In patients with prediabetes and ischemic stroke or TIA, lifestyle optimization (ie, healthy diet, regular physical activity, and smoking cessation) can be beneficial for the preven- tion of progression to diabetes.237,238 In patients with TIA or ischemic stroke, it is reasonable to screen for prediabetes/dia- betes using HbA1c which, among available methods (HbA1c, fasting plasma glucose, oral glucose tolerance), has the advantage of convenience because it does not require fast- ing and is measured in a single blood sample. In patients with an ischemic stroke or TIA who also have diabetes, the usefulness of achieving intensive glucose control (ie, HbA1c 7%) beyond the acute phase of the ischemic event for prevention of recurrent stroke is unknown.239 244 In patients with prediabetes and ischemic stroke or TIA, particularly those with a body mass index (BMI) 35 kg/mP2 those <60 years of age, or women with a history of gestational diabetes, metformin may be beneficial to control blood sugar and to prevent progression to diabetes.245 247 In patients 6 months after TIA or ischemic stroke with insulin resistance, HbA1c <7.0%, and without heart failure or bladder cancer, treatment with pioglitazone may be consid- ered to prevent recurrent stroke.248 Synopsis The principal disorders of glucose metabolism are type 1 diabetes, T2D, and prediabetes. Type 1 diabetes is an autoimmune disorder that results in absolute insu- lin deficiency and accounts for 6% of diabetes in the United States. T2D results from progressive impairment in peripheral insulin sensitivity and pancreatic insulin secretion. It accounts for 91% of diabetes in the United CLINICAL STATEMENTS AND GUIDELINES Kleindorfer States. Prediabetes has the same pathophysiology as T2D but is associated with lower plasma glucose than in T2D. The prevalence of diagnosed diabetes among US adults is 9%.249 Prediabetes and diabetes are asso- ciated with increased risk for first ischemic stroke (RR, Prediabetes is pres- ent in 30% of patients with acute ischemic stroke255 and is associated with increased risk for recurrence.256 Progression of prediabetes to T2D can be prevented by maintaining a healthy weight, exercising, eating a healthy diet, and taking certain medications.237,238,245 T2D is also present in 30% of patients with ischemic and is associated with increased risk for recur- rence (RR, 1.6).209,257 Remission of established T2D can be achieved by weight loss,258 260 although no tri- als have established that weight loss or diabetes remis- sion reduces risk for recurrent stroke. Recent clinical trials demonstrated that at least 1 drug in each of the 3 classes of glucose-lowering medications can reduce risk for MACEs in patients with T2D and established ath- erosclerotic vascular disease, including ischemic stroke or high risk: thiazolidinediones, glucagon-like protein 1 (GLP-1) receptor agonist, and sodium-glucose cotrans- porter 2 inhibitor. Unlike the data for the thiazolidinedi- one pioglitazone and some GLP-1 receptor agonists, the cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors do not suggest a specific effect on stroke but rather on cardiovascular death, MI, and heart failure.261 Recommendation-Specific Supportive Text 1. Intensive control of blood sugar for patients with both type 1 diabetes and T2D has been shown to reduce risk for microvascular complications, includ- ing retinopathy, nephropathy, and peripheral neu- ropathy. The first evidence emerged from the DCCT (Diabetes Control and Complication Trial), which enrolled patients with type 1 diabetes between 13 and 39 years of age.229 Participants were random- ized to conventional glucose control (goal to avoid symptoms of hyperglycemia, to avoid ketonuria, and to preserve normal growth) or intensive control to achieve near-normal glucose. After a mean of 6.5 years, intensive control delayed the onset or pro- gression of nephropathy, retinopathy, and neuropa- thy. The findings were confirmed for patients with T2D in the UKPDS (United Kingdom Prospective As in DCCT, however, inten- sive control was associated with increased risk for hypoglycemia. The American Diabetes Association recommends a target HbA1c <7% for most adult The American Diabetes Association, however, advocates for less stringent goals (eg, 7% 8%) for patients with a limited life expectancy, history of hypoglycemia, long-standing disease, or advanced microvascular or macrovascular disease when the risk and inconvenience of intensive con- trol outweigh the potential benefit. 2. In response to the development of new classes of glucose-lowering medications that also prevent clinical vascular disease, the American Diabetes Association, the European Association for the Study of Diabetes, and other professional organi- zations have revised their algorithms for the man- agement of T2D. An evidence-based consensus report by the American Diabetes Association and European Association for the Study of Diabetes recommends metformin and comprehensive life- style optimization as first-line therapy.263 In patients with established ASCVD, including ischemic stroke, when prevention of further vascular events is the priority, GLP-1 receptor agonist therapy should be added to metformin independently of baseline HbA1c. When concern for heart failure or chronic kidney disease predominates, addition of a sodium- glucose cotransporter 2 inhibitor to metformin is recommended. These developments in manage- ment have implications for the care of patients with diabetes and ischemic stroke. Clinicians should now engage patients in a discussion of the new therapies and alternatives. Through shared decision-making, clinicians should help patients decide if a GLP-1 receptor agonist or a sodium- glucose cotransporter 2 inhibitor is right for them. Risk for future vascular disease is only one consid- eration in selecting among available diabetes med- ications. Cost, side effects, desire for weight loss, aversion to injection therapy, and desire to reduce risk for hypoglycemia are also important. 3. Optimal management of T2D is achieved with a multidimensional approach that includes (1) med- ical nutritional therapy; (2) lifestyle counseling (for physical activity, weight loss, smoking cessation, etc); (3) diabetes self-management, education, and support; and (4) medication therapy.263,264 For patients with overweight or obesity, it can be help- ful to include intensive behavioral counseling for weight loss in medical nutritional therapy. T2D in most patients is highly responsive to weight opti- mization; weight loss can result in diabetes remis- sion for some patients and reduced medication use in most. 4. Multifactorial interventions to simultaneously improve diet quality, increase physical activity, and reduce body weight reduce risk for progression to diabetes among patients with impaired glucose tolerance by 43% to 58% during 3 to 5 years of The benefit achieved is in propor- tion to patients ability to achieve lifestyle goals. 5. Approximately 20% of patients with acute isch- emic stroke will be found to have undiagnosed diabetes after testing with an HbA1c or oral CLINICAL STATEMENTS AND GUIDELINES Kleindorfer glucose tolerance test.255 These patients are at risk for progressing to symptomatic disease and for developing complications related to their dia- betes, including microvascular and macrovascular disease. With the development of drugs that both control glucose and reduce risk for major adverse cardiovascular events, it has become more impor- tant to identify all patients with diabetes after an ischemic stroke so that they can be offered appro- priate therapy. Available methods to screen for diabetes include fasting blood sugar, oral glucose tolerance test, and HbA1c. Of these, HbA1c has advantages in that it is more convenient (ie, it does not require fasting), has less variability day to day, and is less likely to be perturbed by medications, stress, or illness.265 In general, HbA1c may be more accurate than other screening tests in the immedi- ate postevent period. It is probably the preferred method of diagnosis for patients hospitalized with an acute stroke. 