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 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).


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.


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.


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.


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).


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 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.


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.


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.


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 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.


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.


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.


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.


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 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.


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.


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).


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).


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 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.


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).


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.


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.


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.


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.


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.


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.


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 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.


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. Historically, catheter angiography carried an 1% risk of causing a stroke in patients with atherosclerotic disease.513,517 519 The complication rate has been dropping over the past several years, and the perma- nent stroke complication rate is <0.2%.519 Duplex ultrasound is the noninvasive method of screening the extracranial carotid artery for an atherosclerotic stenosis with the lowest cost and risk. Although there can be considerable variation in the accu- racy of duplex scanning among laboratories,520 certification programs are available that set standards for levels of perfor- mance and accuracy. Duplex ultrasound may be insensitive to differentiating high-grade stenosis from complete occlusion.


Duplex ultrasound may be insensitive to differentiating high-grade stenosis from complete occlusion. MR angiography (MRA), with and without contrast, is also used as a noninvasive method for evaluating arterial anatomy and has the advantage of providing images of both the cer- vical and intracranial portions of the carotid artery and its proximal intracranial branches. MRA may overestimate the degree of stenosis, and as with duplex ultrasound, there may be errors when high-grade stenosis is differentiated from com- plete occlusion. MR contrast material may cause debilitating nephrogenic systemic fibrosis in patients with renal dysfunc- tion. When concordant, the combination of duplex ultrasound and MRA is more accurate than either test alone.521 Computed tomographic angiography is another means of identifying and measuring stenosis of the extracranial carotid artery.522 Like MRA, it has the advantage of being able to evaluate the intra- cranial circulation. Disadvantages of computed tomographic angiography include radiation exposure and the need for intra- venous injection of contrast material. Atherosclerotic calcifi- cation may confound accurate measurement of stenosis with computed tomographic angiography. A variety of vascular risk factors reviewed in this guideline are associated with carotid atherosclerosis.523,524 Carotid bruit can reflect an underlying carotid stenosis. However, the sen- sitivity for detecting carotid stenosis is low. In NOMAS, aus- cultation had a sensitivity of 56% and a specificity of 98%.525 Endarterectomy for Asymptomatic Carotid Stenosis The first study with >1000 patients comparing CEA plus best medical therapy to medical therapy alone was the Asymptomatic Carotid Atherosclerosis Study (ACAS).513 The primary outcome was the composite of any stroke or death occurring in the perioperative period and ipsilateral cerebral infarction thereafter. During follow-up after 34 centers random- ized 1662 patients, the Data and Safety Monitoring Committee called a halt to the trial because of a clear benefit in favor of CEA.


During follow-up after 34 centers random- ized 1662 patients, the Data and Safety Monitoring Committee called a halt to the trial because of a clear benefit in favor of CEA. Patients randomized to surgery had contrast angiography showing diameter-reducing lesions of 60% using the North American method of measurement. Both treatment groups received what at the time was considered best medical man- agement. The aggregate risk over 5 years for ipsilateral stroke, any perioperative stroke, and death was 5.1% for the surgical patients and 11% for the medical patients (RR reduction, 53%; 95% CI, 22 72). The 30-day stroke morbidity and all-cause mortality for CEA was 2.3%, which included a 1.2% stroke complication rate for catheter angiography. It was suggested that the complications of angiography should be considered part of the risk of surgery because an angiogram would not have been performed if surgery were not contemplated. It should be noted that ACAS was conducted at a time when best medical management was limited to control of BP, the control of diabetes mellitus, and the use of daily aspirin. The value of statins and newer antiplatelet drugs had not been established. The Asymptomatic Carotid Surgery Trial (ACST), carried out primarily in European centers,514 included 3120 patients with asymptomatic carotid stenoses of 70%, as measured by duplex ultrasonography. Subjects were randomized to imme- diate CEA versus indefinite deferral of the operation. The trial used end points that were different from those used in ACAS (perioperative stroke, MI or death, and nonperiopera- tive stroke). The net 5-year risks were 6.4% in the immediate surgery group and 11.8% in the deferred surgery group for any stroke or perioperative death (net gain, 5.4%; 95% CI, 3.0 7.8; P<0.0001). In subgroup analysis, the benefits of CEA were confined to patients <75 years of age.


