A single-center retrospective study of anticoagulation with a DOAC in 52 patients for the treatment of LV thrombus found resolution of the thrombus in 86% of patients on follow-up echo- cardiography, but the study was too small to address embolic event rates.509 A larger retrospective analy- sis of 514 patients with identified LV thrombi from 3 centers and a median follow-up of 351 days com- pared 300 patients who received warfarin with 185 patients treated with DOAC and noted a higher rate of stroke or systemic embolism in the DOAC group (HR, 2.71 versus warfarin), although this difference was noted beyond the currently recommended duration of therapy for LV thrombi.513 4. Patients with reduced LV systolic function (LV EF <50%) in the setting of acute anterior MI are at the greatest risk of developing LV thrombus.514 The observed rate of LV thrombus in anterior MI was 24% in 1 series by cardiac MRI.505 The risk of stroke among patients with defined LV throm- bus has been reported to be as high as 9% to Therefore, for patients who have stroke or TIA in the context of anterior MI with reduced EF (ie, the cardiac population at the highest risk for CLINICAL STATEMENTS AND GUIDELINES Kleindorfer developing thrombus), one might consider empiri- cal anticoagulation even in the absence of demon- strated thrombus. Knowledge Gaps and Future Research Ventricular thrombus complicating insults to LV function can present a challenge to the care team. Our under- standing is based on aging data and small case series, leaving gaps in our knowledge and opportunities for future research in diagnosis, prognosis, and therapy. Often, the initial manifestation of LV thrombus is stroke. Identifying patients at highest risk of devel- oping LV thrombus before it forms may prevent stroke.


Identifying patients at highest risk of devel- oping LV thrombus before it forms may prevent stroke. Advanced imaging methods offer the prom- ise of identifying features of ventricular remodeling or dysfunction through strain patterns, blood vec- tor mapping, and hematologic assays that point to patients who are at highest risk and would benefit from prophylactic anticoagulation. Furthermore, the optimal timing and frequency of screening for LV thrombus remain poorly characterized and would benefit from longitudinal study. The optimal duration of anticoagulation in the set- ting of thrombus remains elusive. Natural history studies with serial advanced imaging could better determine LV thrombus embolic risk and the need for anticoagulation. Recommendations for Cardiomyopathy Referenced studies that support recommendations are summarized in online Data Supplements 36 and 37. COR LOE Recommendations In patients with ischemic stroke or TIA and left atrial or left atrial appendage thrombus in the setting of ischemic, nonischemic, or restrictive cardiomyopathy and LV dysfunction, antico- agulant therapy with warfarin is recommended for at least 3 months to reduce the risk of recurrent stroke or TIA. In patients with ischemic stroke or TIA in the setting of a mechanical assist device, treatment with warfarin and aspirin can be beneficial to reduce the risk of recurrent stroke or TIA.516 523 In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with warfarin can be beneficial to reduce the risk of recurrent stroke or TIA.


In patients with ischemic stroke or TIA in the setting of a mechanical assist device, treatment with warfarin and aspirin can be beneficial to reduce the risk of recurrent stroke or TIA.516 523 In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with warfarin can be beneficial to reduce the risk of recurrent stroke or TIA. In patients with ischemic stroke or TIA in sinus rhythm with ischemic or nonischemic cardio- myopathy and reduced EF without evidence of left atrial or LV thrombus, the effectiveness of anticoagulation compared with antiplatelet therapy is uncertain, and the choice should be 3: Harm B-R In patients with stroke or TIA and LV assist devices (LVADs), treatment with dabigatran instead of warfarin for the primary or second- ary prevention of ischemic stroke or TIA Synopsis Compared with the general population without cardio- myopathy, patients with cardiomyopathy and impaired LV EF have a higher incidence of thromboembolism. In patients with cardiomyopathy, ischemic stroke, or TIA in sinus rhythm who have intracardiac thrombus dem- onstrated by echocardiography or another imaging anticoagulant therapy with a warfarin is recommended for 3 months (Figure 4). Patients with noncompaction cardiomyopathy represent a peculiar subgroup at higher risk of thromboembolic complica- In patients with ischemic stroke or TIA in the setting of LV noncompaction, treatment with war- farin therapy can be beneficial. The effectiveness of oral anticoagulation compared with antiplatelet therapy in patients with cardiomyopathy and reduced EF and ischemic stroke or TIA in sinus rhythm with no evidence of left atrial or LV thrombus is uncertain, and the choice should be individualized, taking into account the bleed- ing risk and estimated risk of recurrent thromboembo- Patients with LVADs have a high prevalence of neurological complications (thromboembolic/hemor- rhagic).


The effectiveness of oral anticoagulation compared with antiplatelet therapy in patients with cardiomyopathy and reduced EF and ischemic stroke or TIA in sinus rhythm with no evidence of left atrial or LV thrombus is uncertain, and the choice should be individualized, taking into account the bleed- ing risk and estimated risk of recurrent thromboembo- Patients with LVADs have a high prevalence of neurological complications (thromboembolic/hemor- rhagic). Warfarin together with aspirin is the standard antithrombotic regimen to minimize the risk of LVAD and to prevent recurrent ischemic stroke or TIA. At this point, the use of DOACs in patients with LVAD should be avoided.529 Recommendation-Specific Supportive Text 1. The prevalence of intracardiac thrombosis in patients with cardiomyopathy has not been con- clusively determined, and it varies between differ- ent underlying causes. In a retrospective database including 86374 patients, 62 cases (0.7%) of LV thrombosis were identified. The majority of patients (81%) had ischemic cardiomyopathy, and the remaining had a nonischemic type.537 Oral antico- agulation with warfarin has been used in patients with intracardiac thrombus, and the efficacy has been documented in several observational stud- A duration of therapy <3 months has been associated with a higher recurrence rate.539 The evidence for the use of DOACs in patients with intracardiac thrombus is limited largely to isolated case reports and small case series.529,540 546 It is also important to note that DOACs have not been studied specifically to prevent thromboembolism in patients with documented LV or left atrial throm- bus. In addition, uncertainty about the optimal dos- ing of DOACs and the long-term safety remains. Therefore, at the present time, warfarin should be preferred to DOACs in patients with ischemic, non- ischemic, or restrictive cardiomyopathy; ischemic stroke or TIA in sinus rhythm; and documented left atrial or LV thrombus.