6. Compared with evidence for a benefit in microvas- cular disease, there is less evidence for a benefit of intensive glucose control on macrovascular end points such as stroke. No macrovascular benefit was demonstrated in the main publications from DCCT, the UKPDS, or 3 other more recent trials designed to test intensive control for prevention of macrovascular disease.239 241 However, a ben- efit of intensive control emerged during long-term follow-up of the DCCT242 and the UKPDS. Two meta-analysis of 5 trials that included the UKPDS reported a benefit of intensive control for some cardiovascular outcomes but not for stroke.243,244 No trials or meta-analyses have reported the effect of intensive control on patients with a his- tory of stroke. Many experts conclude that the benefit of intensive control on macrovascular dis- ease is likely restricted to younger patients with recent-onset diabetes and without established vascular disease. In this regard, however, some professional organizations recommend targeting reduce the risk for hypoglycemia in elderly indi- viduals with limited life expectancy or significant 7. Although lifestyle change is the safest and most efficacious method to prevent progression from prediabetes to diabetes, several drugs have dem- onstrated benefit. In the Diabetes Prevention Program trial, patients with impaired glucose tolerance were randomized to standard lifestyle recommendations plus metformin 850 mg twice a day, standard lifestyle recommendation plus placebo, or intensive lifestyle counseling. The primary outcome, progression to diabetes, was observed in 11.0%, 7.8%, and 4.8% of patients in the placebo, metformin, and intensive coun- seling groups. The rate of progression was 58% lower (95% CI, 48 66) with intensive counseling and 31% (95% CI, 17 43) lower with metfor- min compared with standard lifestyle counsel- ing. Metformin is well tolerated and inexpensive. Other drugs that have been shown to reduce progression to diabetes include pioglitazone,245 These are not as well tolerated as metformin. Liraglutide is delivered by injection. 8. Approximately 30% of patients with ischemic stroke have prediabetes as defined by HbA1c and other measures of glucose metabolism.255 Most of these patients will have insulin resistance as a contributing cause, but insulin resistance can occur before prediabetes develops. Thus, 50% of patients without diabetes with ischemic stroke have insulin resistance.269,270 Both condi- tions have been associated with increased risk for first ischemic stroke,252,253,271 275 but no research has been designed to test their effect on risk for recurrent vascular events. One large clinical trial has examined the effect of a specific interven- tion for patients with ischemic stroke and insu- lin resistance. The IRIS trial (Insulin Resistance Intervention After Stroke) examined the effect of the insulin-sensitizing agent pioglitazone compared with placebo among patients with- out diabetes who had a recent ischemic stroke and insulin resistance. Patients with heart failure were excluded. After a mean of 3.8 years, pio- glitazone reduced the risk of recurrent stroke or 11.8% among placebo recipients to 9.0% among pioglitazone recipients. Active treatment, however, was associated with weight gain and increased bone fracture risk. These adverse events have restrained clinical use of pioglitazone. Knowledge Gaps and Future Research Having T2D is one of the most prevalent risk factors for future stroke after an initial acute ischemic stroke or TIA. It is a promising target for secondary prevention because diabetes remission can be achieved in many patients through weight management and vascular protection can be achieved by newer glucose-lowering agents. In addi- tion, diabetes is associated with CNS small vessel dis- ease and vascular dementia. Potential areas of research include the following: It is plausible that interventions for prediabetes, established diabetes, and glucose management will reduce risk for neurocognitive outcomes and subclinical ischemic damage and discrete stroke events. The IRIS trial demonstrated that 1 glu- cose-lowering intervention, pioglitazone, prevented CLINICAL STATEMENTS AND GUIDELINES Kleindorfer stroke and MI in patients with insulin resistance without diabetes. The benefit of other interventions for prediabetes, including GLP-1 receptor agonists, dietary improvement, and weight reduction, has not been investigated but would logically follow from the IRIS trial. The same interventions could be examined in patients with established diabetes. Some early investigations have explored the effec- tiveness of poststroke behavioral counseling and physical training, modeled on cardiac rehabilitation, for improving lifestyle after stroke. Because diabetes disproportionately affects Black and Hispanic communities, effective commu- nity-based research for diabetes prevention and management may yield interventions to reduce dis- parities in stroke risk and recovery. Because patients with ischemic stroke or TIA tend to be older and to have established vascu- lar disease, the optimal goal for glycemic control remains uncertain. In this regard, however, some professional organizations recommend targeting reduce the risk for hypoglycemia in elderly indi- viduals with limited life expectancy or significant Recommendations for Obesity Referenced studies that support recommendations are summarized in online Data Supplements 16 and 17. COR LOE Recommendations In patients with ischemic stroke or TIA and who are overweight or obese, weight loss is recommended to improve the ASCVD risk In patients with ischemic stroke or TIA who are obese, referral to an intensive, multicompo- nent, behavioral lifestyle-modification program is recommended to achieve sustained weight In patients with ischemic stroke or ASCVD, calculation of BMI is recommended at the time of their event and annually thereafter, to screen for and to classify obesity. Synopsis Approximately 38% of US adults have obesity.282 By 2030, prevalence is expected to reach 50%.283 In popu- lation studies, obesity increases risk for ischemic stroke by 50% to 100% compared with patients who have a The causal pathway from obesity to stroke risk is mediated by factors that track closely with weight, particularly elevated BP, AF, dyslipidemia, Obesity can be treated with inten- sive behavioral counseling to change eating patterns, medications that reduce appetite, and metabolic surgery. Weight loss of as little as 5% to 10% produces meaning- ful improvements in vascular risk factors.279 Only 1 trial has tested the effect of an intensive lifestyle interven- tion for weight loss on the prevention of vascular disease, and it was stopped early for futility.292 Inadequate aver- age weight loss in the active treatment group and statin therapy in the control group might explain the negative findings. Observational research provides some evidence that weight loss after bariatric surgery may reduce risk Approximately 24% to 30% of patients with acute ischemic stroke are obese.295 Paradoxically, they have a reduced risk for stroke recurrence,296,297 but this is likely attributable to selection bias.298 Weight loss after stroke is expected to improve stroke risk factors, but the effect on future brain health has not yet been directly examined. Recommendation-Specific Supportive Text 1. Our recommendation for weight loss in patients with overweight or obesity after stroke is consis- tent with the 2013 AHA guideline on obesity,27 the 2014 AHA guideline on primary prevention,18 and other professional guidelines on management Even a modest weight loss of 5% to 10% is associated with important improvements in conventional cardiovascular risk factors.279 In particular, weight loss can improve glucose con- trol in patients with diabetes.277 The DiRECT trial (Diabetes Remission Clinical Trial) compared food substitution followed by stepped food reintroduc- tion and structured support with best practice by guideline among patients with diabetes and BMI . After 12 months, 24% of par- ticipants in the intervention group lost 15 kg compared with none in the control group. Diabetes remission was achieved in 46% of patients in the intervention group and 4% in the control group. Studies of metabolic surgery confirm that weight loss is associated with improvements in glucose control, BP, indicators of inflammation, and lipid 2. Available strategies for helping patients achieve meaningful weight loss include intensive behavioral counseling, drugs to reduce appetite, and bariatric surgery. Of these, intensive behavioral counseling is recommended as the first option in evidence- based guidelines because of its greater effective- ness and safety compared with pharmacotherapy and greater safety and lower cost compared with Components of multicomponent behavioral programs typically include goal setting, feedback, problem solving, coaching for physical activity, and frequent indi- vidual or group meetings (at least 12 sessions in the first year).300 Examples include the Diabetes and CLINICAL STATEMENTS AND GUIDELINES Kleindorfer the Counterweight Program.258 On average, behavior-based programs achieve 2.4 kg greater weight loss than control intervention over up to 24 month, and participants are more likely to lose 5% of their body weight.281 Ideally, patients with obe- sity, according to need, are offered care in a com- prehensive bariatric program in which all strategies for weight reduction are offered. 