The use of oral contraceptive agents with exogenous estrogen among women with migraine, especially when combined with active smoking, has been associated with an increased risk of stroke in numerous studies, although the quality of such studies On the basis of these data, avoiding oral con- traceptive agents with exogenous estrogen in women with migraine with aura and prior ischemic stroke may perhaps be appropriate. Knowledge Gaps and Future Research Observational studies provide conflicting evidence about the association between triptan therapy and stroke risk, and these studies excluded patients with prior ischemic stroke.645 There are theoretical risks of cerebral vasoconstriction and ischemia with the use of calcitonin gene related peptide receptor antago- but clinical evidence to quantify such risks is lacking. Therefore, no recommendations can be made for the use of triptans and calcitonin gene related peptide receptors in patients with migraine and prior ischemic stroke. Future studies will be required to better understand the safety of triptans and calcito- nin gene related peptide receptor antagonists in this population. Recommendation for Malignancy Referenced studies that support the recommendation are summarized in online Data Supplement 48. COR LOE Recommendation In patients with ischemic stroke or TIA in the setting of AF and cancer, it is reasonable to consider anticoagulation with DOACs in preference to warfarin for stroke preven- Synopsis Patients with cancer are a population at high risk for The association between cancer and stroke is not surprising given the prevalence of these conditions and the commonly shared risk factors.652 Unfortunately, secondary stroke prevention in the setting of cancer is complicated by the paucity of data in the context of multiple pathogenic mechanisms.652 Potential mecha- nisms include procoagulant conditions, direct invasion or compression of blood vessels, radiation arteriopathies, infections (eg, aspergillosis), and secondary effects of chemotherapy (eg, thrombotic microangiopathy or car- The procoagulant mechanisms have been a main focus of the stroke prevention efforts in these patients, and antiplatelets or anticoagulants are often prescribed. However, there is uncertainty about how to best treat a potential acquired hypercoagulable state,653 including the best choice for antithrombotic agent. Low- molecular-weight heparin agents are commonly used empirically when a hypercoagulable state is suspected, but the benefit is unclear,654 particularly in this patient population with a high tendency for hemorrhage.651 A specific situation in these patients that has been more adequately studied is the best anticoagulation regimen for the prevention of cardioembolism from AF,651 which is extrapolated from subgroup analysis of the large ran- domized clinical trials of anticoagulation. (We also refer the reader to Section 5.13.3, Neoplastic Vasculitis.) Recommendation-Specific Supportive Text 1. A subgroup analysis in the ROCKET AF trial comparing rivaroxaban and warfarin in patients with AF and history of cancer showed similar rates of stroke and systemic embolism 0.52 (95% CI, 0.22 1.21) and nonmajor bleeding Similarly, were comparable to those of warfarin in patients with AF and history of cancer in the ARISTOTLE This was supported by claims data analy- sis looking at bleeding events of rivaroxaban CLINICAL STATEMENTS AND GUIDELINES Kleindorfer CI, 0.17 0.79]) compared with warfarin.649 A lit- erature search of 31 660 patients in 5 trials in patients with AF and cancer DOACs showed a trend for more efficacy and better safety com- pared with warfarin.650 Knowledge Gaps and Future Research Patients who had a stroke attributable to hyper- coagulability from cancer may be at a particularly high risk of bleeding with anticoagulation. In these patients, the benefit of anticoagulants for second- ary stroke prevention is not well established, and further research is needed. The particular need of anticoagulation to prevent stroke in different type of cancers is not known and should be a matter of further research. In patients who had a stroke attributable to hyper- coagulability from cancer who are anticoagulated, there is a paucity of data on the best treatment regi- men for these patients. Although low-molecular-weight heparin is often used in patients with cancer and stroke to prevent thromboembolic complications, the potential ben- efit on stroke prevention is unknown. 5.12. Sickle Cell Disease Recommendations for Sickle Cell Disease Referenced studies that support recommendations are summarized in online Data Supplement 49. COR LOE Recommendations In patients with sickle cell disease (SCD) and prior ischemic stroke or TIA, chronic blood transfusion(s) to reduce hemoglobin S to <30% of total hemoglobin is recommended for the prevention of recurrent ischemic In patients with SCD with prior ischemic stroke or TIA for whom transfusion therapy is not available or practical, treatment with hydroxyurea is reasonable for the prevention of recurrent ischemic stroke.659 665 Synopsis SCD is an autosomal recessive inherited hemoglobin- opathy that affects people predominantly of African or The normal flexible, round red blood cell is transformed into a sickle appearance. These sickled cells have abnormal interactions with the vascular wall endothelium, other blood cells, and clotting This can result in thrombosis or hypoperfusion Globally, >300000 children are born with SCD annually, most in sub-Saharan Africa.668 The pathophysiology of ischemic stroke in patients with SCD is large artery arteriopathy,669 believed to be caused by intimal hyperplasia related to repeated endothelial injury Progressive narrowing of arter- ies at the base of the brain can lead to cerebral vascu- lopathy or moyamoya syndrome, which can predispose a patient to both ischemic stroke and intracranial hemor- rhage. There are no randomized trials for antithrombot- ics for secondary stroke prevention in SCD. Caution is advised when considering antithrombotics for second- ary stroke prevention in patients with SCD because the stroke mechanism is less certain and patients with SCD are also at higher risk for hemorrhagic stroke. If there is evidence for other stroke mechanisms in a patient with SCD (ie, atherosclerosis), then it would be reasonable to administer antithrombotics as supported elsewhere in this guideline. Recommendation-Specific Supportive Text 1. The recommendations for treatment of patients with SCD are based on stroke primary prevention studies in a pediatric population and a secondary stroke prevention study in a population of pediat- ric patients with SCD with silent cerebral infarc- tions (SIT [Silent Cerebral Infarct Transfusion] multi-center clinical trial).671 The STOP trial was a randomized, placebo-controlled trial that showed that a long-term prophylactic transfusion strategy was effective for the primary prevention of stroke in children with SCD and high TCD velocities.655 Blood transfusion was used because it was dem- onstrated effective in reducing recurrent clinical ischemic stroke and progression of arterial steno- sis in a series of children with SCD.656 This was associated with a reduction in the rate of recurrent stroke during a mean follow-up of 3 years com- pared with historical control subjects.657 Most of the patients in the series were children, and it is unclear whether adults have the same untreated risk or benefit from treatment.658 Regular transfu- sions are associated with long-term complications, especially iron overload, typically requiring iron che- lation therapy. The SIT trial showed reduced recur- rent stroke in children with SCD and silent cerebral infarct who underwent transfusion compared with 2. SWiTCH (Stroke With Transfusions Changing to Hydroxyurea) was a randomized secondary stroke prevention trial in a pediatric SCD population that found no recurrent strokes with long-term trans- fusion but 10% with hydroxyurea.659 In situations in which transfusion is not available, a nonran- domized study of patients with an initial stroke suggested that patients who do not receive hydroxyurea have a higher recurrent stroke risk TWiTCH (TCD With Transfusions Changing to Hydroxyurea) was a primary stroke prevention randomized trial of children with SCD and abnormal TCD veloci- ties (>200 cm/s) but no severe vasculopathy who had received 1 year of transfu- sions. Children were subsequently randomized CLINICAL STATEMENTS AND GUIDELINES Kleindorfer to transfusion or hydroxyurea. Noninferiority was shown: 3 TIAs in each group and no new MRI stroke in either group. Hematopoietic cell trans- plantation can be curative for SCD662 but is usu- ally undertaken in children refractory to other treatment; it results in survival without SCD in 80% to 90% of patients. Clinical and subclini- cal infarctions have been reported to be arrested by this procedure.663 Surgical bypass has been reported with improved outcomes in patients with SCD with moyamoya, but no randomized data are Given the lack of experience with antithrombotics, antihypertensive agents, and statins for secondary stroke prevention in SCD, specific recommendations cannot be stated out- side of general treatment recommendations. Knowledge Gaps and Future Research Most studies for primary or secondary stroke preven- tion in SCD were conducted in the pediatric popu- lation. Therefore, there is a gap in understanding whether transfusion or hydroxyurea recommendations in the pediatric population hold true in the adult patient with SCD with symptomatic or asymptomatic stroke, elevated TCD velocities, or vessel imaging notable for vasculopathy. 