In a prospective study of 61 patients with ESUS who underwent investigation with TEE (mean age, 44 12 years; 49% men), TEE revealed additional findings in 52% (95% CI, 40 65) of the study population, and findings changed manage- ment (initiation of anticoagulation therapy, admin- istration of intravenous antibiotic therapy, and PFO In a meta-analysis of 3562 patients with acute isch- emic stroke, the pooled rate of anticoagulation therapy attributed to abnormal TEE findings was In a single-center ret- rospective study of 1458 patients with suspected cardioembolic stroke, findings on TEE significantly changed management in 16.7%.77 Smaller series have found that the addition of TEE to a standard stroke workup identified an indication for antico- Cardiac CT has a modest sensitivity (72%) and high speci- ficity (95%) for detecting potential embolic source in patients with cryptogenic stroke in whom TEE is used as the gold standard.78 A single-center study of consecutive patients with cryptogenic stroke who underwent both TEE and cardiac MRI found that cardiac MRI reduced the percentage of patients with cryptogenic stroke by only slightly >1%.79 14. TCD compares favorably with TEE for detecting right-to-left shunting, which is usually the result of PFO, now a potential target for device closure. A pooled analysis of the OXVASC (Oxford Vascular Study) data with data from 2 previous smaller studies of bubble-TCD in patients 50 years of age found an association between right-to-left shunting and cryp- togenic TIA or nondisabling stroke (OR, 2.35 [95% A pooled analysis of a systematic literature review found that TCD had a sensitivity of (95% CI, 85.5 96.1) compared with TEE (gold stan- dard) for detection of right-to-left shunting.57 Knowledge Gaps and Future Research Randomized trials have provided compelling evidence of specific therapies for specific subsets of patients with ischemic stroke, for example, anticoagulation in the subset of patients with AF and low risk of hemorrhage. Diagnosing these mechanistically related risk factors is an important part of the early evaluation of stroke to opti- mize prevention of recurrent stroke. New risk factors for stroke are being discovered through observational stud- ies, but several knowledge gaps exist relating to the rela- tive importance of testing to identify uncommon or rare conditions associated and potentially causally linked with recurrent stroke. The less prevalent a comorbid condition is among patients with stroke, the more challenging it is to execute successfully a well-powered clinical trial to provide high levels of evidence justifying the diagnostic testing. There are several clinical conditions associated with ischemic stroke for which trial evidence would be helpful to guide therapy: To better prevent cardioembolism, it would be helpful to have trials that clarify optimal duration of heart rhythm monitoring, determine the clinical significance of brief episodes of AF, and define the precise role of cardiac CT/MRI and microembolus detection with TCD. In terms of large artery disease, much is known about atherosclerotic stenosis, but far less is known about the importance of detecting microemboli with TCD or identifying characteristics of unstable plaque such as intraplaque hemorrhage. Further research is also needed to clarify the clinical significance of detecting nonatherosclerotic condi- tions, including carotid dissection, fibromuscular dys- plasia, and carotid webs. Other uncommon causes of stroke such as CNS vasculitis and Susac syndrome suffer from a lack of well-designed clinical trials to guide therapies. 4. VASCULAR RISK FACTOR MANAGEMENT Recommendations for Nutrition Referenced studies that support recommendations are summarized in online Data Supplements 3 and 4. COR LOE Recommendations In patients with stroke and TIA, it is reason- able to counsel individuals to follow a Mediterranean-type diet, typically with empha- sis on monounsaturated fat, plant-based foods, and fish consumption, with either high extra virgin olive oil or nut supplementation, in preference to a low-fat diet, to reduce risk of In patients with stroke or TIA and hypertension who are not currently restricting their dietary sodium intake, it is reasonable to recommend that individuals reduce their sodium intake by at least 1g/d sodium (2.5 g/d salt) to reduce the risk of cardiovascular disease (CVD) events (including stroke).97,98 Synopsis Limited evidence supports dietary interventions to reduce recurrent stroke,96 with recommendations CLINICAL STATEMENTS AND GUIDELINES Kleindorfer drawn from high-risk CVD and coronary heart disease populations, or dietary effects on stroke risk factors, for example, BP and cholesterol.98 Epidemiological diet and nutrition studies identify protective effects for stroke from regular consumption of fish,99 high consumption of fruit and vegetables100,101 and following the Mediterranean diet96 and the DASH (Dietary Approaches to Stop Hypertension) diet,103 reflected in the AHA/American College of Cardiology (ACC) guideline on lifestyle management to reduce PAR for stroke for the lowest versus the highest tertile of the modified Alternative Healthy Eating Index is 18.8% (99% CI, 11.2 29.7).5a In the United States, the REGARDS cohort study (Rea- sons for Geographic and Racial Differences in Stroke Study) identified higher adherence to the Southern diet (high in added fats, fried food, eggs, processed meats, and sugar-sweetened beverages) was associated with a 39% increased risk of stroke (hazard ratio [HR], 1.39 Sodium and potassium con- sumption, unlike many vitamins and minerals in foods, can be adjusted without altering overall dietary pat- Both high potassium consumption106 and low are associated with lower stroke rates. No evidence supports potassium-based inter- ventions for CVD reduction26 ; no dietary interventions of increased potassium consumption alone in stroke survivors were identified. Overnutrition is addressed in Section 4.5, Obesity. Recommendation-Specific Supportive Text 1. The interventional arms of the PREDIMED trial (Prevenci n con Dieta Mediterr nea), compris- ing the Mediterranean diet with either supple- mental extravirgin olive oil or tree nuts (Table 4) compared with a low-fat diet,95 provide evidence of a reduction in stroke events in individuals with high cardiovascular risk (HR, 0.60 [95% CI, The primary end point (MI, stroke. or cardiovas- cular death) identified adjusted HRs of 0.72 (95% CI, 0.54 0.95) for the Mediterranean diet with olive oil supplementation and 0.69 (95% CI, 0.53 0.91) with nut supplementation compared with the control diet. Evidence in secondary pre- vention is drawn from the Lyon Diet Heart trial of the Mediterranean diet with supplemental canola compared with a usual post-MI prudent diet, producing low-quality evidence of reduced CVD mortality and total mortality (adjusted HR, 0.21 0.92], respectively) in a coronary heart One study in first stroke and matched control cases108 shows each unit (1 of 55) in MedDietScore is associated with a 17% lower likelihood of ischemic stroke in participants without hypercholesterolemia (95% CI, 0.72 0.96) and 10% lower likelihood in par- ticipants with hypercholesterolemia (95% CI, 0.81 0.99). 