3. In 2012, the US Preventive Services Task Force issued a Grade B recommendation to screen all adults for obesity.301 The recommendation is con- sistent with the AHA guideline on obesity from 2013 and more recent guidance from other pro- Although there is no direct evidence that weight loss interventions among patients with acute ischemic stroke reduce risk for recurrent stroke or otherwise improve future brain health, there is clear evidence that intensive counseling can help patients achieve meaningful weight loss.281 The US Preventive Services Task Force determined that the risks for intensive counseling were small to none.300 For selected patients, pharmacotherapy and bariatric surgery also may be effective, although surgical trials typically have excluded patients with stroke. Specific benefits of weight loss among patients with ischemic stroke include improved glucose metabolism, BP, and lipid metabolism. It also has a favorable effect on obstructive sleep apnea (OSA), AF, and vascular inflammation. Screening is necessary to identify adults for referral to effective weight loss therapy. Knowledge Gaps and Future Research Treatment of overweight and obesity is a highly prom- ising intervention for primary and secondary preven- tion of stroke. The evidence for this includes the high prevalence of overweight and obesity in the general population at risk for stroke and with completed stroke, the confirmed association between increased weight and increased risk for stroke, and the favorable effect of weight reduction on vascular risk factors, including hypertension. Weight reduction would have additional potential nonvascular benefits for patients at risk for and with established cerebrovascular disease. What holds back research on treatment of overweight and obesity for stroke prevention are the cost and complex- ity of available treatments. The most effective nonsurgi- cal approaches require intensive behavioral counseling, possibly with food substitution. Research is ongoing to understand the biology of obesity and to develop more effective and convenient treatments, which may include pharmacological approaches to appetite sup- pression. Right now, however, trials of counseling and food substitution could be implemented safely and are urgently needed. 4.6. Obstructive Sleep Apnea Recommendations for Obstructive Sleep Apnea Referenced studies that support recommendations are summarized in online Data Supplements 18 and 19. COR LOE Recommendations In patients with an ischemic stroke or TIA and OSA, treatment with positive airway pressure (eg, continuous positive airway pressure [CPAP]) can be beneficial for improved sleep apnea, BP, sleepiness, and other apnea- In patients with an ischemic stroke or TIA, an evaluation for OSA may be considered for diagnosing sleep apnea.302,303,315,316 Synopsis Sleep apnea is diagnosed by polysomnography to calcu- late the apnea-hypopnea index (AHI), the hourly sum of apneas (total cessation of airflow for 10 seconds) plus hypopneas (reduction in airflow by at least 30% for 10 seconds with reduced oxygen saturation). The threshold for diagnosis is AHI 5 with symptoms (eg, sleepiness) or Theprevalenceofmoder- ate to severe sleep apnea (AHI >15) among US adults 50 to 70 years of age is estimated to be 10%.318 Prevalence is higher in men than women and increases sharply with age and BMI. Sleep apnea is associated with increased risk for mortality,302 and risk factors including Sleep apnea affects 38% to 40% (AHI >20) of patients with stroke, with >90% of cases being OSA rather than central sleep Limited data suggest that patients with acute ischemic stroke and OSA are at increased risk for func- tional impairment, stroke recurrence, and death, although causation is not established.314,327 329 Limited data from small trials show that treatment with CPAP is safe after stroke, reduces the AHI, improves sleepiness, and may improve neurological function.304 311 Effects on vascular recurrence are uncertain, although a planned ancillary analysis in the SAVE study (Sleep Apnea Cardiovascular Endpoints) revealed that risk for stroke was lower among participants (all had a history of coronary artery disease or cerebrovascular disease) who had better adherence to CPAP therapy (HR, 0.56 [95% CI, 0.32 1.00]). Recommendation-Specific Supportive Text 1. Our recommendation to treat patients with OSA using CPAP is consistent with a guideline from the American College of Physicians that recom- mends CPAP as the initial therapy.330 In stud- ies of various populations, treatment with CPAP effectively reduced the AHI and improved mea- sures of sleepiness, BP control, sleep-related quality of life, and physical functioning.302,303 As described in the above synopsis, limited data from small trials specifically among patients with stroke show that treatment with CPAP is CLINICAL STATEMENTS AND GUIDELINES Kleindorfer safe, reduces the AHI, improves sleepiness, and may improve neurological function.304 313 Evidence from 1 trial suggests that treat- ment may improve mood.314 In a planned ancil- lary analysis in the SAVE trial, which enrolled patients with either coronary or cerebrovascu- lar disease, CPAP reduced the risk for stroke in patients with better CPAP adherence.303 The American College of Physicians recommends mandibular advancement devices as an alterna- tive for patients who do not tolerate CPAP or who prefer mandibular advancement.330 These devices, however, have not been specifically tested in patients with stroke. 2. OSA is common among patients with stroke, but most cases are undiagnosed.315 The combined prevalence of known and unknown moderate to severe OSA approaches 40%. Arguing against evaluating patients for undiagnosed OSA is the absence of evidence that treatment improves stroke-related outcomes, including recurrence. Since the last version of this guideline, a trial of 2717 patients with moderate to severe OSA and coronary or cerebrovascular disease failed to show a benefit of CPAP on recurrent vascular events.303 In favor of evaluating stroke patients is the high prevalence of undiagnosed OSA, combined with evidence that treatment improves daytime sleepi- ness, BP, sleep-related quality of life, and physi- If an evaluation is undertaken, options include questionnaires to identify patients at high risk for OSA who can be selectively referred However, available questionnaires show inconsistent performance in patients with stroke.332 In addition, the prevalence of OSA after stroke is sufficiently high to justify omitting prescreening before polysomnography when detection of asymptomatic OSA is clinically warranted. Facility-based (ie, sleep laboratory based), multichannel polysomnography is the ref- erence standard for diagnosing OSA. Home (ie, out of sleep laboratory) monitors are appropriate in selected patients.316,317 Although the American Academy of Sleep Medicine recommends against the use of home testing in patients with stroke,334 recent research suggests that home testing can be Knowledge Gaps and Future Research Observational data show a high prevalence of OSA among patients with acute ischemic stroke, and small trials suggest that treatment may improve several important outcomes. Together, this considerable vol- ume of data support the hypothesis that early detec- tion and treatment of OSA may be helpful for selected patients. Proving this hypothesis will require adequately designed clinical trials. Such trials will need to consider the following: The selection of patients who might benefit from CPAP, Timing of testing and treatment in relation to stroke onset, Type of testing (in home or in facility), and Dose/type of CPAP. Currently, at least 3 trials are underway that will help in this regard: 1. Sleep SMART (Sleep for Stroke Management and Recovery Trial), a randomized trial to determine whether early treatment of OSA with CPAP after ischemic stroke or TIA reduces the risk for 2 primary outcome measures: recurrent stroke, acute coro- nary syndrome, and all-cause mortality 6 months after the event and functional status at 3 months (ClinicalTrials.gov identifier NCT03812653). 