5.13.1. Autoimmune Vasculitis Recommendations for Autoimmune Vasculitis Referenced studies that support recommendations are summarized in online Data Supplement 50. COR LOE Recommendations In patients with ischemic stroke or TIA and symptoms attributed to giant cell arteri- tis, immediate initiation of oral high-dose glucocorticoids is recommended to reduce recurrent stroke risk.672 681 In patients with ischemic stroke or TIA and diagnosis of giant cell arteritis, methotrexate or tocilizumab therapy adjunctive to steroids is reasonable to lower the risk of recurrent In patients with ischemic stroke or TIA and diagnosis of primary CNS angiitis, induc- tion therapy with glucocorticoids and/or immunosuppressants followed by long-term maintenance therapy with steroid-sparing immunosuppressants is reasonable to lower the risk of stroke recurrence.691 696 3: Harm B-R In patients with ischemic stroke or TIA and confirmed diagnosis of giant cell arteritis, infliximab is associated with recurrent ocular symptoms and markers of disease activity and should not be administered.697 704 Synopsis Autoimmune vasculitis is a subset of disease that may cause stroke. The overall prevalence of autoim- mune vasculitis in stroke population is very low but age dependent. In cohorts of younger patients (eg, age <45 years), vasculitis may account for 0% to 20% of stroke cases, depending on the depth of workup.705 In older population, the proportion of strokes caused by vas- culitis is smaller because of the increasing burden of aging-related risk factors. Vasculitis may cause stroke by directly causing brain arterial inflammation, which subsequently results in endothelial damage and pro- Alternatively, extracranial vascu- litis may cause stroke by promoting artery-to-artery embolism, flow obstruction attributable to endothelial thickening, or aneurysmatic wall damage.707 The over- all approach to treat vasculitis causing stroke is with immunosuppressants and antiplatelets, but the choice of immunosuppressant and regimens is specific to the type of vasculitis. Recommendation-Specific Supportive Text 1. Giant cell arteritis is a rare vasculitis (incidence rate, 9 16 per 100000 per year in individuals 50 years of age) that can cause stroke in 7% of confirmed cases.672 674 Patients with symptoms of giant cell arteritis should be treated urgently, and high-dose steroids should be initiated quickly within the first 24 hours after symptoms onset to reduce the risk of permanent blindness and to increase the chance of visual recovery.675 678 Practitioners should keep a high index of clini- cal suspicion to consider giant cell arteritis in the differential. Laboratory testing such as elevated sedimentation rate or C-reactive protein and a compatible semiology may be the only available elements to make a decision to initiate treat- If available, ultrasound finding of a halo sign surrounding a temporal artery may be helpful in diagnosis giant cell arteries.680,681 Biopsy con- firmation should not be imperative to initiate treat- ment in cases in which giant cell arteritis seems to be the most likely diagnosis. 2. In addition to steroids, it is reasonable to consider adjunctive, steroid-sparing therapy in the treatment of patients with stroke thought to be caused by giant cell arteritis. In a patient-level meta-analysis of 3 randomized clinical trials, methotrexate use was associated with lower risk of diseases relapses.682 Similarly, 1 phase I clinical trial and 1 phase II clini- cal trial support the use of tocilizumab to increase the rate of sustained glucocorticoid-free remis- Takayasu arteritis is more common in Asian countries compared with Europe or the United States, and it tends to occur in younger people compared with those with giant cell arte- Takayasu arteritis may cause stroke directly by causing cerebral vasculitis or extracra- nial stenosis, most often of the common carotid Observational studies support the use CLINICAL STATEMENTS AND GUIDELINES Kleindorfer of steroids plus adjunctive therapy that may include There are no data to support 1 agent over the other in terms of efficacy in stroke risk reduction among patients with Takayasu arteritis. In adults with ischemic stroke or TIA and diagnosis of giant cell arteritis or Takayasu arteritis, a slow taper of oral steroids to a target of 5 mg/d after 1 year is reasonable in light of reports of exacerbation after rapid steroid withdrawal.690,709 3. Primary CNS angiitis or vasculitis is a rare cause of stroke (2.4 cases per 1 million patient-years),691 and it affects predominantly younger populations (mean age at presentation, 45 years) and is slightly more prevalent in men.692 In cases with confirmed primary CNS angiitis, administration of high-dose steroids is supported by observational data.693,694 In most cases, slow tapering of steroids followed by the addition of a steroid-sparing agent seems pre- ferred over long-term monotherapy with steroids because of a higher rate of relapse and poorer outcomes with steroid monotherapy.694,695 Some commonly used maintenance steroid-sparing agents include cyclophosphamide,693,694,696 aza- meth- There are no robust data related to efficacy between these agents. Therefore, we recommend an interdisciplinary fol- low-up for patient with primary CNS angiitis and that the choice of steroid-sparing agent be made considering the profile of each agent and associ- ated comorbidities. 4. Infliximab should not be used to treat patients with stroke and giant cell arteritis. This recommendation is based on a phase II clinical trial that random- ized patients with giant cell arteritis to infliximab (5 mg/kg body weight) versus placebo after steroid- induced remission. During follow-up, patients who received infliximab had a higher risk of disease activity at 12 weeks (eg, lower chances of remis- sion) than those who received placebo.697 5.13.2. Infectious Vasculitis Recommendations for Infectious Vasculitis Referenced studies that support recommendations are summarized in online Data Supplement 51. COR LOE Recommendations In patients with ischemic stroke or TIA and infectious vasculitis such as varicella zoster virus (VZV) cerebral vasculitis, neurosyphilis, or bacterial meningitis, treating the underlying infectious etiology is indicated to reduce the risk of stroke.710 716 In patients with ischemic stroke or TIA in the context of HIV vasculopathy, daily aspirin plus HIV viral control with combined antiretroviral therapy is reasonable to reduce the risk of Synopsis Infectious diseases may cause stroke through vari- ous mechanisms. Direct infection of cerebral arteries by VZV may cause inflammation, endothelial activation, Infectious cardiomyopathies may cause stroke by increasing the risk of cardioembolic stroke, as in the case of Chagas disease.725 728 Infection with HIV may cause stroke by multiple mechanisms, including increased risk of cerebral infection or oppor- tunistic neoplasias, as well as accelerated atheroscle- rosis in the setting of certain antiretroviral agents.729,730 Basilar meningitis caused by Mycobacterium tubercu- losis, Treponema pallidum, or Cryptococcus may cause stroke by contiguous spreading of the inflammation in the cerebrospinal fluid to the brain arteries at the base of the skull.731 734 Recommendation-Specific