In subgroup analysis, the benefits of CEA were confined to patients <75 years of age. The National Institute of Neurological Disorders and Stroke sponsored Carotid Revascularization of Primary Prevention of Stroke (CREST-2) trial will be comparing centrally managed, intensive medical therapy with or without CEA.526 Careful screening of surgeons participating in clinical trials might lead to results that cannot be generalized to the com- munity. This is particularly evident when the complications from angiography are removed from the surgical group. When this is done, the 30-day rate of stroke and death for CEA in ACAS was 1.54%.517 The perioperative complication rate in ACST was 3.1%. The results of CEA for asymptomatic patients were exam- ined in the National Hospital Discharge Database for 2003 The rate of the combination of stroke and death for CEA was 1.16%. This compares favorably with the rate of the combination of stroke and death for carotid artery stent/angioplasty during the same interval, which was 2.24%. These estimates, however, are based on administrative data and are limited to the procedural hospitalization. A 10-state survey of 30-day complication rates after CEA performed in asymptomatic patients a few years earlier found rates that Thus, it would appear the perioperative complication rates for CEA found in the ACAS trial could be similar or better in the com- munity; however, in at least some areas, rates may be higher. More recently, complication rates from the CREST trial were CEA in asymptomatic patients carried a com- bined risk of stroke and death of 1.4%. Additionally, a registry maintained by the Society for Vascular Surgery documented a 30-day postoperative combined rate of stroke and death of This rate among unselected surgeons was compa- rable to the rate seen among surgeons selected to participate in a trial.


Additionally, a registry maintained by the Society for Vascular Surgery documented a 30-day postoperative combined rate of stroke and death of This rate among unselected surgeons was compa- rable to the rate seen among surgeons selected to participate in a trial. Endovascular Treatment for Asymptomatic Carotid Stenosis Carotid angioplasty and stenting (CAS) is being performed The Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial found that CAS was not inferior (within 3%; P=0.004) to endarterectomy (based on a composite out- come of stroke, MI, or death within 30 days or death result- ing from neurological cause or ipsilateral stroke between 31 and 365 days) in a group of patients considered to be at high risk for CEA.532 About 70% of the subjects had an asymptom- atic stenosis, with rates of stroke, MI, or death of 5.4% with stenting and 10.2% with endarterectomy (P=0.20) at 30 days. At 1 year, the composite end point occurred in 9.9% of the CAS patients and 21.5% of the CEA patients (P=0.02). Three- year outcomes from the SAPPHIRE trial showed that patients receiving CAS had a significantly higher death rate (20.0%) than stroke rate (10.1%),533 raising questions about the long- term value of the procedure in this high-risk cohort. In addi- tion, there was no medically treated control group, and the complication rates in both treatment arms were high enough to raise questions about the benefit of either intervention over medical therapy alone. Several industry-supported registries have reported peri- procedural complication rates of 2.1% to 8.3%.534 The lack of medically treated control groups makes the results of these registries difficult to interpret.


Several industry-supported registries have reported peri- procedural complication rates of 2.1% to 8.3%.534 The lack of medically treated control groups makes the results of these registries difficult to interpret. CREST enrolled both symptomatic and asymptomatic patients with carotid stenosis who could technically undergo either CEA or CAS.535 Asymptomatic patients could be included if they had a stenosis of 60% on angiography, 70% on ultrasonography, or 80% on computed tomographic angi- ography or MRA if the stenosis on ultrasonography was 50% to 69%. Randomization was stratified according to symptom status. The primary end point was a composite of stroke, MI, or death resulting from any cause during the periprocedural period or any ipsilateral stroke within 4 years after random- ization. There was no difference in the estimated 4-year occurrence of the composite primary end point between stent- 0.81 1.51; P=0.51), with no significant heterogeneity based on symptom status. CREST demonstrated an interaction of age on the primary end point, with age >70 years showing a significant benefit for CEA over CAS. CAS had a higher periprocedural stroke/death rate for patients >64 years of Patient age may be among the factors to consider when choosing between the 2 procedures. The periprocedural rate of stroke was higher with CAS than with CEA (4.1% versus 2.3%; P=0.01), and the periprocedural rate of MI was lower with CAS than with CEA (1.1% versus 2.3%; P=0.03). In the periprocedural period, point estimates for the rates of any stroke or death among asymptomatic patients were low (2.5% in CAS versus 1.4% for CEA; HR, 1.88; 95% CI, 0.79 4.42; P=0.15).