2. The RISE-UP trial (Recovery in Stroke Using PAP) focused on optimal timing of CPAP initiation after stroke (NCT04130503). 3. ASAP (Addressing Sleep Apnea Post Stroke/TIA), which will test a quality improvement initiative in the Veterans Affairs Medical Administration and include a secondary aim of recurrent vascular dis- ease (NCT04322162). 5. MANAGEMENT BY ETIOLOGY 5.1. Large Artery Atherosclerosis 5.1.1. Intracranial Large Artery Atherosclerosis Recommendations for Intracranial Large Artery Atherosclerosis Referenced studies that support recommendations are summarized in online Data Supplements 20 27. COR LOE Recommendations Antithrombotic Therapy In patients with a stroke or TIA caused by 50% to 99% stenosis of a major intracranial artery, aspirin 325 mg/d is recommended in prefer- ence to warfarin to reduce the risk of recurrent ischemic stroke and vascular death.335,336 In patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70% 99%) of a major intracranial artery, the addition of clopidogrel 75 mg/d to aspirin for up to 90 days is reasonable to further reduce recurrent stroke risk.336 339 In patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilat- eral >30% stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice a day to aspirin for up to 30 days might be considered to further reduce recurrent stroke risk.340 In patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the addition of cilostazol 200 mg/day to aspirin or clopidogrel might be considered to reduce recurrent stroke risk.341 344 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer In patients with stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, the usefulness of clopidogrel alone, the combination of aspirin and dipyridam- ole, ticagrelor alone, or cilostazol alone for secondary stroke prevention is not well established. Risk Factor Management In patients with a stroke or TIA attributable to 50% to 99% stenosis of a major intracranial artery, maintenance of SBP below 140 mmHg, high-intensity statin therapy, and at least moderate physical activity are recom- mended to prevent recurrent stroke and Angioplasty and Stenting In patients with severe stenosis (70%-99%) of a major intracranial artery and actively pro- gressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of SBP <140 mmHg, and high- intensity statin therapy (so-called medical failures), the usefulness of angio- plasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown.350 352 3: Harm A In patients with stroke or TIA attributable to severe stenosis (70% 99%) of a major intracranial artery, angioplasty and stenting should not be performed as an initial treat- ment, even for patients who were taking an antithrombotic agent at the time of the stroke 3: Harm B-NR In patients with a stroke or TIA attributable to moderate stenosis (50% 69%) of a major intracranial artery, angioplasty or stenting is associated with excess morbidity and mortal- ity compared with medical management Other Procedures Benefit B-R In patients with stroke or TIA attributable to 50% to 99% stenosis or occlusion of a major intracranial artery, extracranial-intracra- nial bypass surgery is not recommended.361 Synopsis ICAS is a common cause of stroke worldwide with a high rate of recurrent stroke.362 Severity of stenosis is a strong predictor of risk of recurrent stroke in the ter- ritory of the stenotic artery, with 1-year rates as high as Therapeutic tri- als have demonstrated that for most patients with ICAS, antithrombotic therapy and vascular risk factor control are effective for stroke prevention. However, there may be a subset of patients (eg, those with low flow or poor collaterals) who have an even higher risk of recurrent stroke despite medical therapy.357,363,364 Current research is focused on identifying characteristics of patients with ICAS at highest risk and studying new therapies for stroke prevention. Recommendation-Specific Supportive Text 1. In the WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease), warfarin (target INR, 2 3) compared with aspirin 650 mg twice a day was found to have a higher rate of major hemorrhages (relative difference, 5.1%) and all-cause death (rela- tive difference, 5.4%) but did not prevent more pri- mary end points (stroke, ICH, vascular death) (22% in both arms at a mean follow-up of 1.8 years) or ischemic strokes in the territory of the stenotic artery (2-year rate: 15% for aspirin versus 13% for The optimal dose of aspirin for second- ary prevention in patients with ICAS has not been determined, but doses <1300 mg/d are probably effective given that lower doses of aspirin have been shown to be effective for secondary prevention in trials of heterogeneous causes of stroke and that patients in the medical arm of the SAMMPRIS trial were treated with 325 mg aspirin once daily alone after the first 90 days with favorable results.336 2. Support for the use of short-term combination aspirin and clopidogrel for secondary prevention in patients with severe ICAS comes from post hoc analyses of clinical trials and RCTs studying surro- gate end points for stroke. Patients in the medical arm of SAMMPRIS with severe stenosis received aspirin and clopidogrel for 90 days followed by aspirin alone for the rest of follow-up and had a lower 1-year recurrent stroke rate (12.2%) com- pared with similar patients from WASID on aspi- rin alone (25%).336,337 Subgroup analysis of the CHANCE trial (Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events) reported that patients with ICAS who were randomized to clopidogrel and aspirin for 21 days followed by clopidogrel alone had a lower rate of stroke at 90 days (11.3%) compared with those on aspirin alone (13.6%), although the difference was not statistically significant.338 Patients in the CLAIR trial (Clopidogrel Plus Aspirin for Infarction Reduction) randomized to aspirin and clopidogrel for 7 days had significantly decreased microemboli in the territory of the stenotic ICA or middle cere- bral artery compared with those on aspirin alone and a lower rate of recurrent stroke at day 7 (0% in combination versus 3.8% in aspirin alone), but this difference was not significant.339 In contrast to patients with heterogeneous causes of minor stroke wherein the risk of recurrent stroke plateaus within a few weeks,365 the risk of recurrent stroke from ICAS extends well beyond 30 days.338,353 Data from these studies also suggest that short-term combination aspirin and clopidogrel up to 90 days is safe. 3. Data from the THALES trial (Acute Stroke or Transient Ischaemic Attack Treated With Recommendations for Intracranial Large Artery Atherosclerosis (Continued) COR LOE Recommendations Antithrombotic Therapy (Continued) CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Ticagrelor and ASA for Prevention of Stroke and Death; discussed in more detail in Section 5.19, Use of Antithrombotic Medications in Secondary Stroke Prevention) also inform recommenda- tions for short-term treatment with combination ticagrelor and aspirin in patients with atheroscle- rosis ipsilateral to the ischemic territory, including ICAS. In this prespecified subgroup analysis,340 risk of recurrent stroke or death at 30 days among patients with 30% intracranial stenosis ipsilateral to the ischemic event was 9.9% in the ticagrelor 90 mg twice a day plus aspirin 100 mg once a day group versus 15.2% in the aspirin 100 mg alone group (HR, 0.66 [95% CI, 0.47 0.93]; P=0.016). In contrast to the THALES patients without atherosclerosis, bleeding events among the ipsilateral atherosclerosis subgroup treated with ticagrelor and aspirin were not significantly higher than in those taking aspirin alone. Of note, THALES required loading doses of both ticagre- lor and aspirin. Also of note, in this analysis, ICAS was not required to be related to the index isch- emic event, so some patients may not have had symptomatic ICAS. Given the lack of comparative data between various dual-antiplatelet regimens in ICAS, the choice of adding ticagrelor or clopido- grel to aspirin should be based on patient factors such as medication adherence (eg, relative cost and dose frequency), but the role of genetic stud- ies or platelet function testing remains unclear. 