2. A meta-analysis of 13 prospective studies and follow-up, 3.5 19 years) identified that higher levels of habitual salt intake are associated with greater stroke risk (relative risk [RR], 1.23 [95% A Japanese population-based study identified that in men the highest compared with the lowest tertile of sodium intake recorded was significantly positively associated with death resulting from ischemic stroke (adjusted HR, 3.22 Meta-analysis in those with established CVD identified through long- term follow-up of participants in 5 salt-reducing reported a reduction of 1 g/d sodium (2.5 g/d salt) is associated with a 20% reduction in further cardiovascular events (RR, 0.80 [95% CI, identified that for a typical US diet in the 1990s (the con- trol diet), a reduction in sodium intake from 3.3 to 2.4 g/d reduced systolic BP (SBP) by 2.1 mmHg (P<0.001), and further reducing sodium intake from 2.4 to 1.5 g/d yielded additional reductions of 4.6 mmHg (P<0.001). The DASH diet was associated with a significantly lower SBP at each sodium level than the control diet. Table 4. Dietary Details of Typical Mediterranean-Type Diets Mediterranean diet (summarized) DASH diet (summarized) High monounsaturated/saturated fat ratio (use of olive oil as main cooking ingredient and/or consumption of other traditional foods high in mono- unsaturated fats such as tree nuts) Limited saturated fat and cholesterol and emphasized nut consumption High intake of plant based foods, including fruits, vegetables, and legumes Emphasizes fruit, vegetables, and legumes consumption High consumption of whole grains and cereals Emphasizes whole grains Increased consumption of fish Low consumption of meat and meat products Discourages red and processed meats Limits red and processed meats Low to moderate red wine con- sumption Moderate consumption of milk and dairy products Emphasizes fat-free/low-fat dairy Discourages soda drinks, pastries, sweets, commercial bakery prod- ucts, and spread fats Limits sweets, added sugars, salt, and sugar-sweetened beverages. DASH indicates Dietary Approaches to Stop Hypertension. Summarized Mediterranean Diet95,96 ; summarized DASH diet.103 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 4.1.2. Physical Activity Recommendations for Physical Activity Referenced studies that support recommendations are summarized in online Data Supplements 5 and 6. COR LOE Recommendations In patients with stroke or TIA who are capable of physical activity, engaging in at least moderate- intensity aerobic activity for a minimum of 10 min- utes 4 times a week or vigorous-intensity aerobic activity for a minimum of 20 minutes twice a week is indicated to lower the risk of recurrent stroke and the composite cardiovascular end point of recurrent stroke, MI, or vascular death.110 In patients with stroke or TIA who are able and willing to increase physical activity, engaging in an exercise class that includes counseling to change physical activity behavior can be beneficial for reducing cardiometabolic risk fac- tors and increasing leisure time physical activity In patients with deficits after stroke that impair their ability to exercise, supervision of an exercise program by a health care professional such as a physical therapist or cardiac reha- bilitation professional, in addition to routine rehabilitation, can be beneficial for secondary stroke prevention. In individuals with stroke or TIA who sit for long periods of uninterrupted time during the day, it may be reasonable to recommend breaking up sedentary time with intervals as short as 3 minutes of standing or light exer- cise every 30 minutes for their cardiovascular Synopsis Regular physical activity reduces stroke risk116 118 ; posi- tively affects stroke risk factors, for example, BP, cho- ; and can improve endothelial function and reduce platelet aggregation, fibrinogen lev- and onset stroke severity.123 Physical inactiv- ity (eg, sitting >4 h/d) as a cardiovascular risk behavior124 is attenuated by increased bouts of moderate- to vigor- ous-intensity physical activity.125 Low levels of physical activity are observed in acute,126 subacute, and chronic phases of stroke, with >78% of recorded time catego- rized as sedentary.127 When able, stroke survivors should aim to achieve population-based recommendations (40-minute sessions, 3 to 4 times per week of moderate- to vigorous-intensity aerobic activity),26 and when this is not possible, their physical activity goals need to be cus- tomized to their exercise tolerance, stage of recovery, environment, available social support, physical activity preferences, and specific impairments, activity limitations, and participation restrictions as identified by the AHA/ ASA guideline for physical activity and exercise.34 Exercise interventions positively affect disability, aerobic fitness, mobility (walking speed), and functional balance indices after stroke.128 Efficacy of exercise inter- ventions compared with usual care was established by a meta-analysis for risk factors after stroke, including BP, cholesterol, glucose levels, and weight.112,113 Physical activity interventions are often delivered in multimodal, lifestyle-based programs. These are addressed in Section 6.2, Interventions Aimed at Changing Patient Behavior. Recommendation-Specific Supportive Text 1. Planned analysis of participants in the medical management arm (n=227) of the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial at the 3-year follow-up identified 49 primary end point events (stroke, MI, and vascular death), including 32 ischemic strokes. For the com- posite end point at 3 years, participants who were not in target for physical activity levels, defined as a Physician-Based Assessment and Counselling for Exercise score of 4, had a significantly higher odds of stroke, MI, and vascular death than those who did achieve this target (OR, 5.4 [95% CI, 2.4 12.1]). The Physician-Based Assessment and Counselling for Exercise score of 4 equates to 10-minute bouts of moderate physical activity (sufficient to break a sweat or to noticeably raise heart rate, eg, walking briskly, using an exercise bicycle) up to 4 times a week or 20-minute bouts of vigorous activity (eg, jogging) up to twice a week. For the end point of ischemic stroke, physical activity was the only risk factor associated with lower stroke events; those who were out of target for defined physical activ- ity levels had an OR of 6.7 (95% CI, 2.5 18.1) for recurrent stroke compared with those who achieved the targets. Multivariable analysis controlling for low-density lipoprotein (LDL), non high-density lipoprotein, and SBP identified that greater physi- cal activity on the Physician-Based Assessment and Counselling for Exercise scale was independently associated with 40% lower risk of stroke, MI, or vas- cular death at 3 years (OR, 0.6 [95% CI, 0.4 0.8]). 