In the periprocedural period, point estimates for the rates of any stroke or death among asymptomatic patients were low (2.5% in CAS versus 1.4% for CEA; HR, 1.88; 95% CI, 0.79 4.42; P=0.15). The overall estimated 4-year rate of any periproce- dural stroke or death or postprocedural ipsilateral stroke, how- ever, was higher with stenting compared with endarterectomy was not powered to evaluate symptomatic and asymptom- atic patients separately, there was a trend favoring CEA over CAS in both the symptomatic (HR, 1.37; 95% CI, 0.90 2.09; P=0.07) groups. Post hoc analysis found that major and minor stroke negatively affected quality of life at 1 year (Short Form- 36, physical component scale), with minor stroke affecting mental health at 1 year (Short Form-36, mental component scale), but the effect of periprocedural MI did not negatively affect quality of life. Having MI or stroke, including minor stroke, was associated with a higher mortality rate. The advantage of revascularization over medical therapy by itself was not addressed by CREST, which did not randomize a group of asymptomatic subjects to medical therapy without revascularization. Hospital costs for CAS tend to be greater than for CEA.536 538 The National Institute of Neurological Disorders and Stroke sponsored CREST-2 trial will be com- paring centrally managed, intensive medical therapy with or without carotid stenting with embolic protection.539 Screening of Asymptomatic Carotid Stenosis Although carotid artery stenosis is a risk factor for stroke, not every carotid stenosis carries the same risk for future stroke. There have been attempts to identify those patients with carotid stenosis who are at high risk for future events. Two meth- ods have shown promise. The first method uses transcranial Doppler (TCD) to count the number of presumed embolic events, known as high-intensity transient signals per unit time.


The first method uses transcranial Doppler (TCD) to count the number of presumed embolic events, known as high-intensity transient signals per unit time. Although this technique has shown that patients with frequent high-intensity transient signals have a higher subsequent stroke rate than those without high-intensity transient signals, the test Meschia et al Guidelines for the Primary Prevention of Stroke 3783 is time-consuming to perform and has not received uniform acceptance. Additionally, the effect of intensive medical ther- apy on high-intensity transient signals has not been adequately assessed. Another method of study uses plaque analysis in a computerized algorithm using B-mode insonation of the carotid plaque. Population screening for asymptomatic carotid artery stenosis is not recommended by the US Preventive Services Task Force, which found no direct evidence that screening adults with duplex ultrasonography for asymptomatic stenosis Screening for other risk factors is addressed in relevant sections of this guideline. Asymptomatic Carotid Stenosis: Summary and Gaps Medical therapy has advanced since clinical trials have been completed comparing endarterectomy plus best medical ther- apy with best medical therapy alone in patients with an asymp- tomatic carotid artery stenosis.541 Recent studies suggest that the annual rate of stroke in medically treated patients with an asymptomatic carotid artery stenosis has fallen to 1%.541 543 In the ACST, the rate of absolute benefit from CEA per year was lower in patients on lipid-lowering therapy (0.6%/y) compared with patients not on lipid lowering therapy (1.5%/y).544 ACST had no explicit targets for LDL, and intensive targets (eg, LDL <70 mg/dL) may further reduce the benefit of revascularization. Statin therapy is appropriate for patients with asymptomatic carotid stenosis, whether or not they undergo revascularization. Interventional therapy has also advanced, particularly in terms of perioperative management and device design.


Interventional therapy has also advanced, particularly in terms of perioperative management and device design. Because the absolute reduction in stroke risk with CEA in patients with an asymptomatic stenosis is small, however, the benefit of revascularization may be reduced or eliminated with current medical therapy.541 The benefit of CEA for carotid stenosis in asymptomatic women remains controversial.545 Given the reported 30-day, 1-year, and 3-year results in the high-surgical-risk population, it remains uncertain whether this group of asymptomatic patients should have any revascu- larization procedure. More data are needed to compare long- term outcomes after CEA and CAS. Currently, the Centers for Medicare & Medicaid Services cover CAS for asymptomatic stenosis only in patients with >80% stenosis at high risk for CEA who are participating in postmarket approval studies. For patients with asymptomatic carotid stenosis who defer revascularization, periodic reassessment of degree of stenosis may be helpful in identifying patients at higher risk of stroke. A retrospective ultrasound-based study of the deferred surgery arm of the ACST trial found that patients who had carotid ste- nosis that worsened in 1 year by 1 stenosis category did not have an increased risk of ipsilateral ischemic events, with cat- Patients who had a progression of 2 categories in 1 year were at high risk of ipsilateral ischemic events relative to nonprogressors. The recommendations below reflect current best evidence. However, modern optimal medical therapy may obviate the need for carotid revascularization. The balance of risks and benefits of revascularization in the setting of modern optimal medical therapy is being assessed in ongoing multicenter clin- ical trials in the United States and elsewhere. Asymptomatic Carotid Stenosis: Recommendations 1. Patients with asymptomatic carotid stenosis should be prescribed daily aspirin and a statin.