Therefore, at the present time, warfarin should be preferred to DOACs in patients with ischemic, non- ischemic, or restrictive cardiomyopathy; ischemic stroke or TIA in sinus rhythm; and documented left atrial or LV thrombus. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 2. Thromboembolic complications represent a major therapeutic challenge in the LVAD population and can occur at any point after LVAD implantation, including the immediate postoperative period and the long-term follow-up.516 519 The pathophysiology associated with ischemic stroke in the LVAD popula- tion is complex, and the postulated underlying mech- anisms are different for early versus late strokes. In the immediate postoperative period, several surgical factors have been reported to possibly increase the risk. These factors include duration of cardiopul- monary bypass and the need for other associated surgeries (eg, coronary artery bypass surgery, valve Pump thrombosis, reduced pump speeds, venous thromboembolism, uncontrolled hypertension, and systemic infections have been associated with late strokes.518,519,521,522 A subopti- mal anticoagulation regimen, which includes either supratherapeutic or subtherapeutic INR and no aspi- rin use, has also been associated with increased risk of ischemic strokes. The use of DAPT compared with acetylsalicylic acid alone in addition to warfarin does not appear to affect the rates of ischemic stroke.523 Therefore, at the present time, the combination of warfarin and aspirin is the preferred regimen in pre- venting recurrent ischemic stroke. 3. LV noncompaction is a rare primary cardiomyopa- thy possibly caused by an arrest of normal embryo- genesis of the endocardium and mesocardium that leads to the formation of prominent trabeculations and deep intertrabecular recesses within the LV wall communicating with the cavity.


LV noncompaction is a rare primary cardiomyopa- thy possibly caused by an arrest of normal embryo- genesis of the endocardium and mesocardium that leads to the formation of prominent trabeculations and deep intertrabecular recesses within the LV wall communicating with the cavity. The inferior and lat- eral walls of the LV from the midcavity to the apex are most commonly involved by this process.547 Among cohorts of patients with cardiac disease, the esti- mated prevalence of LV noncompaction varies from 0.9% by echocardiographic criteria to 9.8% with car- diac magnetic resonance criteria.548 LV noncompac- tion has a broad spectrum of clinical manifestations, ranging from asymptomatic state to severe heart failure, ventricular arrhythmias, and thromboembolic The risk of thromboembolism in LV noncompaction cardiomyopathy has been evaluated in several case series, which have reported an up to 24% risk of cerebral embolism at follow-up.534,549 This increased risk has been theorized to result from blood stasis within the prominent LV trabecula- tions and intertrabecular recesses.533 535 Given the shared pathophysiological basis with LV endocavi- tary thrombus, we make this recommendation. 4.


The inferior and lat- eral walls of the LV from the midcavity to the apex are most commonly involved by this process.547 Among cohorts of patients with cardiac disease, the esti- mated prevalence of LV noncompaction varies from 0.9% by echocardiographic criteria to 9.8% with car- diac magnetic resonance criteria.548 LV noncompac- tion has a broad spectrum of clinical manifestations, ranging from asymptomatic state to severe heart failure, ventricular arrhythmias, and thromboembolic The risk of thromboembolism in LV noncompaction cardiomyopathy has been evaluated in several case series, which have reported an up to 24% risk of cerebral embolism at follow-up.534,549 This increased risk has been theorized to result from blood stasis within the prominent LV trabecula- tions and intertrabecular recesses.533 535 Given the shared pathophysiological basis with LV endocavi- tary thrombus, we make this recommendation. 4. There are 5 randomized trials evaluating the effects of antithrombotic therapy on clinical out- comes, including strokes, in patients with heart failure and reduced LV EF in sinus rhythm.524 528 The WARCEF trial (Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction) documented no ben- efit of warfarin therapy compared with acetyl- salicylic acid at a mean follow-up of 3.5 years for the primary outcome (death, ischemic stroke, or although patients on warfarin had reduced incidence of stroke, par- ticularly patients with an EF 15%,550 The more recent COMMANDER HF trial (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) randomized a total of 5022 patients with chronic heart failure, an EF of 40%, coronary artery disease, and elevated plasma natriuretic peptides to rivaroxaban 2.5 mg twice daily or placebo.528 After a median follow-up of 21.1 months, the primary end point (death, MI, or stroke) occurred in 25.0% of patients assigned to rivaroxaban versus 26.2% of those receiving pla- cebo.


There are 5 randomized trials evaluating the effects of antithrombotic therapy on clinical out- comes, including strokes, in patients with heart failure and reduced LV EF in sinus rhythm.524 528 The WARCEF trial (Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction) documented no ben- efit of warfarin therapy compared with acetyl- salicylic acid at a mean follow-up of 3.5 years for the primary outcome (death, ischemic stroke, or although patients on warfarin had reduced incidence of stroke, par- ticularly patients with an EF 15%,550 The more recent COMMANDER HF trial (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) randomized a total of 5022 patients with chronic heart failure, an EF of 40%, coronary artery disease, and elevated plasma natriuretic peptides to rivaroxaban 2.5 mg twice daily or placebo.528 After a median follow-up of 21.1 months, the primary end point (death, MI, or stroke) occurred in 25.0% of patients assigned to rivaroxaban versus 26.2% of those receiving pla- cebo. Patients with history of ischemic stroke and TIA were underrepresented in these trials, and the main end point always included death, which dwarfs Figure 4. Anticoagulant therapy for patients with cardiomyopathy, ischemic stroke, or transient ischemic attack (TIA) in sinus rhythm. Colors correspond to Class of Recommendation in Table 3. LV indicates left ventricle; and LVAD, left ventricular assist device. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer the ischemic stroke outcomes. Therefore, the effectiveness of anticoagulation versus antiplatelet therapy is uncertain, and the choice should be indi- vidualized by taking into account bleeding risk and estimated risk of recurrent thromboembolism. 5.