4. Several RCTs have studied the efficacy of cilo- stazol 200 mg/d combined with other antiplate- let agents in patients with symptomatic ICAS. The TOSS-1 and TOSS-2 trials (Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis) found that cilostazol (200 mg/d) plus aspirin was as safe as aspirin alone or clopidogrel plus aspirin but was no better for stroke prevention in patients The CATHARSIS trial (Cilostazol- Aspirin Therapy Against Recurrent Stroke With Intracranial Artery Stenosis) reported that the combination of cilostazol and aspirin was superior to aspirin for the prevention of the combined sec- ondary end point of all vascular events and new but had no impact on ICAS progression.343 Subgroup analysis of the CSPS trial reported that patients with ICAS who were randomized to cilostazol plus either aspirin or clopidogrel (dual group) had a lower rate of stroke compared with those on aspirin or clopidogrel alone (4% versus Of note, these trials were conducted in a primarily Asian population, the dose of aspirin when used in com- bination with cilostazol did not exceed 150 mg/d, and many were unblinded. 5. Antithrombotic agents that have been specifically studied in RCTs of patients with ICAS include war- farin, aspirin, cilostazol, and the combination of clopidogrel plus aspirin or cilostazol. 6. Post hoc analyses from WASID (N=567), the med- ical arm of SAMMPRIS (n=227), and the CICAS registry (Chinese Intracranial Atherosclerosis; N=2426) showed that achievement of a mean SBP <140 mmHg during follow-up in patients with ICAS was associated with a lower risk of stroke and vascular events, even in patients with or those treated early Although most patients with ICAS probably benefit from lower BP, some small stud- ies suggest that patients with documented hemo- or those treated to SBP <120 mmHg early after stroke348 may not benefit, and the lower threshold associated with increased stroke risk is not known. High-intensity statin use is supported by an RCT in patients with ICAS that showed that high-intensity statins lowered the rate of cerebrovascular events349 and by general recommendations (see Section 4.3, Treatment of Hyperlipidemia for Secondary Prevention of Stroke). An optimum target LDL for patients with ICAS has not been determined, but WASID and SAMMPRIS post hoc analyses show lower LDLs are associated with lower vascular event rates in patients with ICAS,110,337 and a recent RCT dem- onstrated benefit of an LDL target <70 mg/dL in patients with stroke and atherosclerosis.210 Moderate physical activity at least 3 to 5 times per week was the factor most strongly associated with lower risk of recurrent stroke and vascular events in a post hoc analysis of SAMMPRIS medically 7. Two uncontrolled multicenter registries reported outcomes after percutaneous transluminal angio- plasty and stenting (PTAS) in patients with ICAS who have progressive symptoms or failed medical therapy (ie, had a recurrent stroke or TIA despite treatment with antithrombotic medications or risk factor control). The WEAVE prospective registry (Wingspan Stent System Post Market Surveillance) reported a periprocedural complication rate of 2.6% in 152 patients who met the specific US Food and Drug Administration Humanitarian Device Exemption criteria for Wingspan stent use, but outcomes beyond 72 hours after the procedure have not been published.350 However, the stroke or death rate was 23.9% in the 46 patients treated off- label, many of whom had not failed medical therapy or were treated less than a week from symptom A retrospective registry of 101 patients with ICAS receiving stenting or balloon angioplasty, which included both patients who failed medical CLINICAL STATEMENTS AND GUIDELINES Kleindorfer therapy and those with progressive stroke symp- toms, reported a 90-day ischemic stroke rate of Post hoc analysis of SAMMPRIS patients who had a prior stroke or TIA while on antithrombotic therapy (n=284) showed that medical therapy was supe- rior to PTAS for the prevention of the primary end point in this subgroup (15% for aggressive medical management versus 24% for PTAS; P=0.043).352 Given the lack of efficacy data, PTAS is considered investigational in this population. 8. Three RCTs have compared PTAS with medi- cal therapy for stroke prevention in patients with recent stroke or TIA attributable to 70% to 99% stenosis. The SAMMPRIS trial (N=451) used the Wingspan stenting system; the VISSIT trial (Vitesse Intracranial Stent Study for Ischemic Stroke Therapy; N=112) used the Pharos system; and a single-center RCT in China (N=70) allowed either Wingspan or Coroflex stenting systems. Medical therapy was similar in the 3 RCTs and consisted of risk factor management and combination aspirin and clopidogrel for 90 days and then aspirin alone. All 3 RCTs showed a higher 30-day rate of cere- brovascular events or death in the PTAS group than the medical group and no benefit of PTAS beyond the periprocedural period.353 355 Post hoc analyses of SAMMPRIS baseline characteristics failed to demonstrate any subgroup of patients who ben- efited from PTAS but did identify some possible high-risk features for future study.356,357 Two other RCTs (VAST [Vertebral Artery Stenting Trial] and VIST [Vertebral Artery Ischemic Stenting Trial]) that randomized patients with intracranial and extracra- nial posterior circulation stenosis to PTAS or medi- cal therapy reported no significant benefit of PTAS among the patients with ICAS.358,359 9. No RCTs have directly compared PTAS with med- ical therapy in patients with symptomatic 50% to 69% stenosis. However, the low rate of stroke on medical therapy in patients with 50% to 69% high periprocedural risk, which does not vary by degree of stenosis,368 and lack of demonstrated benefit of PTAS in well-designed RCTs performed in a higher-risk population do not support the use of PTAS. 10. A large multicenter RCT comparing extracranial- intracranial arterial bypass with medical therapy in 1377 patients with recent minor stroke or TIA included patients with 70% intracranial middle cerebral artery (n=109) or ICA (n=149) stenosis and found higher rates of stroke in patients with ICAS treated with extracranial-intracranial arterial bypass than in those in the medical group.361 Knowledge Gaps and Future Research Despite numerous advances in ICAS treatment over the past several decades, the recurrent stroke risk remains high. Further investigation into the following should be prioritized: Studying new therapies in well-designed clinical trials, including novel antithrombotic regimens (eg, direct thrombin inhibitors), improved endovascular treatments (eg, submaximal balloon angioplasty), indirect bypass, and ischemic preconditioning. Determining the interaction between hemodynamic function or collateral flow and treatments (eg, BP management and endovascular therapy). Developing and using surrogate markers of stroke risk (eg, plaque characteristics) or high-risk prognostic fea- tures (eg, diabetes) that may lead to new therapies or improve patient selection for future therapeutic trials. Genetic variants that relate to ICAS (eg, ring finger protein 213) and whether such variants affect the rate of stroke recurrence or treatment responses. 