Patients with asymptomatic carotid stenosis should be prescribed daily aspirin and a statin. Patients should also be screened for other treatable risk fac- tors for stroke, and appropriate medical therapies and lifestyle changes should be instituted (Class I; Level of Evidence C). 2. In patients who are to undergo CEA, aspirin is rec- ommended perioperatively and postoperatively unless contraindicated (Class I; Level of Evidence C). 3. It is reasonable to consider performing CEA in asymptomatic patients who have >70% stenosis of the internal carotid artery if the risk of periopera- tive stroke, MI, and death is low (<3%). However, its effectiveness compared with contemporary best med- ical management alone is not well established (Class IIa; Level of Evidence A). 4. 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). 5. Prophylactic CAS 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). 6. In asymptomatic patients at high risk of complica- tions for carotid revascularization by either CEA or CAS, the effectiveness of revascularization versus medical therapy alone is not well established (Class IIb; Level of Evidence B). 7. Screening low-risk populations for asymptomatic carotid artery stenosis is not recommended (Class III; Level of Evidence C). Sickle Cell Disease SCD, an autosomal-recessive disorder in which the abnormal gene product is an altered hemoglobin -chain, typically man- ifests very early in life.


Sickle Cell Disease SCD, an autosomal-recessive disorder in which the abnormal gene product is an altered hemoglobin -chain, typically man- ifests very early in life. Signs and symptoms associated with SCD are the result of chronic anemia or acute vaso-occlusive crises, most commonly manifesting as painful episodes. Complications of SCD include acute chest syndrome, pulmo- nary hypertension, bacterial infections, and organ infarctions, especially stroke. Other effects include cognitive deficits related to MRI-demonstrated strokes and otherwise asymp- tomatic white matter hyperintensities.547,548 Stroke is a major complication of SCD, with the highest stroke rates occurring in early childhood. The prevalence of stroke by 20 years of age is at least 11%,549 with a substantial number of strokes being silent strokes on brain MRI.548 Stroke prevention is most important for patients with homozygous SCD because the majority of the SCD-associated strokes occur in these patients. TCD ultrasound identifies those at high risk of stroke, allowing evidence-based decisions about optimal primary stroke prevention.550,551 Although the exact mechanism by which high blood flow velocities increase the risk for ischemic stroke is not known, the association is well established. The risk of stroke during childhood in those with SCD is 1%/y, but patients with TCD evidence of high cere- bral blood flow velocities (time-averaged mean velocity >200 cm/s) have stroke rates >10%/y.551,552 Retrospective analysis of the Stroke Prevention Trial in Sickle Cell Anemia (STOP) data suggested that velocity >170 cm/s in the anterior cerebral artery is associated with increased stroke risk after controlling for the middle cerebral artery/internal carotid artery veloci- TCD surveillance of children with SCD remains the gold standard for stroke risk prediction, and its increased use coincides with a decrease in stroke among the pediatric SCD The optimal frequency of screening to detect patients at high risk has not been determined.


The risk of stroke during childhood in those with SCD is 1%/y, but patients with TCD evidence of high cere- bral blood flow velocities (time-averaged mean velocity >200 cm/s) have stroke rates >10%/y.551,552 Retrospective analysis of the Stroke Prevention Trial in Sickle Cell Anemia (STOP) data suggested that velocity >170 cm/s in the anterior cerebral artery is associated with increased stroke risk after controlling for the middle cerebral artery/internal carotid artery veloci- TCD surveillance of children with SCD remains the gold standard for stroke risk prediction, and its increased use coincides with a decrease in stroke among the pediatric SCD The optimal frequency of screening to detect patients at high risk has not been determined. The STOP study, which compared periodic blood transfusion with standard care in 130 children with SCD, used time-averaged means of the maximum velocity. Additionally, peak systolic velocity may be used, in which case a measurement of 250 cm/s is used as a threshold for prophylactic transfusion.556 In general, younger children and those with relatively high cerebral blood flow velocities should be monitored more frequently because of a higher risk of conversion to abnormal velocities in younger patients and in those with TCD velocities closer to 200 cm/s.557 Despite strong evidence of its value, overall TCD screening rates continue to be suboptimal as a result of patient and pro- The National Institutes of Health and the American Academy of Pediatrics recommend annual TCD screening from 2 to 16 years of age.560,561 Few studies have been done to determine whether TCD also predicts stroke in adults with SCD.