Therefore, the effectiveness of anticoagulation versus antiplatelet therapy is uncertain, and the choice should be indi- vidualized by taking into account bleeding risk and estimated risk of recurrent thromboembolism. 5. The only randomized trial evaluating the benefit of DOACs (dabigatran) in stable patients after LVAD implantation was stopped prematurely because of an excess of thromboembolic events.529 At the time of writing, there is no randomized study evaluat- ing the safety and efficacy of other DOACs in the LVAD population, and warfarin remains the only recommended oral anticoagulant in these patients. Knowledge Gaps and Future Research RCTs of stroke prevention in patients with non- valvular AF have demonstrated that DOACs are noninferior to warfarin in preventing ischemic stroke with a lower risk of bleeding. Advantages of DOAC therapy compared with warfarin include a more predictable pharmacokinetic profile requiring no monitoring, fewer interactions with other drugs, and a rapid onset/offset of action. The extent to which data from randomized trials in nonvalvular AF can be generalized to other clinical scenarios such as prevention of thrombo- embolism from intracardiac thrombus in patients with congestive heart failure or prevention of recurrent stroke/TIA in patients with specific types of cardiomyopathy (eg, LV noncompaction) requires further investigation. Data from isolated case reports and small case series suggest that DOACs or low-molecular-weight hepa- rin may be beneficial in these clinical scenarios, but larger-scale multicenter observational data will be necessary to clarify whether DOACs or low-molecu- lar-weight heparin can be used safely and effectively in these patients.551 The role of empirical oral anticoagulation in patients with cardiomyopathy, reduced EF, and a history of stroke/TIA should also be investigated further in future studies because these patients were largely underrepresented in RCTs of prophylactic oral anti- coagulation in patients with cardiomyopathies and reduced EF. 5.4.5.


Data from isolated case reports and small case series suggest that DOACs or low-molecular-weight hepa- rin may be beneficial in these clinical scenarios, but larger-scale multicenter observational data will be necessary to clarify whether DOACs or low-molecu- lar-weight heparin can be used safely and effectively in these patients.551 The role of empirical oral anticoagulation in patients with cardiomyopathy, reduced EF, and a history of stroke/TIA should also be investigated further in future studies because these patients were largely underrepresented in RCTs of prophylactic oral anti- coagulation in patients with cardiomyopathies and reduced EF. 5.4.5. Patent Foramen Ovale Recommendations for PFO Referenced studies that support recommendations are summarized in online Data Supplements 38 and 39. COR LOE Recommendations In patients with a nonlacunar ischemic stroke of undetermined cause and a PFO, recom- mendations for PFO closure versus medical management should be made jointly by the patient, a cardiologist, and a neurologist, taking into account the probability of a causal role for the PFO.


COR LOE Recommendations In patients with a nonlacunar ischemic stroke of undetermined cause and a PFO, recom- mendations for PFO closure versus medical management should be made jointly by the patient, a cardiologist, and a neurologist, taking into account the probability of a causal role for the PFO. In patients 18 to 60 years of age with a nonla- cunar ischemic stroke of undetermined cause despite a thorough evaluation and a PFO with high-risk anatomic features,* it is reasonable to choose closure with a transcatheter device and long-term antiplatelet therapy over anti- platelet therapy alone for preventing recurrent In patients 18 to 60 years of age with a nonla- cunar ischemic stroke of undetermined cause despite a thorough evaluation and a PFO without high-risk anatomic features,* the ben- efit of closure with a transcatheter device and long-term antiplatelet therapy over antiplatelet therapy alone for preventing recurrent stroke is not well established,552 557 In patients 18 to 60 years of age with a nonlacunar ischemic stroke of undetermined cause despite a thorough evaluation and a PFO, the comparative benefit of closure with a transcatheter device versus warfarin is *In the evidence, each study defines high-risk anatomic features in a different way. Synopsis Substantial epidemiological evidence suggesting a causal role of PFO for stroke led to randomized trials of PFO device closure in patients <60 years of age with stroke of undetermined origin. The first 3 trials558 560 compared device closure with either antiplatelet or anti- coagulant treatment, and 2 of these558,560 showed a non- significant trend toward benefit of device closure. Two compared device closure with antiplatelet treatment alone, and each trial showed a significant benefit of PFO closure.


Two compared device closure with antiplatelet treatment alone, and each trial showed a significant benefit of PFO closure. An additional positive did not restrict medical treatment to antiplatelets but did limit eligibility to patients with high-risk anatomic PFO features, including larger shunt size and atrial sep- tal aneurysm. A meta-analysis of all trials561 found that the number needed to treat with device closure to pre- vent 1 recurrent stroke was 131 during 1 person-year of follow-up or 13 during 10 person-years of follow- up, which may be clinically important in this generally young population. Analysis of administrative claims data showed a 4.9% rate of serious periprocedural complica- tion, including AF, in patients 60 years of age.562 RCT data of PFO closure in patients >60 years of age are and the rate of serious periproce- dural complications in this older age group is signifi- cantly higher (10.9%).562 Recommendation-Specific Supportive Text 1. Recommendations for secondary stroke preven- tion in a patient with a PFO should be based on joint input from a neurologist with expertise in vas- cular neurology and a cardiologist with expertise in PFO closure (Figure 5).563,564 Although 1 small trial with 120 patients did include some patients Recommendations for PFO (Continued) COR LOE Recommendations CLINICAL STATEMENTS AND GUIDELINES Kleindorfer >60 years of age, this should not be construed as randomized clinical trial evidence of benefit in this age group; therefore, this procedure should rarely be performed in older patients and only in very unusual clinical circumstances. It is essential that a thorough evaluation has been completed and that there is no alternative cause of the stroke. All that showed benefit from PFO clo- sure excluded lacunar strokes. Thus, the require- ment that the stroke be cryptogenic is equivalent to nonlacunar stroke of undetermined source, or ESUS.


Thus, the require- ment that the stroke be cryptogenic is equivalent to nonlacunar stroke of undetermined source, or ESUS. Furthermore, clinical judgement is required because many strokes in the ESUS category may not have a definite cause but other lower-compet- ing-risk conditions such as a proximal large artery Analysis of observa- indicates that younger patients with- out other vascular risk factors are more likely to have PFOs that are related to their stroke. Similarly, the anatomic characteristics of the PFO need to Figure 5. Patent foramen ovale (PFO) and ischemic stroke management guide. Colors correspond to Class of Recommendation in Table 3. CT indicates computed tomography; DVT, deep vein thrombosis; LP, lumbar puncture; MRI, magnetic resonance imaging; MRV, magnetic resonance venography; RoPE, Risk of Paradoxical Embolism; and TIA, transient ischemic attack. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer be considered in decision-making (see text under Recommendations 2 and 3). in which the comparator was antiplatelet therapy and long-term follow-up from an earlier trial555 in which the comparator was antiplatelet or anticoagulation therapy found a benefit of device closure. There is evidence that patients with high-risk anatomic features, including larger shunt size (defined variably), particularly an atrial septal aneurysm, are more likely to benefit from device closure.563 The individual patient level meta-analysis of the first 3 trials552 found slightly greater benefit among patients with these char- acteristics, but the differences did not approach statistical significance. In contrast, the RESPECT showed significant interactions between treatment and both larger shunt size (>20 micro- bubbles) and atrial septal aneurysm, with benefit shown only when either was present.