2. Physical activity is a complex behavior. The ExStroke Pilot Trial (Physical Exercise After Acute identified no superiority for repeated encouragement and instruction to be physically active over 2 years to information pro- vision after stroke (Physical Activity Scale for the Elderly mean difference [MD], 5.0 [95% CI, 5.8 15.9]). Similarly, wearable activity monitors and smartphone applications demonstrated no clear effect for use in conjunction with other interven- tions in stroke to improve step count in community or inpatient rehabilitation settings (MD, 1400 steps Lifestyle-based interven- tions for stroke secondary prevention111 identified a significant effect for behavioral change interven- tions compared with usual care to increase physi- cal activity participation after stroke (standardized CLINICAL STATEMENTS AND GUIDELINES Kleindorfer reviews identified favorable effects for exercise- based interventions with counseling compared with usual care for reduction in SBP (MD, 5.3 mmHg ; and Exercise interventions initiated within 6 months of stroke/ TIA have a larger effect on SBP ( 8.46 mmHg initiated after 6 months ( 2.33 mmHg [95% CI, 3. Much of the evidence supporting exercise-based programs for stroke secondary prevention is based on participants with ambulatory stroke or TIA.131 134 Many stroke survivors, however, encounter physical and environmental barriers to engaging in regular physical activity for health. Neurological weakness, altered perception or balance, or impaired cogni- tion, for example, may negate their participation in conventional exercises programs. Adaptive equip- ment and skilled personnel can help to overcome many of these barriers to participation. A systematic review of inclusive studies of exercise-based pro- grams in stroke identified that exercise programs are safe and feasible to implement in nonambula- tory individuals, but to date, no evidence supports their impact on recurrent stroke,135 Promising pilot studies of aerobic exercise programs inclusive of those with motor disability have shown that with adequate pre-exercise screening they are safe and feasible in both subacute and community settings and can improve cardiovascular fitness and reduce cardiovascular risk profiles.136,137 4. Stroke survivors were noted to be sedentary for >78% of total accelerometry time measured in a Community-dwelling, inde- pendently mobile (with/without mobility aid) indi- viduals >6 months after stroke were identified as being sedentary for 10.9 h/d and having a low step count (mean, 2411 steps per day). These results were statistically significant compared with age- and sex-matched control subjects.138 This pro- longed sedentary time and inactivity increase future cardiovascular risk in stroke because these levels are associated with overall cardiovascular mortal- ity (HR, 1.15 [95% CI, 1.11 1.19]) and cardiovas- with HRs more pronounced with lower physical Prespecified secondary analysis from the BUST-Stroke trial (Breaking Up Sitting Time After Stroke) identified sitting with 3-minute bouts of light-intensity activity while standing every 1.7 5.4) compared with 8 hours of uninterrupted sitting. For participants not taking antihypertensive medications, sitting with 3-minute interruptions of either walking or light-intensity activity while standing every 30 minutes decreased SBP by with 8hours of uninterrupted sitting. No effect by condition for diastolic BP or plasma fibrinogen lev- els was observed.115 4.1.3. Smoking Cessation Recommendations for Smoking Cessation Referenced studies that support recommendations are summarized in online Data Supplements 7 and 8. COR LOE Recommendations In patients with stroke or TIA who smoke tobacco, counseling with or without drug therapy (nicotine replacement, bupropion, or varenicline) is recommended to assist in quit- Patients with stroke or TIA who continue to smoke tobacco should be advised to stop smoking (and, if unable, to reduce their daily smoking) to lower the risk of recurrent In patients with stroke or TIA. avoidance of environmental (passive) tobacco smoke is recommended to reduce risk of recurrent Synopsis Cigarette smoking is an independent, potent, and dose- respondent risk factor for first ischemic stroke147,151,152 and silent cerebral infarction,153 approximately doubling the risk of stroke.18 Environmental tobacco smoke (pas- sive smoking) has been independently associated with increased risk of stroke and mortality.147 149,155 Tobacco use is an addictive behavior, and cessation is difficult. Even after a life-threatening vascular event, roughly one-third of all smokers continue to smoke.146,156 Persis- tent cigarette smoking after stroke or TIA is associated with increased longer-term mortality rates,157 159 and evidence identifies an 2-fold risk of stroke recurrence in persistent smokers compared with nonsmokers143 145 and a dose-response relationship.143 Behavioral and pharmacological interventions for tobacco dependence are evidence based through multiple meta-analy- but not in cerebrovascular disease popu- No RCTs have examined smoking cessation interventions on recurrent events after stroke compared with no intervention; however, encouraging evidence of increased smoking cessation rates after stroke in mul- tibehavioral interventions compared with usual care is Recommendation-Specific Supportive Text 1. A meta-analysis of smoking cessation inter- ventions in hospitalized patients identified that intensive counseling interventions initiated in hospital with supportive contacts for at least 1 month after discharge increase smoking cessa- tion rates compared with usual care (RR, 1.37 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer [95% CI, 1.27 1.48]), with comparable findings in patients with CVD (RR, 1.42 [95% CI, 1.29 1.56]) and interventions initiated in rehabilitation nicotine replacement therapy to the interven- tion increased cessation