Additionally, peak systolic velocity may be used, in which case a measurement of 250 cm/s is used as a threshold for prophylactic transfusion.556 In general, younger children and those with relatively high cerebral blood flow velocities should be monitored more frequently because of a higher risk of conversion to abnormal velocities in younger patients and in those with TCD velocities closer to 200 cm/s.557 Despite strong evidence of its value, overall TCD screening rates continue to be suboptimal as a result of patient and pro- The National Institutes of Health and the American Academy of Pediatrics recommend annual TCD screening from 2 to 16 years of age.560,561 Few studies have been done to determine whether TCD also predicts stroke in adults with SCD. One study comparing TCD velocities in SCD adults with those of healthy control subjects found that velocities in SCD adults were lower than those found in children, higher than in healthy control sub- jects, and negatively correlated with the hematocrit in both Another study found no examples of high TCD (>200 cm/s) in adults with SCD. The mean velocity was 110 cm/s, which is higher than in normal adults but lower than in children with SCD.563 At present, there are no validated TCD criteria for predicting stroke in adults with SCD. AlthoughTCD remains the most extensively validated stroke prediction tool, other clinical characteristics are also associated with increased risk of stroke. One study found that nocturnal desaturation predicted neurological events in 95 patients with SCD (median age, 7.7 years; range, 1 to 23 years) followed up for a median of 6 years.564 There were 7 strokes among 19 individuals with events.


One study found that nocturnal desaturation predicted neurological events in 95 patients with SCD (median age, 7.7 years; range, 1 to 23 years) followed up for a median of 6 years.564 There were 7 strokes among 19 individuals with events. Mean overnight oxygen saturation and TCD independently predicted events.564 Nocturnal oxygen desaturation appears to place children at risk for developing executive dysfunction, which was not associated with MRI- There is no proven therapy for the cognitive impairment associated with nocturnal desaturation. MRI has also been used to identify children with SCD who are at high risk of stroke. The Cooperative Study of Sickle Cell Disease, which preceded the use of TCD-based monitor- ing, found that 8.1% of children with an asymptomatic MRI lesion versus 0.5% of those with a normal MRI had a stroke during the ensuing 5 years.566 The Silent Cerebral Infarct Multicenter Clinical Trial (SIT), a randomized, controlled trial MRI-guided prophylactic transfusion, found that regular blood transfusion significantly reduced the incidence of the recurrence of cerebral infarction in children with sickle cell In a cohort of 67 patients with indication for cervi- cal internal carotid artery MRA, 15% of patients had occlu- sions or stenoses.568 The role of cervical MRA in stroke risk prediction remains undefined. Additional clinical features identify children at risk for devel- oping elevated TCD velocities and stroke.


Additional clinical features identify children at risk for devel- oping elevated TCD velocities and stroke. G6PD deficiency, absence of -thalassemia (OR, 6.45; 95% CI, 2.21 18.87; P=0.001), hemoglobin levels (OR, 0.63 per 1 g/dL; 95% CI, 0.41 0.97; P=0.038), and lactate dehydrogenase levels (OR, pendent risk factors for abnormally high velocities.569 This con- and found for the first time that G6PD deficiency and hemolysis independently increased the risk of abnormal TCD.571 Another study found independent effects of hemoglobin and aspartate transaminase levels on TCD velocities, whereas age had an Several recent studies of children with SCD identified increased lactate dehydrogenase concentrations and baseline reticulocyte counts to be predictive of stroke573,574 and elevated plasma glial fibrillary acidic protein concentra- tions to be predictive of cognitive impairment, suggesting sub- Markers of systemic inflammation such as interleukin-1 also have been associated with stroke risk.576 A future process that integrates blood biomarkers and TCD blood flow findings may identify children at greatest risk. Other genetic factors also affect stroke risk in patients with SCD. A study evaluated 108 SNPs in 39 candidate genes in 1398 individuals with SCD using bayesian networks and found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke.577 This network of interactions includes 3 genes in the transforming growth factor- pathway and selectin P, which is associated with stroke in the general population.


A study evaluated 108 SNPs in 39 candidate genes in 1398 individuals with SCD using bayesian networks and found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke.577 This network of interactions includes 3 genes in the transforming growth factor- pathway and selectin P, which is associated with stroke in the general population. The model was validated in a different population, predicting the occurrence of stroke in 114 individuals with STOP data were used to confirm previous findings of associations between the tumor necrosis factor phisms and risk of large-vessel stroke in SCD.578 Consistent with prior findings, the tumor necrosis factor ( 308) GG genotype increased the risk of large-vessel disease by >3-fold also showed a previously unidentified association between the leukotriene C4-synthase ( 444) A/C variant and risk of large- The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) study found that of the 38 candidate SNPs in 22 genes studied, 5 polymorphisms had significant influence on stroke risk; SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, and -thalassemia and an SNP in the ADCY9 gene were linked to decreased stroke risk.579 The SIT Trial found that 2 varia- tions in the G6PD gene that are linked to reduced enzymatic function, rs1050828 and rs1050829, were associated with vas- culopathy in male participants with SCD (OR, 2.78; 95% CI, Further validation of these findings is required before these genetic variations can be used for stroke risk prediction. Meschia et al Guidelines for the Primary Prevention of Stroke 3785 Periodic red cell transfusion is the only intervention proven in randomized trials to prevent stroke in patients with SCD.