Supportive Text 1. Stroke associated with CNS infection should be considered a life-threatening emergency and should be triaged accordingly. The risk of stroke recurrence depends on the underlying infection, and the treat- ment should be target as indicated. It may be help- ful to consult with an infectious disease expert as needed. VZV vasculitis may present with large and small artery strokes in the context of arterial luminal irregularities, beading, or stenosis.710,711 Patients in whom VZV vasculitis is suspected should undergo a lumbar puncture for anti-VZV immunoglobulin G, immunoglobulin M, and polymerase chain reaction. Anti-VZV immunoglobulin G has the highest sen- sitivity of the 3 tests. A negative VZV polymerase chain reaction does not rule out VZV vasculitis.712,713 If suspicion of VZV vasculitis is high, it may be rea- sonable to treat empirically while awaiting the results of confirmatory tests. Acyclovir is the drug of choice for the treatment of VZV infection.714 Among patients with stroke and diagnosed neurosyphilis, intense treatment with penicillin G is mandated.735 In some instances, there may be coexisting comorbidities that may also predispose to stroke such as large artery atherosclerosis or AF. In such cases, treating neuro- syphilis is still indicated in addition to the confounding competing risk of stroke. Testing for HIV is indicated in patients with stroke and diagnosis of neurosyphilis. This recommendation is supported by a relatively high coexistence (5% 16%) of both sexually transmitted 2. Secondary stroke prevention among patients with HIV vasculopathy is focused on daily anti- platelets and treatment aimed at restoring the CD4 counts and immune system. There are no randomized data to support these claims. Restoring the immune system as captured by the CD4 count is indicated in all patients with HIV regardless of whether they have stroke.717 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer The presence of stroke may be seen as an even greater indication to treat the most devastating consequences of HIV infection and associated immunosuppression. Observational data support this approach in patients with HIV vasculopa- Some authors have noted a possible link between the initiation of combined antiret- roviral therapy and stroke risk, suggesting an immune reconstitution-like syndrome in these It is uncertain whether steroids may play a role in stroke risk reduction in this clinical setting. 5.13.3. Neoplastic Vasculitis Synopsis Neoplastic vasculitis refers to inflammation of the brain arteries resulting from direct invasion of neoplastic cells, as opposed to paraneoplastic vasculitis in which the inflammation of the brain arteries is not attributable to direct tumor invasion or compression. Conditions in this category are rare and include lymphomatoid granu- lomatosis and angiotropic or intravascular lymphoma (also known as angioendotheliomatosis)736 among other even less common disorders.737,738 Treating the underlying malignancy also reduces the risk of recur- rent stroke. The relatively rare occurrence of neoplastic vasculitis is a challenge for the systematic study of the disease. Even less homogeneous information exists on what strategy may be the most effective to reduce the risk of stroke recurrence thought to be attributable to a neoplastic vasculitis. Angiotropic lymphoma is perhaps the most commonly reported neoplastic vasculitis in the literature. In a large meta-analysis of cases of angiotro- pic lymphoma reported between 1957 and 2012, only 8% presented with stroke-like symptoms.736 Given the observational nature of the report, limited information is available on how to reduce the risk of stroke recur- rence. Therefore, we advise treating the underlying malignancy. A multidisciplinary team is recommended for the management of these complex patients. Vasculitis Knowledge Gaps and Future Research CNS autoimmune vasculitides are a broad spectrum of disorders that may present with stroke. Although studies focused on people with stroke and CNS vasculitis are not common, we inferred that treating the underlying vascu- litis may help reduce the risk of stroke. The treatment of choice varies, depending on each condition. We have identified areas in which further research is needed to better diagnose or treat these heterogeneous conditions: A growing area of interest and future research includes the use of biological drugs that may target more specifically the disputed pathways in some of these disorders. It is highly encouraged that stroke be incorporated as an independent outcome in future trials. Steroids are often used to treat autoimmune vascu- litis. This may be problematic in people with coexist- ing vascular risk such as hypertension and diabetes. Further research is needed on the safety profile of long-term steroids and steroid-sparing agents in stroke populations. Similarly, the timing of steroid initiation and poststeroid biopsy yield should be fur- ther delineated. In adults with ischemic stroke or TIA and symptoms of giant cell arteritis, the benefit of an initial high- dose intravenous pulse of steroids versus oral ste- roids in stroke prevention is uncertain. For the treatment of VZV vasculitis, the role of ste- roids as adjunctive therapy to acyclovir is not well established. Chronic inflammation is often found in people liv- ing with well-controlled HIV infection. It is uncer- tain whether, in addition to comprehensive vascular risk factor control, there may be a role for additional immunomodulation in this population. 5.14. Other Genetic Disorders Recommendations for Other Genetic Disorders Referenced studies that support recommendations are summarized in online Data Supplements 51 and 52. COR LOE Recommendations In patients with ischemic stroke or TIA and cystathionine -synthase deficiency, pyridoxine (in responsive patients) and a low-methionine, cysteine-enhanced diet supplemented with pyridoxine, vitamin B12 , and folate are recommended to reduce plasma homocysteine to population normal levels and thereby reduce the risk of recurrent In patients with ischemic stroke or TIA and Anderson-Fabry disease, agalsidase alfa or agalsidase beta is of uncertain value in preventing recurrent stroke or Synopsis Beyond SCD, other rare diseases cause stroke or stroke-like syndromes for which there are specific therapies. Recently, there have been randomized tri- als of enzyme replacement therapy in Anderson-Fabry disease, but such methodology is rare. Even in Ander- son-Fabry disease, it has been difficult to adequately power studies to assess efficacy for stroke preven- Although in 1 German population the preva- lence of Fabry disease in young men with first-time cryptogenic ischemic stroke was reported to be as high as 2.17%,743 it appears that, for most popula- tions of young men with first-time cryptogenic stroke, the rate is <1%.744 The prevalence rate appears to be higher in young patients with recurrent cryptogenic ischemic stroke relative to young patients with first- time cryptogenic stroke.743 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Recommendation-Specific Supportive Text 1. An ecological study of a newborn screening pro- gram in Ireland supports the effectiveness of interventions to drive free homocysteine to 11 mmol/L to prevent thromboembolic events.739 A study of treatment of severe hyperhomocysteine performed in Australia, the Netherlands, and Ireland on patients who had cystathionine -synthase defi- ciency (mean age, 27.8 years; range, 2.5 70 years) supported a dramatic reduction of risk of vascu- lar events relative to a historical cohort study (RR, 2. A systematic review of RCTs of agalsidase alfa or beta in patients with Anderson-Fabry disease found that the enzyme replacement therapy improved pain-related quality of life but that their effects on morbidity or mortality required further Knowledge Gaps and Future Research Specific treatments are needed for several single- gene disorders associated with high risk of stroke, including mitochondrial myopathy, encephalopa- thy, lactic acidosis, stroke-like episodes, cerebral autosomal dominant arteriopathy with subcorti- cal infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcorti- cal infarcts and leukoencephalopathy, cathep- sin-A related arteriopathy with strokes and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, and cases of pathogenic mutations in the COL4A1/COL4A2 genes.745 Because of the low prevalence of these condi- tions, generating