher among those with mechanical mitral valves than mechanical aortic valves.471,472 ACC/AHA guidelines for the management of patients with val- vular heart disease recommend warfarin (INR, 2.0 to 3.0) after aortic valve replacement with bileaflet mechanical or Medtronic Hall prostheses in patients with no risk factors (Class I; Level of Evidence B), warfarin (INR, 2.5 to 3.5) in patients with risk factors (Class I; Level of Evidence B), and warfarin (INR, 2.5 to 3.5) after mitral valve replacement with any mechanical valve (Class IIa; Level of Evidence C).460 The addition of low- dose aspirin to warfarin is recommended for all patients with mechanical valves (Class IIa; Level of Evidence C). The novel oral anticoagulants (factor Xa inhibitors and direct thrombin inhibitors) are not indicated for the prevention of thromboembolism associated with mechanical heart valves. The randomized, phase II study to evaluate the safety and pharmaco- kinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN) trial showed an increase in thrombo- embolic and bleeding complications with dabigatran compared to warfarin in patients with mechanical heart valves.473 About 20% to 40% of patients with endocarditis suf- fer embolic events, the majority of which affect the central The rate of embolic events decreases rapidly after the initiation of antibiotic therapy.476 478 The risk of embolic stroke is associated with the size of the veg- etation, involvement of the mitral valve, and infection by Anticoagulant therapy does not reduce the risk of embolic stroke and may increase the risk of cerebral hemorrhage.474 Anticoagulant therapy should not be used to treat patients with infective endocarditis unless indicated for other cardiovascular conditions.459 Nonbacterial thrombotic endocarditis, also known as marantic endocardi- tis, is associated with malignant neoplasms, antiphospholipid antibodies (aPLs), and systemic lupus erythematosus (SLE) and may be a source of an embolic stroke.480 Anticoagulant therapy is indicated for patients with nonbacterial thrombotic endocarditis and systemic embolism.459 PFO and ASAs A PFO is present in 15% to 25% of the adult population, and ASA occurs in 1% to 4%. A PFO serves as a right-to- left conduit for paradoxical emboli originating in the veins, whereas ASA may be a nidus for thrombus formation. PFO and ASA have been associated with stroke in many, but not In the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), a PFO was detected by transesopha- geal echocardiography more often in patients with crypto- genic stroke than in those with known causes of stroke (39.2% Another study also found that the prevalence of PFO was greater among patients with cryp- togenic stroke than among those with known causes of stroke, including patients <55 years of age (OR, 4.70; 95% CI, 1.89 A meta-analysis of case-control studies of patients who have had an ischemic stroke found that among patients 55 years of age there are significant associations with PFO (OR, 3.10; 95% CI, 2.29 4.21), ASA (OR, 6.14; 95% CI, 2.47 15.22), and PFO plus ASA (OR, 15.59; 95% In patients >55 years of age, the associa- tion with PFO was not significant (OR, 1.27; 95% CI, 0.80 2.01), although it was for ASA (OR, 3.43; 95% CI, 1.89 6.22) and for PFO plus ASA (OR, 5.09; 95% CI, 1.25 20.74). In a population-based study from Olmstead County, Minnesota, in which the mean participant age was 66.9 13.3 years, PFO was not associated with increased risk of stroke (HR, 1.46; 95% CI, 0.74 2.88), whereas there was an association with In the multiethnic NOMAS, in which the mean age was 68.7 10.0 years, PFO was not associated with increased risk of stroke (HR, 1.64; 95% CI, 0.87 3.09), nor was the coexistence of PFO and ASA Another study examining the characteristics of PFO observed larger PFOs, longer tunnels, and a greater frequency of ASA in patients with stroke than in those without stroke.490 One study of patients with cryptogenic stroke found that the risk of recurrent stroke was 2.3% (95% CI, 0.3 4.3) among patients with PFO alone, 0% in those with ASA alone, 15.2% (95% CI, 1.8 28.6) in patients with both PFO and ASA, and 4.2% (95% CI, 1.8 6.6) in patients with Further analyses from NOMAS with longer follow- up also failed to find evidence for an increased risk