5.1.2. Extracranial Large Artery Atherosclerosis 5.1.2.1. Extracranial Carotid Stenosis Recommendations for Extracranial Carotid Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28. COR LOE Recommendations In patients with a TIA or nondisabling ischemic stroke within the past 6 months and ipsilateral severe (70% 99%) carotid artery stenosis, carotid endarterectomy (CEA) is recommended to reduce the risk of future stroke, provided that perioperative morbidity and mortality risk is estimated to be <6%.369 In patients with ischemic stroke or TIA and symptomatic extracranial carotid stenosis who are scheduled for carotid artery stent- ing (CAS) or CEA, procedures should be performed by operators with established periprocedural stroke and mortality rates of <6% to reduce the risk of surgical adverse In patients with carotid artery stenosis and a TIA or stroke, intensive medical therapy, with antiplatelet therapy, lipid-lowering therapy, and treatment of hypertension, is recom- mended to reduce stroke risk.210 In patients with recent TIA or ischemic stroke and ipsilateral moderate (50% 69%) carotid steno- sis as documented by catheter-based imaging or noninvasive imaging, CEA is recommended to reduce the risk of future stroke, depending on patient-specific factors such as age, sex, and comorbidities, if the perioperative morbidity and mortality risk is estimated to be <6%.369 In patients 70 years of age with stroke or TIA in whom carotid revascularization is being considered, it is reasonable to select CEA over CAS to reduce the periprocedural stroke rate.371 In patients in whom revascularization is planned within 1 week of the index stroke, it is reasonable to choose CEA over CAS to reduce the periprocedural stroke rate.372 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer In patients with TIA or nondisabling stroke, when revascularization is indicated, it is reasonable to perform the procedure within 2 weeks of the index event rather than delay surgery to increase the likelihood of stroke- In patients with symptomatic severe stenosis ( 70%) in whom anatomic or medical condi- tions are present that increase the risk for surgery (such as radiation-induced stenosis or restenosis after CEA) it is reasonable to choose CAS to reduce the periprocedural In symptomatic patients at average or low risk of complications associated with endovascular intervention, when the ICA stenosis is 70% by noninvasive imaging or >50% by catheter-based imaging and the anticipated rate of periprocedural stroke or death is <6%, CAS may be considered as an alternative to CEA for stroke preven- tion, particularly in patients with significant cardiovascular comorbidities predispos- ing to cardiovascular complications with In patients with a recent stroke or TIA (past 6 months), the usefulness of transcarotid artery revascularization (TCAR) for prevention of recurrent stroke and TIA is uncertain.376 Benefit A In patients with recent TIA or ischemic stroke and when the degree of stenosis is <50%, revascularization with CEA or CAS to reduce the risk of future stroke is not recom- Benefit A In patients with a recent (within 120 days) TIA or ischemic stroke ipsilateral to atherosclerotic stenosis or occlusion of the middle cerebral or carotid artery, extracranial- intracranial bypass surgery is not recom- Synopsis Previous randomized clinical trials have compared CEA with best medical therapy in patients with a recent stroke or TIA. A combined analysis of these trials found the greatest benefit for CEA was in severe (70% 99%) ICA stenosis with recent symptoms. Post hoc analysis of these original trials found a greater benefit of CEA when the surgery was done in patients who were enrolled within 2 weeks of their last ischemic event. These trials were initiated >30 years ago, and current optimal medi- cal therapy was not used in these trials. There is a paucity of data on CEA compared with current optimal medical therapy in patients with symptomatic carotid stenosis. CEA also has been compared with CAS. Across several trials, CAS was associated with a higher periprocedural stroke rate, but similar results have been seen with CEA and CAS beyond the immediate periprocedural period. Extracranial-to-intracranial bypass for internal carotid occlusion has not been demonstrated to reduce the risk of recurrent stroke. Recommendation-Specific Supportive Text 1. A combined analysis by Rothwell et al369 of the original CEA trials (NASCET [North American Symptomatic Carotid Endarterectomy Trial], ECST [European Carotid Surgery Trial], and VA [Veterans Affairs Trial 309]) found robust benefit for CEA in patients with severe (70% 99%) ICA stenosis (16.0% absolute benefit over 5 years). In these studies, patients were typically >40 years of age and of either sex. The NASCET method of stenosis measurement was used in the combined analysis of the 3 trials. In the original trials (NASCET and ECST), angiography was used for stenosis mea- surements, but more recent trials (CREST [Carotid Revascularization Endarterectomy versus Stenting Trial]) and routine clinical practice typically use noninvasive imaging, with angiography used for cases with discrepant or ambiguous results from noninvasive tests. 2. Surgical results and statistical modeling from clini- cal trials such as NASCET and CREST support this threshold for perioperative outcomes.24 3. On the basis of trials of antiplatelet therapy for patients with recent stroke or TIA, antiplatelet therapy is recommended for patients with symp- tomatic carotid stenosis. Similarly, antihyperten- sive therapy and statins are recommended for patients with symptomatic carotid stenosis. A recent trial of 2 different lipid targets for patients with a recent stroke or TIA found that an LDL tar- get of <70 mg/dL was associated with a reduced vascular event rate compared with a target of 90 This trial included patients with symptomatic carotid stenosis. The use of multi- modality medical therapy also has been incorpo- rated into clinical trials.18 4. The analysis by Rothwell et al369 found mild ben- efit in patients with 50% to 69% ICA stenosis (4.6% over 5 years). In the NASCET analysis of this stenosis range, there was no clear benefit of CEA seen in women and in patients with retinal ischemic events. In the combined analysis of symp- tomatic CEA trials, the number needed to treat to prevent 1 stroke was higher in women compared with men (36 versus 9). Life expectancy also should be considered when treatment decisions are made because CEA has delayed benefit. 5. Several variables have been analyzed in relation to CEA and CAS outcomes. The Carotid Stenting Trialists Collaboration analyzed outcomes in 4754 patients from 4 clinical trials.371 Within 120 days of study entry, HRs were calculated according to 5-year age intervals to compare CAS with CEA. In the group 65 to 69 years of age, the HR was 1.61 (95% CI, 0.90 2.88). In the group 70 to 74 years of age, the Recommendations for Extracranial Carotid Stenosis (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Kleindorfer HR comparing CAS to CEA was 2.09 (95% CI, 1.32 3.32). This supports the recommendation for consid- ering patient age in the selection of the procedure. 6. In addition, CEA is associated with a reduced complication rate relative to CAS in patients who undergo the procedure within 1 week of a stroke or TIA. The Carotid Stenosis Trialists Collaboration evaluated 4138 patients randomly assigned to CEA or CAS.372 In patients who received the proce- dure within 1 week of the last symptomatic event, the stroke/death rate was 8.3% with CAS versus 1.3% with CEA (RR, 6.7; P=0.002). This supports a preference for CEA in patients who undergo early revascularization. 7. Post hoc analysis of these trials found a greater ben- efit of CEA when the surgery was done in patients who were enrolled within 2 weeks of their last non- disabling ischemic event.373 Therefore, if the patient is suitable for operation, early CEA is preferred. 