rates compared with intensive counseling alone (RR, 1.54 [95% CI, High-quality evidence supports combined pharmacotherapy (nicotine replace- ment therapy, varenicline, or bupropion) and behavioral interventions compared with usual care, brief advice, or less intensive counseling in smoking cessation (RR, 1.83 [95% CI, 1.68 1.98]) in health care and community settings.140 Group behavior therapy programs for smoking cessation are superior to self-help programs but are not superior to individual counseling of In stroke trials, multibehav- ioral interventions have been associated with a greater likelihood of smoking cessation in the STOP trial (Stroke Prevention Trial in Sickle Cell and an increase of 17% in cessation rates compared with usual care (P=0.001) in the INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in TIA and Minor Stroke Patients).142 2. Registry-based stroke studies point to an 2-fold increase in recurrent stroke rates for smokers. The Nanjing Stroke Registry Program (N=3069) reported 9.5% recurrence rates at 2.4 years. With nonsmokers as the reference, adjusted HRs for stroke recurrence were 1.93 (95% CI, 1.43 2.61) in persistent smokers, stroke, and 1.16 (95% CI, 0.75 1.79) in for- mer smokers, delineating the effects in smok- ers, former smokers and quitters. HRs for stroke recurrence ranged from 1.68 (95% CI, 1.14 2.48) in those who smoked 1 to 20 cig- arettes daily to 2.72 (95% CI, 1.36 5.43) for those who smoked >40 cigarettes daily.143 The Cardiovascular Health Study (N=546) similarly identifies a substantially increased risk of stroke recurrence in elderly smokers at a median A longitudinal study in Han Chinese individuals with ischemic stroke (N=421) iden- tified an adjusted HR for smokers at 1 year of The SMART study (Second Manifestations of Arterial Disease; N=4673) identified that smoking cessation increases life expectancy (average 5 years) and recurrent major atherosclerotic cardiovascular events occur 10 years later compared with per- 3. Primary prevention data highlight the risk of exposure to environmental tobacco smoke, also called passive smoking or secondhand smoke, on stroke rates in nonsmokers. The most recent meta-analysis identified that environmental tobacco smoke exposure compared with no exposure can increase the overall risk of stroke Other reports identify comparative rates of an OR of an OR of 1.82 (95% and an RR of 1.23 (95% RR estimates were similar when ever exposure rather than current expo- sure or total rather than spousal exposure was used, and when dose-response estimates were pooled, the combined RR for the highest expo- Data from the US National Health and Nutrition Examination Surveys identified that high expo- sure to environmental tobacco smoke for stroke survivors was associated with an adjusted HR for all-cause mortality of 1.72 (95% CI, 1.02 2.91), with a dose-dependent relationship No trials of interventions to reduce exposure to environmental tobacco smoke as a stroke secondary prevention strategy were identified. 4.1.4. Substance Use Recommendations for Substance Use Referenced studies that support recommendations are summarized in online Data Supplements 9 and 10. COR LOE Recommendations Patients with ischemic stroke or TIA who drink >2 alcoholic drinks a day for men or >1 alco- holic drink a day for women should be coun- seled to eliminate or reduce their consumption of alcohol to reduce stroke risk.141,161 163 In patients with stroke or TIA who use stimulants (eg, amphetamines, amphetamine derivatives, cocaine, or khat) and in patients with infective endocarditis (IE) in the context of intravenous drug use, it is recommended that health care providers inform them that this behavior is a health risk and counsel them to stop. In patients with stroke or TIA who have a substance use disorder (drugs or alcohol), specialized services are recommended to help manage this dependency. Synopsis The PAR for stroke associated with harmful alcohol consumption (>30 drinks per month or binge drinking >5 drinks per day at least once per month) is 3.8%, In addition, binge drinking in those with known hypertension markedly increases cardiovascular mortality risk and is cumulative (HR, CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Alcohol consumption and ischemic stroke have a J-shaped relationship, regardless of sex.162,163 Stroke risk is associated with heavy alcohol consumption (>4 drinks in a day or >14 drinks a week in men; >3 drinks a day or >7 drinks a week in women).18,165 The risk of harmful alcohol consumption in recurrent stroke is not well defined; >60 g/d (>4 drinks a day) has been asso- ciated with stroke recurrence at 90 days,161 matching a meta-analysis of an RR of 1.69 (95% CI, 1.34 2.15) for ischemic stroke at that consumption level.166 The World Drug Report (2017) relates a 23% increase in the number of estimated drug users in 11 years, reach- ing 255 million in 2015.167 A sharp increase in US stroke rates attributable to IE was noted to coincide with the emergent opioid epidemic.168 Evidence sup- porting an association between drug use and ischemic stroke, notably in stimulants and developing in canna- bis use, is emerging18,169 171 and must be addressed in stroke prevention strategies. Recommendation-Specific Supportive Text 1. Although behavioral interventions, for example, the STOP (secondary stroke prevention) trial, can show decreased alcohol consumption levels,141 their impact on recurrent stroke is not delineated. High alcohol intake (>60 g/d), however, has been identified as an independent risk factor for stroke recurrence at 90 days in minor stroke/TIA.161 In ischemic stroke, low to moderate alcohol con- sumption is protective, but increased risk at higher exposure levels exists. The EPIC-CVD observa- tional case-cohort study (European Prospective Investigation into Cancer and Nutrition-CVD) (N>32 000) identified an ischemic stroke HR of in alcohol consumption. Compared with a refer- ence value of 0.1 to 4.9 g/d, HRs for ischemic to 29.9, 30.0 to 59.9, and 60 g/d total alcohol In both men and women, compared with lifetime abstainers, alcohol con- sumption of <12 g/d ( 1 drink a day based on US conversions) is associated with the lowest risk for mortality. 