Meschia et al Guidelines for the Primary Prevention of Stroke 3785 Periodic red cell transfusion is the only intervention proven in randomized trials to prevent stroke in patients with SCD. STOP randomized children with SCD who had abnormal high-risk TCD profiles to either standard care, which included episodic transfusion as needed for pain, or periodic red cell transfusion an average of 14 times per year for >2 years with a target reduction of hemoglobin S from a baseline of >90% to <30%. The risk of stroke was reduced from 10%/y Unless exchange methods in which blood is removed from the patient with each transfusion are used, long- term transfusion results in iron toxicity that requires treatment In STOP, there was no evidence of transfu- sion-related infection, but iron overload and alloimmunization remain important transfusion risks.582 To address these risks, STOP II tested whether long-term transfusions for primary stroke prevention could be safely discontinued after at least 30 months (range, 30 91 months) in children who had not had an overt stroke and who had reversion to low-risk TCD velocities (time-averaged mean velocity in middle cerebral or internal carotid artery, <170 cm/s) with long-term transfusion therapy. The study end point was the first occurrence of rever- sion of TCD to abnormal confirmed by 2 TCDs with mean velocities of 200 cm/s or stroke. The study was terminated earlier than planned when an interim analysis showed worse outcomes with discontinuation of transfusion therapy.


The study was terminated earlier than planned when an interim analysis showed worse outcomes with discontinuation of transfusion therapy. Eight children ( 20%) tolerated removal from long-term transfusion therapy, but there was a high TCD reversion rate and a small risk of stroke despite frequent TCD surveillance.583,584 Further analyses from STOP II also demonstrated increased rates of silent infarcts on MRI in the discontinuation group (27.5% Primary stroke prevention for chil- dren with SCD remains centered on red cell transfusions. Therapies other than transfusion such as hydroxyurea or bone marrow transplantation that reduce the number of pain- ful crises have an uncertain effect on organ damage, including stroke. Of the 127 children with SCD enrolled in the Belgian Hydroxyurea SCD registry, 72 patients were evaluated by TCD. Of these 72, 34 were found at risk of stroke, and only 1 had a cerebrovascular event after a follow-up of 96 patient- years, suggesting a benefit of hydroxyurea in stroke preven- A study of 291 children with SCD included clinical and imaging follow-up of 35 children with abnormal TCDs who were placed on transfusion therapy (median follow- up, 4.4 years). Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was replaced with hydroxyurea.


Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was replaced with hydroxyurea. Four of these 10 patients redeveloped high velocities, so only 6 remained transfusion In another study, the adjusted mean change in TCD velocities was 13.0 cm/s (95% CI, 20.19 to 5.92) in a hydroxyurea-treated group and 4.72 cm/s (95% CI, 3.24 to 12.69) in control subjects (P<0.001).587 In a study of 59 initiat- ing hydroxyurea therapy for severe vaso-occlusive complica- tions who had pretreatment baseline TCD measurements, 37 had increased time-averaged maximum velocities 140 cm/s and were enrolled in a trial with TCD velocities measured at maximum tolerated dose and 1 year later.588 At the hydroxy- urea maximum tolerated dose (mean SD=27.9 2.7 mg/kg per day), decreases were observed in bilateral middle cerebral artery velocities. The magnitude of the TCD velocity decline correlated with the maximal baseline TCD value.588 Most recently, the phase III Pediatric Hydroxyurea Clinical Trial (BABY HUG) demonstrated significantly lower increases in TCD velocities in the hydroxyurea group, but neurocognitive testing of the infants was not statistically different between The SWiTCH study, a phase III noninferiority trial comparing standard treatment (transfusions/chelation) with alternative treatment (hydroxyurea/phlebotomy) for chil- dren with SCA, stroke, and iron overload,579 was stopped for safety reasons when adjudication documented no strokes in patients on transfusions/chelation but a 10% stroke rate in patients on hydroxyurea/phlebotomy. Hydroxyurea therapy for stroke prevention is promising for primary stroke preven- tion but requires additional study. Results from the ongo- ing Transcranial Doppler With Transfusions Changing to Hydroxyurea (TWiTCH) trial may provide greater insight into the benefit of hydroxyurea in stroke prevention. Bone marrow transplantation is usually entertained after stroke, but TCD and other indexes of cerebral vasculopathy have also been used as an indication for myeloablative stem- cell transplantation.