high-quality evidence for thera- pies for single-gene disorders that cause stroke will be challenging but not impossible. For patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, prospective multicenter single-arm studies suggest that oral l-arginine may extend the interictal phase of stroke-like spells and intravenous l-arginine may improve headache, nausea/vomiting, impaired consciousness, and visual disturbances. However, the intravenous treatment may result in fevers and lower hemo- l-Arginine may work by acting as a nitric oxide precursor.747 Although l-citrulline raises nitric oxide production more than l-argi- nine, it has not been systematically studied in Future RCTs are needed to clarify dosage, timing of initiation relative to onset of an attack, duration of therapy, and safety for nitric oxide precursors for treating patients with mito- chondrial myopathy, encephalopathy, lactic aci- dosis, and stroke-like episodes before treatment recommendations can be made. 5.15. Carotid Web Recommendations for Carotid Web Referenced studies that support recommendations are summarized in online Data Supplement 53. COR LOE Recommendations In patients with carotid web in the distribu- tion of ischemic stroke and TIA, without other attributable causes of stroke, antiplatelet therapy is recommended to prevent recurrent ischemic stroke or TIA.748,749 In patients with carotid web in the distribution of ischemic stroke refractory to medical man- agement, with no other attributable cause of stroke despite comprehensive workup, carotid stenting or CEA may be considered to prevent recurrent ischemic stroke.748 750 Synopsis Carotid web is a thin, circumferential shelf-like filling defect that arises from the posterior wall of the ICA bulb visualized on CTA or carotid angiography. Pathologi- cally, carotid web is a variant of fibromuscular dysplasia and can be classified as focal or multifocal. Platelet deposition can occur in the corrugations of carotid web, forming a nidus for potential blood flow stagna- tion and thromboembolism. Carotid web is a known cause of ischemic stroke in young patients <65 years of age; it is detected in up to 9.5% of patients <65 years of age with anterior circulation stroke of unknown Recommendation-Specific Supportive Text 1. The optimal management of symptomatic carotid web is unknown. Medical management with anti- thrombotic therapy is first-line treatment; how- ever, it is not known whether SAPT, short-term DAPT, or anticoagulant therapy is superior. In the absence of such data, it is recommended to treat patients with antiplatelet therapy first line or to follow antithrombotic recommendations in this guideline. 2. There is a high risk of recurrent stroke or TIA in patients with symptomatic carotid web on medi- cal management, estimated in 29% to 56% of Carotid stenting or CEA is a good alternative treatment for patients with symptom- atic carotid web, with published series revealing no recurrent stroke risk.748,749 Knowledge Gaps and Future Research The optimal medical or interventional management of symptomatic carotid web is unknown. Future prospec- tive research evaluating the natural history of symptom- atic carotid web on medical management compared with interventional management would be of interest and evolve to multicenter randomized trials comparing medical management (ie, antiplatelet versus anticoagu- lant, then best medical therapy versus carotid stenting or CEA) if enough patients can be identified. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 5.16. Fibromuscular Dysplasia Recommendations for Fibromuscular Dysplasia Referenced studies that support recommendations are summarized in online Data Supplement 54. COR LOE Recommendations In patients with fibromuscular dysplasia (FMD) and a history of ischemic stroke or TIA without other attributable causes, antiplatelet therapy, BP control, and lifestyle modification are recommended for the prevention of future In patients with a history of ischemic stroke or TIA attributable to dissection, with FMD, and no evidence of intraluminal thrombus, it is reasonable to administer antiplatelet therapy for the prevention of future ischemic events. In patients with cervical carotid artery FMD and recurrent ischemic stroke without other attributable causes despite optimal medical management, carotid angioplasty with or without stenting may be reasonable to prevent Synopsis FMD is a nonatherosclerotic segmental disease of small or medium-sized arteries that can result in arte- rial stenosis, occlusion, intraluminal thrombus, aneu- rysm, or dissection.752 It can involve the extracranial carotid, vertebral. and renal arteries. On a histological level, FMD affects the musculature or media layer of the vessel wall, leading to medial fibroplasia and the appearance of a string of beads on angiography imaging. Multiple fibrous webs can serve as a nidus for platelet deposition755 or obstruct flow, resulting in thromboembolic TIA or ischemic stroke. Women are more commonly affected than men. The frequency of neurological events in the US FMD registry was noted: 13.4% had TIA; 5% had experienced amaurosis fugax; 12% had experienced cervical artery dissection; and 9.8% had had a stroke.756 Recommendation-Specific Supportive Text 1. High BP is common in patients with FMD, from either essential hypertension or renovascular hypertension related to FMD.752 The optimal BP target for patients with FMD is unknown. In the US FMD registry, most patients were on Smoking cessa- tion should be encouraged for all patients with FMD who smoke because of its health benefits in the general population. The recommenda- tion of using antiplatelet therapy for secondary stroke prevention is based on current practice and expert opinion.752,753,755 In the US FMD regis- try, 73% of patients were prescribed antiplatelet therapy; aspirin was the most common agent.753 There are no placebo-controlled randomized tri- als of patients with symptomatic or asymptomatic FMD comparing aspirin with placebo. Statins are not routinely prescribed for isolated FMD in the absence of another indication. 2. Dissection is a common manifestation associated with FMD, present in 11% to 15% of patients with spontaneous carotid or vertebral artery dis- In the US FMD registry, ischemic stroke was present in 19% of patients presenting with cervical artery dissections.759 The CADISS study demonstrated equivalent efficacy for recur- rent stroke risk in patients with spontaneous, symptomatic cervical carotid dissection random- ized to antiplatelet versus anticoagulant for 3 5.7, Dissection). 3. This recommendation has been adapted from a prior guideline by Brott et al25 on carotid angio- plasty with or without stenting in symptomatic patients with patients to COR 2b. There are no comparative data evaluating medical manage- ment versus angioplasty or stenting for patients with FMD and recurrent ischemic stroke. A case series of 7 patients with symptomatic FMD revealed no complications with balloon Knowledge Gaps and Future Research The optimal medical or interventional management of symptomatic FMD is unknown. Future prospective research evaluating the natural history of symptom- atic FMD on medical management compared with interventional management would be of interest and evolve to multicenter randomized trials comparing medical management (ie, antiplatelet versus anti- coagulant, then best medical therapy versus carotid angioplasty or carotid stenting) if enough patients can be identified. Recommendation for Dolichoectasia Referenced studies that support the recommendation are summarized in online Data Supplement 55. COR LOE Recommendation In patients with vertebrobasilar dolichoectasia and a history of ischemic stroke or TIA without other attributable causes, the use of antiplatelet or anticoagulant therapy is reasonable for the prevention of recurrent ischemic events.760 764 Synopsis Vertebrobasilar dolichoectasia is characterized by the fusiform dilatation and elongation and tortuosity of the vertebral and basilar arteries. Vertebrobasilar dolicho- ectasia is associated with traditional ischemic stroke risk factors such as increasing age, hypertension, and male sex. However, its relationship to atherosclerotic disease is less clear.765 767 Although many patients may be asymptomatic, others may present with a variety of CLINICAL STATEMENTS AND GUIDELINES Kleindorfer clinical syndromes, including cranial nerve or brainstem compression, obstructive