8. In the SAPPHIRE trial (Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy), patients with high anatomic or phys- iologic risk for CEA were assigned to CEA or CAS.374 The primary end point was stroke, MI, or death within 30 days or ipsilateral stroke up to 12 months. Among symptomatic patients, the primary end point occurred in 16.8% of patients undergoing CAS and 16.5% of patients undergoing CEA (P=0.95). However, the trial was not powered to evaluate only the symptom- atic group of patients. This study supports the option of CAS in patients at elevated surgical risk. 9. In the CREST multicenter randomized clinical trial, CEA and CAS were directly compared in both symp- tomatic and asymptomatic patients. Among the 1321 symptomatic patients, over the 4-year study period, the primary end point (periprocedural stroke, death, or MI, plus later ipsilateral stroke) occurred in 8.6% of patients undergoing CAS and 8.4% of patients Both surgeons and intervention- alists were required to be credentialed for the study, and a periprocedural stroke/death rate of <6% (or lower) has been suggested in earlier statements. 10. TCAR is a relatively new endovascular technique that has several unique features. The interventional specialist directly accesses the common carotid artery, and flow reversal is provided to have blood drain to the femoral vein. A stent is placed at the site of ICA stenosis with no need to traverse the aortic arch. TCAR results have been analyzed in registries only thus far. A propensity score matched analysis compared TCAR with transfemoral CAS. Among 3286 patient pairs, approximately half of the patients were symptomatic. In symptomatic patients, TCAR, relative to transfemoral CAS, was associated with a lower rate of in-hospital stroke/death (2.1% versus 4.2%), stroke (2.0% versus 3.1%), and death TCAR has not been evalu- ated in randomized trials thus far and has not been compared with CEA or intensive medical therapy. 11. The combined analysis by Rothwell et al369 of CEA in patients with recent stroke or TIA found no ben- efit in patients with <50% ICA stenosis. 12. In COSS (Carotid Occlusion Surgery Study), 195 subjects with recently symptomatic carotid occlu- sion and increased oxygen extraction fraction measured by positron emission tomography were assigned to bypass surgery or medical therapy.377 The primary end point was stroke/death within 30 days and ipsilateral stroke up to 2 years. The pri- mary end point occurred in 21.0% of the surgery group and 22.7% of the medically treated patients (P=0.78). This supports the recommendation against bypass surgery for patients with recently symptomatic carotid occlusion. 5.1.2.2. Extracranial Vertebral Artery Stenosis Recommendations for Extracranial Vertebral Artery Stenosis Referenced studies that support recommendations are summarized in online Data Supplement 28. COR LOE Recommendations In patients with recently symptomatic extra- cranial vertebral artery stenosis, intensive medical therapy (antiplatelet therapy, lipid lowering, BP control) is recommended to reduce stroke risk.378 In patients with ischemic stroke or TIA and extracranial vertebral artery stenosis who are having symptoms despite optimal medical treatment, the usefulness of stenting is not In patients with ischemic stroke or TIA and extracranial vertebral artery stenosis who are having symptoms despite optimal medical treatment, the usefulness of open surgical procedures, including vertebral endarterec- tomy and vertebral artery transposition, is not well established. Synopsis Extracranial vertebral artery stenosis is thought to account for 10% of posterior circulation strokes. Revas- cularization procedures are not performed often for ver- tebral artery stenosis. Small trials (VAST, VIST) did not show a clear benefit for vertebral artery stenting, and a recent combined analysis also did not demonstrate clear benefit for vertebral artery stenting compared with medical therapy. Recommendation-Specific Supportive Text 1. On the basis of trials of antiplatelet therapy for patients with recent stroke or TIA, antiplatelet ther- apy is recommended for patients with symptomatic vertebral artery stenosis. Similarly, antihypertensive therapy and statins are recommended for patients with symptomatic vertebral artery stenosis. The use of multimodality medical therapy also has been incorporated into clinical trials.378 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 2. In a combined analysis of 3 trials (VAST, VIST, and SAMMPRIS), 244 patients were assigned to either vertebral artery stenting or optimal medical The primary end point for this analysis was fatal or nonfatal strokes. Two of these trials (VAST, VIST) contributed data for patients with extracranial vertebral artery stenosis. During 1036 person-years of follow-up, the HR for stenting compared with medical therapy was 0.63 (95% CI, 0.27 1.46). Thus, no clear benefit has been shown for extracranial vertebral artery stenting. 3. No randomized trials have been performed for sur- gical techniques such as vertebral artery endarter- ectomy or transposition. Case series have been reported, but these typically lack a control group with a consistent medical treatment protocol.379 Thus, the utility of these procedures is not well established. Extracranial Large Artery Atherosclerosis Knowledge Gaps and Future Research Knowledge gaps within this area include the following: Risk-benefit ratio of CEA to modern intensive medi- cal therapy should be assessed. Previous CEA trials were initiated >30 years ago, and clinicians need comparisons of CEA with cur- rently available intensive medical therapy options. As a result of the growing elderly population, more data are needed on the merits of carotid revascular- ization in elderly patients (>80 years of age). Additional information is needed on the mecha- nisms of sex differences in outcomes for patients with symptomatic carotid stenosis. Recent studies have identified that carotid plaques with <50% stenosis but high-risk features may be linked to otherwise cryptogenic ischemic strokes. More information is needed on the frequency and optimal treatment of these nonstenotic plaques with high-risk features. 5.1.3. Aortic Arch Atherosclerosis Recommendations for Aortic Arch Atherosclerosis Referenced studies that support recommendations are summarized in online Data Supplement 29. COR LOE Recommendations In patients with a stroke or TIA and evidence of an aortic arch atheroma, intensive lipid management to an LDL cholesterol target <70 mg/dL is recommended to prevent recur- In patients with a stroke or TIA and evidence of an aortic arch atheroma, antiplatelet therapy is recommended to prevent recurrent Synopsis studies using TEE have identified complex aortic arch plaque to be inde- pendently and strongly associated with ischemic stroke. Prospective studies have found an increased stroke recurrence rate among patients with aortic plaques 4 mm in thickness, particularly with ulceration or mobile or without plaque calcifications.389 There are no strong data from randomized clinical trials or even observational studies that management should be dif- ferent from general secondary prevention recommenda- tions for atherosclerotic stroke. Recommendation-Specific Supportive Text 1. There is evidence that treating patients with ischemic stroke and evidence of atherosclerosis to an LDL tar- get of <70 mg/dL is more effective in stroke preven- tion than less intensive lipid management.210 Detailed guidanceforlipidmanagementbasedonageandvery high-risk status is presented elsewhere in this docu- ment (see Section 4.3, Treatment of Hyperlipidemia for Secondary Prevention of Stroke). Many patients with aortic plaque and ischemic stroke will meet the criteria for very high-risk status because of concomi- tant atherosclerotic conditions and risk factors. In the ARCH study (Aortic Arch Related Cerebral Hazard Trial), the only randomized trial of secondary pre- vention of aortic plaque associated stroke,380 the event rate was only 20% to 30% of the >12% rate expected from observational studies.390 This is likely attributable to the better risk factor management in the trial compared with historical studies. During the trial, mean LDL-C was reduced by 40 mg/dL to 83 to 84 mg/d. It is likely that event rates would be even lower with current, more intensive recommendations for hypertension and cholesterol management. 