2. No data confirm drug use and recurrent stroke risk. Current users of amphetamine-type stimu- lants have a higher ischemic stroke risk adjusted and adjusted HR (any) for TIA of 3.4 (95% CI, A systematic review of cocaine identified an increased likelihood of ischemic and stroke (type unspecified; all-female study) for powder/paste cocaine (adjusted OR, 13.9 [95% CI, 2.8 69.0]) and crack cocaine (adjusted OR, 11.2 Khat use is associated with Although the CARDIA study (Coronary Artery Risk Development in Young Adults) identified no significant risk for stroke/TIA as a result of cumulative lifetime can- nabis use of 5 years or recent use,177 increasing evidence of an association is emerging in younger- onset stroke. Acute ischemic stroke hospitalization is higher among cannabis users (OR, 1.41 [95% and the US Centers for Disease Control and Prevention179 identified that young adults (age, 18 44 years) with recent cannabis use have higher odds of stroke compared with nonus- ers (adjusted OR, 1.82 [95% CI, 1.08 3.10]), which increases among frequent cannabis users (>10 d/ mo; adjusted OR, 2.45 [95% CI, 1.31 4.60]). 3. An alcohol or drug use disorder is a chronic relaps- ing brain disease characterized by compulsive use, loss of control over intake, and a negative emo- tional state when not using. Therefore, special- ized care is required to manage the substance dependency. In alcohol use disorders, established screening and counseling strategies such as those described in the 2004 US Preventive Services Task Force update are recommended. Long-term treatment strategies, including medication, psy- chological counseling, and community-based pro- grams, are effective in the management of drug Lifestyle Knowledge Gaps and Future Research Lifestyle recommendations in stroke secondary pre- vention draw from convincing primary prevention data and broader CVD populations. Recurrent stroke lacks robust evidence supporting interventions addressing smoking and diet/nutrition,96,103,183 are limited to non- disabling stroke in physical activity,110 and are absent for substance use. Optimal time windows to deliver lifestyle interventions after stroke are unknown. Future research in established stroke or TIA is required for the following: To identify the effects on recurrent stroke of proven dietary interventions (eg, Mediterranean or DASH diets) compared with usual care. To identify the effect on recurrent stroke of dietary sodium reduction or potassium increase, including the most efficacious and safe target. To establish whether higher recurrent stroke rates in underweight individuals184 are attenuated with nutritional supports. To trial activity-based interventions (including breaking sedentary time), inclusive of individuals with mobility impairment, exploring the role of adap- tive/electromechanically assisted devices when required. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer To establish optimal physical activity prescription (frequency, intensity, time, and type [aerobic, resis- tance, mixed]) for secondary prevention. Potential synergistic effects of aerobic exercise combined with resistance-based strengthening exercises in stroke secondary prevention are unknown. To further develop stroke registries to address knowledge gaps in recurrent stroke, including the contribution of continued smoking (currently lim- ited to Asian and older populations), heavy alcohol consumption (currently lacking), and substance use (currently lacking). To identify the longer-term cardiovascular conse- quences of newer tobacco products, for example, electronic nicotine delivery systems (electronic cig- arettes/vaping), which are not currently known. To consider the dual use of electronic nicotine delivery systems (electronic cigarettes/vaping) with combustible cigarettes in studies relating to the longer-term cardiovascular consequences, includ- ing stroke and recurrent stroke. To examine the association between ischemic stroke and recurrent stroke and therapeutic canna- bis use (currently unknown) and recreational can- nabis use (currently limited to young adults only and using surveillance data). Recommendations for Hypertension Referenced studies that support recommendations are summarized in online Data Supplements 11 and 12. COR LOE Recommendations In patients with hypertension who experience a stroke or TIA, treatment with a thiazide diuretic, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blockers is useful for lowering BP and reducing recurrent In patients with hypertension who experience a stroke or TIA, an office BP goal of <130/80 mmHg is recommended for most patients to reduce the risk of recurrent stroke and vascu- In patients with hypertension who experience a stroke or TIA, individualized drug regimens that take into account patient comorbidities, agent pharmacological class, and patient preference are recommended to maximize In patients with no history of hypertension who experience a stroke or TIA and have an aver- age office BP of 130/80 mmHg, antihyper- tensive medication treatment can be beneficial to reduce the risk of recurrent stroke, ICH, and other vascular events.190,191,193,197 Synopsis The PAR of stroke resulting from hypertension may be as high as 50% in some racial and ethnic groups.198,199 In 2017, the AHA/ACC hypertension guideline defined hypertension as BP consistently >130/80 mmHg.29 Yet, for patients with prior stroke or TIA, there is con- cern that a possible lower BP threshold may increase the risk of stroke, or a J-curve effect. In the past, post hoc analyses of RCTs, meta-analyses, and population-based studies of patients with cerebrovascular disease have shown an inconsistent relationship between achieved SBP <120 mmHg and poor outcomes.200 204 New data from RCTs and large meta-analyses now provide com- pelling evidence that neurologically stable patients with cerebrovascular disease also benefit from a BP goal of <130/80 mmHg and that BP targets for stroke preven- tion should be more aligned with targets for prevention of other cardiovascular conditions. There is insufficient evidence to recommend a lower limit of BP within the normal range for patients with prior stroke. Additional research is needed to determine the optimal timing for BP reduction after stroke205 ; therefore, these recommen- dations pertain to outpatient management of neurologi- cally stable patients. Recommendation-Specific Supportive Text 1. Diuretics, angiotensin-converting enzyme inhibi- tors, and angiotensin receptor blockers have dem- onstrated benefit in RCTs or systematic reviews of Although calcium channel blockers are recommended for the treatment of hyperten- sion, there are limited data on their efficacy for secondary stroke prevention. However, the use of calcium channel blockers is reasonable for patients with stroke who require additional medication 2. Data from 4 RCTs and recent meta-analyses sup- port a benefit of treating patients with prior stroke or TIA to achieve a goal BP of <130/80 mmHg. The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment),190 PAST-BP (Prevention After Stroke Blood