hydrocephalus, subarachnoid hemorrhage, and ischemia.760,764,768 Ischemic events may be related to thromboembolic phenomenon but may also result from the disruption of small perforat- Asymptomatic patients have the most whereas those presenting with compressive symptoms or demonstrating progressive enlargement have a worse prognosis.760,768,770 The rate of recurrent ischemic stroke may be quite high,761,771,772 with 1 study reporting a rate of 19% at just under 2 Increasing basilar artery diameter, diffuse intracranial dolichoectasia, and associated ischemic heart disease increased the risk of recurrent events.761 Many patients with vertebrobasilar dolichoectasia are treated medically with antithrombotic medication, but high-quality evidence on the management strategies for patients with vertebrobasilar dolichoectasia, par- ticularly in the setting of a prior ischemic stroke or TIA, is lacking. Several case series describe endovas- and various surgical interven- ; however, there is little evidence that such treatments reduce the risk of additional ischemic events in patients who present with an ischemic stroke or TIA. The literature on dolichoectasia of the anterior circulation in patients with prior ischemic stroke or TIA is even more sparse; therefore, this topic is not addressed in this guideline. Recommendation-Specific Supportive Text 1. There are no prospective RCTs comparing anti- thrombotic therapies with observation alone. However, case series tend to suggest that anti- thrombotic therapy lowers the risk of recurrent ischemic events compared with the natural his- There are also no prospective RCTs comparing antiplatelet strategies (either aspirin or second-generation antiplatelet drugs) with anticoagulation. The case series reviewed dem- onstrated no clear or consistent benefit for 1 form of antithrombotic therapy over another.760 763 Although 1 small case series favored anticoagu- lation, not all of the patients in that series pre- sented with ischemic symptoms, and the series consisted of patients with fusiform aneurysms rather than true vertebrobasilar dolichoecta- Although the risks of hemorrhage appear to be low in patients presenting with ischemic there are insufficient data to pro- vide a recommendation for anticoagulation over antiplatelet therapy. Knowledge Gaps and Future Research Many important issues about the management of patients with vertebrobasilar dolichoectasia remain unclear. Some of these include the following: Development of an agreed-on definition for ver- tebrobasilar dolichoectasia that is distinguishable from the definition of a fusiform aneurysm. Accumulation of more robust natural history data with detailed clinical outcomes. Clarification of the type, dosing regimens, and efficacy of antiplatelet therapy versus anticoagu- lation for primary and secondary ischemic stroke prevention. Improved understanding of the role of reconstruc- tive procedures, whether endovascular or open surgical, in the management of patients with verte- brobasilar dolichoectasia. 5.18. Embolic Stroke of Undetermined Source Recommendations for ESUS Referenced studies that support recommendations are summarized in online Data Supplement 56. COR LOE Recommendations Benefit B-R In patients with ESUS, treatment with direct oral anticoagulants is not recommended to reduce risk of secondary stroke.779,780 Benefit B-NR In patients with ESUS, treatment with ticagre- lor is not recommended to reduce the risk of Synopsis ESUS is an evolving stroke subtype commonly defined as a nonlacunar cryptogenic ischemic stroke. Lack of a standard definition has complicated studies of ESUS, with 1 review finding that many studies use variable diagnostic criteria, including type and duration of car- diac rhythm monitoring.782 This complexity in defining ESUS is one of the reasons proposed for the nega- tive clinical trials of anticoagulation compared with antiplatelet medication for stroke prevention779,780 and fuels much of the ongoing research to further define the association between markers of atrial cardiopathy and methods of assessing cardiac rhythm disorders and risk of recurrent stroke. Subgroup analyses of the NAVIGATE ESUS study (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Sys- temic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) suggest that patients with left atrial diameter >4.6 cm may benefit from anticoagula- but those with PFO did not.784 A post hoc analysis of patients with ESUS enrolled in the SOCRATES trial (Soluble Guanylate Cyclase Stimulator in Heart Failure Studies) did not find an association between ticagrelor treatment and reduced vascular event risk.781 Ongoing randomized trials that may provide additional informa- tion about the efficacy of treatments to prevent recur- rent stroke among patients with ESUS include studies using prolonged rhythm monitoring to identify patients, studies that select patients with various markers of and trials that include MRI-defined CLINICAL STATEMENTS AND GUIDELINES Kleindorfer new ischemic events (silent strokes) as clinical trial Recommendation-Specific Supportive Text 1. The NAVIGATE ESUS and RESPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source) randomized trials found no reduction in secondary stroke risk among patients with ischemic stroke or TIA who were treated with a direct oral anticoagulant.779,780 2. A post hoc subgroup analysis of subjects with ESUS enrolled in the SOCRATES trial (4329 subjects, 32.8%) found no treatment effect by ESUS category of ticagrelor on recurrent vascu- lar event risk.781 Knowledge Gaps and Future Research Although ongoing trials may help address some of the questions about ESUS, knowledge gaps persist related to the definition of ESUS and optimal treatment for sec- ondary stroke prevention: What markers of atrial dysfunction are most strongly associated with recurrent stroke risk? Are there clinical factors that help identify patients with ESUS who may benefit from anticoagulation rather than antiplatelet treatment for secondary prevention? One of the primary challenges in identifying treat- ments to reduce the risk of second stroke in patients with ESUS is the difficulty of clearly defining criteria for ESUS diagnosis. Future trials should address these topics: The use of different strategies for long-term arrhyth- mia detection and their impact on ESUS diagnosis criteria. The use of additional cardiac markers of atrial pathology, including atrial size, and their impact on ESUS diagnosis criteria, secondary stroke risk, and response to anticoagulation. 5.19. Use of Antithrombotic Medications in Secondary Stroke Prevention As described in prior sections of this guideline, recom- mendations for secondary stroke prevention have been constructed on the basis of the best evidence among patients with a specific cause of their initial ischemic stroke. For patients with noncardioembolic ischemic stroke who do not have a specific identified cause, ques- tions about optimal antithrombotic medication use for secondary prevention may thus arise. In general, when those specific antithrombotic recommendations vary slightly from the general recommendations that follow in this section, the most specific recommendation should be prioritized. Recommendations for Antithrombotic Medications Referenced studies that support recommendations are summarized in online Data Supplements 57 59. COR LOE Recommendations In patients with noncardioembolic ischemic stroke or TIA, antiplatelet therapy is indicated in preference to oral anticoagulation to reduce the risk of recurrent ischemic stroke and other cardiovascular events while minimizing the risk For patients with noncardioembolic ischemic stroke or TIA, aspirin 50 to 325 mg daily, clopidogrel 75 mg, or the combination of aspi- rin 25 mg and extended-release dipyridamole 200 mg twice daily is indicated for secondary prevention of ischemic stroke.