In contrast, the RESPECT showed significant interactions between treatment and both larger shunt size (>20 micro- bubbles) and atrial septal aneurysm, with benefit shown only when either was present. A pooled individual patient data analysis from medically treated patients from 2 observational studies and 2 clinical trials found that atrial septal aneurysm, but not shunt size, was independently associ- ated with recurrent stroke.557 A meta-analysis of PFO closure trials found benefit for closure only for patients with high-risk anatomic features.561 However, this finding may have resulted from con- founding because trials that showed benefit had a higher proportion of high-risk features and limited the alternative therapy to antiplatelet therapy only, not antiplatelets or anticoagulants.567 3. If the PFO is considered low risk on the basis of anatomic features, it is particularly important to consider the other clinical features in deciding whether PFO is likely related to the stroke or is incidental. The Risk of Paradoxical Embolism an index to stratify patients with crypto- genic stroke with PFO by their likelihood that the PFO is stroke related, may be helpful for patient selection. Factors in the score indicative of a higher likelihood of a PFO-dependent stroke mechanism are absence of hypertension, diabetes, prior stroke, or TIA; cortical infarct on imaging; and younger age group. Scores range from 0 to 10, with the esti- mated attributable fraction or probability that the PFO is stroke related ranging from 0% (95% CI, 0 4) for a Risk of Paradoxical Embolism score of 10. The Risk of Paradoxical Embolism score attrib- utable fraction is highly correlated with the RR reduction of device closure compared with medical therapy in randomized trials.568 4.


The Risk of Paradoxical Embolism score attrib- utable fraction is highly correlated with the RR reduction of device closure compared with medical therapy in randomized trials.568 4. The evidence suggests that PFO closure in appropriately selected patients is superior to aspi- rin, but it is not known whether closure is superior to warfarin. A comparison of device closure and anticoagulation was not a prespecified analysis in the CLOSE trial (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence),563 but a post hoc underpowered analysis of recurrent stroke found no events in the device closure group and 3 events in the warfarin group, which was not a sta- tistically significant difference.561 Similarly, if long- term warfarin treatment is planned, the additional benefit of closure with a transcatheter device for preventing recurrent stroke is unknown. An important consideration is that short-term trials in younger adults do not capture the long-term risk of warfarin or the long-term safety of indwelling PFO closure devices. Knowledge Gaps and Future Research Future research is needed within this area: Trials of closure versus medical management in patients 60 years of age with ESUS.569 Further trials and individual-level meta-analysis of all randomized trial data in patients with ESUS <60 years of age addressing the benefit of PFO closure compared with aspirin in patients with a PFO with- out high-risk anatomic features. Further trials and individual-level meta-analysis of all randomized trial data addressing the benefit of PFO closure compared with long-term anticoagulation. Individual-level meta-analysis of all randomized tri- als to determine whether PFO size is independently associated with response to treatment.


Individual-level meta-analysis of all randomized tri- als to determine whether PFO size is independently associated with response to treatment. Given the evidence that residual shunts after PFO device closure are associated with increased risk of stroke recurrence,570 studies to determine the optimal prevention strategy in this setting, including consideration of a second device closure or lifelong anticoagulant therapy. Large long-term prospective registries of patients with PFO closure to assess the risk of device- associated AF and the risks associated with device complications such as device erosion, fracture, and 5.5. Congenital Heart Disease Recommendations for Congenital Heart Disease Referenced studies that support recommendations are summarized in online Data Supplements 40 and 41. COR LOE Recommendations In patients with ischemic stroke or TIA and Fontan palliation, anticoagulation with warfarin is recommended to reduce the risk of recur- rent stroke or TIA.572,573 In patients with cyanotic congenital heart disease and other complex lesions, ischemic stroke or TIA of presumed cardioembolic origin, therapy with warfarin is reasonable to reduce the risk of recurrent stroke or TIA. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Synopsis Patients with congenital heart disease represent a group at higher risk of ischemic stroke and systemic throm- particularly in the presence of cya- notic or other complex anatomic lesions.574 577 In these patients, it is reasonable to start oral anticoagulant ther- apy with a VKA (warfarin) for the secondary prevention of stroke or TIA of presumed cardioembolic origin after careful individual assessment of the competing bleed- ing risks associated with oral anticoagulation.


CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Synopsis Patients with congenital heart disease represent a group at higher risk of ischemic stroke and systemic throm- particularly in the presence of cya- notic or other complex anatomic lesions.574 577 In these patients, it is reasonable to start oral anticoagulant ther- apy with a VKA (warfarin) for the secondary prevention of stroke or TIA of presumed cardioembolic origin after careful individual assessment of the competing bleed- ing risks associated with oral anticoagulation. Fontan repair is associated with high risk of atrial arrhythmias, intracardiac thrombosis related to atrial scarring, and right-to-left shunting from Fontan fenestration.578 580 Patients with Fontan palliation and known or suspected thrombus, ischemic stroke or TIA, or prior atrial arrhyth- mia should be treated with warfarin in the absence of Recommendation-Specific Supportive Text 1. The Fontan circulation is a palliative approach to complex single-ventricle physiology and is associ- ated with complex hemodynamics related to an obligatory chronic elevation in central venous pres- sure and reduced cardiac output.30 Consideration for antithrombotic therapy in Fontan patients should take into account the high prevalence of thrombus formation and potentially catastrophic impact of pulmonary or systemic thromboembo- lism. The physiology associated with the Fontan circulation may lead to stroke/TIA via different mechanisms. The associated ventricular dysfunc- tion and abnormal ventricular morphology, the progressive atrial scarring from the Fontan sur- gery, and the elevated intra-atrial pressures may trigger atrial arrhythmias, increasing the risk of The role of DOACs in patients with Fontan is less defined, and thus far, the published evidence is limited to small obser- Given the lack of conclusive evidence on the safety of DOACs in the presence of the hepatic dysfunction and altered coagula- tion in patients who underwent Fontan palliation, warfarin should be considered the preferred oral anticoagulant regimen. 2.