of first stroke with PFO (adjusted HR, 1.10; 95% CI, 0.64 1.91) and provided further evidence that PFO is not associated with sub- clinical cerebrovascular disease.492 No study has examined treatments to prevent initial strokes in patients with PFO or ASA. Accordingly, given the uncer- tainties and relatively low risk of initial stroke caused by PFO or ASA and the potential risk of antithrombotic therapy or invasive treatments, no treatment is recommended for the pri- mary prevention of stroke in people with PFO orASA. Several studies have examined the treatment of PFO with antithrom- botic therapy or percutaneous closure devices in patients with cryptogenic stroke, but a discussion of secondary prevention exceeds the scope of this document.482,493 495 Cardiac Tumors Benign primary cardiac tumors such as myxomas, papillary fibroelastomas, and primary malignant cardiac neoplasms such as sarcomas may embolize to the brain and cause isch- Embolic stroke is most likely to occur with intracavitary tumors that have friable surfaces. Myxoma is the most common cardiac tumor, and the majority of them occur in the left atrium.498 About 30% to 40% of myxomas Stroke or TIA is the presenting symptoms in half of the patients with papillary fibroelastomas.500 Surgical exci- sion of atrial myxomas is recommended. Surgical interven- tion, including removal or occasionally valve replacement, is recommended for symptomatic fibroelastomas and for fibro- elastomas that are >1 cm in diameter or appear mobile, even if asymptomatic, because they pose a risk for embolism.501 Recommendations for the treatment of malignant cardiac neo- plasms depend on the precise nature and extent of the tumor and are beyond the scope of this document.502 Aortic Atherosclerosis Plaques 4 mm in size, particularly large, complex plaques, are associated with an increased risk of cryptogenic strokes.503 506 In the French Study of Aortic Plaques in Stroke, plaques >4 mm were found to be independent predictors of recurrent stroke Among patients with crypto- genic stroke who participated in PICSS, large plaques detected by transesophageal echocardiography were associated with an increased risk of recurrent ischemic stroke or death over a 2-year follow-up (HR, 6.42; 95% CI, 1.62 25.46), as were those with complex morphology (HR, 9.50; 95% CI, 1.92 47.10).504 Atheroembolism from aortic plaques is also a cause of stroke associated with cardiac surgery.505,506,508 There are no prospec- tive, randomized trials examining the efficacy of medical ther- apy to reduce the risk of stroke caused by embolic events from large thoracic aortic plaques. One nonrandomized study found that warfarin reduced the risk of recurrent stroke in patients with mobile thoracic atheroma detected by transesophageal echo- In another nonrandomized study, patients with aortic plaques >4 mm thick treated with oral anticoagulants had fewer stroke and peripheral embolic events than those treated with antiplatelet therapy.510 A retrospective analysis of patients with severe thoracic aortic plaque found that statin therapy (OR, 1.2) or antiplatelet therapy (OR, 1.4; 95% CI, 0.8 2.4), reduced the risk of stroke, TIA, and peripheral emboli.511 Other Cardiac Conditions: Summary and Gaps Cardiac conditions, including MI, cardiomyopathy, valvular heart disease, PFO and ASAs, cardiac tumors, and aortic ath- erosclerosis, are associated with an increased risk for stroke. Therapies to prevent stroke in many of these conditions are based on well-reasoned consensus of opinion, but random- ized, prospective trials to support these decisions are often lacking. For example, therapy with a vitamin K antagonist is reasonable for patients with STEMI and left ventricular mural thrombi, but clinical trials could inform the duration of treatment. Prospective trials are lacking to determine whether antithrombotic therapy is useful for the primary prevention of stroke in patients with mitral valve prolapse and mitral regurgitation who do not have AF. Comparative-effectiveness trials would be useful to determine which antithrombotic would be most effective in reducing the risk of stroke in patients with large aortic plaques. Other Cardiac Conditions: Recommendations 1. Anticoagulation is indicated in patients with mitral stenosis and a prior embolic event, even in sinus rhythm (Class I; Level of Evidence B). 