*791 794 For patients with recent minor (NIHSS score 3) noncardioembolic ischemic stroke or high-risk TIA (ABCD2 score 4), DAPT (aspirin plus clopidogrel) should be initiated early (ideally within 12 24 hours of symptom onset and at least within 7 days of onset) and continued for 21 to 90 days, followed by SAPT, to reduce the risk of recurrent ischemic For patients with recent (< 24 hours) minor to moderate stroke (NIHSS score 5), high-risk score 6), or symptomatic intra- cranial or extracranial 30% stenosis of an artery that could account for the event, DAPT with ticagrelor plus aspirin for 30 days may be considered to reduce the risk of 30-day recur- rent stroke but may also increase the risk of serious bleeding events, including ICH.797 For patients already taking aspirin at the time of noncardioembolic ischemic stroke or TIA, the effectiveness of increasing the dose of aspirin or changing to another antiplatelet medication is not well established.410,798 800 3: Harm ASR For patients with noncardioembolic ischemic stroke or TIA, the continuous use of DAPT (aspirin plus clopidogrel) for >90 days or the use of triple antiplatelet therapy is associated with excess risk of hemorrhage.381,382,801 SR indicates systematic review. *The subgroup of patients with noncardioembolic stroke who meet clinical cri- teria for DAPT have a more specific recommendation for antiplatelet therapy as described in Recommendation 3. Synopsis Patients with stroke/TIA not attributable to other stroke causes related to specific antithrombotic rec- ommendations (eg, AF, intracranial stenosis) should receive antithrombotic therapy for the prevention of recurrent stroke. If patients with mild stroke or high- risk TIA are evaluated early after the onset of their stroke, starting short-term DAPT followed by long-term SAPT is preferred compared with SAPT according to the reduction of risk of early recurrent stroke.384,410 Beyond 90 days after stroke, DAPT is associated with increased risk of bleeding and no benefit in long-term reduction of recurrent stroke risk.381,382 For patients not treated until later after their stroke event, use of any SAPT is indicated to reduce long-term recurrent CLINICAL STATEMENTS AND GUIDELINES Kleindorfer stroke risk. Although the optimal time to switch from DAPT to SAPT to maximize benefit and reduce risk is not entirely clear, benefit in stroke reduction with DAPT may be maximized as early as the first 21 days after the event.802 This treatment approach is summa- rized in Figure 6, with consideration of clinical event criteria, DAPT versus SAPT, and length of therapy. Tri- ple therapy with aspirin, clopidogrel, and dipyridamole and use of anticoagulation in this population are not recommended on the basis of increased bleeding risk and no benefit in stroke reduction.790,801 Recommendation-Specific Supportive Text 1. The WARSS study randomized 2206 patients with stroke not attributable to cardioembolism or high- grade carotid stenosis to adjusted-dose warfarin The pri- mary end point of 2-year recurrent ischemic stroke or death was no different between the 2 groups (17.8% warfarin versus 16% acetylsalicylic acid; HR, 1.13 [95% CI, 0.92 1.38]). Similarly, a sub- sequent meta-analysis of 8 other trials of VKA among 5762 patients with TIA or nondisabling noncardioembolic stroke found no benefit in sec- ondary stroke prevention with the use of oral anti- coagulation of various intensities compared with antiplatelet agents (medium-intensity anticoagula- both medium-intensity anticoagulation and high- intensity anticoagulation were associated with a significantly increased risk of bleeding.789 2. A series of single antiplatelet trials conducted in patients with noncardioembolic stroke did not use clinical eligibility criteria in the same man- ner as the more recent DAPT trials. Thus, some patients in the general noncardioembolic stroke pathogenesis group may qualify for the more Figure 6. Antiplatelet therapy for noncardioembolic stroke and transient ischemic attack (TIA). Note: Algorithm does not apply to patients who receive acute thrombolysis. Note: Please see Section 5.1.1 for recommendations related to severe symptomatic intracranial large vessel stenosis. Early ischemic stroke (IS), <24 hours from onset; high-risk TIA, ABCD2 score 4; low-risk TIA, score <4; dual antiplatelet, acetylsalicylic acid (ASA)+clopidogrel. Colors correspond to Class of Recommendation in Table 3. NIHSS indicates National Institutes of Health Stroke Scale. Data from Brown et al,15 Pan et al,409 and Wang et al.410 CLINICAL STATEMENTS AND GUIDELINES Kleindorfer specific recommendation for early DAPT. For those who do not meet DAPT clinical criteria, SAPT is recommended. The PRoFESS trial found no dif- ference in secondary stroke prevention after noncardioembolic stroke for aspirin-dipyridamole The ESPRIT trial (European/ Australasian Stroke Prevention in Reversible suggested that aspirin-dipyri- damole may be slightly more effective than aspi- rin alone for vascular event prevention, as did the ESPS2 trial (Second European Stroke Prevention ESPS2 also showed that aspirin alone is more effective than placebo in reducing recur- rent stroke. The CAPRIE trial (Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events) was not focused strictly on secondary prevention but found fewer events among patients treated with clopidogrel compared with those treated with aspirin, although no benefit was seen in stroke reduction among the stroke subgroup. A pooled analysis of trials in patients with lacunar stroke suggested that any of the evaluated antiplatelet agents were similarly effective compared with pla- Aspirin dosing may be guided by a recent patient-level pooled analysis of data from primary prevention RCTs that showed weight-based dos- ing (eg, aspirin 75 100 mg for patients weighing <70 kg and higher doses for those >70 kg) is more effective for the prevention of vascular events.803 However, similar studies have not been performed for secondary stroke prevention. 3. Recommendations for the short-term (21 90 days) use of DAPT with aspirin and clopidogrel are informed by 2 major RCTs,384,410 and a systematic review by an AHA Evidence Review Committee.15 Both the CHANCE and POINT trials compared DAPT with SAPT with aspirin initiated early after onset (<24 and <12 hours, respectively) of minor stroke (NIHSS score 3) or high-risk TIA (ABCD2 score 4) but varied in duration of DAPT treatment (21 and 90 days, respectively). DAPT dosing was also slightly differ- ent in the 2 trials: POINT used a 600-mg clopido- grel load (then 75 mg daily) and an aspirin regimen of 50 to 325 mg daily, whereas CHANCE used a 300-mg clopidogrel load (then 75 mg daily) and an aspirin load of 75 to 300 mg followed by 75 mg daily. Both trials demonstrated a reduction in recurrent ischemic stroke at 90 days. Further anal- yses of POINT revealed that the benefit of DAPT was seen primarily in the first 21 days.365 Meta- analyses that included other DAPT trials also have shown a reduction in recurrent stroke from DAPT compared with aspirin monotherapy, but the ben- efit is limited if not started early (<7 days) after the index event. Although most studies showed some increase in bleeding risk with DAPT, this was offset by the stroke prevention benefit if limited to short- 4. The use of ticagrelor (180-mg loading dose, then 90 mg twice daily) plus aspirin (300- to 325- mg loading does, then 75 100 mg daily) for 30 days was shown in the THALES trial to be slightly superior to aspirin alone in preventing recurrent stroke (recurrent stroke rate, 5% versus 6.3%; P=0.004) but was also associated with signifi- cantly increased risk of severe bleeding (0.5% ver- ICH was also significantly increased among the DAPT group (0.4% versus 0.1%; P=0.01), and significantly more patients in the DAPT group discontinued treatment because number needed to treat to prevent 1 primary out- come event was 92, and the number needed to harm was 263 for severe bleeding. Further study of this DAPT combination is needed to fully evaluate benefit and risk and to determine whether there is a specific subgroup most likely to benefit. The use of ticagrelor alone compared with aspirin was not associated with any reduction in cardiovascu- The use of ticagrelor plus aspirin for the subgroup of patients with ipsilateral carotid artery stenosis and intracranial stenosis is dis- cussed in Section 5.1.1, Intracranial Large Artery 5. No randomized trials have focused on the ques- tion of changing long-term antiplatelet therapy for the prevention of recurrent stroke. A meta-analysis suggested that, among the 4 studies that exam- ined stroke outcomes, there was a reduced risk of among patients who switched from 1 antiplatelet agent to another or to DAPT.800 However, both of the RCTs that specifically examined recur- rent stroke used DAPT rather than switching antiplatelets. In a subgroup analysis of the SPS3 trial, there was no benefit from the addition of clopidogrel to aspirin among patients with isch- emic stroke who were already taking aspirin (risk