Pressure),191 SPS3 (Secondary Prevention of Small Subcortical and PODCAST (Prevention of Decline in Cognition after Stroke Trial)193 RCTs all compared intensive control of BP (SBP targets ranging from <120 <130 mmHg) with standard BP control (SBP targets ranging from <140 <150 mmHg) in patients with prior cerebrovascular disease. These trials all reported nonsignificant tendencies toward lower recurrent stroke rates in the intensive treat- ment groups. However, a meta-analysis of these 4 trials showed a significant reduction in recurrent stroke risk with an intensive versus standard tar- get (RR, 0.78 [95% CI, 0.64 0.96]). An indepen- dent Cochrane analysis185 of SPS3, PAST-BP, and PODCAST (done before RESPECT publication) reported a trend toward benefit of intensive BP CLINICAL STATEMENTS AND GUIDELINES Kleindorfer targets (pooled RR for recurrent stroke, 0.80 [95% CI, 0.63 1.00]). In addition, the largest meta-analy- sis to date including >40000 patients from 14 RCTs showed a significantly lower rate of recurrent stroke in patients with an achieved SBP of <130 mg Hg compared with higher SBP groups.194 It should be noted that for patients with intracranial large artery atherosclerosis, a higher BP target may be appropri- ate (see Section 5.1.1). 3. The magnitude of BP lowering appears to be more important for risk reduction than the class of antihypertensive agent used.188,189,195,196 Therefore, individual patient characteristics that may affect the safety and efficacy of treatment (eg, T2D, chronic kidney disease, AF) should be taken into account in the selection of antihyper- tensive agents. 4. The recommended threshold BP of >130/80 mmHg for starting antihypertensive medications is informed by the baseline BPs of patients with cerebrovascular disease studied in trials of BP treatment. Among the 4 RCTs comparing inten- sive and standard BP targets in patients with prior cerebrovascular disease, the RESPECT190 , trials included patients with baseline SBPs as low as 125 mmHg. 50% of patients had baseline SBP <140 mmHg. Similarly, in the PRoFESS trial (Prevention Regimen for Effectively Avoiding Second Strokes) of >20000 patients with isch- 33% of patients had baseline SBP <135 mmHg. The large number of subjects with prior stroke and SBP <140 mmHg included in these trials supports the safety and efficacy of the use of antihypertensive medications in patients with SBP >130 mmHg, which is the threshold rec- ommended for secondary prevention of vascular events in the AHA/ACC hypertension guideline.29 Knowledge Gaps and Future Research The ongoing randomized ESH-CHL-SHOT trial (Euro- pean Society of Hypertension and Chinese Hyperten- sion League Stroke in Hypertension Optimal Treatment) will provide further insight into the optimal BP target for patients with prior stroke.207 Areas of future research on hypertension and stroke include the following: What is the optimal timing to begin BP lowering after acute stroke? What is the optimal time during the day for BP med- ication administration to prevent recurrent stroke? Do lower BP targets improve or worsen cognition in patients with prior stroke? What is the optimal BP target for very elderly patients with stroke? What is the optimal BP target for patients with dia- betes with stroke? 4.3. Treatment of Hyperlipidemia for Secondary Prevention of Stroke 4.3.1. Treatment and Monitoring of Blood Lipids for Secondary Stroke Prevention Recommendations for Treating and Monitoring Hyperlipidemia Referenced studies that support recommendations are summarized in online Data Supplement 13. COR LOE Recommendations Treatment In patients with ischemic stroke with no known coronary heart disease, no major cardiac sources of embolism, and LDL cholesterol (LDL-C) >100 mg/dL, atorvastatin 80 mg daily is indicated to reduce risk of stroke recurrence.208,209 In patients with ischemic stroke or TIA and ath- erosclerotic disease (intracranial, carotid, aortic, or coronary), lipid-lowering therapy with a statin and also ezetimibe, if needed, to a goal LDL-C of <70 mg/dL is recommended to reduce the risk of major cardiovascular events.210 In patients with ischemic stroke who are very high risk (defined as stroke plus another major ASCVD or stroke plus multiple high-risk conditions), are taking maximally tolerated statin and ezetimibe therapy and still have an LDL-C >70 mg/dL, it is reasonable to treat with PCSK9 (proprotein convertase subtili- sin/kexin type 9) inhibitor therapy to prevent Monitoring In patients with stroke or TIA and hyperlip- idemia, patients adherence to changes in lifestyle and the effects of LDL-C lowering medication should be assessed by measure- ment of fasting lipids and appropriate safety indicators 4 to 12 weeks after statin initiation or dose adjustment and every 3 to 12 months thereafter, based on need to assess adher- ence or safety.214,215 Synopsis Two RCTs, SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)208 and TST (Treat Stroke evaluated lipid-lowering therapy in patients after ischemic stroke. Both trials found significant benefit from cholesterol-lowering therapy in preventing vascular events, including stroke. SPARCL found that atorvastatin 80 mg daily reduced stroke recurrence in patients with- out another indication for statin therapy. TST confirmed that target LDL-C <70 mg/dL was superior to a target of 90 to 110 mg/dL for preventing major cardiovascular events. These 2 trials do not pertain to patients with car- dioembolic stroke and no atherosclerotic disease. These 2 stroke-specific trials are further supported by numer- ous RCTs of lipid-lowering drugs that indicate that high- risk patients with ASCVD should receive high-intensity statin therapy and that if LDL-C remains 70 mg/dL ( 1.8 mmol/L) on maximally tolerated statin therapy, it may be reasonable to add ezetimibe and then a PCSK-9 inhibitor if necessary and if patients are deemed to be at very high risk (Table 5). CLINICAL STATEMENTS AND GUIDELINES Kleindorfer The information in this table is from the 2018 AHA/ ACC guideline on the management of blood choles- For high-intensity statin therapy, the guideline recommends atorvastatin 80 mg daily or rosuvastatin 20 mg daily. Please refer to the guideline for contraindica- tions to high-intensity statin therapy and recommenda- tions for moderate-intensity statin therapy. Recommendation-Specific Supportive Text 1. The SPARCL trial included adults who had an ischemic or hemorrhagic stroke (or TIA presum- ably owing to atherosclerotic causes) in the prior 1 to 6 months and an LDL-C level of 100 to 190 mg/dL. The main exclusion criteria were coronary heart disease, peripheral vascular disease, AF, a prosthetic heart