2. The only randomized trial of this condition, the compared aspirin and clopidogrel with warfarin and was underpowered for the primary end point. Thus, the comparative benefit of these 2 treatments is unknown. However, there were 6 vas- cular deaths (3.4%) in the warfarin arm and none in the dual antiplatelet arm (log-rank test, P=0.013), suggesting no advantage of warfarin over dual anti- platelets. It is not known whether DAPT is prefera- ble to single antiplatelet therapy (SAPT), but recent have suggested that long-term DAPT generally confers increased bleeding risk without a corresponding increased antithrombotic benefit. There is strong evidence that aspirin is effective in the secondary prevention of noncardioembolic stroke or TIA.383,385 Thus, in the absence of compel- ling evidence for an alternative, more effective anti- thrombotic treatment, long-term monotherapy with aspirin is recommended. Minor strokes that meet the inclusion criteria for the POINT study (Platelet- Oriented Inhibition in New TIA and Minor Ischemic Stroke) also should be treated with short-term DAPT with both aspirin and clopidogrel. Knowledge Gaps and Future Research Knowledge gaps within this area include the following: CLINICAL STATEMENTS AND GUIDELINES Kleindorfer For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of long-term DAPT with aspirin and clopidogrel compared with aspirin monotherapy therapy to prevent recurrent stroke is unknown. For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of anti- coagulation with either warfarin or a direct-acting anticoagulant compared with aspirin monotherapy to prevent recurrent stroke is unknown. For patients with a stroke or TIA and evidence of an aortic arch atheroma, the effectiveness of com- bination antiplatelet and anticoagulation therapy compared with aspirin monotherapy to prevent recurrent stroke is unknown. Optimal treatment strategies depending on plaque morphology and duration of treatment strategies remain unknown. 5.2. Moyamoya Disease Recommendations for Moyamoya Disease Referenced studies that support recommendations are summarized in online Data Supplement 30. COR LOE Recommendations In patients with moyamoya disease and a history of ischemic stroke or TIA, surgi- cal revascularization with direct or indirect extracranial-intracranial bypass can be beneficial for the prevention of ischemic stroke In patients with moyamoya disease and a his- tory of ischemic stroke or TIA, the use of anti- platelet therapy, typically aspirin monotherapy, for the prevention of ischemic stroke or TIA may be reasonable.393,394,397 401 Synopsis Moyamoya disease is an idiopathic rare steno-occlusive disease of the arteries of the circle of Willis, typically anterior circulation, with abnormal collateral development in lenticulostriate arteries, resulting in the characteristic angiographic puff of smoke appearance. Moyamoya disease may be more common in individuals of Asian descent, but non-Asian people can be affected.402 404 Moyamoya disease has a bimodal distribution, with a peak in childhood (more ischemic) and adulthood (isch- emic and hemorrhagic), and can be asymptomatic.404 Although a causal relationship is not well established, similar vascular changes also may be seen in association with prior radiation exposure, Down syndrome, sickle cell disease, neurofibromatosis, and atherosclerosis. This sit- uation is often referred to as moyamoya syndrome. Treat- ment focuses on preventing progression and reducing the risk of ischemic or hemorrhagic stroke. One prospec- tive RCT (JAM trial [Japan Adult Moyamoya]) examined the efficacy of surgical revascularization for preventing hemorrhagic stroke, but there are no similar prospective RCTs for ischemic stroke prevention.405 No prospective RCTs have studied medical management of either symp- tomatic or asymptomatic moyamoya disease. Although multiple case series and meta-analyses of varying sizes and quality exist, many include both patients with moy- amoya disease and those with moyamoya syndrome, as well as pediatric and adult patients. Few address second- ary prevention of ischemic stroke specifically or issues of ethnic/geographic variability in general. Selection bias and publication bias are significant concerns. The resulting low-quality evidence related to the second- ary prevention of ischemic stroke precludes any strong recommendations. Recommendation-Specific Supportive Text 1. Within the realm of surgery, there is considerable controversy as to what constitutes the best sur- gical option, direct superficial temporal artery to middle cerebral artery bypass or an indirect bypass procedure such as encephaloduroarteriosynangio- sis or encephalomyosynagiosis. The differences in surgical technique even within the broad catego- ries of direct and indirect bypass, the frequent use of combined procedures, and the heterogeneity of the patient population make it difficult to draw robust conclusions about the superiority of one procedure over another. Again, there are no pro- spective RCTs to inform recommendations in this area. Although several meta-analyses and case series favor direct over indirect bypass,391 395 all but 1 of these studies combined both hemorrhagic and ischemic patients. A propensity score matched analysis on 220 adult patients with ischemic-type moyamoya disease showed that direct bypass was superior to indirect bypass for the prevention of In this series, however, the pri- mary end point of recurrent stroke was defined as both ischemic and hemorrhagic events. In contrast, and a retrospective mul- reported no difference between direct and indirect modalities. 2. Although traditionally thought to result from poor perfusion, there is some evidence that many instances of ischemia in moyamoya disease actu- ally result from thromboembolic phenomenon.406 In a propensity score matched analysis, Onozuka found that prehospital antiplatelet use was significantly associated with good functional sta- tus on hospital admission for patients with non- hemorrhagic moyamoya disease in Japan. Several meta-analyses and case series have compared antiplatelet therapy with surgical bypass or obser- vation alone with mixed results.393,397 399 Although some found a benefit or no difference with anti- others found surgery to However, many studies include patients with both ischemic and hemorrhagic CLINICAL STATEMENTS AND GUIDELINES Kleindorfer moyamoya disease, and conclusions are often based on subgroup analyses. Antiplatelet therapy may also be of benefit in conjunction with surgi- An international survey of perceived experts in the treatment of moyamoya disease reported that the majority of non-Asian respondents recommended antiplatelet therapy, in contrast to their Asian counterparts, perhaps reflecting a difference in the typical pattern of dis- ease seen in the 2 geographic regions.407 Knowledge Gaps and Future Research Significant knowledge gaps exist in our understand- ing of moyamoya disease. No prospective RCT exists comparing medical management with surgical interven- tion for either the primary or secondary prevention of ischemic events in patients with moyamoya disease. Similarly, there are no prospective RCTs comparing the efficacy of the most common surgical revascular- ization procedures used for the prevention of ischemic events in this patient population. Numerous obstacles to the performance of such trials exist, including a lack of equipoise among many treating neurologists and neurosurgeons, particularly for symptomatic patients. Consideration should therefore also be given to com- prehensive, adjudicated long-term registries as an alternative means of investigation. Future investigations should have the following aims: To better understand the natural history of moy- amoya disease, including ethnic and geographic variability. To examine the efficacy of medical management options, including antiplatelet therapy and antico- agulation, with or without surgical intervention for ischemic moyamoya disease. To determine the most effective surgical interven- tion for moyamoya disease. To establish the optimal timing for surgical interven- tion after an acute clinical event in a patient with moyamoya disease. 5.3. Ischemic Stroke Caused by Small Vessel Disease Recommendation for Small Vessel Stroke Referenced studies that support the recommendation are summarized in online Data Supplement 31. 