of recurrent stroke, 3.1% versus 3.3%; HR, 0.91 In a subgroup of patients already on aspirin in the CHANCE trial, there was a reduction in recurrent stroke among patients with clopidogrel added to aspirin versus aspirin alone A prospective registry study found that maintaining aspirin therapy was associated with higher recur- rent stroke rates (8.0%) compared with switching to another antiplatelet (6.9%) or adding another 6. Long-term use of DAPT with aspirin and clopi- dogrel has been shown in 2 secondary stroke CLINICAL STATEMENTS AND GUIDELINES Kleindorfer to have no benefit over SAPT for recurrent stroke prevention and to have a significantly increased risk of ICH and major bleeding. The exact duration of DAPT at which the risk of hemorrhage begins to outweigh the benefit of stroke prevention is unknown, but meta-analyses report as early as 21,802 or and those with more appear to be at higher risk of ICH with DAPT. Triple antiplatelet therapy with aspirin, clopidogrel, and dipyridamole was compared with standard antiplatelet therapy in the TARDIS trial (Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke), which found no difference in stroke outcomes and a significantly increased risk of bleeding with triple antiplatelet therapy.801 There may be other non stroke-related indica- tions for DAPT beyond 90 days after stroke (eg, recent drug-eluting cardiac stent placement), but these indications should be clarified to ensure that DAPT is not continued indefinitely beyond the clinically recommended time frame. Knowledge Gaps and Future Research To date, most DAPT trials have used aspirin and clopi- dogrel in combination for 21 to 90 days, but whether the duration of treatment should be 21 days, 90 days, or some other amount of time is not fully established. Similarly, whether other combinations of medications are equally or more beneficial is not known. The risk of DAPT among patients with stroke who may be more likely to experience hemorrhagic transformation of the ischemic stroke or other bleeding complication such as those with large stroke or microhemorrhages remains uncertain. Pharmacological responsiveness to antiplatelet ther- apy has been studied most extensively in patients with acute CVD, but the utility of such tests for guiding adjust- ment of antiplatelet medications for long-term prevention remains unclear. Relatively few head-to-head compari- sons of antiplatelet medications have been evaluated for the prevention of recurrent stroke, and in the existing trials, the benefit of 1 medication over another is small. Despite the common practice of changing antiplate- let medications in patients already taking 1 medication at the time of stroke, there is relatively little evidence from RCTs to support the benefit of this practice. Finally, although DOACs may be beneficial in vascular event reduction in patients with stable CVD (COMPASS [Cardiovascular Outcomes for People Using Antico- whether they have any role in secondary stroke prevention for patients with recent noncardioembolic stroke remains an unanswered question. In summary, further research is needed in the following areas: Optimal combination of medications, timing of initia- tion, and duration of DAPT. Effectiveness and potential harm of DAPT among specific subgroups of patients according to stroke characteristics, laboratory or genetic tests, or other factors. Effectiveness/selection of a given antiplatelet agent over another in specific subgroups of patients with noncardioembolic stroke. Benefit of switching antiplatelet agent for patients already taking 1 antiplatelet medication at the time of stroke. Effectiveness of DOACs compared with or in com- bination with antiplatelet therapy for secondary stroke prevention among patients with noncardio- embolic ischemic stroke. 6. SYSTEMS OF CARE FOR SECONDARY PREVENTION 6.1. Health Systems Based Interventions for Secondary Stroke Prevention Recommendations for Health Systems Based Interventions Referenced studies that support recommendations are summarized in online Data Supplements 60 62. COR LOE Recommendations In patients with ischemic stroke or TIA, voluntary hospital-based or outpatient-focused quality monitoring and improvement programs are recommended to improve short-term and long-term adherence to nationally accepted, evidence-based guidelines for secondary stroke prevention. In patients with ischemic stroke or TIA, a mul- tidisciplinary outpatient team-based approach (ie, care provision with active medication adjust- ment from advanced practice providers, nurses, or pharmacists) can be effective to control BP, lipids, and other vascular risk factors.810 817 In patients presenting to their primary care provider as the first contact after TIA or minor stroke, it is reasonable to use a decision sup- port tool that improves diagnostic accuracy, stratifies patients in risk categories to support appropriate triage, and prompts the initiation of medications and counseling for lifestyle modification for secondary stroke prevention to reduce the 90-day risk of recurrent stroke Synopsis Optimal treatment recommendations exist for many stroke risk factors. However, treatment targets are often unmet after ischemic stroke and TIA, thereby increasing the risk of recurrent events.819 825 Health system approaches to acute stroke management have transformed care delivery and have led to improved access to stroke treatment and improved stroke outcomes.826 828 Similar approaches to poststroke care and secondary prevention hold promise for improving risk factor control after stroke.829 Risk factor control is affected by patient, provider, and system-level factors. We define health systems-based interventions CLINICAL STATEMENTS AND GUIDELINES Kleindorfer for secondary stroke prevention as those that influence vascular risk factor treatment and control by influencing provider or patient behaviors. These are often multicom- ponent interventions that fit into categories defined by Wensing et al829 and referenced in a Cochrane review of interventions for secondary stroke prevention.830 Cat- egories include interventions that involve revision of pro- fessional roles, collaboration between multidisciplinary teams, integrated care services, knowledge management systems, and quality management systems. We review best available data here but consider that the generaliz- ability of findings may be affected by the study setting, patient access to care after an acute stroke, and other patient demographic characteristics. Recommendation-Specific Supportive Text 1. Adherence to evidence-based guidelines for secondary stroke prevention is affect by health system level, hospital-level, provider-level, and patient- and community-specific factors. Regular hospital and outpatient-based programs for adher- ence and risk factor monitoring provide the oppor- tunity to identify areas of need and to optimize strategies to improve care quality, improve risk fac- tor control, and ultimately reduce the risk of recur- rent stroke and TIA. The Get With The Guidelines registry is an example of an inpatient registry used for quality monitoring and improvement.831 2. Interventions that include a multidisciplinary team based approach to care may be beneficial for risk factor control and secondary prevention after ischemic stroke and TIA. In the ICARUSS study (Integrated Care for the Reduction of Secondary Stroke) conducted in Australia, an integrated shared-care model intervention was associated with a significant decrease in SBP at 12 months compared with usual care.810,811 Several additional studies, including NAILED Stroke (Nurse Based Age Independent Intervention to Limit Evolution of Disease After Stroke; Sweden) and PREVENTION (Preventing Recurrent Vascular Events in Patients With Stroke or Transient Ischemic Attack; Canada), showed significant benefit for BP lowering when nurses or pharmacists were involved in BP man- In the SUSTAIN study (Systemic Use of Stroke Averting Interventions), investigators tested an intervention that included a nurse prac- titioner/physician assistant care manager, group clinics, self-management support, and care coordi- nation to enhance risk factor control. There was no between-group difference in the primary outcome of mean SBP; however, the intervention group was more likely to achieve LDL goals compared with the usual care group.815 Additional evidence for the benefit of team-based interventions for secondary prevention of stroke is derived from