valve, clinically significant mitral stenosis, or sinus node dysfunction. There was no exclusion based on ischemic stroke subtype, although practically, most patients with cardioem- bolic stroke would be excluded on the basis of the exclusion criteria related to cardiac disease. Eligible patients were randomized to atorvastatin 80 mg or placebo. During a median follow-up of 4.9 years, the primary end point of stroke occurred in 11.2% of patients receiving atorvastatin versus 13.1% of patients receiving placebo (adjusted HR, 2. The TST trial included adults with cerebral infarction in the prior 3 months or high-risk TIA (that included at least arm and leg motor deficit or speech disturbance lasting >10 minutes) in the prior 15 days, documented atherosclerotic disease (defined as carotid, aortic, intracranial, or coronary atherosclerotic disease), and a clear indication for statin therapy. The main exclu- sion criteria were a cardioembolic stroke/TIA without documented atherosclerotic disease, a baseline LDL-C <100 mg/dL while not taking a statin, inability to intensify statin therapy (already on maximum dose), or a history of symptomatic hemorrhagic stroke. Eligible patients were ran- domly assigned to an LDL-C target of <70 mg/ dL (lower-target group) versus 90 to 110 mg/ dL (higher-target group). LDL-C targets were pursued by intensification of statin therapy and the addition of ezetimibe if needed. During a median 3.5 years of follow-up, the primary com- posite outcome of major cardiovascular events occurred in 8.5% of those in the lower-target group versus 10.9% in the higher-target group In addi- tion, a secondary analysis of the IMPROVE-IT trial (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) found a significantly lower risk of ischemic stroke with ezetimibe treatment (in addition to simvastatin) among patients with previous MI.216 3. Very high-risk patients include those with history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. In these patients, additional benefit from LDL-C lower- ing when LDL-C is > 70 mg/dL (1.8 mmol/L) or non high-density lipoprotein >100 mg/dL (2.6 mmol/L) by ezetimibe and 2 PCSK9 inhibitors (evo- locumab and alirocumab) was demonstrated by 3 This guideline strongly recommends (COR 1) that ezetimibe be added to maximally tol- erated statin as a first step to further lower LDL-C. Although no RCT tested the strategy of ezetimibe first and then a PCSK9 inhibitor, ezetimibe was allowed at entry with statin therapy in both PCSK9 inhibitor trials (FOURIER [Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk] and ODYSSEY OUTCOMES [Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab]), but only 3% and 5% received ezetimibe during these trials. Ezetimibe use before PCSK9 inhibitor is recom- mended because ezetimibe is available as a generic drug and has proven safety.211 This approach is supported by 2 simulation studies from large popu- lations of very high-risk patients showing that ezeti- mibe plus statin therapy lowers LDL-C to <70 mg/ dL (1.8 mmol/L) in most patients, leaving a minority eligible for a PCSK9 inhibitor.217,218 In addition, the TST trial of patients with ischemic stroke used ezeti- mibe as second-line therapy to achieve the LDL-C Table 5. Very High Risk of Future ASCVD Events Very high risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions: Major ASCVD events History of ischemic stroke Recent acute coronary syndrome (within the past 12 mo) History of MI (other than recent ACS event listed above) Symptomatic peripheral arterial disease (history of claudication with ankle-brachial index <0.85 or previous revascularization or amputation High-risk conditions Age 65 y Heterozygous familial hypercholesterolemia History of coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD events Diabetes Hypertension Chronic kidney disease (estimated glomerular filtration rate, 15 59 ) Current smoking The information in this table is from the 2018 AHA/ACC Guideline on the Management of Blood Cholesterol.31 For high-intensity statin therapy, the guide- line recommends atorvastatin 80 mg daily or rosuvastatin 20 mg daily. Please refer to the guideline for contraindications to high-intensity statin therapy and recommendations for moderate-intensity statin therapy. ACS indicates acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; and MI, myocardial infarction. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer supporting the use of ezetimibe before PCSK-9 inhibitors in patients with ischemic stroke who are not at their LDL-C targets. 4. Goals and clinical efficacy for LDL-C lowering are defined and monitored by percentage LDL-C reduc- tions relative to baseline levels. Baseline LDL-C is estimated by pretreatment measurements, chart reviews, or measurement after drug therapy is inter- rupted. Without a baseline level, response to therapy is difficult to evaluate. Adherence to LDL-lowering diets reduces LDL-C levels 10% to >15%.214 Moderate-intensity statins reduce LDL-C levels by another 30% to 49%; high-intensity statins, by 50%. Adding ezetimibe or bile acid sequestrants to statin therapy reduces LDL-C by an additional 15% to 25%. Adding a PCSK9 inhibitor to statin plus ezetimibe causes greater reductions. Lifestyle changes and statin therapy are commonly introduced together. The maximum percentage change occurs 4 to 12 weeks after therapy is started, at which time drug efficacy or initial adherence to therapy can be evaluated. Periodic remeasurements can confirm adherence to therapy. Because recommended inten- sities of drug therapies vary in adolescents, young adults, adults 40 to 75 years, those with severe hypercholesterolemia, and those treated for second- ary prevention, the recommended LDL-C levels to achieve also vary. Given the modest differences in LDL-C levels associated with the postprandial state, a nonfasting sample is effective to document base- line lipid levels before initiation of statin therapy. 