The associated ventricular dysfunc- tion and abnormal ventricular morphology, the progressive atrial scarring from the Fontan sur- gery, and the elevated intra-atrial pressures may trigger atrial arrhythmias, increasing the risk of The role of DOACs in patients with Fontan is less defined, and thus far, the published evidence is limited to small obser- Given the lack of conclusive evidence on the safety of DOACs in the presence of the hepatic dysfunction and altered coagula- tion in patients who underwent Fontan palliation, warfarin should be considered the preferred oral anticoagulant regimen. 2. Complex congenital heart disease is associated with an increased risk of stroke in adults.574 576 Mandalenakis et al575 conducted a large pro- spective registry in Sweden and documented an almost 11-fold increase in the risk of ischemic stroke in patients with congenital heart disease compared with control subjects matched by age, with the highest risk among patients with complex lesions. In a retrospective large database includ- ing >29000 adult (age >18 years) patients with congenital heart disease, Lanz et al574 reported an overall risk of ischemic stroke of 6.1% in women and 7.7% in men. In addition, in this study, patients with complex congenital heart disease had the highest risk (8.9% [95% CI, 6.0 11.5]). The mech- anisms underlying such an increased risk of stroke are different and multifactorial and are related to the high prevalence of atrial arrhythmias, risk for paradoxical embolization (eg, cyanotic congeni- tal heart disease), atrial mechanical dysfunction resulting from the presence of scar, and associ- ated hyperviscosity/hypercoagulability caused by chronic hypoxemia. In patients with cyanotic and other complex congenital heart disease and isch- emic stroke or TIA of presumed cardioembolic origin, treatment with warfarin is reasonable in the absence of contraindications to oral anticoagula- tion (eg, increased risk of bleeding).


In patients with cyanotic and other complex congenital heart disease and isch- emic stroke or TIA of presumed cardioembolic origin, treatment with warfarin is reasonable in the absence of contraindications to oral anticoagula- tion (eg, increased risk of bleeding). Knowledge Gaps and Future Research A subset of patients with Fontan palliative surgery have a fenestration between the Fontan path- way and the pulmonary venous atrium to provide a controlled right-to-left shunt to augment ven- tricular preload and to partially offload systemic venous (Fontan) hypertension. Right-to-left shunt from a fenestration can be a potential source of thromboembolism and stroke.584 Catheter closure of Fontan fenestration along with anticoagulation has been performed in some patients with a patent fenestration presenting with stroke,585 although more data are needed to determine whether this approach is of real incremental benefit to prevent ischemic stroke or TIA compared with oral antico- agulation therapy alone. DOACs have been demonstrated to be noninferior or superior to dose-adjusted warfarin therapy to prevent thromboembolism and bleeding in patients with nonvalvular AF, and they have rapidly become the standard of care for these patients. Important advantages of DOAC therapy compared with war- farin include a more predictable pharmacokinetic profile requiring no monitoring, fewer interactions with other drugs, and a rapid onset/offset of action. Thus far, data on the efficacy and safety of DOACs to prevent recurrent thromboembolism in patients with congenital heart disease and history of isch- emic stroke or TIA are limited to small observational series. Larger-scale multicenter observational data will be necessary to achieve adequate statistical power and to clarify whether DOACs can be used safely in patients with congenital heart disease.


Larger-scale multicenter observational data will be necessary to achieve adequate statistical power and to clarify whether DOACs can be used safely in patients with congenital heart disease. Multicenter registries such as that for non-VKA anticoagulants for thromboembolic prevention585a are currently ongoing and will provide important and needed data on the safety and efficacy of DOACs for thromboembolic prevention in patients with con- genital heart disease. CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 5.6. Cardiac Tumors Recommendation for Cardiac Tumors Referenced studies that support the recommendation are summarized in online Data Supplement 42. COR LOE Recommendation In patients with stroke or TIA found to have a left-sided cardiac tumor, resection of the tumor can be beneficial to reduce the risk of Synopsis Primary cardiac tumors are uncommon, occurring in 0.02% of people according to a large autopsy series, and the most common primary cardiac tumors are myxoma and fibroelastoma.589 Patients with cardiac tumors are at increased risk for stroke with an over- all rate of embolism of 25% in the largest single- The mechanism of stroke in patients with left-sided cardiac tumors is embolic and can be either embolization of thrombus that has formed on the tumor or embolization of the tumor or piece of the This finding is the basis for recommending antiplatelet or anticoagulation to conservatively man- aged patients. There are no prospective randomized trials of management of patients diagnosed with car- diac tumors after stroke or TIA; however, surgical exci- sion of papillary fibroelastoma has been associated with decreased risk of stroke compared with control subjects in 1 single-center study.592 For patients with metastatic disease to the heart or with right-sided tumors, paradoxical embolism of tumor or venous thrombus through a PFO could occur. Recommendation-Specific Supportive Text 1.


There are no prospective randomized trials of management of patients diagnosed with car- diac tumors after stroke or TIA; however, surgical exci- sion of papillary fibroelastoma has been associated with decreased risk of stroke compared with control subjects in 1 single-center study.592 For patients with metastatic disease to the heart or with right-sided tumors, paradoxical embolism of tumor or venous thrombus through a PFO could occur. Recommendation-Specific Supportive Text 1. Retrospective studies have shown increased risk of stroke with left-sided cardiac myxoma and papil- Atrial myxomas can occur in any cardiac chamber but are noted most frequently in the left atrium adherent to the interatrial septum. Broad morphological variation of atrial myxomas has been described, and more villous tumors are felt to have greater embolic and thromboembolic potential. Papillary fibroelastomas are fibrinous mobile tumors occurring most frequently adher- ent to a cardiac valve with nearly equal distribu- tion across the cardiac valves.587 In a single-center study of 323 patients after excision of a cardiac tumor, the OR of embolism associated with left atrial tumors was 1.95 and higher (4.17) with aortic In another series of 725 patients with papillary fibroelastoma, tumor mobility and aor- tic valve location were independent predictors of Less common tumors and metastatic lesions in the heart have been anecdotally associ- ated with stroke; however, there is not enough evi- dence to make a consistent recommendation for those circumstances. For patients with stroke or TIA whose evaluation reveals a left-sided cardiac tumor, consideration should be given to tumor exci- sion to reduce the risk of recurrent stroke. Knowledge Gaps and Future Research Cardiac tumors are rare, and systematic research has been limited to case series, leaving gaps in our under- standing and opportunities for future research.