Bone marrow transplantation is usually entertained after stroke, but TCD and other indexes of cerebral vasculopathy have also been used as an indication for myeloablative stem- cell transplantation. One study of 55 patients with a median follow-up of 6 years found overall and event-free survival rates of 93% and 85%, respectively. No new ischemic lesions were reported, and TCD velocities decreased.590 In a study of 55 children who underwent bone marrow transplantation for severe SCD, 16 patients without prior stroke and unremark- able MRI before bone marrow transplantation had no clinical or silent stroke on follow-up, and the 10 patients with prior silent ischemia had no further events.591 Bone marrow trans- plantation is promising for primary stroke prevention but requires additional study. No trial has been done on the primary prevention of stroke in adults with SCD. Improvements in care have increased life expectancy in people with SCD, and it is anticipated that stroke prophylaxis in older patients with SCD will pose an increasing challenge in the future. SCD: Summary and Gaps Significant progress has been achieved in the primary pre- vention of stroke in children with SCD. TCD can be used to identify children who are at high risk of stroke and who benefit from transfusion therapy. Although the optimal screening interval has not been established, TCD remains the most extensively validated method for risk assessment. Improvements in prediction may come from incorporating additional predictors such as anterior cerebral artery velocity, blood biomarkers, variations in several genes, and nocturnal oxygen saturation. On the basis of STOP II, even those whose risk of stroke decreases with transfusion therapy on the basis of TCD criteria have an 50% probability of reverting to high risk or having a stroke if transfusion therapy is discontinued.


On the basis of STOP II, even those whose risk of stroke decreases with transfusion therapy on the basis of TCD criteria have an 50% probability of reverting to high risk or having a stroke if transfusion therapy is discontinued. Alternative methods of maintenance therapy that are safer than transfusion need to be developed because studies show the need for ongoing active treatment despite TCD normaliza- tion and the risk of iron toxicity with repeated transfusions. Predictive methods other than TCD (eg, MRI techniques) need to be systematically compared and combined with TCD to further refine the estimation of stroke risk in individuals. Hydroxyurea may be beneficial when red cell transfusions are not feasible but should not be considered as a substitute for transfusion. Data on risk of stroke and prevention options in adults with SCD are needed, and a stroke prevention strategy for adults needs to be developed. Future stroke prevention tri- als are needed for adults with SCD. SCD: Recommendations 1. TCD screening for children with SCD is indicated starting at 2 years of age and continuing annually to 16 years of age (Class I; Level of Evidence B). 2. Transfusion therapy (target reduction of hemoglobin S, <30%) is effective for reducing stroke risk in those children at elevated risk (Class I; Level of Evidence B). 3. Although the optimal screening interval has not been established, it is reasonable for younger children and those with borderline abnormal TCD velocities to be screened more frequently to detect the development of high-risk TCD indications for intervention (Class IIa; Level of Evidence B). 4. Pending further studies, continued transfusion, even in those whose TCD velocities revert to normal, is probably indicated (Class IIa; Level of Evidence B). 5.


Pending further studies, continued transfusion, even in those whose TCD velocities revert to normal, is probably indicated (Class IIa; Level of Evidence B). 5. In children at high risk for stroke who are unable or unwilling to be treated with periodic red cell transfu- sion, it might be reasonable to consider hydroxyurea or bone marrow transplantation (Class IIb; Level of Evidence B). 6. MRI and MRA criteria for selection of children for primary stroke prevention with transfusion have not been established, and these tests are not recom- mended in place of TCD for this purpose (Class III; Level of Evidence B). Less Well-Documented or Potentially Modifiable Risk Factors Migraine Migraine headache has been most consistently associated with stroke in young women, especially those with migraine with A meta-analysis of 21 studies (13 case-control and 8 cohort) reported an overall pooled RR of 2.04 (95% CI, 1.72 The risk was greater in migraine with aura (pooled adjusted OR for 7 studies, 2.51; 95% CI, 1.52 4.14) com- pared with the association of ischemic stroke and migraine without aura (pooled adjusted OR for 6 studies, 1.29; 95% A second meta-analysis of 9 studies (6 case- control and 3 cohort) reported a pooled RR of 1.73 (95% CI, 1.31 2.29) between any migraine and ischemic stroke.594 This study also found a significantly higher risk of stroke among individuals with migraine with aura (RR, 2.16; 95% CI, 1.53 3.03) compared with individuals with migraine with- out aura (RR, 1.23; 95% CI, 0.90 1.69; meta-regression for aura status, P=0.02).594 Furthermore, there was a significant risk among women (RR, 2.08, 95% CI, 1.13 3.84) but not among men (RR, 1.37; 95% CI, 0.89 2.11).