nonrandomized data. In Ontario, Canada, Stroke Prevention Clinics evolved as an interdisciplinary approach to stroke assessment, prevention, and risk factor manage- Patients are referred to these clinics from their primary doctors after TIA or after emergency department visit for TIA or stroke. Care in these clinics has been associated with increased use of evidence-based strategies for stroke prevention and decreased risk of mortality at 1 year compared with patients who are not referred to such clinics.816 In the COMPASS pragmatic trial (United States), there was no benefit of a stroke transitional care model on secondary behavioral outcomes for risk factor control; however, implementation of the model into real-world practice was a major barrier. Additional ongoing and recently completed randomized trials are evaluating the impact of team-based interven- tions on risk factor control and secondary preven- tion after ischemic stroke and TIA.833 838 3. In the FASTEST study (Efficacy and Safety of a Transient Ischaemic Attack [TIA] Electronic Support Tool) conducted in New Zealand, use of an elec- tronic decision support tool for TIA and stroke man- agement by general practitioners was compared with usual care for patients presenting to their gen- eral practitioner as first care contact after stroke or The tool was designed to improve diagnostic accuracy, to support appropriate triage, and to guide providers in appropriate medication and nonphar- macological (lifestyle counseling) management. TIA and stroke recurrence at 90 days was significantly lower in the intervention group compared with the usual care group, and patients receiving the intervention were more likely to receive guideline- adherent care. This study provides evidence for the use of an electronic decision support tool to guide primary care providers in the management of TIA or minor stroke. Knowledge Gaps and Future Research More research is needed to determine the most effective models of postacute care to address risk factor control and secondary stroke prevention in stroke survivors. The following knowledge gaps are highlighted: Effective transitions of care from the acute setting to the community affect access to postacute care for secondary prevention. Research on the most effective transitions of care strategies for second- ary stroke prevention is needed. Many patients have multiple risk factors for recur- rent stroke. Health systems based interventions that address simultaneous control of multiple risk factors for secondary stroke prevention are needed. Patients who are uninsured and underinsured may have limited access to poststroke care. Interventions to improve care access and to mitigate the impact CLINICAL STATEMENTS AND GUIDELINES Kleindorfer of lack of insurance on poststroke risk factor con- trol and secondary stroke prevention are needed. Additional studies are needed to evaluate the impact of decision support tools on risk factor con- trol and secondary stroke prevention after stroke hospitalization. The impact of telemedicine on acute stroke care is well established.839 Although telemedicine offers many potential benefits over in-person care, patients with stroke may face multiple barriers to engaging in telemedicine, including cognitive impairment and physical disability. Research is needed to evaluate the impact of telemedicine on poststroke risk factor control and secondary stroke prevention. Once proven effective, interventions must be imple- mented across hospital and health systems in order to achieve desired outcomes. Research that exam- ines the implementation of interventions across health systems is needed. 6.2. Interventions Aimed at Changing Patient Behavior Recommendations for Behavior Change Interventions Referenced studies that support recommendations are summarized in online Data Supplements 63 and 64. COR LOE Recommendations In patients with ischemic stroke or TIA, behavior change interventions targeting stroke literacy, lifestyle factors, and medica- tion adherence are recommended to reduce In patients with ischemic stroke or TIA, teaching self-management skills or using behavior change theory (eg, motivational interviewing) can be ben- eficial in improving medication adherence.840 843 In patients with stroke or TIA, combined exercise-based and behavior change interven- tions are probably indicated in preference to behavior interventions alone, exercise interven- tions alone, or usual care to reduce physiologi- cal stroke risk factors such as SBP.111 113,829 In patients with TIA or nondisabling stroke, engagement in targeted secondary prevention programs (eg, cardiac rehabilitation programs or exercise and lifestyle counseling programs) can be beneficial to reduce risk factors and recurrent ischemic events.133,134 For patients with disabling stroke who are discharged from acute services, engaging in targeted secondary prevention programs (eg, an adapted cardiac rehabilitation program or struc- tured exercise including aerobic activity and healthy lifestyle counseling) can be beneficial to reduce vascular risk factors and mortality.111,844 Benefit B-R In patients with stroke or TIA, provision of health information or advice about stroke prevention is essential; however, information or advice alone, in the absence of a behavioral intervention, is not an effective means to change modifiable, lifestyle-related risk factors in order to reduce future ischemic events.129,829,845 Synopsis Hypertension, smoking, T2D, physical activity, diet, psy- chosocial factors, abdominal obesity, alcohol, cardiac causes, and apolipoproteins account for 91.5% of the PAR for ischemic stroke, similar across world regions, sexes, and ages.5a,846 One in 3 US citizens has at least 1 of these risk factors,847 which can be modulated by health behaviors, indicating a focus for stroke second- ary prevention and self-care.848 Changing entrenched behavior is difficult, and sustaining change over time is challenging. Several systematic reviews examine lifestyle interventions after stroke; optimal approaches to reduce recurrent stroke remain unknown.112,840,841,849 Guidance on changing behaviors associated with chronic disease at an individual level is available850 ; however, a Delphi consensus identified that interventions to self-manage lifestyle risk factors after stroke need to be contextual- ized to the capacities, needs, and personal priorities of the individual and their families.851 Lifestyle change after stroke is more attainable when the lifestyle counseling is interactive, the advantages of behavior change are perceived as beneficial, and the counselor has sufficient resources (eg, availability of healthcare professionals time; appropriate counseling materials; knowledge and skills), highlighting a training need for healthcare staff to ensure good-quality counseling and patients adherence to healthier behavior.852 Recommendation-Specific Supportive Text 1. Longer-term follow-up in behavioral interventions after stroke addressing recurrent events is lack- However, meta-analysis (from 4 iden- =0) demonstrates that multimodal interventions addressing active educa- tion about risk factors, medications, and medication compliance and interventions to modify 1 lifestyle risk factors decrease the odds of recurrent cardiac no significant difference in the odds of recurrent TIA/stroke was reported in this review.840 Two small multimodal RCTs show promise for reducing cardiovascular end points. However, the small trial numbers dictate that results must be interpreted with caution pending larger, more definitive trials. A 24-week Japanese RCT (N=70)134 compris- ing exercise, salt restriction, and nutrition advice compared with usual care terminated at a median follow-up of 2.9 years when the prespecified effi- cacy point for the intervention was reached for the primary end point (composite stroke death, cardiac death, and hospitalization for stroke recurrence, MI, angina pectoris, or peripheral artery disease; (adjusted HR, 0.194 [95% CI, 0.121 0.737]). Long-term effects (3.5 years) of an exercise and education program, compared with usual care in TIA or minor stroke patients (N=60), found that CLINICAL STATEMENTS AND GUIDELINES Kleindorfer within the intervention group, recurrent stroke, minor stroke, or TIA events were reduced com- pared with the usual care group (RR, 0.23 [95% CI, 0.07 0.72]; number needed to treat, 3) and a reduction in mortality associated with the inter- needed to treat, 8).131 2. 