Knowledge Gaps and Future Research Cardiac tumors are rare, and systematic research has been limited to case series, leaving gaps in our under- standing and opportunities for future research. Most cardiac tumors are found incidentally, car- rying the threat of stroke or recurrent stroke, and open heart surgery is the only established treat- ment option. Better understanding of the risk modification from antiplatelet or anticoagulation in particular tumor subtypes or morphologies may provide alternative therapeutic options for patients. Specifically, pooled experiences including national and multi-institutional data sets may allow a better understanding of tumor subtypes, fractionation by morphology, and natural history. As technology advances, minimally invasive and percutaneous treatment strategies should be inves- tigated. Similarly, advances in imaging technology will allow greater delineation of tumor subtypes and morphologies. The prognostic implications of these findings should be investigated. Recommendations for Dissection Referenced studies that support recommendations are summarized in online Data Supplements 43 and 44. COR LOE Recommendations In patients with ischemic stroke or TIA after an extracranial carotid or vertebral arterial dis- section, treatment with antithrombotic therapy for at least 3 months is indicated to prevent recurrent stroke or TIA. In patients with ischemic stroke or TIA who are <3 months after an extracranial carotid or vertebral arterial dissection, it is reasonable to use either aspirin or warfarin to prevent recur- rent stroke or TIA.593,594 In patients with stroke or TIA and extracranial carotid or vertebral artery dissection who have recurrent events despite antithrombotic therapy, endovascular therapy may be consid- ered to prevent recurrent stroke or TIA.595,596 Synopsis Extracranial carotid or vertebral dissections can be the result of trauma or spontaneous.


In patients with ischemic stroke or TIA who are <3 months after an extracranial carotid or vertebral arterial dissection, it is reasonable to use either aspirin or warfarin to prevent recur- rent stroke or TIA.593,594 In patients with stroke or TIA and extracranial carotid or vertebral artery dissection who have recurrent events despite antithrombotic therapy, endovascular therapy may be consid- ered to prevent recurrent stroke or TIA.595,596 Synopsis Extracranial carotid or vertebral dissections can be the result of trauma or spontaneous. It is a relatively uncom- mon mechanism of ischemic stroke that is relevant mostly to younger individuals.597 The most common mechanism of stroke with extracranial dissection is artery-to-artery from an intraluminal thrombus, which is the rationale for using antithrombotic agents to decrease the rate of ischemic stroke.599 Although most dissections heal spontaneously, a subset of patients will undergo disease progression and arterial complications such as CLINICAL STATEMENTS AND GUIDELINES Kleindorfer Recommendation-Specific Supportive Text 1. The recommendation of using antithrombotic agents is based on expert opinion. Although arterial dissec- tion is a hemorrhagic process within the arterial wall, the most common mechanism for stroke is artery- from an intraluminal throm- bus. This is the rationale for using antithrombotic agents to decrease the rate of ischemic stroke.599 2. CADISS (Cervical Artery Dissection in Stroke Study) was an open-label trial that randomized 250 patients with extracranial dissection within 7 days from symptom onset to receive either antiplatelets or anticoagulants in the following 3 months.593 The specific agents and treatment regimens were left to the treating physician.


CADISS (Cervical Artery Dissection in Stroke Study) was an open-label trial that randomized 250 patients with extracranial dissection within 7 days from symptom onset to receive either antiplatelets or anticoagulants in the following 3 months.593 The specific agents and treatment regimens were left to the treating physician. Stroke or death occurred in 3 patients (2%) assigned to antiplatelets versus 1 patient (1%) in the anticoagulation group (OR, At the 1-year follow-up, there was no difference in the primary end point of stroke or death between the 2 groups: 3.2% in the antiplatelet group versus 1.6% in the anticoagulant group (OR, 0.56 [95% This trial supports that there is equipoise between antiplatelets and anti- coagulants in the first 3 months after a cervical artery dissection. 3. Endovascular procedures are used to reconstruct cervical arterial dissections refractory to medical treatment and to treat complications such as pseu- There is a lack of randomized studies to support benefit of endovascular inter- ventions in dissections, and most of the data stem from small series. Still, reviews of the literature suggest a reasonably low rate of complications from these procedures.595,596 Knowledge Gaps and Future Research Gaps in the management of cervical arterial dissection still exist and would benefit from future research: Early identification of patients at risk for early dete- rioration or complications who might benefit from endovascular therapy. Whether some antithrombotic agents are more effi- cacious if administered early in the course (eg, is anticoagulation more efficacious than antiplatelets in the acute phase?). The benefit of long-term antithrombotic agents. Management of dissections complicated with intra- luminal thrombus. Management of intracranial dissections and risks/ benefits of anticoagulation. The determination of what physical activities are safe and which ones need to be restricted. Optimal monitoring/management of pseudoan- eurysms associated with dissection needs further study. 5.8.


Optimal monitoring/management of pseudoan- eurysms associated with dissection needs further study. 5.8. Hypercoagulable States 5.8.1. Hematologic Traits Recommendation for Hematologic Traits Referenced studies that support the recommendation are summarized in online Data Supplement 45. COR LOE Recommendation In patients with ischemic stroke or TIA of unknown source despite thorough diagnostic evaluation and no other thrombotic history who are found to have prothrombin 20210A mutation, activated protein C resistance, elevated factor VIII levels, or deficiencies of protein C, protein S, or antithrombin III, anti- platelet therapy is reasonable to reduce the risk of recurrent stroke or TIA.600 606 Synopsis Hypercoagulable states refer to heterogeneous hema- tologic traits that predispose to venous or arterial thrombosis, which then may increase the risk of stroke, particularly in younger populations. Hypercoagula- ble states may increase the risk of stroke via various mechanisms. Hypercoagulable disorders may predis- pose to arterial or venous thrombosis. Among people with venous thrombosis, stroke may be caused by paradoxical emboli via right-to-left arterial shunt, either pulmonary or cardiac (often via a PFO). Hypercoagu- lable states that cause arterial thrombosis may cause stroke via distant thrombosis (eg, intracardiac) with embolization or via in situ thrombosis of the brain or cervical arteries. Suspicion for hypercoagulable states as the cause of stroke varies by clinical scenario, but they may be considered in younger populations with no identifiable cause for stroke, self- or family history of unprovoked thrombosis, prior spontaneous abortion, or coexistence of systemic signs and symptoms sugges- tive of hypercoagulability. Recommendation-Specific Supportive Text 1.