Less Well-Documented or Potentially Modifiable Risk Factors Migraine Migraine headache has been most consistently associated with stroke in young women, especially those with migraine with A meta-analysis of 21 studies (13 case-control and 8 cohort) reported an overall pooled RR of 2.04 (95% CI, 1.72 The risk was greater in migraine with aura (pooled adjusted OR for 7 studies, 2.51; 95% CI, 1.52 4.14) com- pared with the association of ischemic stroke and migraine without aura (pooled adjusted OR for 6 studies, 1.29; 95% A second meta-analysis of 9 studies (6 case- control and 3 cohort) reported a pooled RR of 1.73 (95% CI, 1.31 2.29) between any migraine and ischemic stroke.594 This study also found a significantly higher risk of stroke among individuals with migraine with aura (RR, 2.16; 95% CI, 1.53 3.03) compared with individuals with migraine with- out aura (RR, 1.23; 95% CI, 0.90 1.69; meta-regression for aura status, P=0.02).594 Furthermore, there was a significant risk among women (RR, 2.08, 95% CI, 1.13 3.84) but not among men (RR, 1.37; 95% CI, 0.89 2.11). Age <45 years, especially in women (RR, 3.65; 95% CI, 2.21 6.04), smoking CI, 1.51 32.68) further increased the risk.594 Both meta-anal- yses are in general agreement with prior studies.595 Counseling on possible alternative forms of birth control other than OCs in women with migraine may lower the risk of stroke, but this recommendation should be placed in the context of overall health implications of such a change. The WHS, a primary prevention trial of women 45 years of age and free of CVD at enrollment, continues to inform the association between women with migraine and stroke.


The WHS, a primary prevention trial of women 45 years of age and free of CVD at enrollment, continues to inform the association between women with migraine and stroke. After a mean follow-up of 11.9 years, multivariable-adjusted analysis found that high migraine frequency (more than weekly) had an increased association with ischemic stroke (HR, 2.77; 95% CI, 1.03 7.46) but not in lower frequencies.596 When migraine aura status was taken into account, a significant association of migraine frequency was found only in the migraine with aura From this analysis, increased frequency of attacks in migraine with aura appears to increase the risk for ischemic stroke. However, caution in overly interpreting these results is needed because the incident numbers for these subgroup analyses were small. In a separate analysis of the WHS, the association of migraine with aura and ischemic stroke was found to be more pronounced in the absence (HR, 3.27; 95% CI, 1.93 5.51) than in the presence Overall, the WHS found that increased frequency in patients with migraine with aura increases ischemic stroke risk and that this increased risk is more pronounced in the absence of typical migraine features. The WHS also investigated the association between migraines and ICH.


The WHS also investigated the association between migraines and ICH. Although there was no increased risk of ICH in those who reported any history of migraine compared with those without a history of migraine (HR, 0.98; 95% CI, 0.56 1.71), there was an increased risk for ICH in women with active migraine with aura (HR, 2.25; 95% CI, 1.11 The age-adjusted increased risk was stronger for ICH (HR, 2.78; 95% CI, 1.09 7.07) and for fatal events (HR, 3.56; From this study, it is estimated that 4 additional ICH events are attributable to migraine with aura per 10000 women per year.598 Women who reported active migraine without aura had no increased risk for ICH. This increase in risk for ICH for women with migraine with aura, but not for women with migraine without aura, was similar to the increased risk found with ischemic strokes. The association of migraine in middle-aged to late-life infarct-like lesions on imaging was studied in a Reykjavik, Iceland, population-based cohort.599 After multivariable adjustment, midlife migraine with aura had an increased risk of late-life infarct-like lesions (OR, 1.4; 95% CI, 1.1 1.8).599 This was particularly reflected by an association with cerebel- lar lesions in women (OR, 1.9; 95% CI, 1.4 2.6), but not in men, with migraine with aura (OR, 1.0; 95% CI, 0.6 1.8).599 Migraine without aura and nonmigraine headache were not associated with an increased risk.599 Therefore, similar to the risk for ischemic stroke found in women with migraine with aura in the WHS, in this Icelandic population, women with migraine with aura had an increased risk for late-life isch- emic lesions as seen on brain MRI; however, this association was not appreciated in men or in those with migraine with- out aura or nonmigraine headaches.