4.3.2. Treatment of Hypertriglyceridemia Recommendations for Hypertriglyceridemia Referenced studies that support recommendations are summarized in online Data Supplement 13. COR LOE Recommendations In patients with ischemic stroke or TIA, with fasting triglycerides 135 to 499 mg/dL and LDL-C of 41 to 100 mg/dL, on moderate- or high-intensity statin therapy, with HbA1c <10%, and with no history of pancreatitis, AF, or severe heart failure, treatment with icosa- pent ethyl (IPE) 2 g twice a day is reasonable to reduce risk of recurrent stroke.219,220 In patients with severe hypertriglyceridemia (ie, fasting triglycerides 500 mg/dL [ 5.7 mmol/L]), it is reasonable to identify and address causes of hypertriglyceridemia and, if triglycerides are persistently elevated or increasing, to further reduce triglycerides in order to lower the risk of ASCVD events by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consump- tion of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.221 223 Synopsis The categories of hypertriglyceridemia are mod- erate hypertriglyceridemia (fasting or nonfasting triglycerides 175 499 mg/dL [2.0 5.6 mmol/L]) and severe hypertriglyceridemia (fasting triglycerides 500 mg/dL [ 5.6 mmol/L]). In the former, excess triglycerides are carried in very-low-density lipopro- tein (VLDL). In the latter, most patients have elevated VLDL plus chylomicrons. VLDL are atherogenic, simi- lar to LDL. There are many causes of elevated VLDL, and it is reasonable to reduce their levels to reduce the risk of ASCVD. With severe hypertriglyceridemia, elevations of VLDL raise the risk of ASCVD, but as triglyceride levels increase, especially above 1000 mg/dL, increases in chylomicrons impart a risk of acute pancreatitis. In patients with ASCVD receiving recommended statin therapy, residual cardiovascu- lar risk is present. Elevated triglycerides are associ- ated with such risk. Treatment to reduce triglycerides with extended-release niacin and fibrates in addition to statin therapy has not improved cardiovascular outcomes. However, IPE has been shown to reduce major adverse cardiovascular events (MACEs; ie, car- diovascular death, nonfatal MI, nonfatal stroke, coro- nary revascularization, or unstable angina), including ischemic stroke, when added to moderate- or high- intensity statin therapy in patients with LDL-C of 41 to 100 mg/dL. In this study, patient enrollment crite- ria included T2D with multiple risk factors for ASCVD (29%) or history of ASCVD (71%).219 Almost 60% of the entire cohort had T2D. Recommendation-Specific Supportive Text 1. The REDUCE-IT trial (Reduction of Cardiovascular Events With Icosapent Ethyl randomized 8179 patients with ASCVD including history of ischemic stroke or TIA (70%) or diabetes with other risk factors (30%) to IPE 2 g twice daily plus statin versus statin alone. Enrollment crite- ria included fasting triglycerides of 135 to 499 mg/dL and LDL-C of 41 to 100 mg/dL on statin dose for 4 weeks. Follow-up for a median of 4.9 years revealed a 25% reduction mary end point of MACEs. Results for nonfa- tal stroke and TIA were the same for MACEs. No difference occurred in hemorrhagic stroke. A small, significant increase in AF occurred in those treated with IPE (5.3% versus 3.9%). Because benefits were similar across base- line triglycerides and unrelated to triglyceride levels attained, the mechanism by which IPE reduces MACEs, including secondary preven- tion of stroke, is unknown, possibly related to factors other than lowering triglycerides. The JELIS trial (Japan EPA Lipid Intervention found a 20% relative reduction of CLINICAL STATEMENTS AND GUIDELINES Kleindorfer stroke in hypercholesterolemic patients treated with IPE, an ester derivative of eicosapentae- noic acid (EPA), and low-dose statin. Two stud- ies, the STRENGTH trial (Outcomes Study to Assess Statin Residual Risk Reduction With Epanova in High CV Risk Patients With and the OMEMI trial (Omega-3 Fatty Acids in Elderly Patients With Acute Myocardial Infarction)225 (underpow- ered), found no benefit from combined EPA/ docosahexaenoic acid (DHA) in patients with high CVD risk, diabetes, or CVD. Treatment with EPA/DHA resulted in lower median blood EPA levels in STRENGTH than those achieved by treatment with IPE in REDUCE-IT, which had a 25% reduction in the primary end point. Because triglyceride levels were similar, higher EPA levels may account for the results seen in REDUCE-IT. In addition, the differing effects of EPA and DHA on membrane stabilization may contribute to the lack of effect with EPA/DHA compared with EPA alone or IPE. 2. Most patients with triglycerides 500 mg/dL ( 5.6 mmol/L) have increased VLDL and chylomicrons. Increased chylomicrons occur when triglycerides are 500 mg/dL ( 5.6 mmol/L). With increasing triglycer- ide concentrations, chylomicronemia may intensify and cause acute pancreatitis. Higher triglycerides levels convey greater risk.222 Patients with triglycerides from 500 to 999 mg/dL are at risk of developing unrec- ognized marked increases in triglycerides, leading to pancreatitis. Most cases of severe hypertriglyceride- mia have a genetic component, but the hallmark of hypertriglyceridemic pancreatitis is the combination of both genetic and acquired causes of elevated triglycer- To prevent acute pancreatitis, it is reasonable to reduce triglycerides whenever levels exceed 500 mg/ dL. This reduction can be achieved by addressing and eliminating the underlying factors by implementing a very low-fat diet223 and by adding fibrates or omega-3 fatty acids for patients with persistently elevated These are the most reli- able therapies to reduce triglycerides to a safer level. If a fibrate is necessary in a patient being treated with a statin, fenofibrate is safer than gemfibrozil because of a lower risk of severe myopathy.227 Severe hyper- triglyceridemia during pregnancy is best managed in consultation with a lipid specialist.228 Knowledge Gaps and Future Research Areas where our knowledge is limited and therefore would benefit from further research include the following: Combination therapy (combined EPA/DHA com- pared with IPE). The effect that placebo composition might have on lipids and outcomes (eg, mineral oil versus corn oil). Recommendations for Glucose Referenced studies that support recommendations are summarized in online Data Supplements 14 and 15. COR LOE Recommendations In patients with an ischemic stroke or TIA who also have diabetes, the goal for glycemic control should be individualized based on the risk for adverse events, patient characteris- tics and preferences, and, for most patients, especially those <65 years of age and without life-limiting comorbid illness, achieving a goal of HbA1c 7% is recommended to reduce risk for microvascular complications.229,230 In patients with an ischemic stroke or TIA who also have diabetes, treatment of diabetes should include glucose-lowering agents with proven cardiovascular benefit to reduce the risk for future major adverse cardiovas- cular events (ie, stroke, MI, cardiovascular In patients with an ischemic stroke or TIA who also have diabetes, multidimensional care (ie, lifestyle counseling, medical nutritional therapy, diabetes self-management education, support, and medication) is indicated to achieve glyce- mic goals and to improve stroke risk factors. 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. 