Suspicion for hypercoagulable states as the cause of stroke varies by clinical scenario, but they may be considered in younger populations with no identifiable cause for stroke, self- or family history of unprovoked thrombosis, prior spontaneous abortion, or coexistence of systemic signs and symptoms sugges- tive of hypercoagulability. Recommendation-Specific Supportive Text 1. Thrombophilic states such as prothrombin 20210A mutation; activated protein C resistance (often caused by factor V Leiden); deficiencies of protein C, protein S, or antithrombin; and ele- vated factor VIII levels have been associated with higher stroke risk in selected populations without especially among people with The risk of stroke recurrence among stroke survivors with thrombophilic traits is less Furthermore, although individuals who carry 1 of these disease traits may be considered hypercoagulable, the ideal treatment (antiplatelet versus anticoagulation) remains unknown. Among patients with stroke and unprovoked deep vein thrombosis with or without a positive blood test for thrombophilic states, adhering to deep vein thrombosis treat- ment recommendations seems reasonable if they otherwise meet eligibility criteria.606 Therefore, in CLINICAL STATEMENTS AND GUIDELINES Kleindorfer the absence of a diagnosis that would change the default treatment for ischemic stroke, it is uncertain whether testing for these hematologic traits is of benefit in the context of secondary stroke prevention. If in certain clinical scenarios (eg, paradoxical emboli caused by venous throm- bosis or recurrent venous thrombosis) testing for thrombophilic states is considered, testing for protein C, protein S, or antithrombin levels should be deferred or repeated at least 4 to 6 weeks (or up to 6 months for factor VIII609 ) after the acute stroke given that these protein levels may be altered during the acute stroke phase.607,608,610,611 5.8.2. Antiphospholipid Syndrome Recommendations for Antiphospholipid Syndrome Referenced studies that support recommendations are summarized in online Data Supplement 46.


Antiphospholipid Syndrome Recommendations for Antiphospholipid Syndrome Referenced studies that support recommendations are summarized in online Data Supplement 46. COR LOE Recommendations In patients with ischemic stroke or TIA who have an isolated antiphospholipid antibody but do not fulfill the criteria for antiphospho- lipid syndrome, antiplatelet therapy alone is recommended to reduce the risk of recurrent In patients with ischemic stroke or TIA with confirmed antiphospholipid syndrome treated with warfarin, it is reasonable to choose a target INR between 2 and 3 over a target INR >3 to effectively balance the risk of excessive bleeding against the risk of thrombosis.613 615 In patients with ischemic stroke or TIA who meet the criteria for the antiphospholipid syndrome, it is reasonable to anticoagulate with warfarin to reduce the risk of recurrent stroke or TIA.615 3: Harm B-R In patients with ischemic stroke or TIA, antiphospholipid syndrome with history of thrombosis and triple-positive antiphospholipid antibodies (ie, lupus anticoagulant, anticardio- lipin, and anti 2 glycoprotein-I), rivaroxaban is not recommended because it is associated with excess thrombotic events compared with Synopsis Antiphospholipid syndrome is characterized by persistent (repeat testing 12 weeks apart) presence of lupus anti- coagulant, anti-cardiolipin or anti 2 glycoprotein I high- titer antibodies, plus evidence of clinical criteria such as vascular thrombosis or pregnancy morbidity.619 Serum testing for acquired antiphospholipid syndrome may be considered in the presence of a history of prior venous thromboembolism, second trimester abortion, or rheu- matologic disorder. Patients with stroke and persistent seropositivity for any of the antiphospholipid antibodies may be classified as having antiphospholipid syndrome. Recommendation-Specific Supportive Text 1. A large subgroup of WARSS (Warfarin-Aspirin Recurrent Stroke Study) was studied to evaluate whether the presence of a positive antiphospholipid antibody indicated a treatment interaction with warfarin or aspirin for secondary stroke preven- tion.


A large subgroup of WARSS (Warfarin-Aspirin Recurrent Stroke Study) was studied to evaluate whether the presence of a positive antiphospholipid antibody indicated a treatment interaction with warfarin or aspirin for secondary stroke preven- tion. Participants had to be 30 to 85 years of age, to be deemed safe for warfarin therapy, to have experienced an ischemic stroke within 30 days, and to have had a modified Rankin Scale score of 3. Investigators found no differential stroke risk reduction in people with a 1-time positive antiphospholipid antibody with warfarin (RR, 0.99 CI, 0.70 1.28]; treatment-by-antiphospholipid interaction, P=0.91) compared with those without a positive antibody.612 Therefore, aspirin is more preferable than warfarin because of the lower risk of bleeding with aspirin. The prevalence of antiphospholipid syndrome in the stroke popula- tion varies, but younger populations are most com- Approximately 13% of patients with antiphospholipid syndrome have stroke as the initial clinical manifestation of the disease.621 In patients with cryptogenic stroke and a history of thrombosis or rheumatological disease, it would seem reasonable to consider testing for antiphos- In older populations with increasing frequency of vascular risk factors, there is no evidence supporting the systematic testing for antiphospholipid antibodies. 2. Although no trials of antithrombotic intervention have been performed exclusively in stroke patients, the available evidence favors anticoagulation with VKA compared with aspirin to reduce recurrent arterial thromboses. An INR with a target range of 2 to 3 is preferable over an INR with a range >3 because higher-intensity anticoagulation is not superior in preventing thrombotic events and is associated with a higher risk of hemorrhagic com- When anticoagulation has been tested against aspirin, an INR of 2 to 3 is a typi- cal range to be used as a comparison arm, further supporting the use of this therapeutic range as 3.