2. Anticoagulation is indicated in patients with mitral stenosis and left atrial thrombus (Class I; Level of Evidence B). 3. Warfarin (target INR, 2.0 3.0) and low-dose aspi- rin 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 fac- tors* (Class I; Level of Evidence B); and warfarin (tar- get 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). 4. Surgical excision is recommended for the treatment of atrial myxomas (Class I; Level of Evidence C). 5. Surgical intervention is recommended for symptom- atic fibroelastomas and for fibroelastomas that are >1 cm or appear mobile, even if asymptomatic (Class I; Level of Evidence C). 6. Aspirin is reasonable after aortic or mitral valve replacement with a bioprosthesis (Class IIa; Level of Evidence B). 7. It is reasonable to give warfarin to achieve an INR of 2.0 to 3.0 during the first 3 months after aortic or mitral valve replacement with a bioprosthesis (Class IIa; Level of Evidence C). 8. Anticoagulants or antiplatelet agents are reasonable for patients with heart failure who do not have AF or a previous thromboembolic event (Class IIa; Level of Evidence A). 9. Vitamin K antagonist therapy is reasonable for patients with STEMI and asymptomatic left ventric- ular mural thrombi (Class IIa; Level of Evidence C). 10. Anticoagulation may be considered for asymptom- atic patients with severe mitral stenosis and left atrial dimension 55 mm by echocardiography (Class IIb; Level of Evidence B). 11. 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). 12. Anticoagulant therapy may be considered for patients with STEMI and anterior apical akinesis or dyskinesis (Class IIb; Level of Evidence C). 13. Antithrombotic treatment and catheter-based closure are not recommended in patients with PFO for primary prevention of stroke (Class III; Level of Evidence C). *Risk factors include AF, previous thromboembolism, left ventricular dys- function, and hypercoagulable condition. Meschia et al Guidelines for the Primary Prevention of Stroke 3781 Asymptomatic Carotid Artery Stenosis Atherosclerotic stenosis in the extracranial internal carotid artery or carotid bulb has been associated with an increased risk of stroke. What follows is a summary of recommendations for managing asymptomatic patients with carotid atheroscle- rotic stenosis. Further details are available in an earlier guide- line endorsed by the AHA that is dedicated to this topic.512 Previous randomized trials have shown that prophylac- tic carotid endarterectomy (CEA) in appropriately selected patients with carotid stenosis results in a relative risk reduc- tion of stroke of 53% and an absolute 5-year risk reduction of 6% compared with patients treated by medical management However, since these trials were performed, medi- cal management has improved. The question has been raised if invasive treatment of carotid bifurcation disease remains an effective way to reduce stroke risk compared to contemporary medical management alone. Assessment of Carotid Stenosis A hemodynamically significant carotid stenosis produces a pressure drop across the lesion, a flow reduction distal to the lesion, or both. This generally corresponds to a 60% diameter- reducing stenosis as reflected by catheter angiography as mea- sured with the North American method. This method was first described in publications from the Joint Study of Extracranial Arterial Occlusive Disease of the 1960s516 and has been used in multiple trials carried out in North America. This method measures the minimal residual lumen at the level of the stenotic lesion compared with the diameter of the more distal internal carotid artery where the walls of the artery first become paral- lel. It uses the following formula: stenosis=(1 N/D) 100%, where N is the diameter at point of maximum stenosis and D is the diameter of the arterial segment distal to the stenosis where the arterial walls first become parallel. This method is in contrast to the European method, which estimates stenosis of the internal carotid bulb. Because the randomized trials of CEA for symptomatic and asymptomatic disease in North America used catheter angiog- raphy, this has become the gold standard against which other imaging technologies are compared. 