An INR with a target range of 2 to 3 is preferable over an INR with a range >3 because higher-intensity anticoagulation is not superior in preventing thrombotic events and is associated with a higher risk of hemorrhagic com- When anticoagulation has been tested against aspirin, an INR of 2 to 3 is a typi- cal range to be used as a comparison arm, further supporting the use of this therapeutic range as 3. Limited evidence favors anticoagulation with VKA compared with aspirin to reduce recur- rent arterial thromboses. In a small (N=20) RCT, patients with antiphospholipid syndrome were assigned to a single-antiplatelet arm versus tri- ple-therapy arm (dual antiplatelets plus antico- agulation). Participants with single antiplatelets had a higher risk of recurrent stroke (log-rank test, P=0.026) with similar rates of hemorrhage during a mean follow-up of 3.9 years.615 There are limited data to establish whether the addition of antiplatelets to anticoagulation is effective in reducing the risk of recurrent stroke in this pop- ulation. The clinical consensus favors using only CLINICAL STATEMENTS AND GUIDELINES Kleindorfer 4. The role of DOACs in antiphospholipid syndrome treatment is the focus of multiple ongoing and recently completed studies. In an open-label, noninferiority RCT of patient with established antiphospholipid syndrome and triple-positive antiphospholipid antibodies, rivaroxaban was asso- ciated with higher risk of thrombotic events.616 A similar result in favor of VKA over rivaroxaban was reported in an open-label RCT of patients with antiphospholipid syndrome.


In an open-label, noninferiority RCT of patient with established antiphospholipid syndrome and triple-positive antiphospholipid antibodies, rivaroxaban was asso- ciated with higher risk of thrombotic events.616 A similar result in favor of VKA over rivaroxaban was reported in an open-label RCT of patients with antiphospholipid syndrome. In this study, 60% had triple-positive antiphospholipid antibodies, but there was no statistical interaction suggestive of a differential effect among those with antiphospho- lipid syndrome and 1 or 2 antiphospholipid anti- Observational data also suggest a high risk of recurrent thrombosis among patients with antiphospholipid syndrome who receive DOACs.618 Until other ongoing trials such as ASTRO-APS (Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid clarify whether the increased risk of thrombosis with DOACs is a class effect versus an individual drug effect, we do not recommend the use of DOACs in general and, specifically, rivaroxa- ban for antiphospholipid syndrome. Knowledge Gaps and Future Research Although thrombophilic states have been associated with a higher risk of stroke in epidemiological studies, it is uncertain whether specific treatment should be offered to people with stroke and some of these traits. Future research on treatment for hypercoagulable states and stroke should address the following: It is uncertain whether, in the absence of venous thrombosis, there is an indication for anticoagula- tion for secondary stroke prevention in people with thrombophilic states. It is uncertain whether, in the absence of venous thrombosis, the presence of a PFO may modify the risk of stroke recurrence and possible preventive strategies in people with thrombophilic states sus- pected to have paradoxical emboli. Given the relatively low prevalence of thrombophilic traits in populations with stroke, larger, adequately powered multicenter studies are needed to study each trait individually.


Given the relatively low prevalence of thrombophilic traits in populations with stroke, larger, adequately powered multicenter studies are needed to study each trait individually. If a heightened risk of stroke is confirmed, clinical trials may be needed to evaluate whether antico- agulation may be useful to reduce the risk of stroke recurrence. There is less clarity on secondary stroke preventive mea- sures in people with antiphospholipid syndrome; conse- quently, the following knowledge gaps remain: There is an urgent need to clarify whether DOACs may be used instead of warfarin to reduce the risk of stroke in this population. There is a knowledge gap with respect to the role of dual antiplatelets in antiphospholipid syndrome, with reports suggesting a possible role to reduce the risk of stroke alone or in addition to antico- agulation. The absence of definitive data prevents us from providing a stronger recommendation at this point. Recommendation for Hyperhomocysteinemia Referenced studies that support the recommendation are summarized in online Data Supplements 46 and 47. COR LOE Recommendation Benefit B-R In patients with ischemic stroke or TIA with hyperhomocysteinemia, supplementation with folate, vitamin B6 , and vitamin B12 is not effective for preventing subsequent Synopsis Although elevated serum homocysteine has consis- tently been associated with elevated risk of stroke and other vascular events, randomized trials of folate and B vitamin supplementation have not shown ben- efit in secondary prevention of stroke. Challenges in understanding the relationship between vitamin supplementation and secondary stroke prevention stem from limitations in trial design, for example, including patients with both cardiovascular and and enrollment from countries with varying levels of folate supplementa- tion of foods.


Challenges in understanding the relationship between vitamin supplementation and secondary stroke prevention stem from limitations in trial design, for example, including patients with both cardiovascular and and enrollment from countries with varying levels of folate supplementa- tion of foods. Although meta-analyses of patients with vascular disease, including some with cere- brovascular disease, suggest a small but significant reduction in subsequent stroke risk among those receiving supplementation, assessment of factors that may modify this relationship (including genetic variants in folate metabolism, preexisting homocys- teine level, use of antiplatelet medications, renal function, and dose of B vitamin supplementation) is inconsistent among studies.609,629 637 Although 1 pri- mary prevention study among hypertensive patients with high homocysteine found that the addition of folic acid to enalapril was more effective in reducing first stroke among those with the methylenetetrahy- drofolate reductase C677T CC/CT polymorphism,637 it remains unknown whether folic acid or vitamin B supplementation in a specific subgroup of patients with recent stroke or TIA may be beneficial in reduc- ing the risk of secondary stroke. Recommendation-Specific Supportive Text 1. Results from VITATOPS (Vitamins to Prevent and VISP (Vitamin Intervention for did not show a significant reduction in risk of secondary stroke among patients with recent stroke who were randomized CLINICAL STATEMENTS AND GUIDELINES Kleindorfer to receive various doses of folic acid and vitamin B supplementation. Knowledge Gaps and Future Research Questions remain to be addressed about whether there are specific subgroups of stroke patients in whom B vitamin supplementation reduces secondary stroke risk. Randomized trials of B vitamins for secondary stroke prevention are needed in patients with stroke or TIA who do not consume folate-fortified foods.


Randomized trials of B vitamins for secondary stroke prevention are needed in patients with stroke or TIA who do not consume folate-fortified foods. These trials may also need to consider the formulation and dose of B vitamins, the level of hyperhomocysteinemia, specific methylenetetrahydrofolate genetic polymorphisms, and the patient s renal function as possible modifiers of the relationship between B vitamins and secondary stroke Migraine has been associated with ischemic stroke and white matter hyperintensities in numerous stud- In patients with migraine who have had an ischemic stroke, data on the risk of recurrent stroke are limited and conflicting.640 642 Neuroimaging studies sug- gest that there is brain hypoperfusion during migraine attacks, at least in severe migraine attacks with aura.643 On the basis of these limited data, practitioners may consider implementing preventive treatments to reduce migraine frequency in patients with migraine and prior ischemic stroke. 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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.


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.